Академический Документы
Профессиональный Документы
Культура Документы
intentionally left
blank
Copyright © 2007, New Age International (P) Ltd., Publishers
Published by New Age International (P) Ltd., Publishers
Pharmacology has undergone major intellectual changes in the recent years and has become
increasingly important to all medical, dental and other health professionals. The graduate
students of dentistry may have to handle medical emergency during various dental
procedures on the dental chair. Besides this, dentists have to look into various drug
associated interactions. The broad goal of teaching pharmacology to undergraduate
students is to inculcate rational and scientific basis of therapeutics keeping in view the
dental curriculum and profession. A sincere attempt has been made to present a complete
text for undergraduate students of dentistry as per the new syllabus requirement (Dental
Council of India, BDS course regulation, 2006).
The book is divided into thirteen sections, initial sections cover the general and
autonomic pharmacology, followed by other sections of drug acting on different body
systems. A detailed section is devoted only to dental pharmacology which covers all agents
used in pharmacotherapy of dental conditions. The last section covers vaccine, sera and
other immunological agents and drugs used in skin disorders. The chapters have been
arranged in such a way that knowledge gained from initial chapters will be helpful to
students for understanding subsequent chapters. The appendix contains the list of newly
approved and banned drugs in India.
The classification adopted in the books provides pharmacological distinction among
latest drugs with doses and routes of administration along with leading trade name(s)
available in Indian market, but it should not be construed as the recommendation of those
particular brands.
(viii)
Thanks are due to New Age International (P) Ltd., N. Delhi for their keen interest and
attention in bringing out this book in its present form. Further, I am indebted to all my
friends and well wishers for their support and encouragement.
I would like to express my gratitude and indebtedness to all my family members for
their sacrifice, affection and inspiration throughout the present work.
Contents
Preface (vii)
SECTION 1
General Principles of Pharmacology
1.1 Sources and Nature of Drug Dosage Form 3
1.2 Prescription Writing 15
1.3 Rational Use of Drugs & Drug Laws 19
1.4 Pharmacokinetics 25
(Absorption, Distribution, Metabolism and Excretion of Drugs)
1.5 Pharmacodynamics (Mode of Action of Drugs) 39
1.6 Adverse Drug Reactions 47
1.7 Drug Interactions 51
SECTION 2
Drugs Acting on CNS
2.1 General Anaesthetics 61
2.2 Sedative & Hypnotics 69
2.3 Narcotic Analgesics (Opioids) 75
2.4 Non-Narcotic Analgesics (NSAID’s) 83
(x)
SECTION 3
Drugs Acting on ANS
3.1 Sympathomimetics (Adrenergic Agents) 131
3.2 Treatment of Shock & Vasopressor Agents 141
3.3 Sympatholytics (Antiadrenergic Agents) 145
3.4 Parasympathomimetics (Cholinergic Agents) 155
3.5 Parasympatholytics (Anticholinergic Agents) 161
SECTION 4
Drugs Acting on Cardiovascular & Urinary System
4.1 Cardiotonics (Cardiac Glycosides) 169
4.2 Antihypertensive Agents 175
4.3 Antianginal Agents 185
4.4 Antiarrhythmic Agents 189
4.5 Antihyperlipidemic Agents 195
4.6 Plasma Expanders 199
4.7 Diuretics and Antidiuretics 203
SECTION 5
Autacoids
5.1 Histamine and Antihistaminic Agents 215
5.2 Serotonin and its Antagonists 221
5.3 Prostaglandins and Leukotrienes 225
5.4 Drugs Used in Cough and Asthma 229
(xi)
SECTION 6
Drugs Acting on Blood
6.1 COAGULANTS AND ANTICOAGULANTS 239
6.2 HAEMATINICS (Drugs Used in Anaemia) 247
SECTION 7
Drugs Acting on GIT
7.1 Laxatives and Antidiarrhoeal Agents 253
7.2 Emetics & Antiemetic Agents 257
7.3 Antacids and Antiulcer Agents 261
SECTION 8
Drugs Acting on Endocrine System
8.1 Anterior Pituitary Hormones 269
8.2 Antidiabetic Agents 275
8.3 Glucocorticoids & Sex Hormones 281
8.4 Thyroid Hormone & Antithyroid Agents 293
8.5 Hormonal Contraceptives 297
SECTION 9
Chemotherapy
9.1 Sulfonamides, Nitrofurans and Quinolones 303
9.2 Tetracyclines, Chloramphenicol and Chemotherapy of UTI 311
9.3 Beta Lactam Antibiotics 317
9.4 Aminoglycosides Antibiotics 327
9.5 Macrolide and Polypeptide Antibiotics 331
9.6 Antiviral Agents 337
9.7 Antifungal Agents 343
9.8 Antimalarial Agents 349
9.9 Antiamoebic and other Antiprotozoal Drugs 355
9.10 Anthelmintic Agents 361
9.11 Chemotherapy of Tuberculosis 365
(xii)
SECTION 10
Vitamins and Trace Elements
10.1 Vitamins and Trace Elements 383
SECTION 11
Chelating Agents & Treatment of Poisoning
11.1 Chelating Agents & Treatment of Poisoning 395
SECTION 12
Dental Pharmacology
12.1 Antiseptics & Disinfectants 407
12.2 Astringent and Obtundents 413
12.3 Mummifying and Bleaching Agents 415
12.4 Styptics (Local Haemostatics) and Disclosing Agents 417
12.5 Dentifrices and Mouth Washes 419
12.6 Caries and Fluorides 423
12.7 Pharmacotherapy of Common Oral Conditions & Dental Emergencies 425
SECTION 13
Miscellaneous
13.1 Vaccines, Sera and Other Immunological Agents 431
13.2 Drugs Used in Skin Disorders 449
APPENDICES
Appendix I : List of Recently Approved New Drugs and Combinations
in India (During 1999-July 2006) 459
Appendix II : List of Banned Drugs and Fixed Dose Combinations
in India (Updated till January 2007) 473
Index 477
Section 1
General Principles
of
Pharmacology
This page
intentionally left
blank
a p
p tte r
e r Sources and Nature
CChh
of
1.1
1.4 Drug Dosage Form
Table 1.1.1: Classification of different animal products used as drug and surgicals.
Drug Category Animal source
Insulin Hormone Pancreas of beef or pig
Thyroid extract/thyroxine Hormone Thyroid gland
Shark liver oil Vitamin A Livers of shark and allied species
Cod liver oil Vitamin A and D Livers of Gadus species
Antisnake venom Immune serum Blood of horse
Hyaluronidase Enzyme Testis of bull
Pepsin Enzyme Stomach of beef and pig
Surgical ligatures and sutures Used in surgery Intestinal tissues, tendons of animals.
Drugs may also be administered locally • Unpalatable and other irritant drugs
in the form of bougies, jellies for urethra, can not be administered.
pessaries, vaginal tablets, creams and • Can not be used for unconscious and
douches for vagina and suppositories for uncooperative patient.
rectal administration. • May not be useful in the presence of
Due to the rich blood and lymph supply vomiting and diarrhoea.
to rectum the unionised and lipid soluble • Drugs, which can be destroyed by di-
substances are readily absorbed from the gestive juices (i.e. insulin, penicillin
rectum. The advantages of this route are G) or in liver (i.e. testosterone, nitro-
that gastric irritation is avoided and easy glycerine) can not be administered
administration by the patient himself.
orally.
Administration of drug in the form of • The absorption of certain drugs is
liquid into the rectum is called enema, negligible e.g. streptomycin.
which may be soap water or glycerine-
vegetable oil. It is used to remove the Enteric Coated Tablets
faecal matter and flatus and is The drugs which are destroyed by
used in constipation. Certain drugs are the gastric juices in the stomach, are
administered rectally for producing coated with keratin, shellac and cellulose
systemic effects also (e.g. aminophylline, acid phosphate. These substances are not
indomethacin, paraldehyde etc.). dissolved by the acid juice of the
stomach, but are dissolved in the
SYSTEMIC ROUTES intestinal juice (alkaline) only, which is
The drug administered through useful in:
systemic routes (orally or parenterally), is • Preventing gastric irritation and
absorbed into the blood, distributed along
alteration of the drug in the stomach.
through the circulation and produce their
• To get the desired concentration of
desired effects.
the drug in intestine.
Oral Route • To delay the absorption of the drug.
This is the most commonly used route
Time Release/Sustained Release Capsules
for drug administration. It is also the safest,
most convenient and economical. But, there It is a useful solid dosage form of drug,
are some limitation of this route: where the particles of the drug dissolve at
different time intervals.
• Drug action is slow, thus not suitable
for emergencies. The advantages of time-release prepara-
tions are:
• Incapability to absorb some drugs, due
to their physical characteristics i.e. • Reduction in the frequency of admin-
polarity of the drug. istration of drug.
8 Section 1/ General Principles of Pharmacology
anaesthetics, amyl nitrite and vapours of gargles, jellies, liniments, lotions, mouth
liquid anaesthetics, gases like oxygen, washes, ointments, paints, paste,
carbon dioxide and helium. poultices etc.
Nonvolatile substances have to be Inhalation forms include aerosols,
broken down into small particles, and then sprays etc.
inhaled as aerosols.
Drugs given by this route are quick- SOLID DOSAGE FORM (INTERNAL
ly absorbed, which takes place from the USE)
vast surface of alveoli and produce rap-
Capsules: These are small gelatin
id action. Various bronchodilators and
contains shells. Capsules are of two types –
mast cell stabilizers are used in the
hard & soft capsules.
treatment and prophylaxis of bronchial
asthma i.e. salbutamol (ASTHALIN) Hard capsules are used for powdered
and sodium cromoglycate (FINTAL) drugs e.g. capsules ampicillin, tetracy-
inhaler. cline. In hard capsules, certain sustained
released substance, which gradually
DOSAGE FORMS AND ROUTES OF DRUG release the drug in the respiratory tract
ADMINISTRATION (e.g. cap. theophylline).
A dosage form is a medicated product Soft capsules are used for oils and
specially designed for administration solution of active drugs e.g. cap. vitamins
depending upon the routes to the patient for A, A & D, E, garlic pearls, seven seas etc.
the diagnosis and treatment of disease. Soft capsules are also used for semisolid
The dosage form is broadly divided into (ointment) e.g. eye applicaps of chloromycetin.
solid dosage form, liquid dosage form and Granules: These are mixture of active
inhalations which are used both internally medicament, sugar and some flavouring
as well as externally. agent and then moistened to produce a
Solid dosage form includes capsules, coherent mass which is then passed
granules, effervescent granules, powders, through a sieve to form a granule. Gran-
tablets, insufflations, suppositories ules are the unusual means of adminis
(pessaries, bougies and ear cone) etc. tering drug that possess an unpleasant
taste e.g. PAS (para-amino salicylic acid)
Semisolid/liquid dosage form
granules.
includes elixirs, emulsions, gels, linctus,
mixtures, drops, solutions, syrups, Effervescent granules: It is a mixture
tinctures, applicators, creams, enema, of citric and tartaric acids with sodium
Sources and Nature of Drug Dosage Form 11
Lotions are liquid preparation applied They afford greater protection and are more
to skin without friction. Lotions are used for absorptive. The base may be anhydrous or
soothing, astringent and antipruritic affects water soluble e.g. zinc oxide paste.
e.g. calamine lotion. Poultices are paste like preparation for
Mouth washes are liquid preparation external application to reduce inflammation
similar to gargles but are use for oral due to its heat retaining capacity. After
hygiene. heating, the preparation is spread thickly on
a dressing gauze and applied as hot as
Ointments are semi-solid greasy
patient can bear it, to the affected area.
preparation for local application to the skin,
rectum and mucous membrane also. The INHALATION FORM
ointment base is usually anhydrous and
Aerosols are suspension of fine, solid
contain the medicaments in solution or
or liquid particles in a medium like air or
suspension. Ointments are used for its
oxygen and administered with the help of
soothing, astringent, antiseptic and other
nebulizers. They are used to apply drugs
selected actions e.g. chloromycetin eye
to the respiratory tract in asthmatic
ointment.
patients e.g. Asthalin (salbutamol) inhaler,
Paints are liquid preparation containing Fintal (sodium cromoglycate) inhaler.
volatile solvent which quickly evaporate to Sprays are preparation of drugs in oil
leave a dry and resinous film of or water, usually administered by atomizer
medicaments on the skin. or nebulizer. They are applied to the
Throat paints are more viscous in nature mucosae of nose or throat e.g. Tyrothricin
(due to the high proportion of glycerine) which spray.
being sticky and adhere to the affected site and Vitrellae are thin walled glass capsules
prolongs the action of the drug. containing volatile substance (drops) (e.g.
Pastes are semi-solid preparation for ex- amyl or octyl nitrite) and protected by
ternal application that differ from similar absorbent cotton wool and an outer silk bag.
products (i.e. ointment) in containing a high This capsule is crushed and the vapours are
proportion of finely powdered medicaments. inhaled in the treatment of angina.
h a p
p tterer Prescription
CCh
1.2
1.4 Writing
thy. Research activities in these systems III. Animal toxicity requirements for
continued under the aegis of the CCRIMH clinical trials and marketing of a new
until 1978, when it was split into four sepa- drug.
rate research councils, one each for Unani IV. Number of animals for long term
Medicine, Ayurveda and Siddha, Yoga and toxicity studies.
Naturopathy, and Homeopathy, so as to
V. Patient consent form for participation
further develop these systems in conso-
in a phase I clinical trial.
nance with the basic philosophies of the
VI. Four groups of fixed dose combinations
respective systems. Also, with a view to
and their data requirements.
streamlining education and regulating
practice in Indian systems of medicine – NARCOTIC DRUGS & PSYCHOTROPIC
Ayurveda, Unani Medicine and Siddha, the SUBSTANCES ACT & RULES
Government of India set up by an Act of Opium was brought under legislature
Parliament, Indian Medicine Central Coun- control as far back as in 1857. The primary
cil Act 1970, the Central Council of Indian
aim of the Opium Act was the protection
Medicine (CCIM).
of the public welfare by preserving health
In 1995, the Government also set up a & eliminating undesirable social and
full-fledged Department of India Systems of moral effects which are associated with
Medicine & Homeopathy (ISM & H) in the indiscriminate use of opium. Govt. of
Union Ministry of Health & Family Welfare India passed the Dangerous Drug Act in
to further boost the development of Unani 1930 with a view to control certain
Medicine and other Indian systems of operations in the dangerous drugs and to
medicine. The Department of ISM & H has centralise and vest the same in the central
been renamed as Department of Ayurveda, government.
Yoga & Naturopathy, Unani, Siddha and
Further to “consolidate and amend the
Homeopathy (AYUSH).
law relating to narcotic drugs, to make
Second Schedule – Standard to be stringent provisions for the control and
complied with by imported drugs and by regulation of operations relating to narcotic
drugs manufactured for sale, sold, stocked drugs & psychotropic substances, and
or exhibited for sale or distributed. concerned matters”, the “Narcotic Drugs &
In addition the following appendices are Psychotropic Substances Act & Rules was
also prescribed: passed in September 1985.
1957 to provide for the collection of levy and commodities including drugs. The Drugs
collection of duties of excise on medicinal (Price Control) Order, 1955 has been
and toilet preparations containing alcohol, promulgated to ensure equitable distribution
narcotic drugs or narcotics. of essential bulk drugs and to fix the
maximum retail prices of drug formulations.
THE DRUGS & MAGIC REMEDIES
(OBJECTIONABLE ADVERTISEMENTS) THE PREVENTION OF FOOD
ACT ADULTERATION ACT & RULES
The Drugs & Magic Remedies Act, 1954 Food & drugs are generally controlled
was passed with the objective of controlling through a common administration i.e. FDA
the advertisement of drugs in certain cases, (Food & Drugs Administration in various
to prohibit the advertisements for certain states/country). The main objective of the
purposes for remedies alleged to possess Prevention of Food Adulteration Act is to
magic qualities and to provide for related make provision for the prevention of
matters. The Act as well as Rules came into adulteration of food. The Act was passed in
force in April, 1955 and was amended in 1954 & Rules under the Act were passed in
1963. 1955.
h apptterer Pharmacokinetics
CCh (Absorption, Distribution,
under the curve (AUC) represents the total The drug is distributed in such a pattern
amount of drug absorbed into the which reflects physiological factors and
circulation.
physicochemical nature of drug. These
The percent availability can also be patterns of distribution depend on various
calculated from urine data:
factors.
6QVCNCOQWPVQH
FTWIGZETGVGFKP PLASMA PROTEIN BINDING
WTKPGCHVGTQTCN
CFOKPKUVTCVKQP Most of the drugs are transported bound
Percent availability = ×
6QVCNCOQWPVQH to nonspecific sites on plasma proteins, mostly
FTWIGZETGVGF
KPWTKPGCHVGT to albumin (for acidic drugs) and to α1-acid
KPVTCXGPQWU glycoprotein (for basic drugs). Binding to other
CFOKPKUVTCVKQP proteins like ceruloplasmin and transcortin
From blood data: generally occurs to a much smaller extent. The
#7%
1TCN binding is usually reversible and depends on
Percentage availability = × the individual compound.
#7%
+8
AUC = Area under the curve (Total amount of The binding of drugs to plasma proteins
drug absorbed into the circulation). limit its concentration in tissue and
glomerular filtration of the drug. Since only
DISTRIBUTION OF DRUG unbound drug is in equilibrium across
membranes and this process does not
After absorption, the drug may be
distributed into various body fluids immediately change the concentration of
like intestinal fluid, transcellular fluids free drug in the plasma. The free drug is
e.g. fluids in the gastrointestinal tract, cleared from the plasma by the liver and
CSF etc. kidneys, which is rapidly replaced by
Fig. 1.4.2: Drug concentration in the plasma after oral administration (area under the curve versus time plot).
30 Section 1/ General Principles of Pharmacology
formation of drugs to more polar and less endoplasmic reticulum of the liver cells. The
lipid soluble metabolites enhances their CYP important isoenzymes in human being
excretion and reduce their volume of are CYP3A4/5, CYP2C19, 2CYP2D6,
distribution. The primary site of drug CYP2C8/9, CYP2E1 and CYP1A1/2 which
metabolism is liver. The other organs like are responsible for metabolism of large
kidney, intestine, lungs and plasma are also number of drugs. Hydrolytic enzymes are
involved in drug metabolism. mostly located in the cell cytoplasm or in
Many active drugs, during metabolism plasma and conjugation enzymes are
are converted into one or more active metabo- associated with cytoplasm and endoplasmic
lites and produce effect due to the collective reticulum.
effect of parent drug and their metabolites
e.g. phenacetin is converted into paracetamol, OXIDATION
phenylbutazone into oxyphenbutazone, Oxidative reactions involve addition of
primidone into phenobarbitone, amitrip- oxygen/negatively charged radical or
removal of hydrogen/positively charged
tyline into noriptyline, imipramine into radical.
desimipramine and codeine into morphine.
The different oxidative reaction are:
Certain drugs (parent drug) are inactive as
such and has little or no biological activity Hydroxylation
called ‘prodrug,’ but it is metabolized to a It may be followed by oxidation to form a
pharmacologically active compound. For ketone or in the case of oxidative dealkylation
example, levodopa is converted into to form an unstable intermediate, examples
dopamine which is effective in the treat- are:
ment of parkinsonism, the anticancer drug Ring : Phenobarbital in to p-hydroxypheno-
cyclophosphamide is biologically inert but hydroxylation barbital.
is converted into a active cytotoxic com- Cortisol into 7-β-hydroxycortisol.
pound aldophosphamide, and another an- Epoxidation : Benzene into benzene 1,2-epoxide.
ticancer drug fluorouracil is changed into N-oxidation : Drug containing amino groups can
fluorouridine monophosphate, etc. undergo N-oxidation i.e. imipra-
mine into imipramine N-oxide.
The drug metabolism in liver usually O-dealkylation : This reaction probably involves
undergoes three general types of enzymatic formation of an unstable hydroxy
reactions: methyl intermediate i.e. codeine
into morphine.
1. Oxidation-reduction and hydrolysis or Oxidative : Amphetamine into phenylpropa-
stage I reaction. deamination none-2.
into sulfonamide, which was the first The examples are aspirin, phenacetin,
antimicrobial agent in treating the systemic morphine, chloramphenicol, metronidazole,
bacterial infections. steroidal hormones etc.
HYDROLYSIS Sulfate Conjugation
It is a cleavage of drug molecule by Sulfate conjugation is catalyzed by a fam-
taking up a molecule of water. The most ily of enzymes known as ‘sulfotransferases’,
hydrolytic enzymes are found outside the which are present in the cell cytoplasm of
endoplasmic reticulum, and in higher liver and other organs. Example are chloram-
concentrations in liver, kidney and plasma. phenicol and sex steroids etc.
The metabolism of an ester by an enzyme
esterase results in the formation of an acid Acetylation
and alcohol. The examples are meperidine, This reaction is catalyzed by enzymes
procaina-mide, pethidine and lidocaine etc. ‘N-acetyltransferases’ that utilize acetyl-
Meperidine is catalyzed by esterases to be CoA as a cofactor, and are present in the cell
changed into meperidinic acid and cytoplasm of the liver, intestine, kidney and
procainamide is catalyzed by amidases. lung.
Tubular secretion: The active secretory The excretion of these drugs may be affected
systems can rapidly remove the protein- in the presence of lung disease conditions,
bound drugs from the blood and transport which may precipitate the drug toxicity.
them into tubular fluid as the drugs that are
bound to proteins are not readily available BILIARY EXCRETION
for excretion by filtration. The drugs known Certain drugs are excreted in urine only
to be secreted by organic anion secretory in small amounts but appear in high
system (i.e. strong acids) are salicylates, concentrations in the bile for example,
chlorothiazide, probenecid, penicillin etc. erythromycin, novobiocin, tetracycline,
and cation (i.e. bases) includes phenolphthalein etc. The abnormality or any
catecholamines, choline, histamine, disease related to liver may impair bile
hexamethonium, morphine etc. secretion which can lead to the accumulation
Passive diffusion: Passive diffusion can of certain drugs like probenecid, digoxin etc.
occur in both the ways in proximal and distal This can also lead to decreased drug
convoluted tubules. The lipophilic drug metabolism and decreased rates of secretion
molecules are reabsorbed from the of drugs into bile.
glomerular filtrate into the blood stream. Certain drugs that are secreted by the
The pH of the urine can affect the rate of liver into the bile and then to small intestine
passive diffusion and hence drug excretion. are not eliminated out through the faeces,
The changes in urinary pH affect tubular so that the drugs will re-enter the blood that
reabsorption of partially ionized drugs. The perfuses the intestine and again carried to
effect of change in urinary pH on excretion the liver (repeatedly reabsorbed from the
of drugs is more with the drugs having pH intestine and re-excreted in the bile) and
values between 5 to 8. The excretion of basic thereby prolongs the action by the so called
drugs can be increased by making the urine ‘enterohepatic circulation’.
more acidic by using the acidifying salt i.e.
ammonium chloride. EXCRETION IN OTHER BODY FLUIDS
Sweat and Saliva
PULMONARY EXCRETION The excretion of drugs through sweat
Volatile lipophilic substances like and saliva is primarily dependent upon the
volatile general anaesthetics, ethyl alcohol, diffusion of the non-ionized, lipophilic form
paraldehyde are excreted by the lungs. These of the drug across the epithelial cells of the
volatile substances and certain gases that glands. The compounds like lithium,
enter the body through the respiratory tract potassium iodide and heavy metals are
in the form of aerosol are excreted by this present in these secretions.
route.
Ethanol, having high blood gas Milk
solubility is excreted very slowly by the The excretion of drugs into the mother’s
lungs and nitrogen oxide, which are not very milk will depend upon the amount of drug
soluble in blood, will be excreted rapidly. in blood, its lipid solubility and the extent
Pharmacokinetics 37
The figure shows the different types of produces its desired effect in a particular
drugs with different plasma half life, but the time at receptor site and remain there at
steady state concentration is maintained on therapeutic level for particular time and
repetitive dosing in all the three type of drug. after that its therapeutic efficacy declines.
So the next dose should be given in
between this period so that the steady state
concentration is maintained and no toxic
Blood concentration
7
Drug : A = Drug with long plasma half life given
6 Toxic level
in initial loading dose followed by
[Minimum toxic
constant maintenance dose. 5 concentration (MTC)]
B = Drug with short plasma half life given 4
Therapeutic level
in constant repetitive dose. [Minimum effective
3
C = Drug with long plasma half life given concentration (MEC)]
2
in constant repetitive dose.
1
LOADING DOSE
2 4 6 8 10 12 14 16 18 20
It is a single or many quickly repeated Time (hr.)
doses given in the beginning of treatment
Fig. 1.4.4: Drug concentration in plasma vs time curve
to achieve target concentration rapidly.
of drug administered orally.
6 6
5 5
MTC
MTC
4 4
MEC
MEC
3 3
2 2
- Second
- First dose - First - IInd
1 dose 1 dose dose
2 4 6 8 10 12 14 2 4 6 8 10 12 14
Time (hr.) Time (hr.)
Fig. 1.4.5: Shows the administration of 2nd dose Fig. 1.4.6: Shows the administration of 2nd dose after
between the 7-8 hours interval which maintains the 7-8 hours interval which does not maintain the drug
drug plasma levels above minimum effective plasma concentration at MEC level.
concentration.
Plasma concentration (µg/ml)
6
MTC
5
4
MEC
3
— 2nd
2 dose
—Ist
1 dose
2 4 6 8 10 12 14
Time (hr.)
Pharmacodynamics is the study of drug ef- and often drugs like antibiotics, antacids,
fects (biochemical and physiological) and and so many other drugs acts systemically.
their mechanism of action. When the drug The proper localization of the site of
reaches its site of action it has a pharmaco- drug action can be determined pharmaco-
logical effect which may be responsible for logically. When a new drug is introduced
an eventual therapeutic effect and also re- its screening gives an idea about the site and
sponsible for the adverse effects as well as mechanism of drug action, for example, if
some other effects which may be of no clini- any drug is said to be antihypertensive in
cal importance. nature and by blocking this action by prior
administration of an antihistaminic, it will
SITE AND MECHANISM OF DRUG ACTION gives an idea that the drug may act in the
The site of drug action means where a drug same place and same mechanism as hista-
acts and mechanism means how the drug mine. The use of certain blocking agents also
acts. Drug which act only at the site of help in suggesting the probable site of ac-
application (i.e. localized region) are termed tion of drugs.
as local or topical action for example,
ointments, paste, creams and certain other TYPES OF DRUG ACTION
local preparations used externally produce The drug may produce their effects by:
only local effect. The local anaesthetics like
lignocaine, procaine produce anaesthesia i. Stimulation.
(local) in a localized region only. ii. Depression.
The second type of action is systemic or iii. Irritation.
general action which produce their action iv. Replacement.
after absorption, for example, general v. Bactericidal and cytotoxic action.
anaesthetics act centrally after absorption, Stimulation
40 Section 1/ General Principles of Pharmacology
nist prevents the action of an agonist on a On the basis of affinity and efficacy, the
receptor, but does not have any effect of its drugs can be classified as agonists, which
own (Fig. 1.5.1). have both affinity as well as high intrinsic
Receptors are mostly protein macro- activity and can mimic the effects of the
molecules. The cholinergic, adrenergic, hista- endogenous substance after combining with
minergic and other receptors are ‘physiological the receptor (e.g. methacholine produces the
receptors’ on which certain drugs act which effect of acetylcholine at cholinergic
mediate the responses to transmitters, autacoids receptors). Antagonists have only the affinity
etc. Another type of receptor is ‘drug receptors’, but no intrinsic activity. These drugs bind to
which do not have any known physiological the receptor, but do not mimic (rather block)
ligands, for example thiazide receptor, benzo- or interfere with the binding of an
diazepine receptor etc. endogenous agonist (e.g. atropine block the
effect of acetylcholine on cholinergic-
muscarinic receptors). Partial agonists have
+
full affinity to the receptor but with lower
Agonist Receptor Agonist- Response intrinsic activity [e.g. pentazocine is a partial
receptor
interaction agonist at µ receptor (subtype of opioid
receptor)]. Inverse agonist or negative
+ antagonists have full affinity towards the
Antagonist Receptor Antagonist- No receptor but their intrinsic activity is
receptor response absolutely negligible and may be zero or in
interaction
minus.
Fig. 1.5.1: Drug-receptor interaction: The agonist
RECEPTOR TYPE
completely fits (interact) with the receptor site to
produce a pharmacological response and antagonist On the basis of molecular structure and
only partially fit with the receptor site and is unable to nature of transduction mechanism, receptor
produce any pharmacological response, and also
prevents the agonist from combining with the
can be classified into following categories:
receptors. i. G-protein and second messengers.
The ability of a drug to get bound to a
ii. Ligand-gated channels.
receptor is termed as the ‘affinity of the
drug’ for the receptor. The ability of the drug iii. Cytokine receptors.
to produce a pharmacological response after iv. Tyrosine kinases.
its interaction with the receptor is known as v. Intracellular receptors.
‘intrinsic activity of the drug’, it also
determines the degree of receptor response. COMBINED EFFECT OF DRUGS
The agonists produce a maximal receptor
response (high intrinsic activity), partial SYNERGISM
agonists have intermediate intrinsic activity When two drugs are given simulta-
and antagonists have low intrinsic activity neously, and the action of one drug is in-
and high affinity for the receptors. creased by the other, they are treated as
44 Section 1/ General Principles of Pharmacology
synergistic. In the synergism, the drugs can cyanomethaemoglobin and after sodium
have action in the same direction or when thiosulphate injection forms sodium thio-
given alone, one may be inactive. Synergism cyanate which is easily excreted in urine.
can be additive or supradditive in nature. On receptor basis, drug antagonism will
ADDITIVE be of two types competitive and noncompeti-
tive antagonism.
When the effect of two drugs are in the
same direction. For example when aspirin COMPETITIVE ANTAGONISM
is combined with paracetamol the combined
In competitive antagonism, the
effect is analgesic/antipyretic.
antagonist binds with the same receptor as
Another important example is agonist. If the log dose response curve with
combination of theophylline and ephedrine agonist is obtained in the presence of
as bronchodilator, combination of antagonist, it will be found that antagonist
sulfonamides as antibacterial etc. has no effect of its own and there is parallel
SUPRADDITIVE rightward shift in the dose response curve
of agonist (Fig. 1.5.2) with no change in
In this the effect of combined therapy is
shape, slope or maximum response.
greater than the individual effect of the one
drug. Examples are: In competitive antagonism, the
antagonist reduces affinity i.e. potency of the
• Levodopa and peripheral dopa-
agonist.
decarboxylase inhibitor, carbidopa or
benserazide in the treatment of Example of competitive antagonism are:
parkinsonism. • Acetylcholine (as agonist) – atropine (as
• Sulfonamide and trimethoprim (well antagonist).
known preparation ‘Septran’) as • Acetylcholine – d-tubocurarine.
antibacterial.
• Isoprenaline – propranolol.
DRUG ANTAGONISM
Antagonism describes the situation, when
one drug decreases or inhibits the action
of another. The antagonism may be physi-
cal in which the physical property of the
drug can affect the absorption of another
drug, chemical in which two drugs react
chemically and form a biologically inactive
compound. This type of reaction may be
used in the treatment of drug poisoning.
For example in cyanide poisoning nitrites
form methaemoglobin which has high af- Fig. 1.5.2: Log dose response curve showing
finity for cyanide radical and forms competitive antagonism.
h a p
p tterer
CCh Adverse Drug
1.6
1.4 Reactions
Side effects are also based on different drug. It results from previous sensitization to
facet of action (or side effects unrelated to the drug itself or a particular chemical with
its pharmacological or therapeutic effect). similar structure.
All antihistaminics except few newer The B-lymphocytes, when exposed to
compounds e.g. astemizole, terfenadine etc. antigens mature into immunoglobulin
cause sedation which is unrelated to its secreting cells after proliferation, which
therapeutic action i.e. antiallergic action.
often have the appearance of plasma cells.
The history of pharmacology revealed that
The immunoglobulins (Ig) are secreted
certain drugs have been developed from the
by B-lymphocytes in the later stage of their
observation of their side effects for example
development into plasma cells. IgG, IgA,
sulfonamide produce hypoglycemia and
acidosis as side effect, which further gave an idea IgM, IgE and IgD are immunoglobulins, out
for developing a new compound related to of these IgG is the major one.
sulfona-mide – sulfonylurea as hypoglycemic Based on the mechanism of immuno-
agent and acetazolamide as diuretic. logical reactions, the allergic responses have
been divided into four categories:
TOXIC EFFECTS
TYPE-I (ANAPHYLACTIC REACTION)
Toxic effects develop due to excessive
They are mediated by IgE antibodies. On
pharmacological action of drug, which may
be due to overdose or continuous use of exposure to the drug, antigen and antibody
drug for prolonged period. reaction takes place on mast cells and
basophils releasing various mediators e.g.
The overdose toxicity occurs when the
histamine, leukotrienes, 5 hydroxytryptamine
high dose of drug is required for the specific
treatment or the drug is taken accidentally or (5-HT), prostaglandins etc., which are
with the intention of suicide. The effects are responsible for immediate immune reactions
predictable and dose related. For example like skin reaction, anaphylactic shock, asthma
delirium by the use of atropine and respiratory etc. These reactions occur immediately after
failure by morphine occur due to their challenge and are termed as immediate
overdoses. The well known antitubercular hypersensitivity.
drug, streptomycin causes vestibular damage
and deafness on prolonged use. TYPE-II (CYTOLYTIC REACTION;
DELAYED IGG/IGE MEDIATED)
DRUG ALLERGY AND IDIOSYNCRASY These reactions are mediated by IgG and
IgE antibodies, which bind to the target cells
HYPERSENSITIVITY (DRUG ALLERGY) (cells in the circulating system). On
Drug allergy is a cell-mediated immune reexposure antigen-antibody reaction takes
reaction producing symptoms, which are place on the surface of these target cells and
unrelated to the pharmacological effects of the cytolysis occur. Example are penicillin-
Adverse Drug Reactions 49
induced hemolytic anaemia, sulfonamide- act directly on the foetus, or act indirectly on
induced granulocytopenia and quinidine- placenta e.g., vitamin A, 5-HT.
induced cytopenic purpura. It is clear that the major foetal damage
occur by drug when it is taken in early
TYPE-III (ARTHUS REACTION IGG pregnancy (i.e. first 2-9 weeks when
MEDIATED) organogenesis takes place.)
These reactions are predominantly me- The teratogenic drugs can affect
diated by IgG. The antigen-antibody com- different stages of pregnancy i.e.
plexes are deposited in the vascular endot-
• At fertilization and implantation stage
helium, where a destructive inflammatory
(i.e. conception to 3 weeks).
response occurs. Serum sickness, clinical
• Organogenesis period (3 to 9 weeks),
symptoms include fever, skin eruptions, ar-
and
thralgia and lymphadenopathy. The reac-
• In growth and development period
tion usually subsides in 6-12 days.
(i.e., after 9 weeks).
The drugs inducing serum sickness are The drugs, which are proven to be
sulfonamides, penicillin etc. Sulfonamides teratogenic are thalidomide, anticancer
also cause Stevens-Johnson syndrome, a form drugs (specially methotrexate), sex
of immune vasculitis, which is characterized hormones (androgens, progestins,
by the reactions including arthritis, nephritis, stilboesterol) corticosteroids, warfarin,
myocarditis and certain mental symptoms. antithyroid drugs (which can cause foetal
goitre and hypothyroidism), oral antidia-
TYPE-IV (DELAYED betic drugs, and social drugs including
HYPERSENSITIVITY) tobacco, alcohol etc.
These reactions are mediated by
production of sensitized T-lymphocytes. On CARCINOGENICITY
contact with antigen, an inflammatory Certain drugs affect the genes and structural
reaction is generated which includes contact changes in the chromosomes. The drugs that
dermatitis, fever and photosensitization. cause cancer are called as carcinogenic
Drugs which cause these types of drugs, for example, oral contraceptives in-
reactions are penicillin, sulfonamides, crease the incidence of benign liver tumors,
tetracycline, phenylbutazone, salicylates etc. vaginal adenocarcinoma in the female off-
springs of women who have taken
stilboesterol during her pregnancy for abor-
TERATOGENICITY
tion purpose.
Teratogenicity is derived from the word ‘teratos’ Drugs producing carcinogenic effects are
mean ‘monster.’ Teratogens may act directly on anticancer/antineoplastic drugs, radioisotopes
the foetus, e.g., thalidomide and anticancer drugs like P32, I131 and hormonal therapy etc.
50 Section 1/ General Principles of Pharmacology
h a p
p tterer
CCh
Drug Interactions
1.7
1.4
Drug interactions may be defined as an drug is effective only in very low per-
alteration in duration and/or onset of action centage of patients. Likewise, in the
of the pharmacokinetic and/or pharmaco- treatment of heart failure, a combined
dynamic of one drug produced by another therapy of diuretic with vasodilator
drug. The multiple drug therapy produced and/or cardiac glycoside has to be
a combined effect, which may be antagonis- given to achieve a adequate cardiac
tic or synergistic in nature. In antagonism output and control over edema. Mul-
the effects of one drug are reduced or abol- tiple drug therapy also required in che-
motherapy of cancer, tuberculosis and
ished by the second drug, and in synergism
certain infectious diseases.
the effects may be additive or potentiative
in nature, which may be harmful or useful • To minimize the side effects of drugs
e.g. to supplement potassium by giving
to the patient in a particular disease.
potassium sparing diuretic with
The clinically established drug digitalis.
interactions can be minimized to some The use of combined drug therapy can
extent by the avoidance of combined drug not be avoided in certain cases to attain a
therapy, which are proven to be desired therapeutic level, but the risk of
incompatible. incompatibility/interactions involved in the
But, in certain cases, the single drug is treatment increases.
effective only to a certain degree or stage of The drug interactions may be divided
disease condition. The multiple/combined into:
drug therapy is required in many medical
i. Pharmacokinetic, which occur at the
and dental conditions. level of absorption, distribution,
• To produce a desired pharmacody- metabolism and excretion of one drug
namic/ therapeutic effect which is not by another.
obtained by single drug, e.g. in the ii. Pharmacodynamic, which occur at the site
treatment of hypertension, a single of drug action involving the receptors.
52 Section 1/ General Principles of Pharmacology
binding site thereby causing bleeding. Tolb- Table 1.7.2: Interactions caused by displacement of
drugs from plasma protein binding sites.
utamide is displaced by dicumarol resulting
in severe hypoglycemia (See table 1.7.2). Drug displaced Displacing agent
Coumarin Diazoxide, ethacrynic acid,
Drug Interactions During Metabolism phenylbutazone, NSAIDs
This type of interaction occurs when the Tolbutamide Dicumarol, phenylbutazone
metabolism of a drug is inhibited or Phenytoin Tolbutamide, NSAIDs
decreased by another drug. Diazepam Heparin
These type of interactions are of two types: which are enhanced by potassium
The direct pharmacodynamic interactions depletion e.g., potassium-sparing
occur when two drugs either act on the same diuretics, corticosteroids and
site or on two different sites with a similar purgatives.
effect. • Diuretics like frusemide may attenuate
When two drugs act on same site, they the effects of oral hypoglycemic drugs.
are either antagonist or synergist. For • Drugs like salicylates, dipyridamole,
example: phenylbutazone decrease the ability
Antagonism: Reversal of the effect of of platelets to aggregate, and thus
opiates with naloxone. impairing the haemostasis if war-
Reversal of anticholinergic effects with farin induced bleeding occurs.
tricyclic antidepressants and physostigmine. • The nonsteroidal antiinflammatory
Synergism: Increased anticoagulation of drugs like aspirin, indomethacin and
warfarin with clofibrate, corticosteroids, phenylbutazone causes ulceration in
tetracycline, vitamin K and naloxone. gastro-intestinal tract which provides
Arrhythmias with the use of b-adreno- a site for bleeding in patients on
receptor antagonists and verapamil together. anticoagulants.
The indirect pharmacodynamic interac- The pharmacodynamic interactions are
tions are unrelated to the effects of the ob- relatively common in practice, but they can
ject drug, for example: be minimized if the interactions are antici-
• Drugs which alter potassium con- pated and appropriate precautions are
tent may have effect on the thera- taken by avoiding irrational and unneces-
peutic effect of cardiac glycosides, sary drugs combination.
Cardiovascular system
Antiarrhythmic drugs Any combination of two or more Increased myocardial depression.
Disopyramide Potassium salts, amiodarone Hyperkalaemia, increased risk of
ventricular arrhythmias due to
prolongation of QT interval.
Contd.....
Drug Interactions 55
Antihypertensive drugs
Captopril Antiinflammatory analgesics such Reduced effects.
as indomethacin, phenylbutazone,
corticotrophin, estrogens, oral con-
traceptives
Alcohol, antidepressants, hypnotics, Potentiation.
sedatives, tranquillizers, fenfluramine,
levodopa, vasodilators such as nitrates,
nifedipine, verapamil
Potassium supplements, potassium Hyperkalaemia.
sparing diuretics.
Clonidine Beta-adrenoceptor blocking drugs Increased risk of clonidine with-
drawal hypertension.
Tricyclic antidepressant Antagonism.
Beta-adrenoceptor Indomethacin Antagonism of antihypertensive
blocking drugs effect.
Nifedipine Severe hypotension and heart
failure occasionally.
Sympathomimetic amines such as Severe hypertension reported.
adrenaline, amphetamines, phenyl-
ephrine
Labetalol Cimetidine Potentiation possible because of
reduced metabolism.
Contd.....
56 Section 1/ General Principles of Pharmacology
Contd.....
Drug Interactions 57
Endocrine system
Antidiabetic drugs Alcohol Antabuse like reaction.
Beta-adrenoceptor blocking drugs, Potentiation.
MAO inhibitors
Corticosteroids, corticotrophin, diazo- Antagonism.
xide, diuretics (bumetanide, furosemide,
thiazides), oral contraceptives
Metformin Alcohol Increased risk of lactic acidosis.
Corticosteroids, cortico- Diuretics (bumetanide, ethacrynic acid, Increased potassium loss.
trophin furosemide, thiazides)
Cortisone, dexamethasone, Barbiturates, carbamazepine, Reduced effect.
hydrocortisone, predni- phenytoin, primidone, rifampicin
solone, prednisone.
Gynaecology
Oral contraceptives Barbiturates, carbamazepine, dichloral- Reduced effect.
phenazone, phenytoin, primidone,
rifampicin.
Oral antibiotics such as ampicillin, Reduced effect.
tetracycline
This page
intentionally left
blank
Section 2
Drugs Acting on
CNS
This page
intentionally left
blank
h a p
p tterer General
CCh Pharmacodynamics
Anaesthetics
2.1
1.4 (Mode of Action of Drugs)
General anaesthetics are the group of tion used is 70 percent N2O + 30 percent O2
drugs which bring about a reversible loss of along with some muscle relaxants or other
pain sensation and consciousness. The depth potent anaesthetics. Nitrous oxide, if admin-
of anaesthesia appropriate for the conduct istered along with air, it produces a stage of
of surgical procedures can be achieved by a excitement and delirium and also produce
wide variety of drugs, either alone or by a amnesia. Hence, the name ‘laughing gas.’
combination of drugs, each drug for a spe- It is eliminated unchanged from the
cific purpose. General anaesthetics can be body, via the lungs. Despite its high fat solu-
administered by a variety of routes, but in- bility, it is rapidly eliminated through lungs
tra-venous or inhalation administration is within 2 to 5 minutes after its withdrawal.
preferred, because the effective dose and the
Nitrous oxide, due to its analgesic action
time course of action are more predictable
in subanaesthetic concentration, is employed
when these techniques are used.
for minor operation like tooth extraction, for
The general anaesthetics are divided into obstetrical analysis, painful procedures such
two main groups (table 2.1.1). as changing dressing of burns. It is cheap and
very commonly used.
INHALATIONAL ANAESTHETICS
Prolonged administration of nitrous ox-
ide as in cases of tetanus, may cause bone
NITROUS OXIDE (N2O)
marrow depression and agranulocytosis.
It is a colourless, odourless, noninflammable
gas which is approx. 1½ times heavier than CYCLOPROPANE
air. It is non-irritating with a sweet taste. It is a colourless gas with sweet odour and
Nitrous oxide is used for induction and taste, available as liquid under pressure. It
maintenance of anaesthesia. It is widely produces analgesia without loss of conscious-
used as carrier gas for other volatile agents ness in 1 to 2 percent concentration, in 6 to 8
in general anaesthesia. The usual concentra- percent it produces loss of consciousness while
62 Section 2/ Drugs Acting on CNS
20 to 25 percent is required to produce surgi- dium to adrenaline and may produce a va-
cal anaesthesia. It has a low blood solubility. riety of cardiac irregularities such as tachy-
The induction and recovery are rapid and cardia and fibrillation. That is the reason for
smooth. Blood pressure and cardiac contrac- avoiding cyclopropane anaesthesia in pheo-
tility are well maintained with cyclopropane chromocytoma and thyrotoxicosis. Cyclo-
even on prolonged administration. Muscle propane shock (in patients with sepsis) is
relaxant activity is fairly good. Because of its another drawback, which produces a sud-
highly inflammable and explosive nature, the den fall of blood pressure with collapse.
close circuit has to be used to conserve the
drug and to keep its concentration in the op- VOLATILE LIQUIDS
erating room low.
Because of its smooth induction and ETHER (DIETHYL ETHER)
non-irritant to the respiratory passage, the It is a colourless, volatile liquid with a pun-
danger of overdosage must be watched for. gent odour and produces irritating vapours
Cyclopropane also sensitizes the myocar- which are inflammable and explosive. It is
General Anaesthetics 63
one of the first substances to be employed pharyngeal reflexes in upper planes of sur-
for general anaesthesia. It is a potent agent gical anaesthesia.
and produces full anaesthesia when inhaled Halothane causes relatively greater de-
in low concentration. A concentration of 10 pression of respiration. It inhibits intesti-
to 15% in the inspired air is usually required
nal and uterine contractions. Cardiac out-
for induction. It produces prolonged and
put is also reduced by 20 to 50 percent when
unpleasant induction with salivation and
anaesthesia is induced by inspiration of ha-
marked respiratory secretions. For this at-
lothane at 0.8 to 1.2 percent concentration,
ropine must be given prior to anaesthesia
for inhibition of these secretions. which is necessary for surgical anaesthesia.
Heart rate is slowed during anaesthesia,
Respiration and blood pressure are gen- tachyarrhythmias may also occur in the
erally well maintained because of reflex presence of halothane.
stimulation and high sympathetic tone.
Halothane causes dose-dependent re-
Because of its slow induction and recov- ductions of renal blood flow and glomeru-
ery, irritant property and other disadvan- lar filtration rate as a result of fall in blood
tages ether is rarely used these days and may pressure.
be occasionally used as a supplement to ni-
Hepatitis occurs in susceptible individu-
trous oxide-oxygen mixture in children.
als with repeated use.
TRICHLOROETHYLENE It causes decrease in uterine muscle tone.
It is a clear, colourless liquid with a char- Elimination of halothane may continue
acteristic odour but a blue dye is added for for 24 to 48 hours after prolonged adminis-
distinction from chloroform. It is a potent tration. Recovery is smooth and reasonably
analgesic with a rapid onset of action but quick. It is currently one of the most popu-
muscular relaxation with this agent is inad- lar anaesthetic used due to its non-irritant,
equate. Induction and recovery are slow. non-inflammable, pleasant and rapid action.
It may produce tachypnoea and brady-
cardia and sensitizes the myocardium to ENFLURANE
adrenaline and cardiac arrhythmias can oc- It is a clear, colourless, noninflammable
cur probably due to hypoxic release of liquid with a mild, sweet odour and consid-
adrenaline. ered to be a useful alternative to halothane.
Now-a-days, it is occasionally used in Induction of anaesthesia, appropriate for
obstetrics, burns dressings etc. as a self surgery may be achieved within 10 minutes
medication analgesic. after approximately 4 percent enflurane in
inhaled. Arterial blood pressure decreases
HALOTHANE progressively as the depth of anaesthesia is
It is a volatile liquid, non-irritant and increased with enflurane, about the same
non-inflammable. It is most widely used degree as it does with halothane inhalation.
volatile anaesthetic due to its smooth and The anaesthesia produces rapid induction
rapid induction. It inhibits laryngeal and with quick recovery.
64 Section 2/ Drugs Acting on CNS
Enflurane can be used for prolonged these changes are rapidly reversed during
operations such as cholecystectomy and recovery.
other abdominal surgery which requires
profound muscular relaxation. It stimulates METHOXYFLURANE
salivary and respiratory secretions. Uterine It is a clear, colourless liquid with a
relaxation is similar to halothane. sweet and fruity odour. It is noninflammable
No unusual effect on the gastrointes- and non-explosive in air or oxygen in an-
tinal tract has been reported with aesthetic concentrations. It is the most po-
enflurane anaesthesia, however, certain tent inhalational anaesthetic which has a
evidence of hepatic impairment has good analgesic and muscle relaxant prop-
been obtained during and after surgi- erties. Renal blood flow, glomerular filtra-
cal anaesthesia. Hepatic necrosis prob- tion rate and urine flow are reduced as with
ably occurs with enflurane in rare the halothane.
instances. It also produces the respiratory and car-
Heart rate decreases little and reduction diovascular depression as with halothane
of cardiac output is less marked. Fall in but bradycardia is more prominent.
blood pressure is similar to that caused by Methoxyflurane damages renal tubules
halothane, arrhythmias are rare. leading to inability to concentrate urine and
uraemia. Because of its renal toxicity, it
ISOFLURANE
should not be used to achieve profound
It is a isomer of enflurane and its chemi- anaesthesia nor for prolonged periods of
cal and physical properties are similar to time.
enflurane, but it is approximately 1½ times
more potent, more volatile. It has a lower This agent is used due to certain advan-
blood: gas solubility coefficient than tages i.e. it provides profound analgesia and
enflurane. It produces rapid induction and good relaxation of skeletal muscles, uterine
recovery. contractions are not inhibited and postop-
erative nausea and vomiting are not
Systemic arterial blood pressure de-
troublesome. But, due to its renal toxicity,
creases progressively with increasing depth
its use as a general anaesthetic is limited.
of anaesthesia with isoflurane. It also in-
creases heart rate but arrhythmias are not DESFLURANE
precipitated. Isoflurane depresses respira- It is a noninflammable, non-irritant
tion as concentration is increased. Uterine agent and chemically related to ether. Induc-
and skeletal muscle relaxation is similar to tion with this agent is smooth and rapid. The
enflurane. respiratory, hemodynamic and other
During anaesthesia, depression of renal changes caused by desflurane are similar to
blood flow, decrease in rate of glomerular those of isoflurane. This agent is undergo-
filtration and urinary flow are reported but ing clinical trial.
General Anaesthetics 65
h a p
p tterer Sedative
CCh Pharmacodynamics
Pharmacodynamics
&
2.2
1.4 (Mode of Action of Drugs)
Hypnotics
Sedative (anxiolytic) are the agents which Pain: Barbiturates do not have any an-
reduce anxiety and exert a calming effect algesic effect.
with little or no effect on motor or mental Anaesthesia: The ultra short acting bar-
functions. biturates produce general anaesthesia (de-
Hypnotics are the drugs which produce tails are given in chapter ‘General
drowsiness and encourage the onset and anaesthetics’).
maintenance of sleep. They are classified Anticonvulsant action: In anaesthetic
into different categories (Table 2.2.1.)
dose all barbiturates e.g. phenobarbitone,
mephobarbitone possess anticonvulsant ac-
BARBITURATES tion. Phenobarbitone is drug of choice for
Barbiturates are the derivatives of the treatment of grandmal epilepsy (details
barbituric acid. They are general CNS are given in chapter ‘Antiepileptic drugs’).
depressants. They can cause sedation, CVS: In hypnotic dose, hypotension and
hypnosis and general anaesthesia decrease in heart rate occurs. In toxic dose,
depending upon the particular barbiturates there is a severe decrease in blood pressure
used and its dose. due to ganglionic blockade.
• For general anaesthesia: Ultra short agents exhibit good efficacy, are relatively
acting barbiturates are used. safe and have minimum toxicity. They are
• As preanaesthetic medication. indicated for short term relief of anxiety.
• As obstetrical analgesia. Benzodiazepines have no action on respira-
tion and cardiovascular system. They have
Barbiturate Poisoning no action on other body systems. They have
It produces severe toxic manifestations. a muscle relaxant action, probably due to
Either suicidal or accidental intake of toxic CNS depressant action and have anticonvul-
doses of barbiturates is characterized by sant action. They have lower abuse liabil-
depressed respiration, circulatory shock, ity. Benzodiazepines when administered
pupils are initially constricted & then dilated cause sedation, hypnosis, muscle relaxation,
due to asphyxia, hypothermia, renal failure relieve anxiety and some have anticonvul-
and pulmonary complications such as acute sant action.
pulmonary edema. Benzodiazepines exert their pharmaco-
logical effect mainly by potentiation of
Treatment of Acute Barbiturate Poisoning
neural inhibition in CNS which is medi-
• Gastric lavage to remove unabsorbed ated by GABA.
drug. Emesis can be produced by
apomorphine and activated charcoal is Pharmacokinetics
administered to adsorb the unabsorbed
The pharmacokinetic profile is different
drug.
with different compounds. Diazepam after
• Maintenance of respiration: oral administration is completely and rap-
Oxygen inhalation. idly absorbed from the proximal small in-
Endotracheal intubation or tracheo- testine. Oxazepam is least rapidly absorbed
stomy. while lorazepam is an intermediately ab-
Mechanical ventilation. sorbed between these two. They are
• Intravenous fluids. metabolised in liver by dealkylation and
• Forced diuresis: Diuretics like mannitol hydroxylation and excreted in urine as glu-
and furosemide can be used. curonide conjugates. They cross the placen-
tal barrier and are secreted in milk.
• Alkalinization.
• Prophylactic antimicrobial therapy to Adverse Reactions
avoid any secondary infection e.g.
The common side effects are drowsiness,
pneumonia and infection due to
lethargy, ataxia. They also cause behavioural
tracheostomy or urinary catheterization.
changes and dose dependent impairment of
• Dialysis (peritoneal or haemodialysis).
visual motor coordination. Other side effects
which occur rarely are vertigo, headache,
BENZODIAZEPINES
allergy, photosensitization, leucopenia, im-
Benzodiazepines are commonly used paired sexual function and menstrual irregu-
anxiolytics in clinical practice because these larities.
72 Section 2/ Drugs Acting on CNS
Delta and kappa receptors can also con- fectively than sharp intermittent pain and
tribute to analgesia, particularly at spinal is very effective in visceral pain.
level. Although morphine also acts on kappa Morphine also produces a sense of anxi-
and delta sites but it is not clear that up to ety, known as dysphoria. The morphine pro-
what level they contribute in its analgesic duces euphoria (which makes morphine as
action. one of the main drugs of abuse) and analge-
sia by acting on higher centres and spinal
Pharmacological Actions cord.
Effect on CNS: The main action of mor- On intrathecal injection, it acts on substan-
phine is CNS depression which further re-
tia gelatinosa of dorsal horn of spinal cord and
sults in analgesia, depression of respiratory
inhibit the release of excitatory transmitters.
centre, cough centre and sleep. In addition
At supraspinal sites, it acts on medulla, mid
it causes euphoria or dysphoria and depen-
brain, limbic and cortical areas.
dence.
Action on eye: Morphine causes con-
Analgesia: Morphine produces analge-
striction of pupil (miosis) due to action on
sia by elevation of pain threshold, thereby
reducing the perception of pain. It also al- oculomotor nerve nucleus.
tered psychic reaction to pain which may be Action on respiration: Morphine de-
associated with feeling of well being e.g. presses the medullary respiratory centre in
euphoria. It also produces lethargy and medulla oblongata and by reducing the sen-
sleep, morphine relieves all types of pain, sitivity of the medullary respiratory centre
but dull constant pain is relieved more ef- to increased plasma CO2. The rise in arterial
Narcotic Analgesics (Opioids) 77
CO2 causes an increase in cerebrospinal fluid in body temperature. It also depresses tem-
pressure. perature regulating centre.
Action on cough centre: Morphine sup-
Pharmacokinetics
presses cough reflexes, but cough suppres-
sion by opioids may allow accumulation of Morphine orally is less effective and
respiratory secretions and may produce air- absorption is very slow. It has variable and
way obstruction. high first pass metabolism when given by
subcutaneous route, its analgesic effect starts
Chemoreceptor trigger zone (CTZ): within 10 minutes which persists for 4 to 5
Morphine stimulates CTZ and produces hours and by IV route, it produces immedi-
nausea and vomiting. These effects are more ate action. In plasma, it binds to plasma pro-
marked in upright position due to vestibu- teins (approx. 30%). In liver it is metabolized
lar involvement. by conjugation to glucuronic acid to form
Vagal centre: Morphine stimulates the active and inactive products, which are ex-
vagal centre and produces bradycardia. creted in urine. It is also excreted though bile
Effect on GIT: It increases the tone of and in the faeces.
smooth muscle as well as sphincters but at
Adverse Reactions
the same time it decreases the propulsive
movements and gastrointestinal secretions CNS side effects include confusion, anxi-
are diminished, the overall action is consti- ety, lethargy, nausea and vomiting. GIT re-
pation. lated effect is constipation. Other side effects
are urinary retention, dry mouth, miosis,
Other smooth muscle: Morphine causes dysphoria, hypotension, skin rash, itching
bronchoconstriction which is due to hista- and urticaria. Tolerance, drug dependence
mine release and may be dangerous in pa- and drug abuse are the main drawbacks of
tients suffering from bronchial asthma. morphine.
Morphine also cause flushing and itch-
ing of skin due to histamine release. Acute Overdose/Toxicity (Morphine
Urinary system: Morphine causes Poisoning)
spasm of detrusor as well as sphincters of It is characterised by respiratory depres-
urinary bladder and causes distension, ur- sion, miosis, cyanosis, reduced body tem-
gency and difficulty in micturition. perature, urinary retention, hypotension,
Endocrine system: Morphine and other pulmonary edema and coma.
opioid analgesics stimulate the release of The acute poisoning can be treated by:
vasopressin and prolactin and inhibit the • Maintenance of airway and oxygen in-
release of luteinizing hormone, ACTH and halation. Maintenance of BP.
follicle stimulating hormone. • Specific antagonists: Naloxone 0.4-0.8
Metabolism: Morphine decreases the mg IV; alternatively nalorphine (3-5 mg
metabolic rate which can lead to decrease IV) can be given.
78 Section 2/ Drugs Acting on CNS
gated with glucuronic acid and excreted in pharmacology and side effects are similar to
urine. Only a small amount of pethidine is that of morphine. It is used in the treatment of
excreted unchanged. Pethidine differs from visceral pain and as an antitussive. It is also used
morphine in that toxic doses sometimes as substitution therapy of opioid dependence.
cause CNS excitation, characterized by trem-
ors, muscle twitches and seizures; these ef- DEXTROPROPOXYPHENE
fect are largely due to norpethidine. It is dextro isomer of propoxyphene
Adverse effects include nausea, vomit- which is an analgesic and possesses antitus-
ing, respiratory depression, dizziness, dys- sive property. It has low analgesic activity
phoria, constipation, urinary retention. Tol- even half of codeine. It is metabolized in liver.
erance develops to some of these effects and Side effects include vomiting, epigastric dis-
it has abuse potential. tress and sedation. The demethylated me-
It is mainly indicated for analgesia, as tabolite of propoxyphene is cardiotoxic. It is
preanaesthetic medication, for epidural and used in the treatment of mild type of pain.
intrathecal analgesia.
TRAMADOL
FENTANYL It is centrally acting synthetic analgesic
It is a potent opioid analgesic. Chemi- compound that is not derived from natural
cally it is N-phenyl-N-propanamide. It in- sources nor is chemically related to opiates.
teracts predominantly with opioid µ-recep- It acts via opioid receptors in CNS to pro-
tor in human brain, spinal cord and other duce analgesia and has no abuse potential.
tissues. It exerts its principle pharmacologic It also inhibits the reuptake of noradrena-
effects on the CNS. It is 80-100 times more line and serotonin.
potent than morphine, both in analgesia and It causes less respiratory depression, se-
respiratory depression. dation, constipation and urinary retention
Adverse effects include respiratory de- than morphine. Its hemodynamic effects are
pression (death from hypoventilation), de- minimal.
pendence, apnoea, muscle rigidity, bradycar- Side effects include nausea, vomiting
dia, arrhythmia, chest pain, GI symptoms, and dizziness.
haemoptysis, abdominal pain, headache, It is indicated in moderate to severe,
somnolence, confusion and hallucinations. acute or chronic pain and in painful diag-
It is indicated as a narcotic analgesic nostic procedures and surgery; arthralgia,
supplement in general or regional anaesthe- dental pain, musculoskeletal pain, pain as-
sia, as an anaesthetic agent with oxygen and sociated with fractures, dislocation and
skeletal relaxant in selected high risk pa- other related type of pain.
tients (e.g. open heart surgery).
ETHOHEPTAZINE
METHADONE It is orally active analgesic, similar to
It is synthetic compound having same or pethidine with low abuse potential. It is gen-
more analgesic activity than morphine. It’s erally used in combination with nonsteroi-
80 Section 2/ Drugs Acting on CNS
dal antiinflammatory drugs for mild to mod- actions are produced by kappa receptor ac-
erate type of pain. tivation and antagonistic properties are due
to action on mu receptor which antagonizes
OPIOID AGONISTS/ANTAGONISTS all morphine actions (mainly reverses the
analgesia and respiratory depression). It is
They are classified as in table 2.3.2. used mainly in the treatment of acute mor-
phine poisoning.
PENTAZOCINE
It is agonist-antagonist of morphine and NALBUPHINE
is used as an analgesic. It exerts morphine like It is a strong kappa receptor agonist and
action. It is a partial agonist at opioid receptors mu receptor antagonist. Its agonistic prop-
and is effective in mild to moderate type of erty is approximately three to four times
pain associated with surgery, trauma, burns, more than pentazocine and its antagonistic
colics, toothache, cancer, in labour and as property is approximately 10 times more
preanaesthetic medication. It is kappa receptor than pentazocine. It has less abuse liability
agonist with weak mu antagonist or partial in comparison to pentazocine. It is useful
antagonist properties. It causes tachycardia in postoperative pain, myocardial infarction
and rise in BP due to sympathetic stimulation. and labour.
Tolerance and dependence develops on
repeated use. It is effective orally. It is oxidized BUPRENORPHINE
and glucuronide conjugation occurs in liver It is a potent and long acting opioid with
and excreted in urine. partial mu receptor agonist property. 25
times more potent than morphine. Effects
NALORPHINE are similar to morphine but constipation is
It is an N-allylnormorphine, semisyn- less marked. It undergoes extensive
thetic congener of morphine. The agonistic presystemic elimination and therefore is
given by parenteral route. It is excreted un- It is inactive orally because of high first
changed in urine. Side effects include dizzi- pass metabolism in liver. Metabolised by
ness, sedation, miosis, respiratory depres- glucuronidation in liver. The main use of
sion, sweating and vomiting. naloxone is in the treatment of acute opioid
It is indicated in moderate to severe pain, overdose (acute morphine poisoning). It
premedication to surgery, pain due to myo- also precipitates withdrawal syndrome
cardial infarction and in postoperative pain. when administered to morphine addicts.
The constricted pupils of addicts dilate af-
BUTORPHANOL ter administration of naloxone. This has
It is a kappa agonist. It produces anal- been used as a diagnostic tool for opioid
gesia equivalent to nalbuphine and addiction.
buprenorphine but produces more sedation.
NALTREXONE
It is used in postoperative pain and re-
nal colic pain. It is a pure antagonist and chemically
related to naloxone. It is more potent than
NALOXONE naloxone and because of its longer dura-
It is N-allyl analogue of oxymorphone, tion of action, it can be used as maintenance
have a high affinity for mu receptor and drug for morphine addicts. It has no eu-
lower affinity at delta and kappa sites. It phoric effect and no physical dependence
selectively antagonizes the respiratory de- liability. It is effective orally. It is also
pression produced by opioids. After intra- claimed to be beneficial in decreasing crav-
venous administration, it antagonizes all ing for alcohol in alcoholics. Side effects
actions of morphine. It also blocks the ac- include gastrointestinal disturbances and
tions of endogenous opioid peptides. muscular pain.
This page
intentionally left
blank
h a p
p tterer Non-Narcotic
CCh
Analgesics
2.4 (Mode of Action of Drugs)
(NSAID’s)
Non-steroidal antiinflammatory drugs verted in the body to salicylic acid and pro-
(NSAIDs) are also known as nonopioid an- duce the pharmacological actions.
algesics. They relieve pain without interact- Analgesic action: Salicylates relieve
ing with opioid receptors and do not depress pain by both central and peripheral action.
CNS and have no drug dependence or drug The site of action of central analgesia seems
abuse property and possess antipyretic ac-
to be the hypothalamus. It does not have
tivity also. They act primarily on peripheral
cortical action on the reaction component of
pain mechanisms and also in CNS to raise
the pain but raises the threshold to pain per-
pain threshold.
ception. Unlike morphine, they do not pro-
They can be classified as in table 2.4.1. duce sedation and there is no drug tolerance
NSAIDs exert analgesic, antipyretic, or dependence and are not effective against
anti-inflammatory and related effects. Dur- visceral pain.
ing pain, fever and inflammation the arachi- The peripheral component of their an-
donic acid is liberated from the phospho- algesic action is due to the inhibition of
lipid fraction of the cell membrane which is prostaglandin synthetase and thereby in-
then converted to prostaglandins (PGs) via hibiting the synthesis of prostaglandins
cyclooxygenase pathway (both COX-1 & (PGs) which sensitise the pain receptors to
COX-2). COX-1 is present in kidney, stom- mechanical and chemical stimuli. Aspirin
ach and blood vessels and COX-2 is present inhibits prostaglandin synthesis and blocks
in activated leukocytes and other inflamma- the sensitization of pain mechanism.
tory cells.
They are useful in relieving all dull
itching, throbbing pain of muscles and
SALICYLATES
joints, dysmenorrhoea, toothache, head-
Salicylates are esters or salts of salicylic acid. ache etc. The NSAID’s are the mainstay for
Acetyl salicylic acid (aspirin) is rapidly con- the management of acute dental pain.
84 Section 2/ Drugs Acting on CNS
Combination of two drugs e.g., paracetamol can cause uric acid retention while in higher
+ ibuprofen or diclofenac) also used for its dose, it also inhibits tubular reabsorption of
additive effect. uric acid and have beneficial effect in gout
Antipyretic action: Salicylates lower the by producing uricosuric action.
elevated body temperature. Hypothalamic Acid-base and electrolyte balance: High
thermoregulatory centre acts as a thermo- therapeutic dose especially when used in
stat of the body which maintains the balance rheumatic fever, stimulates respiration and
between heat production and heat loss. Sali- causes respiratory alkalosis. Reduction in
cylates reset the hypothalamic thermostat bicarbonate and potassium level reduces the
which is disturbed during fever. They do not buffering capacity of the extracellular and
affect the heat production but they increase intracellular fluid. Hypokalemia may lead
the heat loss by causing vasodilatation and to dehydration and hypernatremia. They
sweating. The antipyretic action of salicy- also interfere with carbohydrate metabolism
lates is probably due to the inhibition of PG resulting in accumulation of pyruvic acid
synthesis. and lactic acid.
Effect on respiratory system: Salicylates Effect on GIT: Aspirin and related com-
stimulate respiration by increasing the con- pounds irritate gastric mucosa which may
sumption of oxygen primarily by skeletal cause epigastric distress, nausea and vom-
muscles and this results in increased pro- iting as a result of gastric irritation. The sali-
duction of carbon dioxide, which leads to cylates are unionised at the pH of the stom-
direct stimulation of the respiratory centre ach and can easily enter the mucosal cell
in the medulla oblongata producing an in- and at the pH of the cell they get ionised
crease in the depth and to some extent in thus unable to cross it and accumulate in-
the rate of respiration. Toxic doses depress side the gastric mucosal cell and causing
the respiratory centre. damage to the gastric mucosa and the dam-
Antiinflammatory and antirheumatic aged mucosa permits back flow of H+ ions
action: Salicylates suppress the clinical signs which may damage the endothelium of
and symptoms of rheumatoid arthritis and submucosal capillaries and gastric bleed-
other related inflammatory disorders by in- ing occurs.
hibiting prostaglandin synthesis, reducing Metabolic effects: Salicylates cause un-
the capillary permeability and inhibition of coupling of oxidative phosphorylation
neutrophil aggregation. Salicylates by inhib- which leads to conversion of energy into
iting the prostaglandin synthesis, prevent heat and may thus produce hyperpyrexia
sensitization of the pain receptors to certain and increased protein catabolism. Larger
biological amines such as histamine, 5-HT dose produces hyperglycemia and glyco-
(serotonin) and bradykinin, the chemical suria in normal individual while in diabetic
mediators of inflammation and pain. patient it produces hypoglycemia which
Effect on kidney: In low doses, aspirin may be due to an enhanced peripheral utili-
inhibits the tubular secretion of uric acid and zation of glucose and inhibition of
86 Section 2/ Drugs Acting on CNS
neoglucogenesis induced by salicylates and within 24 hours and plasma half life is two
related compounds. Chronic use can also to eight hours. After absorption, about 80
lead to negative nitrogen balance by in- percent of salicylate is bound to plasma pro-
creased conversion of protein to carbohy- tein (mainly albumin) and rapidly distrib-
drate. uted in the tissues. Aspirin is deacetylated
Effect on blood: Platelets are the to salicylic acid which is the major circulat-
important factors in thrombus formation ing and active form. Salicylates are mainly
and aspirin has been shown to inhibit plate- metabolized in the liver and excreted in
let aggregation. They reduce the blood urine in the form of conjugates with glycine
prothrombin level by inhibition of pro- (mainly) and glucuronic acid.
thrombin synthesis and prothrombin time
is prolonged. The aspirin suppresses the
Adverse Effects
synthesis of thromboxane (TXA2) in the These include nausea, vomiting, gastric
platelets. They also prolong the bleeding irritation and occult blood in stool.
time due to prevention of platelet aggrega- Allergic reactions include urticaria, skin
tion which may be due to inhibition of re- rash, rhinorrhoea, asthmatic attack and ana-
lease of adenosine diphosphate (ADP) from phylactic reactions.
the platelets by salicylates. Prolonged administration of salicylates
Effect of CVS: In therapeutic doses, as- cause a syndrome called ‘salicylism’ which
pirin has no direct effect on CVS but in larger is characterized by headache, dizziness, tin-
doses, it can lead to increase in cardiac out- nitus, vertigo, difficulty in hearing, dimness
put to meet increased peripheral oxygen of vision, mental confusion, drowsiness,
demand and can cause direct vasodilatation. lethargy, hyperventilation and electrolyte
Endocrine effects: Salicylates decrease imbalance.
the plasma protein bound iodine due to dis- Overdose/acute salicylate poisoning is
placement of thyroxine from prealbumin characterized by salicylism which consists
and stimulation of central sympathetic cen- of tinnitus, vertigo and deafness, hyperther-
tre causes release of adrenaline from the mia, toxic encephalopathy (agitation, con-
adrenal medulla. fusion and convulsions followed by coma),
dehydration (due to hyperpyrexia, sweating
Pharmacokinetics and vomiting), disturbances of acid base
Salicylates are well absorbed after oral balance and petechial haemorrhages.
administration. They are absorbed from the
stomach and largely from the upper part of Treatment of Overdose/Toxicity (Salicy-
small intestine. After oral administration, late Poisoning)
appreciable plasma concentrations are i. Gastric lavage.
found within half an hour, peak plasma level ii. Intravenous fluid to correct dehydration.
is achieved within two hours and approxi- iii. Cold water/alcohol sponges for hyper-
mately 50 percent of the drug is eliminated thermia.
Non-Narcotic Analgesics (NSAID’s) 87
iv. To prevent intracellular potassium loss, ing and morning stiffness in the rheu-
potassium is given along with sodium matoid arthritis patients.
bicarbonate.
5. Treatment of gout: In large dose, aspi-
v. For ketoacidosis and hypoglycemia,
rin is effective in the treatment of gout.
glucose may be given.
vi. In severe intoxication, dialysis (perito- 6. As antiplatelet agent: By inhibiting
neal dialysis and haemodialysis) may platelet aggregation aspirin may lower
be used. the incidence of reinfarction. It has been
used to prevent the formation of plate-
Therapeutic Uses
let-fibrin thrombus in ischemic heart
1. In Dentistry: The NSAID’s are the disease patients.
most important drugs for the manage-
ment of acute dental pain. The particu- PYRAZOLONE DERIVATIVES
lar drug may be selected on the basis
of severity of pain and presence of PHENYLBUTAZONE
other related symptoms e.g. for mild
It is a potent antiinflammatory agent. It has
to modrate pain, paracetamol is gen-
poor analgesic and antipyretic action.
erally recommended and in accute
Mechanism of action is similar to other
pain diclofenac alone or combined
with paracetamol is generally pre- NSAIDs.
ferred. But care must be taken when It is readily absorbed from the GI tract
given to patient who is having peptic with peak plasma concentration occurring
ulcer, asthama or any hypersensitivty two hours after ingestion. It is 98% bound
history. to plasma proteins and it is extensively
2. As analgesic-antipyretic: Salicylates metabolised in the liver by oxidation and by
are effective in the treatment of mild conjugation with glucuronic acid.
to moderate types of pain. They are Adverse effects include nausea, epigas-
used in the treatment of headache, tric distress, aplastic anaemia, vomiting, di-
bodyache, arthralgias, neuralgias and
arrhoea, peptic ulcer, depression, neutrope-
dysmenorrhoea. They are also effective
nia, hypothyroidism, skin rash and urticaria.
in fever of any origin.
3. As an antiinflammatory: Salicylates It is indicated in ankylosing spondyli-
are commonly used in the treatment of tis, rheumatoid arthritis, rheumatic fever,
various inflammatory conditions such osteoarthritis, after blunt injuries, frac-
as arthritis and fibromyositis. tures, tooth extraction, vasectomy and
4. As antirheumatic: Salicylates are the acute gout.
drug of choice in the treatment of rheu-
OXYPHENBUTAZONE
matoid arthritis. In larger dose they
suppress the swelling, immobility and It is a metabolite of phenylbutazone and
redness of the joints involved. They are having similar pharmacodynamic and phar-
also useful in the acute rheumatic fe- macokinetic properties and similar thera-
ver. They produce relief in pain, swell- peutic uses.
88 Section 2/ Drugs Acting on CNS
Paracetamol is given orally and is well ab- similar to or greater than that of indometha-
sorbed, peak plasma concentration is reached cin, diclofenac, piroxicam and ibuprofen in
in 30 to 60 minutes. About 1/3rd is bound to standard animal models of inflammation.
plasma proteins and the drug is inactivated in
Oral drug absorption is nearly complete
the liver, being conjugated to give the glucu-
and concomitant administration of food may
ronide or sulphate which are excreted in urine.
decrease the rate, but not the extent of ab-
Adverse effects include nausea, epigas- sorption. The drug is 99% bound to plasma
tric distress. Rarely it can cause skin rash.
proteins and metabolised (1 to 3% of a dose
Acute toxicity may result in hepatic failure.
is excreted unchanged in the urine) to sev-
Paracetamol is used for the rapid relief eral metabolites which are excreted mainly
of fever, pains and aches such as headache, in the urine or the faeces.
earache, toothache, fibrositis, myalgia, neu-
ralgia, arthralgia, osteoarthritis and postop- The adverse effects are gastrointestinal
erative pain. disturbances (epigastralgia, heart burns,
nausea, diarrhoea and vomiting). It can also
NEWER COX-2 INHIBITORS lead to rash, pruritus, dizziness, somnolence
and headache.
KETOROLAC There were reports of hepatotoxicity es-
Ketorolac is a NSAID chemically related pecially in children, due to which it should
to indomethacin and tolmetin. not be used in children and in the presence
Ketorolac has antiinflammatory and an- of hepatic dysfunction.
tipyretic action that, together with its anal- It is indicated in the treatment of a vari-
gesic effects. ety of painful inflammatory conditions, in-
The absorption is rapid with maximum cluding osteoarthritis, oncology, postopera-
plasma concentration being attained 30 to tively, trauma, sports injuries, ear, nose and
40 minutes after oral administration. Highly throat disorders, dental surgery, bursitis/
plasma protein bound and metabolised by tendinitis, thrombophlebitis, upper airways
glucuronidation. 60% is excreted unchanged inflammation and gynaecological disorders.
in urine. Nimesulide has shown to be well tolerated
Adverse effects include, nausea, vom- even by aspirin sensitive asthmatic patients.
iting, epigastric distress, diarrhoea, drowsi-
ness, dizziness, skin rash etc. CELECOXIB
After oral administration it is rapidly mal small joints of hand (usually) and large
absorbed from the GI tract and undergoes joints as well. It is also associated with a
predominantly hepatic metabolism with number of extra-articular and systemic fea-
little unchanged drug recovered in the urine tures. There is joint inflammation, synovial
and faeces. It is widely distributed into tis- proliferation and destruction of articular
sues. All metabolites are inactive. cartilage by inflammatory cells. There is no
Adverse effects include headache, diar- single treatment for RA and the principles
rhoea, rhinitis, nausea, sinusitis, dyspepsia, of treatment are directed towards relief of
abdominal pain etc. symptoms and suppression of active and
It is used in rheumatoid arthritis, osteo- progressive disease with conservation and
arthritis and other conditions including maintenance of joint function.
rheumatic pain, neuralgia, gout and Initial treatment consists of NSAIDs, low
ankylosing spondylitis etc. dose corticosteroids. If the symptoms are not
controlled then second line/disease modi-
NABUMETONE fying drugs (DMDs) are added. Since it is a
Nabumetone selectively inhibits COX- progressive disease, spontaneous remis-
2. It is metabolised into 6-methoxy-2- sions are rare and joint damage occurs early,
naphthylacetic acid (MNA), that is a potent DMDs are started early and continued in-
inhibitor of COX-2. It has no inhibitory ef- definitely with regular monitoring.
fect on COX-1 which is responsible for pros- The disease modifying drugs (DMDs/
taglandin synthesis in gastric mucosa, DMARDs) used are gold, d-penicillamine,
thereby minimising the risk of problems like hydroxychloroquine, sulfasalazine and
ulcers and hypertension. After oral admin- immuno-suppressants like methotrexate,
istration 80% of dose is excreted in the urine. azathioprine, cyclosporin etc.
Peak plasma concentration is reached after
2.5 to 4 hours. GOLD COMPOUNDS
Adverse effects include nausea, vomit- It appears to reduce immune respon-
ing, heartburn, diarrhoea, constipation, siveness. It inhibits the migration of mono-
headache and dizziness. nuclear cells in area of inflammation. It may
also stabilise lysosomal membrane, hence
It is indicated in osteoarthritis, rheuma- damage to cartilage is prevented.
toid arthritis, inflammatory conditions and
soft tissue injuries. It can be used orally and bioavailability
is 25%. After administration it binds exten-
sively to plasma albumin and is distributed
DRUGS USED IN RHEUMATOID ARTHRITIS
to inflamed synovium, liver and kidney.
Rheumatoid arthritis (RA) is an autoim- Adverse effects include diarrhoea, der-
mune chronic inflammatory joint disease. It matitis, stomatitis, glossitis, pharyngitis,
is a progressive symmetrical, destructive pruritus, exfoliative dermatitis, alopecia,
and deforming polyarthritis affecting proxi- blood dyscrasias including thrombocytope-
Non-Narcotic Analgesics (NSAID’s) 93
nia, leucopenia, renal and hepatic damage (increased production) or is drug induced
and encephalopathy. (due to reduced renal excretion by uric acid).
Drugs used for gout can be divided into
PENICILLAMINE
two groups:
The exact mechanisms of action of peni-
cillamine in rheumatoid arthritis is not a. Drugs for acute attack of gout: NSAIDs,
known. After oral administration it is partly colchicine, corticosteroids.
metabolised and partly excreted unchanged. b. Drugs for chronic gout/hyperuricemia:
Can be uric acid synthesis inhibitors
Adverse effects include Gl upset, dose
(allopurinol) and uricosurics (increase
related impairment of taste, thrombocytope-
renal excretion of uric acids) e.g.
nia, aplastic anemia, allergic reactions, skin
probenecid and sulfinpyrazone.
rash, fever, SLE and proteinuria.
NSAIDS
SULFASALAZINE
Drugs useful are indomethacin,
When taken orally, it liberates 5-ASA (5- piroxicam or naproxen. Their usefulness is
aminosalicylic acid) and sulfapyridine in due to strong antiinflammatory action and
colon. 5-ASA acts locally by inhibiting PG can be continued for 3-4 weeks. They also
synthesis and provide symptomatic relief in inhibit chemotactic migration of leukocytes
ulcerative colitis. Sulfapyridine is absorbed into the affected joint.
systemically and inhibits generation of su-
peroxide radicals and cytokine elaboration CORTICOSTEROIDS
by inflammatory cells and is responsible for
Systemic/intraarticular steroids can be
beneficial effects in RA.
used in those cases not responding to or tol-
METHOTREXATE erating NSAIDs/colchicine.
h a p
p tterer
CCh Psychotropic
Pharmacodynamics
2.5
1.4 (Mode Agents
of Action of Drugs)
2. MAO inhibitors along with barbitu- cardia. They also lead to postural hypoten-
rates, alcohol, narcotic analgesic can en- sion due to a1 blockade and inhibition of
hance and prolong the action of these cardiovascular reflexes. They also produce
drugs. T wave suppression or inversion. Oral
3. Potentiate the toxic effects of tricyclic absorption is good and they are highly
antidepressants. bound to plasma proteins. They are exten-
4. It’s use with anticholinergic antiparkin- sively metabolized in liver and metabo-
sonian drugs can lead symptoms simi- lites are excreted in urine.
lar to atropine poisoning.
Because of their toxic effects and seri- IMIPRAMINE
ous interactions, they are not commonly It is an efficacious drug in alleviating
used. However, a new selective inhibitor is depression. When the drug is given to de-
used clinically. pressed patients, elevation of mood occurs
in about three weeks. Tolerance to anticho-
MOCLOBEMIDE linergic effects occurs with continued use of
It is a reversible and selective MAO-A imipramine.
inhibitor used in the major depression. It is It is highly protein bound and is metabo-
devoid of anticholinergic, sedative and car- lized to pharmacologically active metabo-
diovascular effects of TCAs. lite. It crosses placental barrier.
Side effects include sleep disturbances, Adverse effects include dry mouth, ta-
dizziness, nausea, headache, restlessness, chycardia, palpitation, impotence, constipa-
agitation, confusion state and nausea. tion, difficulty in accommodation, rarely hy-
perpyrexia and paralytic ileus; lethargy,
headache, drowsiness, tremors, ataxia, sweat-
TRICYCLIC ANTIDEPRESSANTS
ing, convulsion, urticaria, skin rash, pruritus,
Tricyclic antidepressants are the most cholestatic jaundice, cardiac arrhythmias,
commonly used drugs. They produce an- orthostatic hypotension, agranulocytosis,
tidepressant effect by blocking the neu- gynaecomastia, galactorrhoea and depen-
ronal uptake of noradrenaline and exert dence; loss of weight or gain.
anti-cholinergic activity. They also inhibit It is indicated in all types of depression,
neuronal uptake of 5HT and dopamine. nocturnal enuresis, intractable chronic pain,
The exact mechanism of action is not narcolepsy, chorea, cachexia, mood distur-
known. The antidepressant effect is no- bances and sleep apnoea syndrome.
ticed after three to four weeks of drug ad-
ministration. AMITRIPTYLINE
TCAs lower seizure threshold and It causes sedation and after oral admin-
overdose leads to convulsions. The side istration it is metabolised to nortriptyline
effects are due to anticholinergic effect which is active form.
leading to dry mouth, blurring of vision, Adverse effects include epigastric dis-
constipation, urinary hesitancy and tachy- tress, sedation, drowsiness, orthostatic hy-
102 Section 2/ Drugs Acting on CNS
potension, palpitation, dry mouth, urinary hyperpyrexia and paralytic ileus. Lethargy,
retention, blurred vision, confusion and low- headache, drowsiness, tremors, ataxia,
ering of seizure threshold. sweating, convulsion, urticaria, skin rash,
It is indicated in depression, illness accom- pruritus, cholestatic jaundice, cardiac
panied by anxiety, agitation, restlessness and arrhythmias, orthostatic hypotension,
disturbances of sleep; masked depression; agranulocytosis, gynecomastia, galactor-
dysphoria and depression in alcoholics; rhoea and dependence are also seen.
childhood bed wetting. It is also useful for
prophylaxis of migraine. TETRACYCLIC ANTIDEPRESSANTS
NORTRIPTYLINE MIANSERIN
It is same as amitriptyline and its anti-
It exerts potent presynaptic central a2, adr-
depressant effect may persist up to six
energic blocking activity which may cause
weeks.
increased noradrenaline release. It does not
Adverse effects include dry mouth, con- effect noradrenaline or 5-HT uptake in
stipation, nausea, epigastric discomfort, seda- CNS.
tion, confusion, arrhythmias, altered vision,
Adverse effects include hypersensitiv-
skin rash, jaundice and impaired alertness.
ity reaction, nausea, drowsiness, jaundice,
It is indicated in neurotic, reactive, may precipitate seizures, blood dyscrasias,
masked endogenous, recurrent depression; lethargy and tremors.
depression with insomnia, depression, en-
It is used in psychotic and neurotic
uresis, panic disorder, neurogenic pain, ur-
ticaria and nausea and vomiting during che- depression and obsessive compulsive neu-
motherapy; maniac depressive psychosis in rosis.
depressive phase.
MIRTAZAPINE
TRIMIPRAMINE It acts as an antagonist at central presyn-
It has more sedative effect than other tri- aptic a2 inhibitory adrenergic auto-receptors
cyclic antidepressants and is suitable for and hetero-receptors. This results in an in-
patients showing depression with agitation crease in central noradrenergic and seroton-
and anxiety. ergic activity. Mirtazapine is a potent an-
tagonist of 5-HT2 and 5-HT3 receptors.
DOTHIEPIN Adverse effects include asthenia, flu like
The mechanism of action is same as of syndrome, back pain, dry mouth, increased
tricyclic antidepressant and used in depres- appetite, constipation, weight gain, periph-
sion and anxiety associated with depression. eral edema, myalgia, somnolence, dizziness,
Adverse effects include dry mouth, ta- abnormal dreams, abnormal thinking,
chycardia, palpitation, impotence, constipa- tremor, confusion, dyspnea and urinary
tion, difficulty in accommodation, rarely frequency.
Psychotropic Agents 103
h a p
p tterer Antiepileptic
CCh Pharmacodynamics
Agents
2.6
1.4 (Mode of Action of Drugs)
neuronal Na+ channels & governs the refractory varieties of migraine (particularly
period of a neurone. childhood, basilar artery and hemiplegic
After oral administration peak plasma con- migraine) and in treatment of myotonia.
centration of phenytoin usually takes 2 to 4
hours with a second peak at 10 to 12 hours. IMINOSTILBENE DERIVATIVES
When administered intramuscularly, pheny-
toin is eventually absorbed completely, the CARBAMAZEPINE
drug first crystallises out at the injection site It is structurally and chemically related
and then slowly redissolves in tissue fluids be- to tricyclic antidepressant drug imipramine
fore entering into the circulation. As a result and pharmacologically it is similar to
absorption of phenytoin by IM route is too slow diphenyl hydantoin sodium. It is effective
to produce a reliable effect. In contrast a phos- in grandmal and psychomotor epilepsy and
phate prodrug, fosphenytoin, is more soluble also in the treatment of trigeminal neuralgia
and is well absorbed after IM administration. (a condition characterized by paroxysms of
In liver it is extensively biotransformed intense pain of stabbing nature within the
by oxidation, with less than 5 percent of the area of distribution of trigeminal nerve
dose excreted unchanged in urine. Majority without sensory loss).
of dose is excreted in urine with up to 15 It also exerts antidiuretic action by
percent of the dose is eliminated in the faeces. enhancing ADH action on renal tubules.
Adverse effects include gum hypertro- Carbamazepine, because of its poor
phy, hirsutism, hypersensitivity reaction, water solubility has slow oral absorption. It
megaloblastic anemia, osteomalacia and is metabolized in the liver to an active
hyperglycemia. metabolite, (10-11 epoxy carbamazepine) by
During pregnancy produces foetal oxidation as well as by hydrolysis and
hydantoin syndrome. At higher conjugation to inactive forms.
concentration produces ataxia, vertigo, Adverse effects include sedation, ataxia,
diplopia, nystagmus, behavioural alteration dizziness and extrapyramidal side effects, dry
and mental confusion. mouth, blurred vision and urinary retention;
It is used in prophylactic treatment of hepatic damage, bone marrow depression,
all varieties of partial epilepsy whether or hypertension, left ventricular failure and
not seizure becomes secondarily cardiovascular collapse in toxic doses.
generalised. It is also used in prophylactic
treatment of generalised convulsive OXCARBAZEPINE
seizures and treatment of status It is a keto analog of carbamazepine. It
epilepticus; prophylactic management of produces blockade of voltage sensitive
certain forms of supraventricular cardiac sodium channels, leading to stabilisation of
arrhythmia as it has an ability to hyperexcited neural membranes, inhibition
selectively inhibit high frequency firing; of repetitive neuronal firing and diminution
prophylactic management of certain of propagation of synaptic impulses.
108 Section 2/ Drugs Acting on CNS
Muscle Relaxants 111
a p
p tte r
e r Muscle
CChh Pharmacodynamics
Relaxants
2.7
1.4 (Mode of Action of Drugs)
receptors which in turn inhibit the release culoskeletal conditions. Mechanism of ac-
of glutamate and aspartate. tion is not known, however, it is thought that
After oral administration, it is rapidly the skeletal muscle relaxation is due to its
and completely absorbed and eliminated central nervous system depressant action.
from the body by kidney in unchanged form. It probably acts by inhibiting polysynaptic
pathways but has no effect on monosynap-
Adverse effects include weakness,
tic pathways.
fatigue, dizziness, headache, insomnia,
hypotension, confusion, skin rash, It is well absorbed from GIT and mostly
constipation, nausea, anorexia, dry mouth metabolised in liver and excreted in urine.
and taste disturbance etc. Peak plasma levels are reached at two hours
and onset of action occurs within one hour.
It is mainly used in the treatment of
spasticity in multiple sclerosis, spastic spinal Adverse effects include blurred or
paralysis etc. It is also used in the treatment double vision, dizziness, drowsiness,
of trigeminal neuralgia. abdominal cramps, confusion, headache,
hiccups, anaemia etc.
METAXALONE It is mainly used to relieve pain and
It is a skeletal muscle relaxant, discomfort caused by strains, sprains and
oxazolidinone derivative used in conjunc- other painful muscular conditions in which
tion with other therapeutic agents to treat muscles are in spasm i.e. fibromyalgia,
and discomfort associated with acute mus- dislocations and fractures.
Local Anaesthetics 115
h apptterer Local
CCh Pharmacodynamics
Anaesthetics
2.8
1.4 (Mode of Action of Drugs)
h a p
p tterer
CCh CNS
Pharmacodynamics
2.9
1.4 Stimulants
NIMODIPINE TACRINE
It is a calcium channel antagonist. It It is the first centrally acting anti-ChE
enters the brain and acts by blocking the used in mild to moderate cases of AD. Side
122 Section 2/ Drugs Acting on CNS
effects include diarrhoea, abdominal months and has been shown to improve
cramps, polyuria etc. The major side effect cognitive functions in patients of AD and it
is rise in serum transaminase and has central ChE inhibitory action.
hepatitis.
GALANTAMINE
DONEPEZIL It acts by dual mechanism i.e. inhibition
It is another predominant centrally acting of central ChE and as an agonist on central
ChE inhibitor and does not cause hepatotox- acetylcholine nicotinic receptors.
icity. It is given in dose of 5-10 mg OD HS. Other drugs which may have beneficial
property in the AD are antioxidants, beta
RIVASTIGMINE blockers and drugs from natural origin e.g.
It is given in a dose 6-12 mg/day for six Ginkgo biloba.
Drugs used in Parkinsonism 123
h apptterer
CCh Drugs Used in
Pharmacodynamics
2.10
1.4 Parkinsonism
(Mode of Action of Drugs)
become more alert and interested in life 3. Endocrine system: Dopamine inhibits
and surroundings. prolactin release in human being. It also
2. CVS: The levodopa produces its CVS acts on somatotrophs to increase
effect by being converted into growth hormone release.
dopamine. It acts by stimulating alpha 4. Miscellaneous actions: Peripherally
adrenergic receptors in blood and formed dopamine (converted peripher-
produce vasoconstriction and may ally after levodopa therapy) gains access
raise the blood pressure. It also acts to the CTZ (chemoreceptor trigger zone)
by stimulating betaadrenergic causing nausea and vomiting.
receptors in heart and produce
tachycardia and increase force of Pharmacokinetics
myocardial contraction (positive Levodopa is rapidly absorbed when
inotropic action). given orally and peak plasma level is
Drugs used in Parkinsonism 125
This page
intentionally left
blank
Section 3
Drugs Acting on
ANS
This page
intentionally left
blank
h a p
p tterer
CCh Sympathomimetics
3.1
1.4 (Adrenergic Agents)
adenylyl cyclase. The important agonist of blood vessels of the skeletal muscles on
dopamine receptors is fenoldopam (D1) and account of the preponderance of β 2
bromocriptine (D 2 ) and antagonist is receptors.
clozapine (D4). Blood pressure: Because of vasocon-
These receptors are distinct from alpha striction (α1) and vasodilatation (β2) action
and beta receptors and are particularly of adrenaline, the net result is decrease in
important in the brain. total peripheral resistance. Although
Adrenergic drugs can also be classified adrenaline increases the systolic blood pres-
into: sure but simultaneously lowers the blood
pressure by its peripheral action. The rise in
a. Direct sympathomimetics: These act systolic blood pressure is often followed by
directly on a or/and b adrenoceptors decrease in blood pressure, adrenaline in
e.g. adrenaline, noradrenaline, isopre- such doses activates both a and b receptors.
naline, phenylephrine, methoxamine, But mean blood pressure rises with increase
salbutamol etc. in pulse pressure.
b. Indirect sympathomimetics: They act Noradrenaline causes rise in systolic,
on adrenergic neurones to release diastolic and mean blood pressure and does
noradrenaline e.g. tyramine. not cause vasodilatation (because of no
c. Mixed action sympathomimetics: They action on β 2 receptors) and increase in
act directly as well as indirectly e.g. ephe- peripheral resistance due to its a action.
drine, amphetamine, mephentermine
etc. Isoprenaline causes rise in systolic blood
pressure (because of β1 cardiac stimulant
Pharmacological Action of action) but marked fall in diastolic blood
Sympathomimetics (Particularly pressure (because of b2 vasodilatation action)
adrenaline and noradrenaline) but mean blood pressure generally falls.
Heart: Direct effects on the heart are GIT: Adrenaline causes relaxation of
determined largely by β 1 receptors. smooth muscles of GIT and reduce its
Adrenaline increases the heart rate, force of motility. Relaxation of smooth muscles of
myocardial contraction and cardiac output GIT can be brought about by both alpha and
which is associated with increased beta stimulants. It decreases the tone,
metabolism by the myocardium, increased frequency and amplitude of contraction of
oxygen consumption and thus decreasing smooth muscles.
cardiac efficiency. Respiratory system: The presence of β2
Blood vessels: Adrenaline and receptors in bronchial smooth muscle causes
noradrenaline constrict the blood vessels of relaxation and activation of these receptors
skin and mucous membranes. Constriction by β2 agonists cause bronchodilatation.
predominates in cutaneous and mucous Among catecholamines, adrenaline and
membranes which occur through both α1 isoprenaline are potent bronchodilators due
and α2 receptors. Adrenaline also dilates the to its β2 action but not noradrenaline.
134 Section 3/ Drugs Acting on ANS
Uterus: The response of the uterus to the f. Adrenaline produces leucocytosis and
catecholamines varies according to species eosinopenia and accelerates blood
and absence or presence of pregnancy. In coagulation and also stimulates platelet
rats both pregnant and nonpregnant uterus, aggregation.
relaxation is produced while in rabbits both Action on CNS: Catecholamines do not
pregnant and nonpregnant uterus is produce any marked CNS effects because
contracted. In human beings, nonpregnant they do not cross blood brain barrier
uterus is contracted while pregnant uterus satisfactorily. However, adrenaline may
is relaxed in the last month of pregnancy. produce restlessness, apprehension,
excitement and tremors on intravenous or
Eye: Mydriasis occur due to contraction
intracarotid injection.
of radial muscles of iris, intraocular tension
is lowered due to less production of the Pharmacokinetics
aqueous humor secondary to vasoconstric-
Catecholamines are absorbed from the
tion and conjunctival ischemia due to con-
intestines, but are rapidly degraded in gut
striction of conjunctival blood vessels.
and liver by enzymes MAO and COMT.
Action on other smooth muscles & other Thus they are inactive on oral
miscellaneous actions: administration.
a. Urinary bladder: Detrusor is relaxed Adverse Effects
(b) and trigone is constricted (a) and
Restlessness, anxiety, tremor, head-
both the actions tend to inhibit
ache. Both adrenaline and noradrenaline
micturition.
cause sudden increase in blood pressure,
b. Spleen: In animals, it causes precipitating sub-arachnoid haemorrhage
contraction (due to its a action) of the and occasionally hemiplegia, and ven-
splenic capsule resulting in increase in tricular arrhythmias. May produce angi-
number of RBCs in circulation. nal pain in patients with ischemic heart
c. It also cause contraction of retractor disease.
penis, seminal vesicles and vas
deferens. Contraindications
d. Adrenaline causes lacrimation and a. In patients with hyperthyroidism.
salivary glands are stimulated. b. Hypertension.
e. Adrenaline increases the blood sugar c. During anaesthesia with halothane and
level by enhancing hepatic glyco- cyclopropane.
genolysis and also by decreasing the d. In angina pectoris.
uptake of glucose by peripheral tissues.
Adrenaline inhibits insulin release by Therapeutic Uses
its a-receptor stimulant action whereas Allergic reaction: Adrenaline is drug of
it stimulates glycogenolysis by its b choice in the treatment of various acute al-
receptor stimulant action. lergic disorders by acting as a physiological
Sympathomimetics (Adrenergic Agents) 135
antagonist of histamine (a known mediator c. Anoretic drugs can help the obese
of many hypersensitivity reactions). It is people.
used in bronchial asthma, acute angion- d. Amphetamine may be useful in
eurotic edema, acute hypersensitivity reac- nocturnal enuresis in children.
tion to drugs and in the treatment of ana-
e. Isoxsuprine (uterine relaxant) has been
phylactic shock.
used in threatened abortion and
Bronchial asthma: When given dysmenorrhoea.
subcutaneously or by inhalation, adrenaline
is a potent drug in the treatment of status DOPAMINE
asthmaticus. It is an immediate metabolic precursor of
Cardiac uses: Adrenaline may be used noradrenaline. It activates D1 receptors in
to stimulate the heart in cardiac arrest. several vascular beds, which causes
Adrenaline can also be used in Stokes-Adam vasodilatation. It acts on dopaminergic and
syndrome, which is a cardiac arrest other adrenergic receptors (α & β1).
occurring at the transition of partial to
complete heart block. Isoprenaline or Pharmacological Actions of Dopamine
orciprenaline may be used for the temporary The actions of particular sympathomi-
treatment of partial or complete AV block. metic amine depend on its relative activity
Vascular uses: Pressor agents like at different types of adrenergic receptors.
adrenaline (more appropriate dopamine or The overall actions are:
dobutamine) may be useful in hypotensive
crisis. Cardiovascular system:
Adrenaline along with local anaesthetics a. Blood vessels: D1 receptors promote
may be used for infiltration, nerve block and vasodilatation of renal, splanchnic,
spinal anaesthesia for prolonging the action coronary and cerebral arteries.
and to reduce the systemic toxicity of local Activation of the D1 receptors in the
anaesthetics. renal vasculature may play a major role
in the natriuresis induced by
Adrenaline may be useful in control of
pharmacologic administration of
haemorrhage from the skin and mucous dopamine.
membrane such as epistaxis and after tooth
b. Heart: In the heart, intraventricular
extraction.
pressure rises and falls more rapidly,
Also used as nasal decongestant. and ejection time is decreased. These
direct effects are easily demonstrated
Miscellaneous uses:
in the absence of reflexes evoked by
a. Phenylephrine is used in fundus changes in blood pressure, e.g. in
examination as mydriatic agent. isolated myocardial preparations and
b. Amphetamines are sometime used as in patients with ganglionic blockade. In
adjuvant and to counteract sedation the presence of normal reflex activity,
caused by antiepileptics. the direct effects on heart rate may be
136 Section 3/ Drugs Acting on ANS
ORCIPRENALINE AMPHETAMINE
Is a potent β-adrenergic agonist. It is a synthetic compound with
Receptor sites in the bronchi and bronchioles structural similarity to ephedrine and is
are more sensitive to the drug than those in available in racemic and dextro isomers. It
the heart and blood vessels. increases the systolic and diastolic blood
pressure. Amphetamine is a potent CNS
It decreases reversible bronchospasm
stimulant and causes alertness, insomnia,
associated with chronic bronchitis, increased concentration, euphoria or
pulmonary emphysema, bronchial asthma, dysphoria and increased work capacity.
silicosis, tuberculosis and sarcoidosis. The Amphetamine produces wakefulness and
resultant decrease in airway obstruction improved physical performance. It contracts
may relieve the dyspnea associated with the sphincter of the bladder and relaxes the
bronchospasm. bronchial smooth muscle in large doses.
It is effective both by oral route as well Amphetamines are drugs of abuse and can
as inhalation. produce behavioural abnormalities and can
precipitate psychosis. It can produce
There is more rapid onset of action psychological but no physical dependence.
following inhalation administration.
Because of its misuse especially by
Absorption via the bile is 45 percent of teenagers, its use is limited to the treatment
renal excretion. Bioavailability of the active of Attention Deficit Hyperactivity Disorder
substance is 33% owing to a first pass effect. (ADHD) and narcolepsy.
It is indicated in bronchial asthma and
PHENYLEPHRINE
reversible bronchospasm associated with
chronic bronchitis and pulmonary emphy- It is a vasopressor agent with some struc-
sema, including bronchospasm due to the tural similarity to adrenaline and has a power-
use of b-blocking agents. ful alpha1 receptor stimulant action. The pres-
sor response is accompanied by reflex brady-
Can be used as a supportive therapy cardia. It is used as a nasal decongestant and
with antibiotics, secretomucolytics, mydriatic agent and also in the treatment of
corticosteroids, physiological saline and paroxysmal supraventricular tachycardia.
disodium chromoglycate.
Side effects such as palpitation, restless- UTERINE RELAXANTS (TOCOLYTICS)
ness and finger tremor may occur; in iso-
These are the agents which decrease uterine
lated cases, flushing, headache, sleep distur-
motility and have been used to delay or postpone
bances, nausea, ventricular disturbances or labour and to arrest threatened abortion which
angina pectoris and allergic skin reactions is needed to allow fetus to mature.
have been observed.
The injection or infusion of high doses ISOXSUPRINE
may also cause tachycardia, arrhythmia and Both nylidrin and isoxsuprine have got
a decrease in blood pressure. beta receptor stimulant action and is used
Sympathomimetics (Adrenergic Agents) 139
in the treatment of peripheral vascular should not be used if mother has a history of
diseases. But nylidrin is not used clinically. diabetes, heart disease or is on β-blocker or
Isoxsuprine has a potent inhibitory steroid therapy.
effect on vascular and uterine smooth Certain other drugs also having uterine
muscle and has been used in the treatment relaxant property are calcium channel
of dysmenorrhoea, threatened abortion, blockers, prostaglandin synthesis inhibitors,
premature labour and peripheral vascular progesterone, nitrites, anticholinergics,
diseases. Adverse effects include nausea, ethyl alcohol etc.
tachycardia, flushing and dizziness.
FENFLURAMINE
RITODRINE It is a sympathomimetic amine. the
mechanism of action is related to brain
It is β2 selective agonist with uterine
levels (or turnover rates) of serotonin or
relaxant property and preferred to suppress to increase glucose utilization. Its
premature labour and delay delivery of fetus. antiappetite effect is suppressed by
But, use of ritodrine in suppressing labour has serotonin blocking drugs. Its use in clinical
been found to increase maternal morbidity and practice is recently banned in ‘India’
neonate may develop hyperglycemia. So it because of severe toxicity.
This page
intentionally left
blank
a p
p tte r
e r Treatment of Shock
CChh Pharmacodynamics
&
3.2
1.4 Vasopressor Agents
the inability of the ventricle of fill during in severe vasomotor collapse. Septic shock is
diastole markedly limiting the stroke characterized by a low systemic vascular
volume and cardiac output. Another cause resistance and an elevated cardiac output and
is massive pulmonary embolism it usually begins with a nidus of infection that
In pericardial temponade, administra- releases microbes and/or one or more
tion of sympathomimetic amines e.g. nore- mediators e.g. histamine, kinine,
pinephrine and/or dopamine may improve prostaglandins, endorphins, TNF, interlukin
haemodynamics temporarily and surgical 1 & 2 etc. into the blood stream which
pericardial drainage is the only effective produce vascular dilatation and
treatment. vasoconstriction (some PG’s & leukotrienes).
The peripheral vasodilatation result in a
DISTRIBUTIVE SHOCK reduced systemic vascular resistance and
Anaphylactic, septic and neurogenic high cardric output.
shock are the examples of distributive shock Management of septic shock may be
and all of which usually cause profound carried out in three simultaneous ways,
decrease in periperal vascular resistance. firstly, the nidus of infection must be
In anaphylactic shock, when a sensitized identified and eliminated, using surgical
person is re-exposed to the specific antigen drainage and antimicrobial therapy.
and due to antigen-antibody reaction there Sacondly, using cardiovascular monitoring
is large amount of histamine release along and support, adequate organ system
with other mediators of anaphylaxis, perfusion and function must be maintained.
resulting in fall in blood pressure with savere Thirdly, to interrupt the pathogenic
allergic reaction and bronchospasm. sequence leading to septic shock.
Penicillin is the common example of Neurogenic shock is generally occur in
anaphylactic shock in sensitized individuals. abdominal trauma, spinal anasthesia, spinal
Epinephrine is a life saving drug of choice cord injury and is managed by vasopressor
in this type of case. Dopamine may be given agents e.g. dopamine.
This page
intentionally left
blank
h apptterer
CCh Pharmacodynamics
Sympatholytics
3.3
1.4 (Antiadrenergic Agents)
These are the agents, which block the action GENERAL CHARACTERISTICS OF
of adrenaline and noradrenaline. They block
ALPHA BLOCKERS
either alpha or beta or both adrenergic
receptors. They are classified as in table 3.3.1 Alpha blockers are the drugs which block
and 3.3.2. the pressor response to noradrenaline and
A. Non-equilibrium
Phenoxybenzamine (FENOXENE) 20-60 mg orally, 1 mg/kg IV infusion
B. Equilibrium
I. Nonselective (α1+α2 blockers)
i. Ergot alkaloids
Ergotamine (GYNERGEN) 1-3 mg oral, 0.25-0.5 mg IM/SC
Dihydroergotamine 2-6 mg oral, 0.5-1 mg IM
Dihydroergotoxine (HYDERGINE) 1.5 mg oral TDS, 0.15-0.6 mg IM
ii. Imidazolines
Phentolamine mesylate (FENTANOR) 50 mg QID
Tolazoline (PRISCOL) 25-50 mg TDS
iii. Phenothiazines
Chlorpromazine (LARGECTIL) 25-50 mg oral/IM
II α1 Selective
Prazosin (MINIPRESS) 0.5-1.0 mg TDS
Terazosin (OLYSTER) 2-10 mg/day, 1 mg HS
Triamazosin 25-200 mg TDS
Doxazosin (DOXACARD) 1-4 mg/day
Tamsulosin (DYNAPRES) 0.4-0.8 mg OD
III. α2 Selective
Yohimbine 2-4 mg TDS
146 Section 3/ Drugs Acting on ANS
This page
intentionally left
blank
h apptterer
CCh Parasympathomimetics
3.4
1.4 (Cholinergic Agents)
These are the drugs which stimulate the inhibitors together comprise a large group
parasympathetic system and mimic the of drugs that initiate the action of
action of acetylcholine. The acetylcholine acetylcholine. They belong to the various
receptor stimulants and cholinesterase groups (Table 3.4.1).
Parasympatholytics (Anticholinergic Agents) 161
a p
p tte r
e r
CChh Parasympatholytics
Pharmacodynamics
3.5
1.4
(Anticholinergic Agents)
(Mode of Action of Drugs)
temperature regulating centre in hypothalamus clearly only at a long distance and can not
and also inhibits sweating. constrict the pupil for viewing the near
Effect on gastrointestinal system: objects clearly). Atropine induced mydriasis
Atropine decreases the tone and motility of can be distinguished from the mydriasis
all parts of gastrointestinal tract. It also produced by sympathomimetic amines as
decreases the amplitude of contraction and the latter do not produce cycloplegia.
frequency of peristaltic wave of stomach and
Pharmacokinetics
intestines. Atropine also exerts a weak
antispasmodic action on biliary tract and All the belladonna alkaloids are well
gall bladder. absorbed from the GIT, from the site of
injection and the mucous membrane. They
Effect on other smooth muscles: are distributed throughout the body and
Atropine relaxes the smooth muscles of cross the blood-brain barrier. About 50% of
bronchi and bronchioles which results in the atropine is metabolized in liver and
widening of the airways. It is effective in remaining portion is excreted unchanged in
relieving bronchospasm produced by urine. Atropine cross the placental barrier
cholinergic agents. and is secreted in milk and saliva.
Atropine also produces reduction in
normal and drug induced ureteral Adverse Reactions
peristalsis. It also tends to reduce the tone The adverse reactions are due to the
of the fundus of urinary bladder and peripheral muscarinic blockade and cen-
enhances the tone of trigonal sphincter and tral actions. The general side effects
may cause of retention of urine. include dry mouth, difficulty is swallow-
Effect on secretions: Atropine reduces ing, thirst, dry skin, skin rash, flushed skin
the various body secretions e.g. sweat, etc. It also produces constipation, urinary
salivary, bronchial and lacrimal etc. It also retention, impotence, difficulty in mictu-
reduces the volume and total acidity of rition, tachycardia, palpitation, postural
gastric secretion and, reduce the secretion hypotension, dilatation of pupil, photo-
of mucin and enzymes in the gastric phobia, blurred vision, dizziness, fatigue,
secretions induced by cholinergic drugs. anxiety and tremors etc.
It has no significant effect on intestinal Toxic doses can gives rise to acute bella-
and pancreatic secretions. donna poisoning which is characterized by
Effect on eye: Atropine produces depression of vasomotor centre, vasomotor
mydriasis by blocking the cholinergic nerves collapse, coma and depression of respiratory
supplying the smooth muscles of sphincter centre.
of the iris on local administration into the Acute belladonna poisoning can be treated
eye. It also produces paralysis of by administering universal antidote before
accommodation or cycloplegia (the gastric lavage, physostigmine in the dose of
condition in which, one can see things 1-4 mg SC can be administered after a interval
164 Section 3/ Drugs Acting on ANS
This page
intentionally left
blank
Section 4
Drugs Acting on
Cardiovascular &
Urinary System
This page
intentionally left
blank
a p
p t e
t r
e r
CChh Cardiotonics
Pharmacodynamics
4.1
1.4
(Cardiac Glycosides)
(Mode of Action of Drugs)
Congestive heart failure (CHF) is a clinical physician and botanist identified digitalis
syndrome with multiple causes and involve and other ingredients, which was found
the right or left ventricle or both and in CHF, useful in the treatment of dropsy. In 1911,
cardiac output is usually below the normal Mackenzie and Cushney studied the effect
range. This ventricular dysfunction may be of digitalis on heart and its use in congestive
systolic, which leads to inadequate force heart failure.
generation to eject blood normally and
The important cardiac glycosides are
diastolic, which leads to inadequate
listed in table 4.1.1.
relaxation to permit normal filling. Systolic
dysfunction, with decreased cardiac output Pharmacological Actions
and significantly reduced ejection fraction
is typical of acute heart failure, especially
Effect on Heart
that resulting from myocardial infarction. Contractility: Digitalis increases the force of
myocardial contraction without causing
CARDIAC GLYCOSIDES corresponding increase in the oxygen
consumption. This pharmacological action
There are the drugs having cardiac inotropic forms the basis of its use in treatment of
property. They increase myocardial CHF. In a patient of CHF, force of
contractility and cardiac output in a contraction of the heart at a given fibre
hypodynamic heart without increase in length is decreased, thus the stroke volume
oxygen consumption and overall is decreased. As digitalis increases the force
myocardial efficiency is increased. of contraction of the heart and subsequently,
The cardiac glycosides are mainly it increases the cardiac output, increase in
obtained from plants e.g. digitalis, circulating velocity, residual volume is
stropanthus and squill species and also decreased, diastolic volume is decreased
present in certain other plants and animals. and size of heart is decreased but these
In 1776, William Withering, a Birmingham effects are noticed secondary to increase in
170 Section 4/ Drugs Acting on Cardiovascular & Urinary System
contractility and are not the primary effects sympathetic tone and thus reducing the
of digitalis. heart rate.
Cardiac output: Digitalis increases the Refractory period: It is a period after onset
cardiac output in CHF patients by increasing of depolarization during which a stimulus can
the force of myocardial contraction. It also not evoke a propagated action potential. In
increases the contractility of normal heart atrium, refractory period is shortened by vagal
but cardiac output remains unchanged or is action and increased by direct action.
slightly decreased. In normal individuals, it SA node: Digitalis sensitizes the SA node
increases the tone of arteries as well as that to normal vagal impulse resulting in
of the veins. bradycardia. In a patient suffering from
Heart rate: In CHF patients, the heart paroxysmal supraventricular tachycardia, it
rate is decreased. Digitalis produce a decreases the heart rate due to vagal action on
decrease in heart rate by stimulation of SA node which is associated with decrease in
vagus. The ‘vagal effect’ is probably evoked the slope of slow diastolic depolarisation and
by sensitization of carotid baroreceptors, increase in the transmembrane negativity and,
and by direct stimulation of vagal centre. also lower the SA rate by antiadrenergic action.
The vagal action can be blocked by atropine Automaticity: It is the ability to generate
but after full digitalising dose the effect can propagated impulse. Digitalis increases the
not be blocked by atropine and it is due to ability of the Purkinje cell and the
its direct cardiac action. In CHF patients, ventricular muscle to initiate impulses.
the sympathetic activity is increased as a Conductivity: Conduction through AV
compensatory phenomenon which leads to node is depressed whereas conduction is
tachycardia. Digitalis decreases the slightly increased in the auricle and ventricles.
Cardiotonics (Cardiac Glycosides) 171
ECG changes: Digitalis, in therapeutic may probably explain reversal of toxic effects
doses causes inversion of T wave, sagging of digitalis by potassium. Inhibition of the Na+
of S-T segment and shortening of Q-T K+-ATPase leads to increase in intracellular
internal (shortening of systole). In toxic dose, sodium and decrease in potassium.
it causes prolongation of P-R interval Calcium also forms a link between the
(slowing of AV conduction), atrial electrical events in the membrane and
arrhythmias (atrial tachycardia and atrial contractile proteins. Digitalis makes more
fibrillation) with AV block and ventricular calcium available for excitation-contraction
arrhythmias. coupling and increasing cardiac contractility.
Extracardiac Actions Digitalis also exerts some indirect action
on heart mainly by increase in vagal activity
• Digitalis produces diuresis in CHF which ultimately influences activity of AV
patients, it increases excretion of node, SA node and auricles.
sodium and water by the kidney
which may be due to decrease in the Pharmacokinetics
venous pressure bringing about
Among the cardiac glycosides, digitoxin is
shifting of edema fluid into the
absorbed rapidly and completely from the
circulation and also improves the
gastrointestinal tract with oral absorption of
renal circulation.
approximately 90 to 100 percent with plasma
• Digitalis can produce nausea and protein binding of approx. 95 percent with
vomiting which is probably due to the plasma half life of 5 to 7 days. It enters the liver
chemoreceptor trigger zone (CTZ) cells where it is metabolised to epidigitoxigenin
stimulation. and is excreted in bile and urine.
• Digitalis has mild vasoconstrictor action
increasing the peripheral resistance. But Adverse Effects
in CHF patients peripheral resistance
It includes anorexia, vomiting which
decreases due to withdrawal of reflex
may be of central origin. Headache, visual
sympathetic overactivity. Venous tone
disturbance, xanthopsia (yellow vision),
improves in normal as well as CHF
white vision, diplopia, drowsiness,
patients. It has no significant effect on
disorientation, delirium and psychotic
coronary circulation.
behaviour. Cardiac related effects include
Mechanism of Action of Digitalis cardiac arrhythmias e.g. tachyarrhythmias,
Digitalis acts by interfering with the ventricular arrhythmias, supraventricular
sodium and potassium transport across the arrhythmia, AV block and bradycardia.
cell membrane and by increasing the
Treatment of Digitalis Induced
amount of coupling calcium i.e. making
more calcium available for excitation- Arrhythmias
contraction coupling. Tachyarrhythmias
Cardiac glycosides inhibit Na + K + - K+ tends to antagonise digitalis induced
ATPase by competing with potassium and enhanced automaticity and decreases bind-
172 Section 4/ Drugs Acting on Cardiovascular & Urinary System
ing of the cardiac glycosides to Na+ K+-AT- and is equal to the amount eliminated
Pase. Infuse KCl 20 mmol/hr intravenously during the day.
or orally depending upon the case.
Methods of Digitalization
Supraventricular Arrhythmias 1. Intravenous digitalization is done in
Can be treated by beta blockers e.g. emergency conditions of CHF or in atrial
propranolol 10-40 mg every 6 hourly orally fibrillation. Digoxin 0.25 mg followed by
or 0.5-1 mg IV. 0.1 mg hourly be given by slow IV route
with close monitoring of cardiac function.
Ventricular Arrhythmias
2. Oral digitalization: Digoxin 0.5-1.0 mg
Lignocaine (1-2 mg/kg IV) is the drug
stat and followed by 0.25 mg 6 hourly
of choice. Phenytoin is also useful (250 mg
with monitoring of toxicity.
IV) and has the added advantage of
• Digitoxin 1.2 mg is administered as
countering the depression of AV conduction
a single dose. This can be given in
by digitalis.
divided dose also, in 8 hours interval.
AV Block and Bradycardia 3. Maintenance dose method: Administration
Can be treated by atropine (0.6-1.2 mg IM). of a daily maintenance dose (0.5 mg) of
digoxin will digitalise the patient within
Therapeutic Uses a week.
Digitalis is used therapeutically in the
Atrial Fibrillation
treatment of:
Digitalis is the drug of choice in atrial
Congestive Heart Failure fibrillation for controlling ventricular rate.
Digitalis increases stroke volume and Its effect is due to the prolongation of the
cardiac output. Digitalis by increasing the refractory period of the conducting tissue.
cardiac output, brings about more complete The dose in so adjusted as to maintain the
emptying of the ventricles during systole. ventricular rate of 60 to 80 beats per minute
This reduces the pulmonary congestion and at rest and approximately 100 beats per
edema and decrease in systemic venous minute during light exercise.
pressure. The cardiac glycosides primarily
correct systolic dysfunction. Atrial Flutter
The dosing schedule is dependent on the The reversal to normal rhythm is
desired speed of action and urgency. Like because digitalis converts flutter into
other drugs having a longer duration of ac- fibrillation. Digitalis enhances the AV block
tion the treatment is initiated with a load- and reduces the ventricular rate.
ing dose which is followed by maintenance
dose for achieving a rapid onset of action Paroxysmal Supraventricular
and to avoid cumulative toxicity. Tachycardia
The maintenance dose is the amount Its effects is due to vagomimetic activity,
required to maintain the therapeutic effect generally one fourth total IV digitalizing
Cardiotonics (Cardiac Glycosides) 173
dose in given. In this condition, drugs like Side effects include nausea, abdominal
verapamil is more effective. pain, diarrhoea, fever, thrombocytopenia (tran-
sient and dose related) and hepatotoxicity.
Left Ventricular Failure
Digitalis is used in chronic pure, left MILRINONE
ventricular failure with hypertension and It is relatively selective inhibitor of
ischemic heart disease. peak III cyclic AMP phosphodiesterase
isoenzyme in cardiac and vascular
OTHER POSITIVE INOTROPIC muscle. In patients with CHF, it produces
DRUGS USED IN CHF dose related and plasma concentration
related increase in the maximum rate of
increase of left ventricular pressure.
BIPYRIDINE COMPOUNDS
Milrinone has a direct inotropic and
AMRINONE direct arterial vasodilator activity. It is
administrated by IV infusion 0.50 mg/kg
It is a relatively selective inhibitor of cyclic
over 10 min with a maximum daily dose
GMP, cyclic AMP-PDE (phosphodiesterase)
of 1.13 mg/kg.
type III family. It causes vasodilatation with
a consequent decrease in systemic vascular Side effects include ventricular
resistance. It increases both the force of arrhythmias, sustained ventricular tachycar-
contraction and velocity of relaxation of dia, angina, ventricular fibrillation, head-
cardiac muscles. It is administered IV 0.75 ache and hypokalemia.
mg/kg/min as a bolus dose followed by 5- Both the compounds are indicated in short
10 µg/kg/min IV infusion and total dose not term management of CHF in patents unre-
to exceed 10 mg/kg. sponsive to digitalis, diuretics or vasodilators.
This page
intentionally left
blank
h apptterer
CCh Antihypertensive
Pharmacodynamics
4.2
1.4 (ModeAgents
of Action of Drugs)
Hypertension is the most common cardiovas- mmHg with low diastolic blood pressure is
cular disease and pathophysiologically hyper- termed as ‘isolated systolic hypertension’
tension can be classified into two main groups. commonly seen in elderly person.
a. Essential or primary hypertension, The blood pressure is mainly con-
where the cause for rise in blood trolled by two systems. Firstly through the
pressure is not known. Responsible for baro-receptors and the adrenergic nervous
majority of cases. system. The baroreceptor reflexes protect
b. Secondary hypertension, where rise is the circulation against stresses which
due to renal disease e.g. chronic diffuse shows the changes in the arterial blood
glomerulonephritis, pyelonephritis; pressure. Secondly through renin angio-
due to some vascular disease e.g. renal tensin system, which is involved in the
artery disease or due to some pathogenesis of some forms of secondary
endocrinal disorders e.g. pheochro- hypertension. Renin is a proteolytic en-
mocytoma, Cushing’s syndrome and zyme released from the juxtaglomerular
primary aldosteronism. cells of kidneys. The reaction between re-
Systemic arterial blood pressure is de- nin and plasma protein, serum globulin
termined by cardiac output and total periph- (angiotensinogen) forms an inactive com-
eral resistance. In most of the cases, rise in BP pound ‘angiotensin I’ (decapeptide),
is due to increase in total peripheral resistance. which further changed into ‘angiotensin
II’ (octapeptide) by the action of angio-
Clinically, hypertension can be divided
tensin converting enzyme (ACE) and is the
into three stages e.g. mild, moderate and
most powerful vasoconstrictor agent. An-
severe hypertension. The diastolic blood
giotensin II also stimulates the synthesis
pressure between 90-104 mmHg is graded
as mild, 105-114 mmHg is graded as and release of aldosterone from adrenal
moderate and above 115 mmHg is graded cortex of adrenal gland.
as severe hypertension. The person having The drugs used in the treatment of
systolic blood pressure more than 160 hypertension can be classified as in table 4.2.1.
176 Section 4/ Drugs Acting on Cardiovascular & Urinary System
opathy, peripheral vascular disorders, con- pressure more than systolic blood pressure
gestive heart failure, acute myocardial inf- by lowering peripheral vascular resistance.
arction, myocardial preservation during Due to preferential arteriolar dilatation, pos-
surgery, migraine, oesophageal spasm and tural hypotension is uncommon. It increases
exercise induced bronchial asthma. heart rate and cardiac output.
After oral administration its absorption
AMLODIPINE is almost complete and rapid. It is subject to
Amlodipine is a long-acting calcium significant first pass metabolism in liver.
channel blocker that inhibits the transmem-
Adverse effects include nausea, vomiting,
brane influx of calcium ions into vascular
tachycardia, dizziness, fatigue, weakness, pal-
smooth muscle and cardiac muscle. By in-
pitations, headache, paresthesia, tremor, con-
hibiting calcium ion influx it directly dilates
vascular smooth muscle. stipation, anxiety, nasal congestion, lupus like
syndrome and sleep disturbances.
After oral administration of S-
amlodipine besylate, bioavailability is 65- It is indicated in hypertension (moderate
80%. Approximately 93% drug is bound to or severe) and hypertension with renal
plasma proteins. It is extensively converted involvement.
to inactive metabolites via hepatic
SODIUM NITROPRUSSIDE
metabolism. It is excreted in urine as 10%
parent drug and 60% of the metabolites. It has a brief duration of action. It relaxes
directly arteriolar and venous smooth
Amlodipine is generally well tolerated.
muscle. It decreases both preload and
The most commonly observed side effects
afterload thus both cardiac output and
are headache, edema, fatigue, flushing and
dizziness. peripheral resistance are reduced.
Other side effects include nausea, It is given parenterally and onset of ac-
abdominal pain, somnolence, palpitations, tion occurs quickly (within 1 minute). On
muscle cramps, frequency of micturition or stopping IV infusion, the effect dissipates
nocturia, cough, breathlessness, epistaxis, rapidly. It is converted to NO by endothe-
impotence, nervousness and conjunctivitis. lial cells and RBCs which relaxes vascular
smooth muscle. It is converted to thiocyan-
It is indicated in the treatment of
ate in liver which is excreted slowly.
essential hypertension and angina pectoris.
Adverse effects include nausea, vomiting,
DIRECT VASODILATORS nervousness, palpitation, sweating, headache,
disorientation, methaemoglobinaemia.
HYDRALAZINE It is indicated in hypertensive crisis,
It acts directly on arteriolar smooth muscle congestive heart failure and acute mitral
to cause relaxation. It decreases diastolic regurgitation.
This page
intentionally left
blank
h apptterer
CCh Pharmacodynamics
Antianginal Agents
4.3
1.4 (Mode of Action of Drugs)
act by inhibiting the uptake and degrada- Adverse effects include nausea, dizzi-
tion of adenosine (a local mediator involved ness, skin rash and headache. Though it is
in auto regulation of coronary flow in re- not useful as an antianginal drug, but it has
sponse to ischemia). It has also weak plate- been employed for prophylaxis of coronary
let inhibiting action. It reversibly inhibits and cerebral thrombosis in post MI and
platelet phosphodiesterase hence cAMP post stroke patients, as well as to prevent
concentration is increased and there is re- thrombosis in patients with prosthetic heart
duction of platelet reactivity. valves.
h apptterer Antiarrhythmic
CCh Pharmacodynamics
(ModeAgents
4.4
1.4 of Action of Drugs)
b. Automaticity: Quinidine decreases the Its antivagal action prolongs the re-
slope of slow diastolic depolarisation fractory period of atrium and short-
(phase 4 of action potential) and thus ens that of AV node. The antivagal
decreases the spontaneous rate of fir- action on the AV node causes para-
ing of pacemakers. By depressing the doxical tachycardia in a patient of
entry of sodium into the cell during atrium fibrillation.
depolarization, quinidine depresses e. Contractility: Quinidine produces a
diastolic depolarization and ultimately negative inotropic action on the heart
automaticity. and contractility is depressed with
c. Conductivity: Quinidine depresses in- toxic doses.
terventricular and atrioventricular con- f. AV conduction: Quinidine depresses
ductivity. PR and QRS intervals are the conduction in atrium and Purkinje
also prolonged. Also decreases the rate system.
of rise of action potential. g. Electrophysiological effect (effect on
d. Effective refractory period: Quini- ECG):
dine depresses the potassium efflux 1. It reduces the rate of rise of action
during repolarization and prolongs potential i.e. phase zero of action
repolarization. The refractory period potential which is due to
increases due to its antivagal action. depolarisation.
Antiarrhythmic Agents 191
2. Increase in the duration of ventricu- It decreases the rate of rise of action po-
lar systole (QT interval). tential and prolongs the effective refractory
3. Decrease in amplitude of T waves. period.
4. Depression of ST segment. After oral administration it is absorbed
5. Reduction in conduction velocity quickly, about 20% is bound to plasma pro-
(widening of QRS complex). tein up to and 70% of a dose is excreted in
urine in unchanged form.
Extracardiac actions:
Adverse effects include renal failure,
a. Quinidine in normal individuals pro-
hypotension (when given IV), anorexia, nau-
duce a decrease in blood pressure af-
ter oral and IV administration. sea, vomiting, Q-T prolongation. Rarely there
is diarrhoea, giddiness, psychosis, hallucina-
b. Quinidine has got antimalarial, anti-
tion, mental depression, hypersensitivity,
pyretic, oxytocic and skeletal muscle
relaxant activity also. agranulocytosis, myalgia, angioedema, skin
It is well absorbed orally, undergoes ex- rash, digital vasculitis. Procainamide can
tensive hepatic oxidative metabolism. 90% cause syndrome that resembles SLE, which
quinidine is bound to plasma protein. The is reversible on discontinuation of
drug is distributed to most tissues except procainamide; leukopenia and thrombocy-
brain. About 20% is excreted unchanged by topenia.
the kidney. It is indicated in ventricular arrhyth-
Adverse effects include SA block or ar- mia, ventricular premature depolarization
rest, high grade AV block, ventricular tachy- and paroxysmal ventricular tachycardia,
cardia, arrhythmia or ventricular asystole, supra-ventricular tachycardia and atrial ar-
polymorphic ventricular tachyarrhythmia, rhythmia.
hypotension (particularly when given IV),
cinchonism, tinnitus, loss of hearing, gas- DISOPYRAMIDE
trointestinal upset, severe headache, diplo- It has got anticholinergic and mem-
pia, photophobia, etc. brane depressant properties and like qui-
It is indicated in prevention of atrial ar- nidine, it is effective against most of the
rhythmia, atrial fibrillation or flutter, par- atrial and ventricular arrhythmias. It has no
oxysmal supraventricular tachycardia, ven- effect on sinus rate.
tricular premature beats and ventricular ta-
Adverse effects include dry mouth, con-
chycardia.
stipation, blurred vision, urinary urgency
PROCAINAMIDE and occasional urinary retention, nausea,
vomiting, diarrhoea, abdominal pain,
It has got quinidine like cardiac prop-
erty. It depresses the excitability of both hypoglycaemia, jaundice, coronary heart
atria and ventricles. Contractility and con- failure and hypotension.
ductivity are also depressed. It has got mini- It is indicated in atrial and ventricular
mal vagolytic action. arrhythmias in digitalised and non-
192 Section 4/ Drugs Acting on Cardiovascular & Urinary System
riness in Purkinje and ventricular muscle echolamines and has direct antiarrhythmic
fibers. property. Bretylium may reverse the short-
Amiodarone is slowly and poorly absorbed ening of action potential duration caused by
after oral administration. It is metabolised ischemia. It acts due to K+ channel blockade.
slowly in liver to active metabolite. It is used in the treatment of ventricular
Adverse effects include hypotension tachycardia and ventricular fibrillation.
due to vasodilatation and depression of
myocardial performance is frequent with the CALCIUM CHANNEL BLOCKERS
IV route. Heart block, bradycardia, corneal
The detailed pharmacology is discussed in
microdeposits, photosensitivity, hepatitis,
gastrointestinal upset may occur. chapter ‘Antihypertensive agents’.
These drugs inhibit Ca2+ mediated slow
It is indicated in tachyarrhythmias asso-
ciated with WPW syndrome, atrial flutter and channel inward current, thus inhibiting Ca2+
fibrillation, paroxysmal tachyarrhythmias mediated depolarization. Phase 4 depolar-
not responding to other agents. Ventricular ization in SA node and Purkinje fibres is re-
tachycardia and ventricular arrhythmia re- duced. They also prolong AV nodal effec-
fractory to other treatment. tive refractory period thus AV conduction
is slowed. There is also negative inotropic
BRETYLIUM action.
It has direct action on myocardium and It is indicated in PSVT, to control ventricu-
interferes with the neuronal release of cat- lar rate in atrial flutter or atrial fibrillation.
This page
intentionally left
blank
h appt etrer
CCh Antihyperlipidemic
Pharmacodynamics
4.5
1.4 (ModeAgents
of Action of Drugs)
These drugs are used for treatment of Atherosclerosis is main cause of cardio-
hyperlipidemia. They lower the levels of vascular deaths. It is characterized by a
lipoproteins and lipids in blood. The plasma localised plaque in the intima and is
lipids are present in lipoproteins after composed of cholesterol esters, deposition
combining with apoproteins. They are high of fibrous proteins and calcification. These
density lipoproteins (HDL), low density plaques may narrow the arterial lumen and
lipoproteins (LDL), very low density can cause distalischemia. The coronary and
lipoproteins (VLDL) and intermediate density cerebral circulation are main sites of
lipoproteins (IDL). atherosclerosis. Raised levels of VLDL, LDL
triglyceride plasma levels may be due to HDL level and it is administered with HMG
reduction in hepatic synthesis of VLDL and CoA reductase inhibitors e.g. simvastatin.
increase in VLDL clearance.
CHOLESTYRAMINE AND COLESTIPOL
It is completely absorbed from gastro-
intestinal tract and is excreted in urine. They are useful only in hyperlipopro-
teinemias involving elevated levels of LDL
Adverse effects include nausea,
i.e. type IIa, IIb and V. They are basic ion
diarrhoea, abdominal pain, dyspepsia,
exchange resins. They are neither digested
fatigue, skin rash, weight gain, leucopenia, nor absorbed in the gut. They bind bile ac-
alopecia, blurred vision etc. ids in intestine and interrupt their entero-
hepatic circulation, leading to increased
NICOTINIC ACID
faecal excretion of bile salts and cholester-
Nicotinic acid and nicotinamide ol. There is increased hepatic conversion of
together represent the essential vitamin choles-terol to bile acids. More LDL recep-
niacin in the diet. Of these two, only nicotinic tors are expressed on liver cells leading to
acid is active as a lipid modifying drug. increased clearance of IDL, LDL and indi-
Nicotinic acid is preferred in patients with rectly of VLDL.
triglyceride levels exceeding 200 mg/dl Adverse effects include nausea, heart
because bile acid sequestrants tend to raise burn, constipation and acidosis etc.
triglyceride levels. Nicotinic acid reduces
production of VLDL by liver, thus its PROBUCOL
degradation products IDL and LDL are It is cholesterol lowering agent with
subsequently reduced. It inhibits lipolysis antioxidant property. It is only 1/10
in adipose tissue and increases activity of absorbed when given orally. It reduces the
lipoprotein lipase. It has no effect on serum cholesterol levels without reduction
cholesterol and bile acid metabolism. in serum triglycerides level and also reduces
Combination drug therapy has been shown the HDL levels. It has no effect on VLDL and
to decrease cholesterol levels in triglyceride levels.
hyperlipidemic patients.
Adverse effects include headache, dizzi-
Adverse effects include, flushing, ness, diarrhoea and eosinophilia.
itching, vomiting, diarrhoea and dyspepsia.
It may also lead to hyperpigmentation of GUGULIPID
skin, liver dysfunction, hyperglycaemia and Is an indigenous drug obtained from
hyperuricaemia. gum guggul used for treatment of
It is indicated in type III, IV & V hyper- hyperlipidemia, hypercholesterolemia and
triglyceridemia. It lowers VLDL and raise hypertriglyceridemia.
h apptterer
CCh Pharmacodynamics
Plasma Expanders
4.6
1.4 (Mode of Action of Drugs)
Plasma substitutes/expanders are high blood can be arranged. These do not have
molecular weight substances when infused O2 carrying capacity.
intravenously into blood stream retain flu- The clinically used plasma expanders
id in the vascular compartment and exert are classified as in table 4.6.1.
oncotic pressure. But before infusing into the
blood stream, the following requirement HUMAN ALBUMIN
may be present. It is obtained from heat treated pooled
human plasma. 100 ml of 20% human albu-
• Should have same oncotic pressure
min solution is osmotic equivalent of 800 ml
with plasma. of whole blood. It draws and holds addi-
• Should remain in blood stream for ad- tional fluid from tissues. It can used irrespec-
equate period. tive of patient’s blood group. For optimum
• Should not be disposed rapidly by benefit it should be used with electrolyte
metabolic degradation or by excretion. solutions. It does not interfere with coagu-
lation and there is no risk of sensitization.
• Should remain stable on storage.
Table 4.6.1: Classification of plasma substitutes/
• Should not interfere with blood group- expanders.
ing and cross matching.
I. Human albumin (20% solution; ALBUSAFE)
• Should be compatible with other IV
II. Dextran
fluid and other drugs.
Dextran 70 (Mol. wt. 70,000; 6% solution;
• Should be easily sterilized. LOMODEX-70)
• Should be pharmacologically inert and Dextran 40 (Mol. wt. 40,000; 10% solution;
LOMODEX-40)
have a viscosity suitable for infusion
III. Degraded gelatin polymer – polygeline (3.5% in
into blood stream. electrolyte solution; HAEMACCEL)
They are used in conditions where IV. Hydroxyethyl starch (HES; Hetastarch; 6%
blood plasma has been lost e.g. shock, burn solution; HESTAR)
cases, severe trauma and extensive tissue V. Polyvinylpyrrolidone (PVP; 3.5% solution in
buffered normal saline; OSMOPLASMA)
damage as a temporary measure till the
200 Section 4/ Drugs Acting on Cardiovascular & Urinary System
It is used in burns, shock, in patients of Side effects include transient skin reac-
acute liver failure and on dialysis. tions (urticaria, wheals), hypotension, tachy-
cardia, bradycardia, nausea/vomiting, dysp-
DEXTRAN noea, a rise in temperature and/or chills may
They are most commonly used plasma ex- occasionally occur. In rare cases of severe hy-
panders. It is polysaccharide isolated from beet persensitivity reactions leading to shock.
sugar which is formed by the action of If side effects occur, the infusion should
Leuconstec mesenteroides. It is available in mainly be discontinued at once. Anaphylactic reac-
two forms depending upon the molecular tions associated with polygeline are due to
weight. Dextran 70 (mol. wt. 70,000) available
histamine release.
in 6% solution and Dextran 40 (mol. wt. 40,000)
available in 10% solution. They are infused in- It is indicated in hypovolaemic shock,
travenously in the treatment of shock. Dextran loss of blood and plasma (e.g., trauma,
40 acts more rapidly than dextran 70. It de- burns, preoperative autologous blood or
creases the blood viscosity and prevents the plasma donation), and for priming the heart-
sludging of RBC’s. Dextran 70 remains in cir- lung machine. In addition, it can be used as
culation for longer period (upto 24 hrs) and is a vehicle for various drugs.
slowly excreted by glomerular filtration.
HYDROXYETHYL STARCH
It is commonly used cheap plasma ex-
pander and can be stored for a longer period It is similar to glycogen, the starch mol-
of time but it may interfere with blood group- ecule is substituted to a selected degree to
ing and cross matching. It may trigger ana- achieve a distinct plasma retention and vol-
phylactic reaction characterized by urticaria, ume effect. It improves haemodynamics,
bronchospasm and decrease in blood pres- macrocirculation, microcirculation, organ
sure etc. It can also prolong bleeding time by function, oxygen supply.
interfering in coagulation of blood. After IV administration it is enzymatically
metabolised by endogenous amylase. The
DEGRADED GELATIN POLYMER – smaller fragments undergo rapid glomerular
POLYGELINE filtration. The 6% iso-oncotic infusion solution
It is a polypeptide and exerts oncotic allows precise blood volume control and leads
pressure similar to albumin. It remains in to an effective stabilisation of blood volume,
circulation for 12 hours and is slowly ex- whereas 10% hyperoncotic infusion solution
creted by the kidney. It does not interfere has a greater expansive volume effect. It im-
with blood grouping and cross matching. proves plasma volume for 24 hours or more.
It is a plasma substitute which corrects Adverse effects include anaphylactoid
circulatory insufficiency due to plasma/ reactions, manifesting as itching, chills, ur-
blood volume deficiency, absolute (e.g., re- ticaria, shock and bronchospasm. In rising
sulting from bleeding) or relative (e.g., re- doses it can influence coagulation mecha-
sulting from a shift in the blood volume be- nism without triggering clinical haemor-
tween the circulatory compartments). rhage.
Plasma Expanders 201
to reduce glomerular filtration rate by their therapy in controlling the edema asso-
action to reduce blood volume, also decrease ciated with CHF and cirrhosis.
positive free water formation. Although this 2. Hypertension: They are widely used in
response is less than that seen with ADH- the treatment of hypertension with or
deficient diabetes insipidus patients treated without edema and often serve as the
with ADH, it is sufficient to reduce first drug of choice.
significantly urinary frequency and water 3. Diabetes insipidus: They reduce urine
consumption. volume in both pituitary and renal dia-
betes insipidus. They are especially
Pharmacokinetics valuable for the latter in which ADH is
All thiazides and related compounds are ineffective.
well absorbed from the GIT and begin to
produce diuresis within one hour after oral HIGH-CEILING OR LOOP DIURETICS
administration, but the duration is variable,
These are the most efficacious agents
which are due to variation in rates of renal
available for inducing marked water and
tubular secretion and clearance, metabolism, electrolyte excretion. The peak diuresis is far
and enterohepatic circulation. Approximately greater than that observed maximally with
50 percent of an oral dose is excreted in urine other diuretics. The drugs in this group
within 6 hours. Most of the agents undergo little include furosemide, bumetanide and
hepatic metabolism and excreted as such. ethacrynic acid and the main site of action
However indapamide is extensively is the thick ascending limb of loop of Henle,
metabolized. thus they are often called ‘loop diuretics.’
The thiazides may induce hyperglyce- inhibit its transport function in ascending
mia and aggravate pre-existing diabetes limb of loop of Henle.
mellitus, the pharmacological effect of oral These agents tend to increase renal blood
hypoglycemic agents may also be reduced. flow without increasing filtration rate, which
Occasionally, they can cause allergic reduces fluid and electrolyte reabsorption
reactions like rashes, photosensitivity, in the proximal tubule and may augment the
thrombocytopenic purpura, dermatitis etc. initial diuretic response.
diuretic action starts within one hour and commonly in patients with renal
lasts up to 4 to 6 hours. Furosemide produces insufficiency.
more loss of chloride than sodium, potassium
loss also occurs, which is probably an indirect Therapeutic Uses
effect due to the large Na+ load reaching to Edema: The high ceiling diuretics are
the distal tubules. In low doses, these drugs effective for the treatment of edema of
do not appreciably effect HCO 3– or H + cardiac, hepatic or renal origin. They are the
excretion. drug of choice in case of congestive heart
failure. These are preferred initially in all
Pharmacokinetics cases for rapid mobilization of edema fluid.
All the loop diuretics are rapidly IV administration of furosemide
absorbed from the GIT, usually within 30 produces prompt relief in acute pulmonary
minutes after oral, and 5 minutes after IV edema (acute left ventricular failure,
administration. The bio-availability of following myocardial infarction). This is due
furosemide is about 60% while that of to the vasodilator action that precedes the
bumetanide is nearly 100%. They are saluretic action.
extensively bound to plasma proteins, but
In the management of refractory edema,
they are rapidly secreted by the organic acid
the high ceiling diuretics may be used in
transport system of the proximal tubule. They
conjunction with other types of diuretics.
produce a peak diuresis in about 2 hours with
They are also useful for forced diuresis in
a total duration of diuretic action of 6 to 8 hypnotic or other poisonings.
hours.
Furosemide is mainly excreted BUMETANIDE
unchanged by glomerular filtration as well Bumetanide is chemically similar to
as tubular secretion. furosemide. It induces very rapid diuresis.
The site and mechanism of action is similar
Adverse Reactions to furosemide but it is 40 times more potent
Abnormalities of fluid and electolyte than furosemide.
imbalance are the most common forms of It is highly effective in pulmonary
clinical toxicity, overdose may result in rapid edema. Adverse effects such as
reduction of blood volume, dizziness, hyperuricaemia, potassium loss and
orthostatic hypotension, headache, ototoxicity are less than furosemide.
hypokalemia.
ETHACRYNIC ACID
Gastrointestinal symptoms of nausea,
Ethacrynic acid is chemically distinct
vomiting, diarrhoea are common with
from the thiazides and furosemide but
ethacrynic acid. ceiling effect is similar. It is a phenoxyacetic
Ototoxicity has been reported with all acid derivative that also contains an adjacent
the three loop diuretics, which is seen more ketone and methylene group.
Diuretics and Antidiuretics 207
It does not inhibit carbonic anhydrase. tion. Peak concentrations in plasma occur
Loss of potassium is less marked but chance with in 2 hours and persists for 12 hours
of hypochloremic alkalosis are greater. It is after a single dose. Acetazolamide is ex-
an irritant and upon oral administration it creted unchanged in urine. Ethoxzolamide
produces diarrhoea, gastrointestinal is similar to acetazolamide but more
bleeding may occur at higher dose. Chances potent.
of hearing loss are greater. So, due to their
uniform toxicity, they are no longer used. Adverse Reactions
Serious toxic reactions include acidosis,
CARBONIC ANHYDRASE INHIBITORS hypokalemia, drowsiness and paresthesia
are common with larger doses.
ACETAZOLAMIDE Hypersensitivity reactions are rare, they
It is a potent, noncompetitive reversible consists of fever, skin reactions, bone-
carbonic anhydrase inhibitor. Carbonic marrow depression and sulfonamide like
anhydrase is an enzyme which catalyses the renal lesions.
reversible reaction Drug induced osteomalacia has been
H2O + CO2 H2CO3 reported with the simultaneous use of
Carbonic anhydrase influences the phenytoin.
tubular reabsorption of sodium in proximal
tubule where biocarbonate absorption occurs Therapeutic Uses
and in the distal tubule where sodium is Carbonic anhydrase inhibitors are rarely
exchanged for potassium or hydrogen ion used as primary diuretics, because of self-
and bicarbonate is formed as the limiting action, production of acidosis, and
accompanying anion. The hydration of hypokalemia. They are used in:
carbon dioxide takes place under the
i. Glaucoma, as adjuvant to miotics.
influence of enzyme carbonic anhydrase
which forms carbonic acid which dissociates ii. In urinary tract infections or to
and breaks into hydrogen and carbonate ions. alkalinise urine to promote the excre-
tion of acidic drugs.
Acetazolamide inhibits the enzyme
iii. In petit mal epilepsy as adjuvant.
carbonic anhydrase, and interferes with the
ability of the renal tubules to produce and iv. In the management of periodic paraly-
secrete hydrogen ions. And, the diuretic sis.
action is due to the decreased sodium v. Effective in ameliorating the symptoms
biocarbonate absorption in proximal tubules of acute mountain sickness.
and diminished hydrogensodium exchange
in the distal tubules. DIRECTLY ACTING DIURETICS
i. It is widely used in the treatment of tubular fluid to exert an osmotic effect and
hypertension and in the management thus continue urine formation.
of refractory edema. It is also used to reduce intraocular
ii. Hypokalemia: Potassium sparing di- pressure prior to eye surgery for glaucoma.
uretics have been used in patients with Mannitol has been used to reduce cerebral
low serum K+ resulting from other di- edema.
uretics, like thiazide and loop diuretics.
The adverse reactions associated with
iii. Edema: It has been used in cirrhotic and mannitol administration are nausea,
nephrotic edema.
vomiting, headache and hypernatremia.
OSMOTIC DIURETICS
UREA
Osmotic diuretics are non-electrolytes, Urea is administered intravenously and
freely filterable at the glomerulus, undergo useful for reducing a raised cerebrospinal
limited reabsorption by the renal tubules. fluid pressure during neurosurgery and
The amount of diuresis produced is cerebral edema after head injury.
proportional to the quantity of osmotic
Urea is contraindicated in patients with
diuretic, therefore for more diuresis, a large
quantity of osmotic diuretic should be given. severe impairment of renal, hepatic or
The primary effect of osmotic diuretics cardiac function due to their potential effect
involves an increased fluid loss caused by on expansion of the extracellular fluid
osmotically active diuretic molecule. This volume.
results in reduced reabsorption of sodium
and water in proximal tubule and since the ISOSORBIDE
tubule is permeable to water, there is a Isosorbide is an orally active diuretic,
passive back diffusion of water, such a most commonly used in the emergency
process keeps the tubular fluid isotonic. treatment of acute angle-closure glaucoma.
They also tend to increase glomerular
filtration rate. ORGANIC MERCURIALS
MANNITOL In earlier twenties, these agents were
Mannitol is not absorbed from the GIT diuretics of choice, but after the introduc-
and must be given IV and is osmotically tion of thiazides and loop diuretics, the
more active than urea. organomercurials have been almost re-
placed.
Mannitol is useful in clinical conditions
which are characterized by hypotension and Mercurials depress the tubular
decreased glomerular filtration. It is useful reabsorption of sodium at several sites
in maintaining kidney function under these including loop of Henle and some portions
conditions, even at low rates of filtration a of proximal and distal tubules. They inhibit
sufficient amount of mannitol may enter the the reabsorption of Cl– and Na+.
210 Section 4/ Drugs Acting on Cardiovascular & Urinary System
Adverse effects include nausea, belching, reducing the volume of urine produced
abdominal cramps, hypersensitivity without any pressor effects.
reactions etc.
Oral administration of 0.1-0.2 mg
DESMOPRESSIN desmopressin provides an antidiuretic effect
lasting for 8-12 hours. Desmopressin does not
Desmopressin is a synthetic analogue cross blood brain barrier and maximal plasma
of vasopressin. Two chemical changes have
concentrations are reached within 2 hours.
been made to natural hormone, namely
After oral administration, t½ varies between
dissemination of cysteine and substitution
2.0 hours and 3.2 hours. 65% of oral
of 8-L-arginine by 8-D-arginine. These
desmopressin absorbed is excreted unchanged
structural changes result in a compound
in the urine. It is also used as a nasal spray.
with significantly increased antidiuretic
potency, very little activity on the smooth Adverse effects include headache,
muscles, hence the avoidance of nausea and stomach pain and in very rare
undesirable pressor effects. Desmopressin cases epistaxis. Treatment without
proved to be a highly selective diuretic concomitant restriction of water intake may
agent with a ratio between antidiuretic and lead to water retention with accompanying
vasopressor activity in excess of 2,000 : 1. signs and symptoms (reduced serum
Desmopressin is more stable than sodium, weight gain and in serious cases,
vasopressin and this is reflected in its convulsions).
prolonged duration of action.
Therapeutic Uses
Desmopressin is a pure V2 receptor
agonist. When bound to V2 receptors in the • Nocturia in adults.
kidney, it increases the permeability of the • Primary nocturnal enuresis.
collecting ducts and tubules thereby • Central diabetes insipidus: Desmo-
enhancing water reabsorption and pressin is preparation of choice.
This page
intentionally left
blank
Section 5
Autacoids
This page
intentionally left
blank
(Drugs used in A
a p
p t e
t r
e r Histamine and
CChh Pharmacodynamics
Antihistaminic
5.1
1.4 (Mode of Action of Drugs)
Agents
Indications for levocetirizine remain the Side effects include headache, fatigue,
same as those of cetirizine. drowsiness, nausea, tachycardia, palpita-
tions, dry mouth, GIT disturbances, taste
Adverse reactions include headache, disturbances, photosensitivity, dysmenor-
fatigue etc. rhoea and menstrual disorders.
FEXOFENADINE The newer antihistaminics agents e.g.
Azelastine inhibits histamine release and also
It is a pharmacologically active
inflammatory reactions evoked by
metabolite of terfenadine, is a non sedating
leukotrienes and plasma activating factor
antihistaminic with selective peripheral H1
(PAF). It is used for seasonal and perennial
receptor antagonist activity. allergic rhinitis in the form of nasal spray.
Fexofenadine inhibited antigen-induced Mizolastine, a non-sedating antihistaminic is
bronchospasm and histamine release from mast used in allergic rhinitis and urticaria. Ebastine,
cells. No anticholinergic or alpha adrenergic- another non-sedating antihistaminic is used
receptor blocking effects were observed. in nasal and skin allergies.
Moreover, no sedative or other CNS effects
were observed. Fexofenadine does not cross the H2-RECEPTOR ANTAGONISTS
blood-brain barrier. It inhibits skin wheal and As discussed earlier, H2 receptors are
flare responses produced by histamine responsible for histamine induced gastric
injection. Following single and twice daily oral acid secretion. H2-receptors antagonists such
administration, antihistaminic effects occurred as cimetidine, ranitidine, famotidine etc. are
within 1 hour, achieved a maximum at 2-3 used in the treatment of peptic ulcer and are
hours, and lasted a minimum of 12 hours. discussed in chapter ‘Antiulcer agents’.
This page
intentionally left
blank
(Drugs used in A
a p
p t e
t r
e r
CChh Serotonin and its
Pharmacodynamics
5.2
1.4 Antagonists
(Mode of Action of Drugs)
can also stimulate the smooth muscles of uterus. It antagonises the vasoconstrictor and
Nerve endings: 5-HT is less potent than pressor effect of 5-HT as well as the action
histamine in releasing catecholamines from of the amine on a variety of extravascular
adrenal medulla. 5-HT3 receptors located on smooth muscles.
various sensory neurons mediate a It has been used for migraine prophy-
depolarising response, which may cause laxis, vascular headaches, postgastrectomy
pain & itching. dumping syndrome and also used to
combat diarrhoea and malabsorption in car-
5-HT ANTAGONISTS cinoid patients.
5-HT antagonists are classified in table 5.2.1. Common side effects include nausea,
vomiting, heartburn, diarrhoea. Central
Many of the drugs are partial agonists
effects include drowsiness, weakness,
or antagonise certain action of 5-HT but
stimulate others. The two drugs that are nervousness, insomnia, confusion, excite-
usually classified as 5-HT antagonist namely ment and hallucinations.
methysergide and cyproheptadine is used
CYPROHEPTADINE
as a potent 5-HT1 antagonist, while another
drug, ketanserin is highly selective for Chemically, it is a phenothiazine
blocking 5HT2 receptors. derivative and has equal potency at both
H 1-histamine and 5-HT receptors as an
METHYSERGIDE antagonist. As H1-histamine antagonist it
Chemically, methysergide is 1-methyl-d- has been used in various allergic
lysergic acid butanolamide, congener of conditions. It increases the appetite and
methylergonovine and of LSD. promotes weight gain.
Serotonin and its Antagonists 223
This page
intentionally left
blank
a p
p t e
t r
e r Prostaglandins
CChh Pharmacodynamics
and
5.3 (Mode of Action of Drugs)
Leukotrienes
PGE’s & PGI2 also inhibit gastric acid renal blood flow and may serve to regulate
secretion stimulated by gastrin or histamine. urine formation. It also plays a role in the
Cardiovascular system: PGE’s are regulation of the secretion of renin (PGI2,
potent vasodilators. However, PGF’s PGE2 & PGD2 evoke release of renin). PGE2
constricts arterioles and veins. PGI2 inhibits and PGI2 cause renal vasodilatation while
the aggregation of human platelets in vitro. TXA2 causes renal vasoconstriction.
TXA2 is a very powerful inducer of platelet
Uses of Prostaglandins
aggregation. LTB 4 stimulates the
aggregation of polymorphonuclear 1. Abortifacient: Intra-amniotic adminis-
leukocytes. tration of PGF2a produced abortion with
Endocrine system: Systemic less severe adverse effects. It is used to
administration of PGE2 increases circulating induce second trimester abortion & usu-
ally administered as a single 40 mg in-
concentration of ACTH, GH, prolactin &
traamniotic injection.
gonadotrophins.
Synthetic PGE2 analogues are also used
It has also been observed in experimental as suppositories for abortion. It directly
animal that PG’s cause regression of corpus affects the collagenase of the cervix and
luteum and reduction in secretion of also stimulates the contraction of the
progesterone. uterus.
Central & peripheral nervous system: 2. Induction of labour: PG’s do not have
PGE1 & PGE2 increase body temperature. They any advantage over oxytocin for the
also contribute importantly to the genesis of induction of labour. The adverse effects
the signs and symptoms of inflammation. of the prostaglandins are slightly higher
When injected intracerebroventrically, PGE2 than that produced by oxytocin. PGF2a
produces sedation, rigidity and increased has more gastrointestinal toxicity than
body temperature. PGE2 and is a bronchoconstrictor also.
Kidney: PGE2 and PGI2 increases water, Oral PGE2 is superior to oral oxytocin.
Na+ and K+ excretion and have a diuretic PGE 2 & PGF 2a is used in place of
effect. Prostaglandins probably modulate oxytocin in renal failure patients.
This page
intentionally left
blank
(Drugs used in
a p
p tte r
e r
CChh Drugs Used in Cough
Pharmacodynamics
5.4
1.4 and
(Mode Asthma
of Action of Drugs)
secretions. Certain salts which are used as sensitive to iodine and chronic use can
emetics, when used in subemetic dose, in- induce hypothyroidism and goitre.
crease the bronchial secretion and expel it Sodium and potassium citrate and ace-
out, they are known as saline expectorants. tate act by increasing bronchial secretion by
Ammonium salts (as chloride and car- their salt actions.
bonate) are gastric irritant in nature and re- Certain alkaloids such as vasicine
flexly increase bronchial secretion. obtained from plant Adhatoda vasica act as
Potassium salts (as iodide) act by both potent expectorant and mucolytic agent.
direct action and reflexly to increase the Bromhexine, a derivative of vasicine
respiratory secretions and decrease its depolymerises mucopolysaccharides directly
viscosity thus they are easy to expel out. and by liberating lysosomal enzymes.
Potassium iodide is generally used for cough Another compound acetylcysteine opens
associated with chronic bronchitis and disulfide bonds in mucoproteins present in
asthma but it interferes with thyroid sputum and decrease its viscosity.
function tests, so it is dangerous in patients Carbocisteine acts in same manner.
Drugs Used in Cough and Asthma 231
rotransmitter of the adrenergic nervous sys- terbutaline and salbutamol are invariably
tem. They also protect effectively against the used as bronchodilators both oral as well as
challenge with various bronchoconstrictor aerosol inhalants. Salmeterol is long-acting
agents and may inhibit microvascular leak- analogue of salbutamol in which the amine
age into the airway. β2-agonists are the drug substituent is a long lipophilic chain, but
of choice to relieve acute exacerbation of found to be slower in achieving the peak
asthma and prevent bronchoconstriction bronchodilatation effect. The detailed phar-
following exercise or other stimuli. After macology is discussed in chapter ‘Adrener-
inhalation the β2-agonists have rapid onset gic Agents’.
of action (within minutes), but are active Specific agents used in bronchial asth-
only for 4 to 6 hours. ma are discussed here.
Their adverse effects are dose-related
and are more common after oral than aero- SALBUTAMOL
sol administration because of the manifold It is highly selective β2-adrenergic stim-
higher dose required for oral drugs. Some ulant having a prominent bronchodilator
of the important β2-agonists like salmeterol, action. It has poor cardiac action compared
Drugs Used in Cough and Asthma 233
drop) is used in allergic conjunctivitis and increase the peak expiratory flow rate in
in chronic cases. asthmatic patients. They are not effective
during an acute attack or in status
KETOTIFEN
asthmaticus. Side effects are sore throat,
It is a cromolyn analogue. It is an hoarseness of voice, dysphonia, oropharyn-
antihistaminic (H1 antagonist) and probably geal candidiasis.
inhibits airway inflammation induced by
platelet activating factor (PAF) in primate. LEUKOTRIENE PATHWAY INHIBITORS
It is not a bronchodilator. It is used in asthma
and symptomatic relief in atopic dermatitis, Apart from histamine, leukotrienes liberated
rhinitis, conjunctivitis and urticaria. It is during inflammation are more powerful
absorbed orally and well tolerated. bronchoconstrictor and longer acting.
Bioavailability is 50% due to first pass Leukotrienes also increase bronchial mucus
metabolism and is primarily metabolized. secretion and increase vascular permeability.
The common side effects include dry All the leukotrienes are derived from 5-
mouth, sedation, dizziness and nausea. lipoxygenase pathway of arachidonic acid
and are synthesized by a variety of
CORTICOSTEROIDS inflammatory cells in the airways e.g.
eosinophils, mast cells, basophils and
Like mast cell stabilizer, corticosteroids do macrophages. The LTB4, C4 & D4 exert many
not relax airway smooth muscle directly but effects known to occur in bronchial asthma,
reduce bronchial reactivity, increase air- including bronchoconstriction and increased
way caliber, suppress inflammatory bronchial reactivity. The drug, montelukast
response to antigen antibody reaction or (LTB4 antagonist) and zafirlukast (LTD4
trigger stimuli and reduce the frequency antagonist) have the advantage of being used
of asthma exacerbations. They produce when taken orally in asthmatic patients.
more sustained symptomatic relief than any
bronchodilator and mast cell stabilizer. MONTELUKAST
Systemic steroids are used in both se- It is a cysteinyl leukotriene receptor
vere chronic asthma and in acute emergen- antagonist indicated for the management of
cy of asthma (status asthmaticus). persistent asthma. It has been shown to have
Among the inhaled steroids, substantial blockade of airway leukotriene
beclomethasone is a halogenated corticoster- receptors 24 hours after oral dosing. Mon-
oid ester used in aerosol form. It suppresses telukast appears to be a useful alternative
asthma by a topical antiinflammatory action or adjunct to inhaled corticosteroid therapy
without causing any systemic side effects. in adults and an alternative to sodium cro-
They reduce the bronchial hyperreactivity moglycate in children.
This page
intentionally left
blank
Section 6
Drugs Acting On
Blood
This page
intentionally left
blank
a p
p t e
t r
e r
CChh Coagulants and
Pharmacodynamics
6.1
1.4 Anticoagulants
(Mode of Action of Drugs)
denoted by Roman numeral, denoting the contact with the blood in the intact blood
order of their discovery (Table 6.1.1). vessels. No outside tissue damage is
Table 6.1.1: Clotting factors. required. Rough vessels with exposed
collagen is sufficient. Contact with
I. Fibrinogen.
collagen activates factor XII. This in turn
II. Prothrombin.
activates factor IX. Factor IX joins factor
III. Thromboplastin.
VIII and this gives active factor X. Factor
IV. Calcium.
X joins with calcium to bring about the
V. Proaccelerin.
formation of prothrombinase.
VI. Accelerin.
VII. Serum prothrombin conversion accelerator. Once prothrombinase has been formed,
VIII. Antihaemophilic factor. the common pathway is followed. In stage
IX. Plasma thomboplastin component. 2, prothrombinase and calcium catalyze the
X. Stuart Prower factor. conversion of prothrombin to thrombin. In
XI. Plasma thromboplastin antecedent. stage 3, thrombin, in the presence of calcium
XII. Hageman factor. converts soluble fibrinogen to insoluble
XIII. Fibrin stabilizing factor. fibrin threads.
Stages of Clotting
COAGULANTS
Formation of prothrombinase: It can be
formed by extrinsic pathway and intrinsic These are the agents which promote
pathway. coagulation and are mainly used in any
haemorrhagic condition. They are classified
Extrinsic pathway: This pathway has as in table 6.1.2.
fewer steps than the intrinsic pathway and
occurs rapidly, within a matter of seconds if VITAMIN K
the trauma is severe. It is called the extrinsic Vitamin K is a fat soluble vitamin
pathway because a protein tissue factor, also found primarily in leafy green veg-
called thromboplastin or coagulation factor etables. There are two normal forms ex-
III, takes into the blood stream from outside ist, K 1 found in food (called phytona-
and initiates the formation of dione), K 2 found in human tissue (syn-
prothrombinase. Tissue factor is released thesized by intestinal bacteria) known as
from the surface of the damaged cells. It menaquinone. The synthetic compound
activates factor VII. Factor VII combines with is known as K 3. Synthetic analogues of
factor X, activating it. Factor X in the presence natural vitamin also show biological ac-
of Ca++ combines with factor V to give active tivity. Most of the vitamin K is synthe-
enzyme prothrombinase. sized by intestinal microorganisms and
Intrinsic pathway: This pathway is there is a risk of vitamin K deficiency in
more complex and is much slower. It is so new born infants.
named as the activators are in direct Vitamin K is necessary for final stage of
Coagulants and Anticoagulants 241
heparin like effect by degrading fibrinogen highly bound to plasma proteins and it
into an unstable form of fibrin. crosses the placental barrier.
Danaparoid containing mainly heparan Adverse effects include haemorrhage,
sulfate isolated from porcine intestinal rash, alopecia, diarrhoea, hepatic dysfunction,
mucosa and is used in heparin induced nausea, vomiting and pancreatitis.
thrombocytopenia and deep venous It is used in venous thromboembolism,
thrombosis. pulmonary embolism, atrial fibrillation and
Lepirudin is a recombinant derivative for prophylaxis after insertion of prosthetic
of hirudin (direct thrombin inhibitor heart valves.
secreted by salivary glands of leech). It WARFARIN
inhibits thrombin directly and is mainly
It is most commonly used oral anticoagulants
used in heparin induced thrombocytopenia.
employed for long term anticoagulant therapy
HEPARIN ANTAGONISTS and having less toxic effects including alopecia
and dermatitis. It is rapidly and completely
The agents like protamine sulfate react absorbed from intestines and is 99% plasma
with the strongly acidic groups of heparin protein bound. It crosses the placental barrier and
and can abolish its anticoagulant activity. is secreted in milk. The other properties are same
Approximately 1 mg of protamine sulfate as acenocoumarol.
neutralizes 80 to 100 units of heparin. It is
used only in severe bleeding or when PHENINDIONE
heparin action needs to be terminated The mechanism of action and adverse
rapidly e.g. after cardiac or vascular effects are same as acenocoumarol. It
surgery. produces more serious nonhaemorrhagic
toxic effects, their use is now very limited.
ORAL ANTICOAGULANTS
FIBRINOLYTICS
They act by interfering with synthesis of
vitamin K dependent clotting factors in liver. These are agents used to lyse clot to
They act as competitive antagonists of vitamin recanalise occluded blood vessels, mainly
K and reduce plasma levels of clotting factors used in coronary arteries.
in a dose dependent manner. They act by
interfering with regeneration of active form STREPTOKINASE
of vitamin K. Factor VII levels are reduced first It is a purified preparation of bacterial
followed by factor IX, X and II. protein obtained from β hemolytic streptococci.
a p
p t e
t r
e r
CChh Haematinics
Pharmacodynamics
Pharmacodynamics
6.2
(Drugs
(Mode Used in Anaemia)
Anaemia is the decrease in number of red even if its mother has low stores, but
blood cells or hemoglobin content caused mother becomes anaemic.
by blood loss, deficient erythropoiesis, Anaemia may be classified into different
excessive hemolysis, or combination of groups according to the pathophysiology.
these changes. Iron deficiency anaemia is
probably the most common nutritional 1. Dietary deficiency anaemia, which is
due to deficient supply of various
deficiency in the world. It is estimated that
factors e.g. iron, folic acid, vitamin B12,
at least 500 million people are affected. Iron
vitamin C and pyridoxine which are
deficiency anaemia is much more common
essential for normal blood formation.
in developing countries, as people are
2. Anaemia due to blood loss e.g. in
consuming too little food or a limited
severe gastric blood loss (ulcers),
variety of food.
protozoal or worm infestation.
Infants and young children have higher 3. Anaemia due to excessive destruction,
iron requirement. For the first six months of blood e.g. sickle cell anaemia and
of life, these requirements are met by iron haemolytic anaemia.
store in the infant’s body alone with 4. Anaemia due bone narrow depression
supplementation from breast or formula e.g. aplastic and hypoplastic anaemia.
milk. Iron requirement increases during
adolescence because of growth, muscle IRON
development and, for girls, at the start of The body iron is distributed mainly in two
menstruation. Adult women have higher forms, one as haem in haemoglobin and
iron requirement because of menstrual cytochrome oxidase enzyme and other as
losses. During pregnancy it is not necessary iron bound to protein as storage compounds
to have extra iron in the diet because ferritin and hemosiderin, and as transport
absorption increases and menstruation iron bound to transferrin. The total body iron
stops. The fetus is likely to get enough iron in human adult is approximately 3.5 g out
248 Section 6/ Drug Acting on Blood
of which 66% is in haemoglobin and 25% is Iron is transported via transferrin. When
stored as ferritin and hemosiderin and rest body stores of iron are high, ferric iron
is in muscles and enzyme. combines with apoferritin to form ferritin.
Iron absorption occurs predominantly in Ferritin is the protein of iron storage. About
80 percent iron in plasma goes to erythroid
the duodenum and upper jejunum. The
marrow. The excretion of iron is minimal.
physical state of iron entering the duodenum
Only little amount of iron is lost by exfoliation
greatly influences its absorption. At
of intestinal mucosal cells and trace amount
physiological pH, ferrous iron is rapidly
is excreted in urine, sweat and bile.
oxidized to the insoluble ferric form. Gastric
acid lowers the pH in the proximal duodenum, After confirmation of iron deficiency
enhancing the solubility and uptake of ferric iron therapy can be given by oral or
parenteral route. Generally oral iron therapy
iron. When gastric acid production is
is given unless the patient is suffering from
impaired, iron absorption is reduced subs-
severe anaemia, malabsorption syndrome,
tantially. Ascorbic acid enhances iron
gastrectomy or patient is showing adverse
absorption. Ascorbic acid mobilizes iron from
effects to oral iron therapy.
iron-binding proteins in vivo, which in turn
could catalyze lipid peroxidation. Iron Uses
absorption is inhibited by antacids, phytates,
Nutritional iron deficiency anaemia; other
phosphates and tetracyclines.
causes in which iron deficiency can occur are
The iron is transferred by the mucosal pregnancy, lactation, infants, children. In
epithelium to the body and is bound to plasma patients with malabsorption syndrome,
transferrin in the ferric state. In the plasma, iron patients who are taking NSAIDs for long
takes part in a dynamic transferrin-iron period, patients with chronic inflammatory
equilibrium and is distributed into vascular and disease and in patients of gastrectomy.
interstitial extravascular compartment. 50 to Preparations of iron alone or in
60% of transferrin is extravascular. The plasma combination with vitamin B12, folic acid or
iron pool in adults is about 3 mg and has an other vitamins are available (see table 6.2.1).
estimated turnover of 20 to 30 mg per 24 hours.
Most of the oral formulations contain
Daily and obligatory losses of iron in healthy
one of the iron compound with many
men are about 1 mg; in healthy menstruating vitamins, amino acids, liver extract,
women these average 2 mg and in either case minerals, folic acid, appetite stimulants
are compensated by a net absorption of 1 to 2 (cyproheptadine like compound).
mg from the intestine, which enters the mobile
pool of transferrin iron. Adverse Effects
Oral administration can cause nausea,
Pharmacokinetics vomiting, epigastric pain, metallic taste,
After oral administration iron is absorbed staining of teeth, constipation and diarrhoea
in ferrous form. The conversion of ferric iron both can occur, but constipation is more
to ferrous iron is aided by hydrochloric acid. common.
Haematinincs (Drugs Used in Anaemia) 249
Drugs Acting On
GIT
This page
intentionally left
blank
(Drugs used in A
a p
p t e
t r
e r Laxatives and
CChh Pharmacodynamics
Antidiarrhoeal
7.1
1.4 (Mode of Action of Drugs)
Agents
ABSORBENTS AND BULK FORMING DRUGS may occur leading to abdominal obstruction.
These are usually not prescribed for bacterial
They are colloidal bulk forming agents which diarrhoea in children because by delaying the
swell by absorbing water. They modify the passage of liquid faeces there is proliferation of
consistency and frequency of stools. They are pathogens which is undesirable.
used for functional bowel disease associated
with diarrhoea. They are safe substances but SULFASALAZINE
their effect occurs slowly. It is an antisecretory drug. It is 5-ami-
nosalicylic acid with linked sulfapyridine
ANTIMOTILITY AND ANTISECRETORY DRUGS through azo bond. The drug is poorly ab-
sorbed from the intestine and the azo link-
Antimotility drugs are opioid drugs. They
age is broken down by the bacterial flora in
increase small bowel smooth muscle tone and
the distal ileum and colon to release 5-ami-
segmentation activity. They also reduce
nosalicylic acid (5-ASA) and sulfapyridine.
propulsive movements and decrease intestinal
secretions while increasing absorption. They 5-ASA inhibits locally prostaglandin synthe-
mediate these actions through µ receptors. sis, decreases mucosal secretion. It is used
in rheumatoid arthritis and ulcerative coli-
LOPERAMIDE tis. Side effects include fever, rashes, blood
dyscrasias, nausea, vomiting and headache.
It has a direct action on intestinal muscu-
lature and having a weak anticholinergic MESALAZINE
property. It is used to treat acute and chronic
diarrhoea. Adverse effects include 5-ASA is prepared as delayed release
addominal cramps and skin rash. preparation by coating with acrylic polymer,
which releases 5-ASA in distal ileum and colon.
DIPHENOXYLATE It is used in ulcerative colitis to prevent relapses.
Chemically it is an opioid, related to Olsalazine and balsalazine are the
pethidine. It is used in acute and chronic newer compounds of 5-aminosalicylic acid
diarrhoea but since it crosses the blood brain linked with azo bonds.
barrier it can cause CNS effect similar to
opioids. Atropine is added with diphenoxylate ANTIMICROBIAL THERAPY
(LOMOFEN) to discourage abuse.
Loperamide and codeine are preferred to Antimicrobials have a limited role in
diphenoxylate in chronic diarrhoea, because treatment of diarrhoea because only a small
they have less tendency to produce drug percentage of diarrhoeas are caused by
dependence. Long-term use of these drugs may bacterial infection. Majority of cases are due
aggravate irritable bowel syndrome. These to non infective causes, Rota virus and food
drugs are used cautiously in attacks of colitis poisoning in which antimicrobial therapy
because there is increased risk of toxic has no role.
megacolon. Also all these drugs should be used Specific antimicrobial drugs are discussed
with caution in elderly because faecal impaction in chapter ‘Chemotherapeutic agents.’
(Drugs used in A
a p
p t e
t r
e r
CChh Emetics & Antiemetic
Pharmacodynamics
Agents
7.2
1.4 (Mode of Action of Drugs)
the 5-HT4 receptor in the presynaptic nerve thetic nerve endings and thereby increas-
endings in the myenteric plexus promoting es the release of acetylcholine. It decreases
the release of acetylcholine at the neuro- the metabolism of acetylcholine by inhibit-
muscular junction, strengthening tone and ing the enzyme acetylcholinesterase.
contractions of the gut wall, in particular the It is highly protein bound (approx. 96%),
tone of the lower oesophageal sphincter. metabolised in the liver by N-oxidation to
Adverse effects include nausea and inactive metabolites by the enzyme flavin-
diarrhoea. containing monooxygenase. It is excreted
It is indicated in gastroesophageal reflux mainly by the kidneys in the form of
disease and functional dyspepsia, diabetic metabolites and as unchanged drug.
gastropathy. Adverse effects include rash, itching
Renzapride is also a selective 5-HT4 sensation, tremor, increase in SGOT, SGPT
receptor agonist. levels, diarrhoea, abdominal pain, gyneco-
mastia etc.
ITOPRIDE It is indicated in upper abdominal
It is a novel prokinetic agent, it inhibits digestive symptoms associated with chronic
dopamine D2 receptors at the parasympa- gastritis.
(Drugs used in A
a p
p t e
t r
e r
CChh Antacids and
Pharmacodynamics
Antiulcer Agents
7.3
1.4 (Mode of Action of Drugs)
persists for much longer as it strongly binds Adverse effects include nausea, diarr-
to H+ K+ ATPase. The disposition is not hoea, skin eruptions, headache and dizziness.
altered in patients with renal disease or in Other proton pump inhibitors e.g., lanso-
those undergoing haemodialysis. Increased prazole is more potent than omeprazole and
age and liver disease delays plasma clearance has higher bioavailability, rapid onset of ac-
of the drug but this does not necessitate tion and longer duration of action.
dosage adjustment in these patients. Pantoprazole is the new H+K+ATPase inhibi-
It is indicated in: tor with similar properties and action to
omeprazole.
• Treatment of duodenal ulcer.
• Treatment of gastric ulcer.
PROSTAGLANDIN ANALOGUES
• Treatment of reflux oesophagitis.
• For control of acid secretion in patients PGE2 and PGI2 are the main prostaglandins
of Zollinger-Ellison syndrome. synthesized by gastric mucosa. They decrease
It is well tolerated. Nausea, headache, acid secretion and improve mucosal defense
diarrhoea, constipation and flatulence have mechanism by:
been reported occasionally, Rarely skin rash • Stimulation of synthesis and release of
has occurred in few patients. mucus.
• Enhance bicarbonate production.
RABEPRAZOLE
• Enhancement of tight junctions of cell
Rabeprazole belongs to substituted ben- membrane architecture.
zimidazole proton-pump inhibitors. In
• Inhibit gastrin production.
gastric parietal cells, rabeprazole is proto-
• Stimulation of a number of cellular
nated, accumulates and is transformed to
transport processes.
an active sulfenamide.
• Stimulation of DNA content in
Following oral administration of 20 mg,
damaged gastric mucosa by a process
rabeprazole is absorbed and can be detected
termed as cytoprotection.
in plasma by one hour. Rabeprazole is 96.3%
The important use of prostaglandin
bound to plasma proteins.
analogues is in the arthritic patients who are
Rabeprazole is extensively metabolized. on chronic use of NSAID’s and are not
The thioether and sulfone are the primary responding to H2 receptor antagonists.
inactive metabolites. 90% of the drug is
eliminated in the urine, primarily as MISOPROSTOL
thioether carboxylic acid, its glucuronide 200 µg QID was of similar efficacy to
and mercapturic acid metabolites. cimetidine 300 mg TDS in healing duodenal
It is indicated in erosive and ulcerative and gastric ulcer. Pain relief occurred more
gastroesophageal reflux disease, healing of slowly than with cimetidine. Shown to heal
duodenal ulcers and Zollinger Ellison syndrome. erosions, ulcers due to NSAIDs.
266 Section 7/ Drugs Acting on GIT
Section 8
Drugs Acting on
Endocrine System
This page
intentionally left
blank
(Drugs used in A
a p
p t e
t r
e r
CChh Anterior Pituitary
Pharmacodynamics
Hormones
8.1
1.4 (Mode of Action of Drugs)
the uptake of iodine, synthesis of thyroxine which stimulates the reabsorption of sodium
(T4) and triiodothyronine (T3) by the thyroid by the renal tubules and when the amount
gland and their release into the blood of sodium reabsorbed is increased the
stream. amount of potassium excreted is increased.
Details are discussed in chapter ‘Thyroid Angiotensin (vasopressor agent) produced
& antithyroid agents’. by the renin (from kidneys) stimulates the
secretion of aldosterone.
ADRENOCORTICOTROPHIC
HORMONE (ACTH) Sex Hormones
It is a polypeptide of 39 amino acid The secretion of estrogens in females and
residues of molecular weight approximately androgens in males by the adrenal cortex is
4,500. It is secreted by basophil cells under controlled by ACTH. They are responsible
the control of CRF (corticotropin releasing for the development and maintenance of
factor) from the hypothalamus. ACTH secondary sexual characters in both males
controls the growth of adrenal cortex and the and females. They also increase the
synthesis of corticosteroids and is essential deposition of protein in muscles and reduce
to life. The action of ACTH on adrenal cortex the excretion of nitrogen in males.
is mediated through cyclic AMP. Hyposecretion of hormones from the
This hormone stimulates the cortex of adrenal cortex leads to development of
adrenal gland to produce its hormones. The ‘Addison’s disease’ which is characterized by
amount of ACTH secreted depends upon loss of appetite, muscular weakness, loss of
the concentration in the blood of the weight due to loss of water, hypoglycemia,
hormones from the adrenal cortex and on subnormal body temperature, decreased
stimulation by hypothalamus. basal metabolic rate, increased blood
The cortex of adrenal gland produces potassium, decreased blood sodium and
three types of hormones – the glucocorticoids, inability to maintain the normal protein
mineralocorticoids and the sex hormones. deposition in the muscles.
Hypersecretion from the adrenal
Glucocorticoids cortex leads to condition known as
The secretion is stimulated by ACTH ‘Cushing’s syndrome’ which leads to
from the anterior lobe of pituitary gland. ‘feminism’ in males, which is the tendency
Cortisone and hydrocortisone are the main to develop female sex characters and in
glucocorticoids and their main function is females ‘virilism’ develops, which is the
to regulate carbohydrate metabolism. tendency to develop male sex characters
such as excess growth of hair on chest and
Mineralocorticoids pubic region, increase and darkening of
It is associated with the maintenance of facial hair, atrophy of mammary glands
the electrolyte balance in the body. (breasts) and cessation of menstrual cycle
Aldosterone is the main mineralocorticoid (amenorrhoea).
272 Section 8/ Drugs Acting on Endocrine System
inhibit the synthesis and release of prolactin axons into the posterior lobe of pituitary.
by agonist action on dopaminergic receptors. It promotes contraction of the uterine
Adverse effects are nausea, vomiting, muscle. It also causes contraction of the
postural hypotension, behavioral alterations, myoepithelial cells of the lactating breast
mental confusion, psychosis. and squeezing milk into the large ducts
It is used in hyperprolactinemia and for situated behind the nipple of the mammary
suppression of lactation and breast gland.
engorgement. It is also useful in Oxytocin takes part in the onset of
parkinsonism because it has levodopa like parturition, expulsion of the foetus and
actions and in the treatment of acromegaly. placenta. It also facilitates the transport of
Dose: PROCTINAL 1.25 mg BD. sperm in the female genital tract.
Oxytocin is used in induction of labour,
POSTERIOR LOBE OF PITUITARY GLAND
in postpartum haemorrhage, abortion and
The posterior lobe secretes two hormone in breast engorgement. It is used by IM/IV
namely oxytocin and antidiuretic hormone route (PITOCIN, 2-5 IU/ml inj).
(ADH or vasopressin).
ERGOMETRINE
ADH OR VASOPRESSIN
It increase force, frequency and duration
Discussed in detail in chapter ‘Diuretics of uterine contractions. It is used to control
and antidiuretics’. and prevent postpartum haemorrhage. It is
also used to prevent uterine atony after
UTERINE STIMULANTS cesarean or instrumental delivery.
(OXYTOCICS, ABORTIFACIENTS)
PROSTAGLANDINS
OXYTOCIN PGE2, PGF2α and 15-methyl PGF2α are
Oxytocin is an octapeptide synthesized potent uterine stimulant (Other details are
in hypothalamus and transported down the given in chapter 5.3).
(Drugs used in A
a p
p t e
t r
e r
CChh Pharmacodynamics
Antidiabetic Agents
8.2
1.4 (Mode of Action of Drugs)
Diabetes mellitus (DM) is a chronic crystallized by Abel and it’s amino acid
disorder characterized by altered sequence was established by Sanger in 1960.
metabolism of carbohydrates, proteins and It’s formed from proteolysis of proinsulin
fats. Epidemiological survey conducted in to give rise to two peptide chains (A with 21
several developing countries show that amino acid residues and B with 30) which
prevalence rates of diabetes mellitus vary are interconnected by disulphide bond.
from two to four percent in different
population groups. Roughly two percent of Mechanism of Insulin Action
the world population suffers from diabetes Insulin acts by binding to insulin
mellitus. receptors on cell membrane. The insulin
receptor complex is internalized. By
Types of Diabetes Mellitus phosphorylation and dephosphorylation
• Insulin dependent or type I diabetes reactions there is stimulation or inhibition of
(IDDM). Formerly called juvenile onset, enzymes involved in metabolic actions of
or ketone prone diabetes. It is an insulin. Second messengers like phosphatidyl
autoimmune disease of pancreatic β- inositol glycan and DAG also mediate the
cells. Arises due to insulin insufficiency. action of insulin on metabolic enzymes.
• Non-insulin dependent or type II Normally, insulin stimulates storage of
diabetes (NIDDM). Formerly called glucose in liver as glycogen and in adipose
non ketotic or maturity onset diabetes. tissues as triglycerides and storage of amino
It arises due to insulin resistance in acids in muscle as protein. It also promotes
peripheral tissues. utilization of glucose in muscle for energy.
Insulin inhibits the breakdown of
INSULIN triglycerides, glycogen, and protein and
Insulin (MW 5,800) a polypeptide conversion of amino acids to glucose
hormone secreted from β-cells of islets of (gluconeogenesis). Conversion of amino
Langerhans in pancreas was discovered by acids to glucose and glucose to fatty acids
Banting and Best in 1921. It was purified and occur mainly in liver.
276 Section 8/ Drugs Acting on Endocrine System
In diabetes mellitus, there is either insulin reaction is hypoglycemia. It can occur in any
deficiency or insulin resistance in peripheral diabetic patient due to heavy dose of insulin,
tissues which lead to hyperglycemia and failure to eat or missing a meal, performing
glycosuria. Insulin corrects the various extensive exercise or by consuming alcohol.
abnormalities of carbohydrate metabolism by The hypoglycemia caused by insulin is
its action on various tissues. characterized by neuroglucopenic
symptoms that include confusion, dizziness,
Pharmacokinetics behavioural changes, visual disturbances,
Insulin is not given orally. After IV or SC fatigue, muscle incoordination and may be
injection, it circulates as free, monomer in blood fall in blood pressure.
and has a short plasma half life. Insulin is The other side effects include insulin
degraded mainly in liver, muscle and kidney. allergy which consists of local itching,
swelling, redness at the site of injection.
Adverse Reactions Urticaria and anaphylactic reactions are rarely
The most frequent and serious adverse seen. Other rare side effects include insulin
Antidiabetic Agents 277
lipodystrophy (atrophy at the site of injection), experience redness, swelling, and itching at
insulin neuropathy and weight gain (obesity). the site of injection of insulin.
Systemic allergy: Less common, but
Therapeutic Uses potentially more serious, is generalized
Insulin is used in: allergy to insulin, which may cause rash
• Insulin dependent diabetes mellitus over the whole body, shortness of breath,
(IDDM). wheezing, reduction in blood pressure, fast
pulse, or sweating. Severe cases may be life
• Diabetic ketoacidosis or diabetic coma.
threatening.
HUMINSULIN
ORAL ANTIDIABETIC AGENTS
Huminsulin 30/70 [biphasic isophane
insulin injection (30% soluble insulin and 70% These are the agents which are effective
isophane insulin)] is a mixture of soluble orally and lower the elevated blood glucose
human insulin injection, a short acting blood levels. They are classified as in table 8.2.2.
glucose lowering agent and isophane insulin
human suspension, an intermediate acting SULFONYLUREAS
blood glucose lowering agent. These drugs stimulate insulin secretion
from pancreatic β -cells (so called
Adverse Effects ‘sulfonylurea receptors’) which cause
Local allergy: Patients occasionally depolarisation by reducing conductance of
ATP sensitive K + channels. They lower 1. The pancreatic effect, in the case of
down the blood sugar level in type II failure of β-cell function together with
diabetics and non-diabetic individuals. They an existing but inadequate insulin
also decrease the elevated plasma free fatty secretion, gives rise to an intensified
acid levels. They also sensitize the target insulin secretion as a result of a greater
tissues to action of insulin by increasing the response of the β-cells to glucose.
number of insulin receptors. 2. The extrapancreatic effect, in the case
Sulfonylureas inhibit neoglucogenesis of resistance to insulin due to a reduced
and glycogenolysis. Sulfonylureas are sensitivity of the peripheral tissue to
rapidly absorbed from the gastrointestinal insulin, there is intensification of the
tract after oral administration and are more insulin effect as a result of:
than 90 percent bound to plasma proteins Adverse reactions include visual dis-
and excreted unchanged in urine. turbances (transient, at the beginning of
therapy), nausea and epigastric bloating
CHLORPROPAMIDE (rare) and diarrhoea. Hypersensitivity in-
After oral administration, it is rapidly cluding allergic skin reactions, thrombocy-
absorbed and has long plasma half life and topenia, leucopenia, agranulocytosis,
excreted by kidney slowly. haemolytic anaemia, vasculitis, cholestatic
Adverse effects include nausea, vomiting, jaundice and hepatitis.
cholestatic jaundice, skin rash, anaemia, It is indicated in non-insulin dependent
leucopenia, hypoglycemia and intolerance to diabetes mellitus (type II, maturityonset
alcohol (disulfiram like reaction). diabetes) whenever treatment by diet alone
It is indicated in the treatment of proves to be inadequate.
maturity onset non ketotic diabetes mellitus
unresponsive to diet and neurogenic GLIPIZIDE
diabetes insipidus. It is an oral blood glucose lowering drug
of sulfonylurea class.
TOLBUTAMIDE
It is fast acting and post prandial
It is a short acting, less potent oral insulinemic action persists even after
hypoglycemic agent and after administration prolonged use.
it is readily metabolized in liver.
Glipizide is completely and rapidly
Adverse effects include, nausea, absorbed ensuring prompt and constant
vomiting, skin rash and epigastric distress.
activity.
It is mainly used in maturity onset diabetes
mellitus. It is indicated in management of type II
diabetes where diet control alone is not
GLIBENCLAMIDE effective in controlling the hyperglycemia.
Glibenclamide is a second generation Adverse effects include hypoglycemia,
sulfonylurea. There are two mechanisms of GIT disturbances, allergic reactions include
action for the lowering of the blood glucose: urticaria and erythema.
Antidiabetic Agents 279
Cholesterol
Pregnenolone
Progesterone 17α-Hydroxy- Dehydroepiandro-
pregnenolone sterone
Desoxy-
corticosterone 17α-Hydroxy- Androstenedione
progesterone
Corticosterone
Desoxyhydro- Testosterone
cortisone
Aldosterone
Hydrocortisone Estrogens
Fig. 8.3.1: Biosynthesis of various steroid hormones.
282 Section 8/ Drugs Acting on Endocrine System
It also stimulates the development of skin estrogen are metabolized very slowly and
pigmentation particularly in the region of the are more potent.
nipples and areolae and in the genital regions. Adverse effects include breast discomfort,
Estrogens also play a role in stimulation pruritus, exanthema, thrombophlebitis and
of the proliferative or preovulatory phase local skin irritation, increased risk of gall stones.
of endometrium and vasodilatation of
endometrial capillaries. Therapeutic Uses
Estrogens are anabolic but weaker than The most common use of estrogen are
testosterone. Estrogens also cause retention as oral/parenteral contraceptive and for
of nitrogen, sodium and fluid in tissues. hormone replacement therapy.
Estrogens also protect from osteoporosis in • Primary hypogonadism: Estrogens
postmenopausal women, which occur as a have been used for replacement
result of estrogen deficiency. therapy in estrogen deficient patients
(treatment of amenorrhoea).
Pharmacological Actions • In post menopausal hormonal
Estrogens act by interacting with the therapy:
specific estradiol receptors in the cytoplasm Estrogen have been used in preven-
of the target cells and mediate the tion and treatment of osteoporosis.
transcription of the relevant mRNA by Improve the general physical,
attaching itself to the appropriate gene. mental and also sexual activity.
Estrogens produce proliferative changes in Maintain calcium balance.
the endometrium. On chronic administration, Decreases the risk of cardiovascular
estrogen suppresses the secretion of FSH and (coronary artery) disease.
somewhat LH resulting in inhibition of Transdermal estradiol is equally
ovulation. In testes it may reduce the secretion effective:
of androgens and inhibit spermatogenesis. • In atrophic vaginitis.
Estrogens suppress lactation without • In atrophic urethritis.
affecting the prolactin level in plasma. • For the treatment of vaginal complaints
On chronic administration it may inhibit such as dyspareunia, dryness and itching.
the growth of epiphyseal cartilage. • Pre and postoperative therapy in
postmenopausal women undergoing
Pharmacokinetics vaginal surgery.
Natural estrogens are inactive orally due • Infertility due to cervical hostility.
to rapid metabolism in liver. Synthetic • As a diagnostic aid in case of doubtful
estrogens are well absorbed after oral atrophic cervical smear.
administration as well as by transdermal
application. Estradiol is metabolized to TIBOLONE
estrone and estriol. All these are conjugated It is a synthetic steroid which combines
and excreted in urine and bile. Synthetic oestrogenic and progestogenic activity with
Glucocorticoids & Sex Hormones 287
weak androgenic activity. It needs to be overstimulation and can also lead to rupture
given continuously without cyclical and bleeding.
progestogen. Clomiphene is mainly used in the treatment
It restores plasma endorphin level in of female infertility due to ovulatory failure and
postmenopausal women and act centrally to is also found useful to aid in vitro fertilization.
affect the thermoregulatory system. It is also used to promote spermatogenesis
in male due to oligospermia and asthenosper-
Adverse effects include weight changes,
mia.
ankle edema, dizziness, headache, abdominal
pain, GI disturbances, vaginal bleeding, TAMOXIFEN
arthralgia, myalgia, migraine, visual
It is a competitive partial agonist inhibitor
disturbances, liver function changes, of estradiol at the estrogen receptor and is
increased facial hair, depression, skin rash used mainly in the treatment of advanced
and pruritus. breast cancer in postmenopausal women. It
It is indicated in vasomotor symptoms is also used in male infertility due to its
in estrogen deficiency and osteoporosis weaker estrogen effect and lesser side effects.
prophylaxis. It is effective on oral administration and
is excreted in bile.
ANTIESTROGENS Adverse effects include hot flushes,
vaginal bleeding, menstrual irregularities,
Also known as estrogen antagonists or anorexia, depression and dermatitis.
ovulation inducing agents. They act by
binding to estrogen receptors.
PROGESTINS
CLOMIPHENE CITRATE Progesterone is naturally secreted by the
It is a triphenyl ethylene compound and corpus luteum and placenta and functions
a competitive partial agonist inhibitor of to maintain pregnancy after conception.
endogenous estrogen. It can produce Their derivatives are of two types, which are
regression of estrogen induced proliferative classified as in table 8.3.3.
endometrium. It can also prolong the luteal
PROGESTERONE
phase in normal menstruating women.
The physiological functions of
Due to its probable direct effect on
progesterone include:
ovaries, it may increase the gonadotrophin
secretion. It also exerts a weak estrogenic • Induction of secretory phase of the
action on endometrium. menstrual cycle.
It is well absorbed after oral • Development of alveolar system of
administration, metabolized and excreted in breasts.
bile and main side effects include hot • Preparation of endometrium for the
flushes, ovarian enlargement and cyst implantation of fertilized ovum for
formation which may be due to further pregnancy.
288 Section 8/ Drugs Acting on Endocrine System
prevent the oxidation of iodide and uptake of iodide by the gland through
iodotyrosyl residue which subsequently competitive inhibition of iodide transport
inhibits the formation of tyrosine residue in mechanism. But it requires higher dose
thyroglobulin and coupling of iodotyrosine which can cause aplastic anaemia and due
residues to T3 and T4. to this major drawback they are not used
clinically.
CARBIMAZOLE
It inhibits oxidation of iodide, inhibits Agents Which Inhibit Hormone
iodination of tyrosine residue and inhibits Release
the coupling of iodotyrosine residue. After Iodine inhibits hormone release. They
oral administration, it is rapidly absorbed inhibit organification and hormone release
and metabolised to methimazole which is and also decrease the size and vascularity
active form and crosses the placental barrier. of hyperplastic gland on regular
Adverse reactions include agranulocytosis, administration. Peak antithyroid affect is
transient leucopenia, arthralgia, nausea, fever, seen in two weeks after which thyrotoxicosis
loss of hair and hepatic damage. may reoccur. It is well absorbed orally and
It is used in hyperthyroidism due to crosses the placental barrier.
Graves’ disease, prior to surgical treatment Adverse effects include angioedema,
of hyperthyroidism i.e., thyroidectomy. It is fever, thrombocytopenia, arthralgia,
also used in the treatment of paroxysmal lymphadenopathy, salivation, sneezing and
tachycardia and intractable congestive swelling of lips and eyelids.
cardiac failure. Iodine is used in thyroid storm,
hyperthyroidism, preoperatively before
Agents Which Inhibit Iodide Trapping thyroidectomy and prophylaxis of endemic
Monovalent anions such as thiocyanates, goitre. Iodine is also useful as antiseptic and
perchlorates and pertechnetate can block the in expectorants.
Thyroid Hormone & Antithyroid Agents 295
The iodinated contrast agents, ipodate concentrated by the thyroid and incorporat-
and iopanic acid are used in the treatment ed into the storage follicles. Beta radiation
of hyperthyroidism. These drugs rapidly penetrates up to 3 to 5 mm into the soft
inhibit the conversion of T4 to T3 in the liver, tissue, they destroy some of the thyroid
kidney, brain and pituitary gland. follicles and produce fibrosis.
Adverse reactions include hypothyroid-
Agents Which Destroy Thyroid Gland ism, thyroid carcinoma, damage to foetal
Tissue thyroid and possibility of genetic damage, so
131
I is the only radioisotope of iodine contraindicated during pregnancy.
used in the treatment of thyrotoxicosis. The Radioactive iodine is indicated in
other isotopes 123I and 125I are used only in hyperthyroidism due to Graves’ disease or
diagnosis. 131I emits gamma and beta radia- toxic nodular goitre and also used as
tions. It is available as sodium solution. palliative therapy after thyroidectomy for
When taken orally, it is rapidly absorbed, papillary carcinoma of thyroid.
This page
intentionally left
blank
a p
p tte r
e r
CChh Hormonal
Pharmacodynamics
8.5
1.4 Contraceptives
(Mode of Action of Drugs)
Hormonal contraceptive are the most this is considered the first day of cycle). The
effective spacing methods of contraception. pill is to be taken everyday at a fixed time,
They are used for reversible suppression of preferably before going to bed at night.
fertility.
PHASED PILLS
ORAL CONTRACEPTIVES This is a combined pill but biphasic or
triphasic in nature e.g. the estrogen level is
The oral hormonal contraceptive can be kept constant but the progestin amount is
classified as in table 8.5.1. low in early phase and increasing in
subsequent phases of menstrual cycle.
COMBINED PILLS
Fifth day to tenth day menstrual cycle
It is a combination of estrogen and (ethinyl estradiol 30 µg + levonorgestrel 50
progestin given together for remarkable µg), eleventh to fifteenth day (ethinyl
efficacy, safety and ease in administration. It estradiol 30 µg + levonorgestrel 75 µg),
has total 21 pills, each pill is given orally for sixteenth to twenty fifth day (ethinyl
21 consecutive days beginning on the 5th day estradiol 30 µg + levonorgestrel 125 µg).
of menstrual cycle (when the bleeding occurs They are supplied in one pack of different
coloured pills starting from fifth day of in 3 month and 400 mg given once in 6
menstrual cycle to twenty-fifth day and next month.
pack can be started after a gap of seven days Some subcutaneous and intrauterine
as in case of combined pills. implants of progesterone have also been
used which are prepared in biodegradable
MINIPILL
polymeric matrices.
It is also known as progestin only pill
(POP). It contains only progestins, which is Mechanism of Action of Oral
given in small amount throughout the men- Contraceptives
strual cycle (without interruption) but because
The oral contraceptives act by the dif-
of lower efficacy rate, it is not much popular.
ferent mechanisms.
Norgestrel (OVRETTE) 0.075 mg • Inhibiting ovulation by blocking the
Norethindrone (MICRONOR) 0.35 mg release of follicle stimulating hormone
POSTCOITAL CONTRACEPTION and luteinising hormone from the
anterior lobe of pituitary gland.
The postcoital (morning after)
• Increasing the thickness of cervical
contraception is recommended within 48
mucus due to progestins and producing
hours after an unprotected intercourse, rape
an unfavourable environment for pen-
or contraceptive failure.
etration of sperm and further conception.
Diethylstilbestrol 5 mg per day is given • Inducing other changes in the uterine
for five days. mucosa which may be unfavourable for
Other regimens used are combination of the implantation of fertilized ovum.
ethinyl estradiol 0.1 mg + levonorgestrel 0.5 to This action is important in minipills
1 mg. Two tablets are taken 12 hours apart and postcoital pills.
within three days of intercourse. Levonorgestrel
0.75 mg (1 tablet) is also used and is taken as Adverse Effects
early as possible (within 72 hrs) and second The most common side effects are nausea,
tablet after 12-24 hours of first tablet. vomiting, headache, dizziness, fatigue, weight
Withdrawal bleeding occur within 3-7 days. gain and breast fullness. The other side effects
which appear after sometime of therapy are
INJECTABLE FORMULATIONS acne, increased body hair, pigmentation of
cheeks, nose and forehead (chloasma).
They are usually given by IM route. They
The other serious side effects include
lead to higher incidence of menstrual
high blood pressure, increased risk of myo-
irregularities and amenorrhoea.
cardial infarction, thromboembolic diseas-
• Norethindrone enanthate es like thrombophlebitis, venous thrombo-
(NORISTERAT) 200 mg given once in sis, cerebral thrombosis.
two months. They were suspected to lead to increased
• Depot medroxyprogesterone acetate risk of cancer of breast and carcinoma of
(DEPOT PROVERA) 150 mg given once cervix and endometrium.
Hormonal Contraceptives 299
This page
intentionally left
blank
Section 9
Chemotherapy
This page
intentionally left
blank
a p
p tte r
e r Sulfonamides,
CChh Pharmacodynamics
Nitrofurans and
9.1
1.4 (Mode of Action of Drugs)
Quinolones
in CSF is higher than other fluoroquinolones, respond well to ofloxacin in vitro. It does not
therefore is preferred drug for meningeal inhibit the cytochrome P450.
infections. It is used in the treatment of
gonorrhoea and typhoid. Genotoxicity has LEVOFLOXACIN
been reported at higher concentration of It is the levoisomer of ofloxacin and
pefloxacin. having better activity than ciprofloxacin and
ofloxacin against S. pneumoniae. It is also
SPARFLOXACIN used in chronic bronchitis, sinusitis,
It is difluorinated quinolone effective pyelonephritis, and other related infections
against gram positive bacteria, anaerobes of soft tissues. Due to high oral
and mycobacteria. It is used in the treatment bioavailability, patient can be shifted from
of pneumonia, chronic bronchitis, sinusitis IV to oral therapy. It can be administered
etc. just once a day regimen as an alternate to
other fluoroquinolones in the treatment of
OFLOXACIN respiratory infections.
It is more potent than ciprofloxacin for
GATIFLOXACIN
gram positive organisms. It also inhibits
Mycobacterium tuberculosis and The antibacterial action of gatifloxacin
Mycobacterium leprae and used as alternative result from inhibition of DNA gyrase and
in multidrug resistant therapeutic regimens. topoisomerase IV. DNA gyrase is an
It is also used in the treatment of chronic essential enzyme that is involved in the
bronchitis and other ENT infections. Also replication, transcription and repair of
used in gonorrhoea, gonococcal urethritis bacterial DNA. Topoisomerase IV is an
and urinary tract infections due to E. coli, K. enzyme known to play a key role in the
pneumoniae, P. mirabilis, Citrobacter diversus partitioning of the chromosomal DNA
or paeruginosa. Mycoplasma pneumoniae, U. during bacterial cell division.
urealyticum are also susceptible. The Gatifloxacin ophthalmic solution is the
anaerobes like Bacteroides fragilis, Clostridium first FDA approved fourth generation
perfringens, B. intermedium, C. welchii, fluoroquinolone and is available in Indian
Peptococcus niger, Peptostreptococcus sp. market.
r
e r Tetracyclines,
a p
p tte
CChh Chloramphenicol
Pharmacodynamics
9.2
1.4 and Chemotherapy
(Mode of Action of Drugs)
of UTI
ducreyi, granuloma inguinale caused by binding reversibly to the 50S submit of the
Calymmatobacterium granulomatis. bacterial ribosome. It inhibits the peptidyl
As an alternative drug in the treatment transferase step of protein synthesis. It is
of gonorrhoea and syphilis in patients bacteriostatic broad-spectrum antibiotic
allergic to penicillin. active against gram positive and negative
4. Dermatological infections: Acne organisms, Rickettsia, the Chlamydia of the
vulgaris, when antibiotic therapy is psittacosis, lymphogranuloma group and
considered necessary. Mycoplasma pneumoniae. The other organisms
5. Ophthalmic infections: Due to suscep- sensitive to chloramphenicol are E. coli, K.
tible strains of N. gonorrhoeae, staphy- pneumoniae, Shigella, and certain strains of
lococci, H. influenzae and in the treat- Brucella, Pasteurella, Proteus and Vibrio comma.
ment of trachoma. It exerts bactericidal against H. influenzae,
6. Prophylaxis and treatment of Traveller’s Strep. pneumoniae and N. meningitidis.
diarrhoea.
7. Miscellaneous infections caused by Pharmacokinetics
susceptible strains of bacteria causing Chloramphenicol is completely absorbed
psittacosis, cholera, melioidosis, lep- after oral administration, bound to plasma
tospirosis, brucellosis, bartonellosis, protein (approximately 60%) and widely
plague, tularemia, Campylobacter fetus distributed in body. It crosses the blood-brain
infection, rickettsial infections including and placental barrier and shows its presence
typhus and Q fever, relapsing fever due in CSF, bile and milk. It is conjugated with
to Borrelia recurrentis and actinomyco- glucuronic acid in liver and excreted in urine.
sis in penicillin allergic patients. Small amount is excreted in urine in
unchanged form.
9. As an adjunct in acute intestinal
amoebiasis.
Adverse Effects
10. Prophylaxis of malaria due to P.
Allergic reaction includes skin rashes,
falciparum.
drug fever, dermatitis, angioneurotic
CHLORAMPHENICOL edema.
Bone marrow depression includes
It is a broad spectrum antibiotic originally aplastic anaemia, leukopenia, agranulocy-
derived from Streptomyces venezuelae and later tosis, thrombocytopenia.
on became the first completely synthetic
Gray baby syndrome: Premature babies
antibiotic. It is used as palmitate and sodium
develop vomiting, hypothermia, abdominal
succinate salt in given dosage.
distension, shallow irregular respiration and
Dose: 250-500 mg QID oral, 1-2 g IM further leading to gray cyanosis, vascular
injection, 0.5-1.0% topical (eye ointment/ collapse, shock and death.
drops/applicap and ear drops). CNS toxicity includes headache, mental
Chloramphenicol is a potent inhibitor of confusion, internal ophthalmoplegia, periph-
microbial protein synthesis. It acts by eral neuritis, depression, optical neuritis.
314 Section 9/ Chemotherapy
Other adverse effects include superin- antagonizes the action of nalidixic acid and
fection, hepatotoxicity and typhoid shock. its activity is enhanced by lower pH. After
oral administration it is rapidly and
Therapeutic Uses completely absorbed from GIT,
Because of bone marrow toxicity of metabolized in liver and less than half is
chloramphenicol, its use is restricted to the excreted unchanged in urine.
treatment of infection caused by S. typhi and It is used exclusively for urinary tract
paratyphi (treatment of typhoid fever). infections. The side effects include nausea,
Other indications in which chlorampheni- vomiting, diarrhoea, anorexia, leukopenia,
col can be used are H. influenzae meningitis, haemolytic anaemia, jaundice, dizziness and
urinary tract infections, anaerobic infections headache. On chronic use can lead to periph-
caused by Bacteroides fragilis and locally in eye eral neuritis and interstitial pulmonary fi-
and external ear infections. brosis.
This page
intentionally left
blank
a p
p tte r
e r
CChh Beta Lactam
Pharmacodynamics
9.3
1.4 Antibiotics
(Mode of Action of Drugs)
portion is rapidly excreted by the kidney rash, pruritus, serum sickness like syndrome,
mainly by tubular secretion and small eosinophilia, angioneurotic edema, asthma,
amounts appear in bile, saliva, and milk. haematuria, albuminuria, haemolytic
anemia, granulocytopenia and anaphylaxis.
Adverse Effects To avoid that, a skin test using a 10,000
The penicillins are nontoxic and U of benzyl penicillin per ml is to be done
remarkably safe drug. The hypersensitivity and if any local edema or wheal occurs
reaction leading to anaphylaxis is only major within 15 minutes, it is considered to be as a
problem which is seen in approximately 5 positive test and in that person penicillin
to 10% of the patients taking penicillin. should not be used.
The minor adverse effects include
nausea, vomiting, pain and inflammation at Therapeutic Uses
the site of injection after intramuscular Penicillin G is the drug of choice for the
administration has been reported. After following categories of infection:
intrathecal administration (which is a
• Dental infections: Penicillin G is
contraindication) it may lead to convulsions, effective in majority of infections
arachnoiditis and encephalopathy. caused by both aerobic and anaerobic
The major side effect is allergic reactions and bacteria in dentistry. It is used in acute
anaphylaxis which is characterized by skin suppurative pulpits, pericoronitis, oral
Beta Lactam Antibiotics 319
This page
intentionally left
blank
a p
p tte r
e r
CChh Aminoglycosides
Pharmacodynamics
9.4
1.4
Antibiotics
(Mode of Action of Drugs)
This page
intentionally left
blank
a p
p tte r
e r Macrolide and
CChh Pharmacodynamics
Polypeptide
9.5
1.4 (Mode of Action of Drugs)
Antibiotics
BACITRACIN TYROTHRICIN
This antibiotic is obtained from Bacillus It is obtained from Bacillus bravis and
subtilis. It is effective against gram positive effective against gram positive and some
(cocci and bacilli), Neisseria and H. influenzae. gram negative organisms. It acts on bacte-
It is used only topically as antibacterial pow- rial cell membrane causing leakage and
der, skin and eye ointment and acts by inhib- uncoupling of oxidative phosphorylation.
iting the cell wall synthesis. It is bactericidal. Used topically as skin cream and solution.
This page
intentionally left
blank
a p
p tte r
e r
CChh Pharmacodynamics
Antiviral Agents
9.6
1.4 (Mode of Action of Drugs)
Viruses have no cell wall and made up of It prevents the replication of DNA
nucleic acid core enclosed in a protein coat viruses and its clinical use is limited to
which consists of identical subunits. herpes simplex keratitis.
Viruses are of two types, DNA Toxicity includes alopecia, leucopenia,
(deoxyribonucleic acid) viruses and RNA thrombocytopenia and liver damage.
(ribonucleic acid) viruses. DNA viruses are
It is used in herpes simplex keratocon-
herpes simplex, small pox, hepatitis B,
junctivitis in 0.1 to 0.5% solution/eye oint-
varicellazoster etc. and RNA viruses are
ment applied one to two hourly.
rabies, measles, dengue, rubella, yellow
fever, poliomyelitis and HIV etc. ACYCLOVIR
In viral infections, replication of viruses Acyclovir is a synthetic purine
are at peak, at or before the manifestation nucleoside analogue with in vitro and in
of clinical symptoms. So, the treatment vivo inhibitory activity against human
generally depends either on early initiation herpes viruses.
of therapy or prevention of infection i.e.
Acyclovir triphosphate interferes with
chemoprophylaxis.
the viral DNA polymerase and inhibits
The various antiviral agents are viral DNA replication with resultant chain
classified as under (the doses for specific termination following its incorporation into
infections is given in text) in table 9.6.1. the viral DNA.
Acyclovir is only partially (20%)
ANTI-HERPES AGENTS absorbed from the gut.
Most of the drug is excreted un-
IDOXURIDINE changed by the kidney by tubular secre-
It is chemically related to thymidine and tion and glomerular filtration.9-
acts by competing with it in the Carboxymethoxymethylguanine is the
synthesis of DNA and ultimately only significant metabolite of acyclovir re-
preventing the utilization of thymidine. covered from the urine.
338 Section 9/ Chemotherapy
for 5 days. For herpes zoster infection 1 g TDS HIV infected patients. However, it does not
for 7 days is required. Dose of 2 g QID has protect individuals from contracting HIV
also been used in preventing cytomegalovirus infection even if started soon after
(CMV) disease after organ transplantation. inoculation. Thus, it can not be used as a
prophylactic in health care workers who
GANCICLOVIR are accidently exposed to HIV infection.
It is an acyclic guanosine analog which
require triphosphorylation for activation LAMIVUDINE
prior to inhibition of viral DNA polymerase. It is synthetic nucleoside analogue
It is active against cytomegalovirus (CMV), active against HIV. It is phosphorylated to
varicellazoster virus, Epstein-Barr virus and its active 5’-triphosphate metabolite (L-TP).
human herpes virus-8. It is almost 100 times Lamivudine triphosphate inhibit HIV
more potent than acyclovir against CMV. reverse transcription via viral DNA chain
Its use is restricted in severe CMV termination.
infections in immunocompromised especially It is rapidly absorbed after oral
CMV retinitis, CMV pneumonia or colitis. administration. The major part of the dose
is excreted in unchanged form in urine.
ANTI-RETROVIRAL AGENTS Adverse effects include pancreatitis
with symptoms of nausea, vomiting, severe
ZIDOVUDINE abdominal or stomach pain and is more
It is a thymidine analogue. After frequent in children. Paresthesia and
phosphorylation in body zidovudine peripheral neuropathy with tingling,
triphosphate selectively inhibits viral burning, numbness or pain in the hands
reverse transcriptase i.e. RNA dependent and feet are also more frequent in children.
DNA polymerase. It is effective against Lamivudine may be used prophylactically
retrovirus only. in health care workers at risk of acquiring HIV
It has rapid oral absorption and 65% infection after occupational exposure to the
bioavailability. It can cross the placenta. It virus and in combination with zidovudine for
is eliminated primarily by renal excretion treatment of HIV infection.
following glucuronidation in the liver. It is to be given in a dose of 150 mg BD
Adverse effects include anorexia, nau- in combination with zidovudine (in
sea, headache, abdominal pain, myalgia, children 4 mg/kg BD, max 150 mg BD).
anaemia insomnia, neutropenia, convul-
sions and encephalopathy. STAVUDINE
It is used in asymptomatic and It is synthetic thymidine nucleoside
symptomatic HIV disease in a dose range analogue, active against HIV.
of 200 mg six times a day on initial basis Stavudine rapidly enters cells by diffu-
and thereafter upto 500 to 1500 mg daily sion. Stavudine triphosphate acts as a com-
in four to five divided doses. petitive inhibitor of reverse transcriptase
It decreases the rate of clinical with respect to deoxythmidine triphos-
progression and prolongs the survival in phate and incorporation causes termina-
Antiviral Agents 341
tion of DNA chain elongation. It inhibits life (40-55 hrs) and administered once daily.
replication of HIV in human cells. It is metabolised by CYP3A4 and CYP2B6
It is rapidly absorbed after oral to inactive hydroxylated metabolites and
administration. Approximately 40 percent of eliminated in feces. It is used in
stavudine appears unchanged in the urine combination with other retroviral drugs for
through tubular secretion and glomerular the treatment of HIV infection in a dose of
filtration. Nonrenal clearance mechanisms 600 mg once daily.
account for about 50 percent of elimination of Adverse effects include drowsiness,
a dose. insomnia, dizziness, agitation, confusion,
Adverse effects include peripheral depression, delusions, vomiting, diarrhoea,
neuropathy which is a major clinical tox- crystalluria, elevation in liver enzyme and
icity. Other side effects include pancreati- total serum cholesterol. Serious side effect
tis, anaemia, arthralgia, headache, fever, is skin rash including Stevens Johnson
rash, nausea, vomiting, diarrhoea, elevated syndrome as in case of nevirapine.
transaminase values.
It is indicated in the treatment of INDINAVIR
advanced HIV infection in a dose range 30 It is an inhibitor of the enzyme HIV
to 40 mg BD. protease which is required for the pro-
teolytic cleavage of the viral polyprotein
NEVIRAPINE
precursors into the individual functional
It is non-nucleotide reverse proteins found in infectious HIV.
transcriptase inhibitor extensively
Indinavir binds to the protease active
metabolized by the CYP3A P450 isoform to
site and inhibits the activity of the
hydroxylated metabolites and excreted in
enzyme HIV protease preventing
urine. It is indicated in combination with
cleavage of the viral polyproteins resulting
other anti-retroviral agents in a dose of 200
in the formation of immature noninfectious
mg OD-BD for first 14 days. It is also been
shown to be effective in the prevention of viral particles.
transmission of HIV from mother to new Adverse effects include nausea,
born. vomiting, diarrhoea, abdominal discomfort,
The serious side effect is life threaten- dry mouth, taste disturbances; headache,
ing rash including Stevens Johnson syn- dizziness, insomnia; myalgia, rash, pruritus,
drome and rarely toxic epidermal dry skin, hyperpigmentation, nephrolithiasis,
necrolysis. Other side effects are hepatitis, dysuria, haematuria, crystalluria, proteinuria;
nausea, vomiting, fatigue, fever, headache, elevated liver enzymes and bilirubin,
hypersensitivity reactions, urticaria, an- hepatitis; neutropenia, haemolytic anaemia
gioedema and anaphylactic shock. and hyperglycaemia etc.
It is indicated in treatment of HIV
EFAVIRENZ infection and is used in combination with
It is also an non-nucleotide reverse other anti-retroviral agents in a dose 800
transcriptase inhibitor having long half- mg every eight hourly.
342 Section 9/ Chemotherapy
a p
p tte r
e r
CChh Pharmacodynamics
Antifungal Agents
9.7
1.4 (Mode of Action of Drugs)
It is well tolerated but some patients of superficial and deep seated fungal
reported skin reactions including burning, infections.
stinging or redness. It impairs the synthesis of ergosterol
KETOCONAZOLE in fungi.
It is orally effective broad spectrum After oral administration, it is widely
imidazole antifungal drug. It is useful in both distributed in the body. CSF and saliva
dermatophytosis and deep mycosis. Oral contain negligible amounts of the drug. It
absorption is facilitated by gastric acidity. It is is extensively metabolised in liver and the
highly protein bound, metabolised in liver and metabolites are excreted in urine.
metabolites are excreted in urine and faeces. It is indicated in dermatophytoses, tinea
Its spectrum is similar to that of miconazole versicolor, onychomycoses, oropharyngeal
and is more active against Coccidioides. candidiasis, cutaneous candidiasis, chronic
Adverse effects include gastric mucocutaneous candidiasis, oculomycoses;
irritation, nausea, vomiting, headache, systemic mycoses like cryptococcosis, candidi-
paresthesia, rash, hair loss, allergic reaction asis and aspergillosis; subcutaneous mycoses
and gynecomastia. like sporotrichosis and chromomycosis.
MICONAZOLE Adverse effects include nausea,
vomiting, skin rash, depression, dizziness,
It has broad spectrum antifungal and
vertigo and loss of libido, hypokalemia and
antibacterial activity and is effective against
hypertriglyceridemia.
Cryptococcus, Blastomyces, dermatophytes,
Microsporum, Coccidioides and Candida. FLUCONAZOLE
Used topically as ointment, lotion, gel, ear
It has broad range of antifungal
drop and vaginal gel. Adverse effects
activity. It is well absorbed orally (94%). It
include fever, chills, allergic reaction and
is primarily excreted unchanged in urine.
even anaphylaxis.
Fungicidal concentration is achieved in
It is indicated in vulvovaginal nail, saliva and vagina and also penetrates
candidiasis, Trichomonas vaginitis, brain. Adverse effects include nausea,
otomycosis, tinea and Pityriasis versicolor. vomiting, headache, abdominal pain,
ECONAZOLE diarrhea and skin rash.
It is similar to clotrimazole and is It is indicated in mucosal candidiasis,
effective in dermatophytosis, otomycosis systemic candidiasis, crypttococcosis,
and oral thrush. It causes local irritation. prophylaxis of fungal infections following
cytotoxic chemotherapy or radiotherapy;
ITRACONAZOLE maintenance to prevent relapse of
It is a triazole antifungal drug closely cryptococcal meningitis in patients with
related to ketoconazole and is meant for AIDS; sporotrichosis, histoplasmosis and
oral use. It is very effective in a wide range vaginal candidiasis.
Antifungal Agents 347
This page
intentionally left
blank
app t
t eerr
CChha Pharmacodynamics
Antimalarial Agents
9.8
1.4 (Mode of Action of Drugs)
Human malaria is caused by four species has antiinflammatory and local irritant
of Plasmodium namely Plasmodium properties.
falciparum, P. vivax, P. malariae and P. ovale. It probably influences haemoglobin
P. vivax is mainly responsible for most of degradation by parasitic lysosomes by
the infections (70%) which results in raising intravesicular pH in malarial
benign tertian malaria. In P. falciparum parasite cells. It also interferes with
and P. vivax infections, the patient has fever synthesis of nucleoproteins by the parasite.
with rigors every third day and termed as It is well absorbed (about 90%) from
tertian. The other two, P. ovale and P. gastrointestinal tract. After IM injection
malariae are mild in nature in which fever absorption is rapid. Elimination is very slow
develops every fourth day and termed as and it may persist in tissue for months or
benign quartan. Symptoms and years after discontinuation of therapy
complications in P. falciparum malaria are Adverse reactions include nausea,
more severe than P. vivax malaria. vomiting, epigastric distress, headache,
anorexia, difficulty in accommodation and
The antimalarial drugs can be classified
chronic therapy may cause loss of vision
as in table 9.8.1.
due to retinal damage. On prolonged use
it may also cause skin rash, photoallergy,
4-AMINOQUINOLINE DERIVATIVES myopathy, loss of hearing, greying of hair
and mental disturbances.
CHLOROQUINE Parenteral administration may cause
Chloroquine is a 4-aminoquinoline hypotension, arrhythmia and CNS toxicity.
antimalarial agent used for the suppression
and clinical cure of malaria. It is an Therapeutic Uses
excellent erythrocytic schizontocide. It It is a drug of choice for clinical cure
does not prevent relapse in P. vivax and P. and suppressive prophylaxis of acute ma-
ovale malaria. It has no effect on pre and laria but not for the resistant cases of P.
exoerythrocytic phase of the parasite. It also falciparum. It can be safely used in preg-
350 Section 9/ Chemotherapy
cated falciparum malaria but is not recom- It is absorbed after oral administration
mended for prophylaxis. and presence of food may enhance the
absorption. It is extensively metabolised in
8-AMINOQUINOLINES liver and primarily secreted in bile.
Adverse reactions include nausea,
PRIMAQUINE vomiting, dizziness, diarrhoea, abdominal
Primaquine, a 8-aminoquinoline, is a pain, anxiety disorder, sinus bradycardia,
poor erythrocytic schizontocide. It is ataxia. It is reported that mefloquine is
highly effective against gametocytes and teratogenic in nature so should not be given
exoerythrocytic stages. in first trimester of pregnancy.
It disrupts the parasites mitochondria It is used in multiresistant P. falciparum
and binds to native DNA, resulting in malaria. It is not useful in complicated/
inhibition of gametocytes and exoeryth- cerebral malaria.
rocytic forms.
BULAQUINE
Adverse effects include nausea, vom-
Bulaquine is a mixture of 3{-1-4-6(-
iting, weakness, abdominal pain and
methoxy-8-quinolinyl) aminopentyl}
methaemoglobinaemia. Haemolytic
ethylidenedihydro-2-(3H) furanone and it’s
anaemia in patients with G-6-PD defi-
tautomers.
ciency. Passage of dark urine is indica-
tion of haemolysis. In larger dose it can The exact action is not fully eluci-
cause leucopenia. dated. However, bulaquine inhibits
protein synthesis in protozoa and
It is effective in radical cure of P. vivax
indirectly inhibits polymerisation of
and P. ovale malaria.
amino acids by the plasmodia. Treat-
ment prevents emergence of either
QUINOLINE-METHANOL DERIVATIVES primary or secondary liver stage para-
sitaemia and the disease.
MEFLOQUINE
Since bulaquine is a tissue schizonto-
It is a highly effective erythrocytic cide it is effective against the dormant
schizonticide especially against mature hepatic stages of P. vivax only. It has to be
trophozoite and schizont forms of malarial combined with chloroquine which acts on
parasite. the erythrocytic stage of the plasmodium.
It behaves like quinine in many ways For convenience bulaquine is available
but does not inhibit haem polymerase. It along with chloroquine as an anti-relapse
probably acts by forming toxic complexes treatment pack.
with free haem that damages membranes It is an erythrocytic schizontocide used
and interacts with other plasmodial in the treatment and prevention of P. vivax
components. malaria relapse.
352 Section 9/ Chemotherapy
dihydrofolate reductase. It is slow acting isolated from plant Artemisia annua, active
erythrocytic schizontocide. It can eliminate against P. falciparum resistant strains.
preerythrocytic phase of P. falciparum and the
secondary tissue phase of P. vivax. ARTESUNATE
Absorption of pyrimethamine from GIT is It is a new, potent antimalarial drug
slow but good. It is concentrated in liver, and is a water soluble synthetic analogue
spleen, kidney and lungs. It is metabolised of artemisinin.
and excreted in urine. If it is employed alone
It is concentrated in parasitized
development of resistance occurs fast.
Pyrimethamine alone is used for prophylaxis erythrocytes, where it is activated by
occasionally. parasite haem, generating free radicals.
Hence it causes increase in oxidant
PYRIMETHAMINE-SULFONAMIDE stress on the infected red cells pro-
COMBINATION moting cytotoxicity and death of para-
Ultra long acting sulfonamides in sites. It rapidly clears parasitaemia,
combination with pyrimethamine are used. faster than any other antimalarial drug.
The effect is supraadditive due to sequential After administration it is rapidly
block. It may be employed as a clinical absorbed and distributed in tissue e.g. liver,
curative. Another advantage of the drug intestine and kidneys. It is metabolised in
combination is that the development of liver and converted to active metabolite
resistance is retarded. dihydroartemisinin.
Its action is based on differential Adverse effects include nausea, vom-
requirement between host and parasite for iting, dizziness, anorexia, gastrointestinal
nucleic acid precursors involved in growth disturbances and convulsions.
as it selectively inhibits plasmodial
dihydrofolate reductase. It is indicated in acute attack of multi-
drug resistant P. falciparum malaria where
It is very well absorbed after oral use
quinine is not effective.
and is metabolised in the liver.
Pyrimethamine is a safe drug and cause ARTETHER
only nausea, vomiting, skin reaction e.g. skin It is an ethyl ether derivative of
rash, pruritus and higher dose can cause dihydroartemisinin in sterile arachis oil.
megaloblastic anaemia and granulocytopenia.
A racemic mixture of a, β-artether
The combination is indicated in chloro- (30:70 ratio) has greater solubility and
quine resistant malaria and prophylaxis. Py- stability than artemisinin and is more
rimethamine-sulfadiazine combination is cost-effective.
used for treatment of toxoplasmosis.
It shows rapid schizonticidal action and
brings about quick clinical improvement in
ARTEMISININ DERIVATIVES
falciparum malaria with low recrudescence
Artemisinin is the active plant principle rate. It has some gametocidal action too.
354 Section 9/ Chemotherapy
a p
p tte r
e r Antiamoebic and
CChh Pharmacodynamics
other Antiprotozoal
9.9
1.4 (Mode of Action of Drugs)
Drugs
Side effects include nausea, epigastric having longer plasma half life and
discomfort, metallic taste, furred tongue, administered orally as single dose. It is used
skin rash, urticaria and leucopenia. in intestinal amoebiasis, hepatic amoebiasis,
It is indicated in giardiasis, amoebic liver giardiasis and trichomonal vaginitis.
abscess, intestinal amoebiasis, trichomoniasis, Side effects include nausea, anorexia,
ulcerative gingivitis, treatment and epigastric pain, diarrhoea, skin rash,
prophylaxis of anaerobic infections. urticaria, headache and leucopenia.
It is also used in combination with
diloxanide furoate and dicyclomine to ORNIDAZOLE
eradicate intestinal and extraintestinal It is a 5-nitroimidazole derivative with
amoebiasis and also asymptomatic cyst the same antimicrobial profile as that of
passers.
metronidazole, except that it has a much
SECNIDAZOLE longer half-life.
It is 5-nitroimidazole derivative with Readily absorbed from the GI tract,
properties similar to metronidazole and widely distributed in body tissues and fluids
Antiamoebic and other Antiprotozoal Drugs 357
including the CSF and metabolised in the liver, it is used in the treatment of hepatic
liver. It is excreted mainly in the urine as amoebiasis concurrently or immediately
conjugates and to a lesser extent in faeces. after metronidazole for complete cure. It is
Adverse effects include nausea, skin not effective in amoebic dysentery and in
rash, abdominal pain and headache. cyst passers.
It is indicated in giardiasis, severe EMETINE DERIVATIVES
hepatic and intestinal amoebiasis,
Emetine and dehydroemetine are
trichomoniasis of urogenital tract and natural alkaloid obtained from Cephaelis
bacterial vaginosis. ipecacuanha and synthetic analog respective-
ly. They are effective against tissue tropho-
8-HYDROXYQUINOLINES zoites of E. histolytica. It has no effect on cysts
Diiodohydroxyquinoline, iodochloro- but effective in amoebic liver abscess also. It
hydroxyquin are effective against E. acts by inhibiting protein synthesis by
histolytica, Trichomonas and Giardia. arresting intraribosome translocation of
Diiodohydroxyquinoline is directly tRNA-amino acid complex. Dehydroemet-
ine is less toxic than emetine and very effec-
amoebicidal. It has activity against motile
tive drug for tissue amoebiasis. It is more rap-
and cystic forms. It kills cyst forming
idly eliminated from the body than
trophozoites in intestine but has no tissue
emetine.
amoebicidal action. It is ineffective in
extraintestinal amoebiasis. It is also effective Adverse effects include nausea,
vomiting, diarrhoea, myalgias and because
in cyst passing patients.
of its serious side effects including cardiac
Diiodohydroxyquinoline is partly and arrhythmia, CHF and hypotension, they
irregularly absorbed from the GI tract. have been almost completely replaced by
Metabolised in liver and excreted in urine metronidazole.
as glucuronide and sulfate conjugates.
Adverse effects include nausea, diar- DILOXANIDE FUROATE
rhoea, abdominal discomfort, headache It is a dichloroacetamide derivative,
and goitre (so contraindicated in patients very effective luminal amoebicide. Used
with intolerance to iodine). Prolonged use alone for cyst passers or usually with
of iodochlorohydroxyquin causes subacute metronidazole for other forms of amoebic
myelooptic neuropathy (SMON). They are infections.
indicated in giardiasis, trichomonas It directly kills trophozoites. It has no
vaginitis, intestinal amoebiasis and amoe- antibacterial activity.
bic colitis. After oral administration it is rapidly
absorbed and excreted rapidly in urine as
CHLOROQUINE glucuronide conjugate.
It kills trophozoites of E. histolytica and Adverse effects include flatulence,
because of its selective concentration in nausea, vomiting, anorexia and pruritus.
358 Section 9/ Chemotherapy
SURAMIN NIFURTIMOX
It is a sulfated napthylamine and used Chemically it is nitrofuran, used for
American trypanosomiasis which is
as first line therapy for early
commonly known as ‘Chagas disease.’
hemolymphatic African trypanosomiasis
After oral administration, it is well
(caused by T. brucei gambiense). It has very absorbed and plasma half life is about three
tight protein binding and having short hours.
initial half life but terminal half life is about
50 days and is excreted by kidney. It is also Adverse effects include nausea,
vomiting, fever, rash, abdominal pain,
used for chemoprophylaxis against African
neuropathies and seizures.
trypanosomiasis.
Adverse effects include nausea, TRICHOMONIASIS
vomiting, fatigue, dermatitis, fever,
photophobia, haemolytic anaemia, It is caused by Trichomonas vaginalis and is
albuminuria and hematuria. mainly associated with vulvovaginitis
which is characterized by greenish yellow
MELARSOPROL and cheesy vaginal discharge.
Chemically it is trivalent arsenical used The various agents used in trichomo-
for advanced CNS African trypanosomiasis. niasis are metronidazole, tinidazole and
It is administered IV in propylene glycol and secnidazole which are already described
after administration it is rapidly excreted. It earlier. They produce 100% cure.
is highly toxic and used only in advanced Other protozoal infection is giardiasis
trypanosomiasis when no alternative is there. which is caused by Giardia lamblia and the
Adverse effects include vomiting, drug of choice in its treatment are
fever, abdominal pain, renal and cardiac imidazole derivatives.
This page
intentionally left
blank
a p
p tte r
e r
CChh Pharmacodynamics
Anthelmintic Agents
9.10
1.4 (Mode of Action of Drugs)
Anthelmintic agents are used to eradicate Poorly absorbed from the GI tract, oral
(either kill or expel) the infesting helminths. bioavailability being enhanced when given
The important anthelmintic agents with a fatty meal (up to 5 fold). Its active
along with their specific uses and dosage sulphoxide metabolite is widely distributed
are listed in table 9.10.1. throughout the body and is excreted in
urine.
MEBENDAZOLE Adverse effects include nausea,
It is a synthetic benzimidazole having vomiting, epigastric distress, abnormal
a wide spectrum of anthelmintic activity. LFTs, reversible alopecia.
After administration it is poorly absorbed
and approximately 90 percent of the drug THIABENDAZOLE
is passed in faeces. Complete clearance of Apart from anthelmintic property, thia-
the parasites from the GIT may take up to bendazole also possesses antiinflammatory,
three days. analgesic and antipyretic actions. It also in-
Mebendazole binds to microtubular hibits development of eggs of worms and
β tubulin’ of parasite and inhibits
protein ‘β kills the larvae.
its polymerization, thus irreversibly It is rapidly absorbed, metabolised by
impairing glucose uptake. hydroxylation and conjugation to inactive
Adverse effects include nausea, metabolites and excreted through kidney.
diarrhoea, abdominal pain. Alopecia and Adverse effects include nausea, vomiting,
granulocytopenia may occur at high skin rash, anorexia, giddiness, abdominal
doses. pain, diarrhoea, fever and headache.
ALBENDAZOLE LEVAMISOLE
Congener of mebendazole. It is given It is a synthetic imidazothiazole
only as single dose. derivative and is highly effective in
362 Section 9/ Chemotherapy
in liver and excreted in urine. It can be Ivermectin binds selectively and with
safely used in pregnancy. high affinity to glutamate gated chloride
Adverse effects include nausea, ion channels in invertebrate nerve and
vomiting, epigastric distress, skin rash, muscle cells. This leads to an increase in
urticaria, headache and seizures. the permeability of cell membrane to
PYRANTEL PAMOATE chloride ions with hyperpolarization of
nerve of muscle cell, resulting in paralysis
It is a broad spectrum anthelmintic effective
in pinworm, ascariasis and hook worm and death of the parasite.
infestation. It exerts its action by producing Following the oral administration of
persistent nicotinic receptor activation which ivermectin, peak plasma concentration is
results in spastic paralysis of worms. achieved in four hours. Ivermectin is
It is poorly absorbed from GIT and is absorbed well on an empty stomach. The
active against luminal organisms. It is bioavailability is 50 to 60%. It is mainly
excreted in urine as metabolites and in metabolized in the liver and the tissue
unchanged form. Adverse reactions concentration is maximum in liver and fat.
include rash, nausea, vomiting, headache,
Ivermectin and its metabolites are excreted
dizziness, anorexia and elevation of SGOT
levels. mainly in faeces.
Adverse effects include nausea,
DIETHYLCARBAMAZINE
vomiting, abdominal pain, constipation and
It is the drug of choice for filariasis. It is fatigue.
effective against W. malayi, W. bancrofti, Loa
loa and Onchocerca volvulus. It is mainly indicated in scabies,
ascariasis trichuriasis, strongyloidiasis,
It has a dual action. Hyperpolarization
effect of piperazine moiety causes enterobiasis, filariasis, onchocerciasis (River
paralysis of the worms and alteration in blindness) and elephantiasis. It is drug of
microfilarial surface membrane makes choice for onchocerciasis producing long
them susceptible to destruction by host lasting reduction in microfilaria without
defence mechanism. affecting adult worm.
It is absorbed after oral administration,
distributed all over body, metabolized in PRAZIQUANTEL
liver and excreted in urine. Effective against schistosomes, other
Adverse effects include anorexia, trematodes, cestodes and their larval forms
nausea, vomiting, skin rash, urticaria, but not against nematodes.
fatigue, dizziness and headache.
It causes spastic paralysis of worms
It is indicated in filariasis and due to leakage of intracellular calcium
tropical eosinophilia.
from membranes. At high concentration
IVERMECTIN it causes vacuolization of tegument and
Semisynthetic derivative of drug release of contents of worms and their
obtained from Streptomyces avermitilis. destruction by host defence mechanism.
364 Section 9/ Chemotherapy
SURAMIN EFLORNITHINE
It is a sulfated napthylamine and used in It is an inhibitor of ornithine
first line therapy for early hemolymphatic decarboxylase and is used as second
African trypanosomiasis. (caused by T. brucei therapy for advanced CNS African
gambiense). It is very tight protein binding and trypanosomiasis. After oral or intravenous
having short initial half life but terminal half administration, peak plasma level reached
life is about 50 days and is excreted by kidney. rapidly and elimination half life is
It is also used for chemoprophylaxis against approximately 3 hours.
African trypanosomiasis. Adverse effects It is effective against advanced T. brucei
include nausea, vomiting, fatigue, dermatitis, gambiense infection. Adverse effect includes
fever, photophobia, haemolytic anaemia, vomiting, diarrhoea, leukopenia, thrombocy-
albuminuria and hematuria. topenia, anemia and seizures.
a p
p tte r
e r
CChha Chemotherapy of
Pharmacodynamics
9.11
1.4 Tuberculosis
(Mode of Action of Drugs)
KANAMYCIN RIFAPENTINE
It is used in the treatment of It is an analog of rifampicin active against
tuberculosis caused by streptomycin M. tuberculosis and M. avium. It inhibits bac-
resistant strains but since agents with lesser terial RNA polymerase and it is a potent
toxicity e.g. capreomycin and amikacin are inducer of cytochrome P450 enzymes.
available, its use is obsolete. It is indicated in the treatment of tu-
The pharmacology of quinolones e.g. berculosis caused by rifampicin susceptible
ciprofloxacin and ofloxacin is discussed in strains.
a p
p tte r
e r
CChha Pharmacodynamics
Chemotherapy of
9.12 (Mode of Action of Drugs)
Leprosy
Leprosy is caused by Mycobacterium leprae. (PABA) incorporation into folic acid (in-
The various drugs used in the treatment of hibition of folate synthesis). In large
leprosy are classified as in table 9.12.1. proportion of Mycobacterium leprae infec-
tions e.g. in lepromatous leprosy,
SULFONES resistance can develop, so combination of
dapsone, rifampicin and clofazimine is
DAPSONE used in initial therapy.
It is diamino diphenyl sulfone (DDS), After oral administration, it is
chemically related to sulfonamides, have completely absorbed and is concentrated in
been used effectively in the long term treat- lepromatous skin, liver, kidney and muscles.
ment of leprosy. Its mechanism of action It is metabolized in liver and excreted in
is same as that of sulfonamides i.e. inhi- urine as glucuronic acid and sulfate
bition of paraamino benzoic acid conjugates.
Cancer is a disease of cells characterized cells or modify their growth. The various
by a shift in the control mechanism which anticancer agents are classified according
govern cell proliferation and differentiation to their mode of action as in table 9.13.1.
and the anticancer agents either kill cancer
Table 9.13.1: Classification of anticancer agents.
I. Alkylating agents
Cyclophosphamide (CYCLOXAN) 2-3 mg/kg/day oral; 10-15 mg/kg IV every 7-10 days
Mesna (UROMITEXAN) 20% of a dose of anticancer agent IV
Chlorambucil (LEUKERAN) 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily
for maintenance
Busulfan (MYLERAN) 4-8 mg/day, 1-3 mg/day for maintenance
Lomustine (LUSTIN) 120-130 mg/m2 BSA single dose orally every 6
weeks
Thio-TEPA (THIOTEPA) 0.3-0.4 mg/kg IV every 1-4 week interval
II. Antimetabolites
Methotrexate (ONCOTRAX) 15-30 daily for 5 days orally repeat after one week
or 20-40 mg/m2 BSA IM/IV twice weekly.
6-Mercaptopurine (ZYPURIN) 2.5 mg/kg daily
5-Fluorouracil (FLURACIL) 12 mg/kg OD for 4 successive days IV, 10-15 mg/
kg/week maintenance
Cytarabine (Cytosine arabinoside; CYTABIN) 1.5-3.0 mg/kg IV BD for 5-10 days
III. Cytotoxic antibiotics
Dactinomycin (Actinomycin-D) (COSMEGEN) 15 µg/kg IV daily for 5 days
Doxorubicin (ONCODRIA) 60-75 mg/m2 BSA every 3 wks slow IV
Bleomycin (ONCOBLEO) 30 mg twice weekly IV/IM
Mitomycin-C (MITODUS) 2-10 mg/m2 BSA IV twice weekly
Contd.…
372 Section 9/ Chemotherapy
…Contd.
IV. Vinca alkaloids
Vincristine (Oncovin; BIOCRISTINE) 1.5 mg/m2 BSA IV weekly
Vinblastine (CYTOBLASTIN) 0.1-0.15 mg/kg IV weekly (total 3 doses)
Vinorelbine (VINELBINE) 30 mg/m2 BSA IV weekly
V. Taxanes
Paclitaxel (MITOTAX) 175 mg/m2 BSA IV infusion repeated every 3 weeks
Docetaxel (DOXOTEL)
VI. Topoisomerase-I inhibitors
Irinotecan (IRINOTECAN) 125 mg/m2 BSA weekly IV
Topotecan (TOPOTEL) 1.5 mg/m2 BSA IV infusion for five consecutive days
VII. Hormone & hormone antagonists
Fosfestrol (Stilboestrol) 40-80 mg IM every 2-4 weeks
Ethinyl estradiol (LYNORAL) 1-3 mg daily
Tamoxifen (ONCOTAM) 10-20 mg BD
VIII. Radioactive isotopes
Radioactive iodine (131I) 3-6 mci oral/IV
Radioactive phosphorus (32P) 2.5-5.0 mci IV
Radioactive gold (198AU) 35-150 mci IP
IX. Miscellaneous agents
Hydroxyurea (CYTODROX) 20-30 mg/kg daily or 80 mg/kg every 3rd day
Procarbazine 100-300 mg/day
L-Asparaginase (LEUNASE) 50-200 KU/kg daily IV infusion for 2-4 weeks
Cisplatin 50-100 mg/m2 BSA single IV dose every 3-4 wks
Interferon alfa (ALFERON) 3-36 million IU daily SC/IM (depending upon the
X. Immunosuppressants type of cancer)
Azathioprine
Cyclosporine
and blocks generation of cytidylic acid DNA intercalator and it generates free
and is a drug of choice for acute myeloid radicals.
leukaemia. It is usually administered by
It is indicated in acute myelocytic intravenous route. It does not cross blood
leukaemia, acute lymphocytic leukaemia, brain barrier.
chronic myeloid leukaemia (blast phase), Adverse effects include nausea, vom-
non-Hodgkin’s lymphoma in children, iting, diarrhoea, fever, red urine (harmless),
treatment and maintenance of meningeal ventricular arrhythmia, severe local tissue
neoplasms, erythroleukaemia. damage on extravasation, cardiotoxicity,
Adverse effects include depression of bone marrow depression, anorexia, stoma-
bone marrow which gives rise to leukopenia, titis, alopecia, conjunctivitis.
thrombocytopenia, reticulocytopenia. GI It is indicated in GI tract carcinoma,
disturbances, oral and anal ulceration, acute myeloblastic leukaemia, bronchogenic,
hepatic and renal dysfunction and breast and ovarian carcinoma, soft tissue
peripheral neurotoxicity with high doses. and bone sarcomas, malignant lymphoma;
primary management of nonmetastatic
CYTOTOXIC ANTIBIOTICS bladder carcinoma (intravesical administra-
tion), Wilm’s tumor and neuroblastoma.
These drugs are obtained from various
microorganisms and have antitumor activity. Epirubicin (FARMORUBICIN) is
They act by binding to double stranded DNA structurally similar to doxorubicin and is
and interfere with its functions. similarly effective in the treatment of breast
cancer, lung cancer and lymphoma.
DACTINOMYCIN (ACTINOMYCIN D)
BLEOMYCIN
It is a potent antitumor antibiotic
isolated from Streptomyces organism. It It is a mixture of cytotoxic glycopeptide
binds tightly to double stranded DNA antibiotic isolated from a strain of
Streptomyces verticillus.
through intercalation between adjacent
guanine cytosine base pair and inhibit all It exerts its cytotoxic action by causing
forms of DNA dependent RNA synthesis. fragmentation of DNA and it generates
free radicals.
It is used in choriocarcinoma,
Hodgkin’s disease and Wilm’s tumour in It is usually administered by parenteral
combination with irradiation. route. It does not cross blood brain barrier.
Adverse effects include damage of Adverse effects include nausea, vom-
skin, alopecia, bone marrow depression, iting, allergic reactions, fever, anaphylaxis,
vomiting and diarrhoea. skin rash, Raynaud’s phenomenon, stoma-
titis, pulmonary fibrosis, hyperpigmenta-
DOXORUBICIN tion, renal and hepatic toxicity.
It is a cytotoxic anthracycline antibiotic Bleomycin is used as palliative and ad-
isolated from Streptomyces pneuceticus. It is juvant to surgery and radiation therapy in
376 Section 9/ Chemotherapy
testicular tumour, squamous cell carcinoma After oral administration the absorp-
of skin, neck and head, genitourinary tract tion is unpredictable. It is metabolised in
and oesophagus neoplasm, malignancy of liver.
cervix, Hodgkin’s and non Hodgkin’s lym- Adverse effects include local reaction
phoma, choriocarcinoma and embryonal if extravasation occurs, constipation, para-
cell carcinoma of testis, brain tumour and lytic ileus, jaw pain, alopecia, bone mar-
glioma. row depression, peripheral neuropathy,
inappropriate ADH secretion, shortness of
MITOMYCIN-C breath and bronchospasm.
It is a highly toxic antibiotic with It is indicated in acute leukaemias, lym-
antitumour activity isolated from phomas, Ewing’s sarcoma, neuroblastoma,
Streptomyces caespitosus. Wilm’s tumour and idiopathic thrombocy-
It inhibits DNA synthesis and cross topenic purpura.
links DNA.
VINBLASTINE
After oral administration it exhibits
inconsistent absorption. Hence it is It interferes with metabolic pathways
administered by IV route and is metabolised of amino acids leading from glutamic acid
in liver. to the citric acid (Krebs) cycle and urea.
CISPLATIN IMMUNOSUPPRESSANTS
It acts by cross-linking of DNA. It also
has radiomimetic property. It is bound to The drugs like azathioprine and
plasma proteins and is excreted slowly cyclosporine A are used chiefly to prevent
unchanged in urine. It is effective in transplant rejection and in the treatment
metastatic testicular and ovarian of autoimmune diseases. They are used to
carcinoma, advanced bladder carcinoma prevent graft rejection after kidney, liver,
and refractory squamous cell head and neck lung, pancreas transplant or bone marrow
carcinoma. transplantation.
Adverse effects include nausea, vomit-
ing, fever, anaphylactic reactions, hypokale- AZATHIOPRINE
mia, hypomagnesaemia, haemolysis, renal It is a purine antimetabolite which has
damage, sterility, teratogenesis, ototoxicity, marked effect on T-lymphocytes, suppresses
peripheral neuropathy, Raynaud’s disease cell mediated immunity (CMI). It selectively
and bone marrow depression.
affects differentiation and functions of T
INTERFERON ALFA cells and inhibits cytolytic lymphocytes. It is
used primarily as immunosuppressant in
It is highly purified protein containing
organ transplantation, progressive rheuma-
165 amino acids and is manufactured by
recombinant DNA technology. toid arthritis and some other autoimmune
diseases.
Mechanism of action is not clearly
understood but direct antiproliferative CYCLOSPORINE
action against tumour cells and modulation
of the host immune response may play It is a cyclic polypeptide with 11 amino
important roles. acids. It selectively inhibits T-lymphocytes
proliferation, IL-2 and other cytokine pro-
It exhibits half life of 3.7-8.5 hours.
Alpha interferons are filtered through the duction. It is the most effective drug for
glomeruli and undergo rapid proteolytic prevention and treatment of graft rejec-
degradation during tubular reabsorption. tion reaction. It is used in cardiac, hepatic,
renal, bone marrow transplantation and
It is indicated in hairy cell leukemia,
as second line drug in rheumatoid arthri-
AIDS related Kaposi’s sarcoma (the
detailed pharmacology and its use as tis, inflammatory bowel disease, dermato-
antiviral agent is discussed in chapter myositis, bronchial asthma and certain
‘Antiviral agents’). other autoimmune diseases.
Adverse effects include GI haemor- Mycophenolate mofetil, a semisynthetic
rhage, leukopenia and elevation in liver derivative of mycophenolic acid, isolated
enzyme levels. from the mould Penicillium glaucum is used
Recently introduced interferon a-2b is in kidney and liver transplant patient.
used in chronic myeloid leukaemia, chronic Another newer compound mizoribine is
hepatitis B and C. used in kidney transplantation.
This page
intentionally left
blank
Section 10
Vitamins are exogenous chemical soluble vitamins can cause toxicity, while
substance required by the body in very small water soluble vitamins are rapidly excreted
amount for the various metabolic functions in the urine and cause very less toxicity.
of the body and categorized as essential The different market preparation
nutrients. They do not yield energy but available for vitamins are given in table
enable the body to use other nutrients and
10.1.1 and the deficiency diseases which
are primarily used in the prevention and
occur with deficient supply of various
treatment of certain deficiency diseases.
vitamins are listed in table 10.1.2.
Vitamins are vital for normal metabo-
lism in body. They vary in their chemical Table 10.1.1: Classification of various preparations
of vitamins.
structure and are supplied in very small
Vitamin A (ROVIGON)
quantity in diet, because they are not syn-
thesized in body or their rate of production Vitamin D (CALCIROL)
is not sufficient for maintenance of health. Vitamin E (EVION)
Vitamin deficiency leads to development of Alfacalcidol (ALCIDOL)
deficiency symptoms. Different vitamin Vitamin B complex group
preparations are available for treatment and Vitamin B1 (Thiamine; BENALGIS)
prophylaxis. Most of the vitamins are non- Vitamin B2 (Riboflavin; LIPABOL)
toxic but on chronic administration can Vitamin B 5 (Calcium pantothenate; SIGMA
cause toxicity especially vitamin A and D. PANTOTHENATE)
Vitamin B6 (Pyridoxine; PYRICONTIN)
Vitamins are classified into two main
Vitamin B 12 (Cyanocobalamin/Mecobalamin;
groups: METHYCOBAL)
I. Fat soluble vitamins, includes Folic acid (FOLVITE)
vitamin A, D, E and K. Vitamin C (Ascorbic acid; CELIN)
II. Water soluble vitamins, includes B- Multivitamins preparations
complex group and vitamin C. B1 + B6 + B12 (NEUROBION)
The fat soluble vitamins are stored in the B complex (B 1 , B 2 , B 3 , B 5 , B 6 , B 12 + folic acid;
body and excessive administration of fat BECOSULE)
384 Section 10/ Vitamins and Trace Elements
This page
intentionally left
blank
Section 11
Chelat ng Agents
&
Treatment of Po son ng
This page
intentionally left
blank
app t
t eerr Chelating Agents &
CChha Pharmacodynamics
Treatment of
11.1
1.4 (Mode of Action of Drugs)
Poisoning
Antidotes are used in life threatening iii. Systemic antidotes: They produce the
situations and are administered for a short action which are opposite to that of
treatment course. They can be divided into poison e.g. caffeine for morphine and
three main categories: atropine for pilocarpine.
• Antidotes that remove active poison iv. Universal antidotes: These antidotes
from its site of action e.g. hydroxylamine can be given in all such conditions
used in organophosphate anticholinest- where nature of poison is not known
erase poisoning. or where more than one poison is
• Antidotes that act pharmacologically suspected to be taken e.g. charcoal as
e.g. naloxone used in opioid poisoning. adsorbent of toxins and alkaloids,
• Antidotes that antagonised other tannic acid for precipitating alkaloids,
macromolecules e.g. carbon monoxide glycoside and many metals.
produce poisonous condition by
binding the haemoglobin and other CHELATING AGENTS
cellular components. Chelating agents are widely used as specific
The antidotes are classified into four antidotes for heavy metals. They form stable,
main types. soluble, nontoxic complexes and in easily
i. Mechanical antidotes: These sub- excreted form. They promote dissociation of
stances interfere with the absorption of bound metal from tissue enzymes and other
poison. They act by forming a coat over functional macromolecules. These metal
mucous membrane of the stomach. e.g. chelates are water soluble. e.g. EDTA, BAL,
fats, oils, albumin, activated charcoal desferrioxamine etc.
is specifically used in adsorbing alka-
loidal poisons. DIMERCAPROL (BRITISH ANTI
ii. Chemical antidotes: They react with LEWISITE, BAL)
poison to form harmless insoluble form It acts by forming chelation com-
e.g. acids are neutralised by alkalis, plexes between its sulphydryl groups and
KMnO4 used in opium poisoning. metals. Its effectiveness is much more, if
396 Section 11/ Chelating Agents & Treatment of Poisoning
This page
intentionally left
blank
Section 12
Dental Pharmacology
This page
intentionally left
blank
a p
p tte r
e r
CChh Antiseptics &
Pharmacodynamics
12.1
1.4 Disinfectants
(Mode of Action of Drugs)
These are the agents which inhibit or kill Factors which Modify the Activity of
microbes on contact. Conventionally Germicides
• Antiseptics are used on living 1. Temperature & pH.
surfaces.
2. Period of contact with the microor-
• Disinfectants are used for inanimate ganisms.
objects.
3. Nature of microbes involved.
The practical distinction of these two
– Spectrum of activity of majority of
agents is on the basis of a growth inhibiting
antiseptic disinfectants is wide re-
or direct lethal action. There are
flecting non selectivity of action.
concentration dependent. Germicide covers
However, some are selective e.g.
these two category. Potency of germicide is
hexachlorophene, chlorhexidine,
generally expressed by its “phenol
quarternary ammonium antisep-
coefficient or Rideal Walker (RW)
tics, gentian violet, acriflavine are
coefficient” – “which is the ratio of the
more active for gram +ve than gram
minimum concentration of the test drug
–ve. Silver nitrate is highly active
required to kill a 24 hour culture of B. typhosa
against gonococci and benzoyl
in 7.5 minutes at 37.5°C to that of phenol
peroxide against P. acnes.
(as standard) under similar conditions.”
4. Size of inoculum.
In dentistry, they are used for
sterilization of certain instruments and 5. Presence of blood, pus & other organic
prevention and treatment of dental plaque matter.
and peridental diseases. They are also used Mechanism of Action (Cidal or
in root canal therapy (RCT), treatment of Inhibiting Action)
acute necrotizing gingivitis and other
infective oral conditions. Antiseptics and i. Oxidation of bacterial protoplasm.
disinfectants are also used as ingredient in ii. Denaturation of bacterial proteins
various dentifrices. including enzymes.
408 Section 12/ Dental Pharmacology
a p
p tte r
e r
CChh Astringent and
Pharmacodynamics
12.2
1.4 Obtundents
(Mode of Action of Drugs)
PHENOL
OBTUNDENTS
On local application, it causes
Obtundents are the agents which are used to irritation followed by numbness. It is used
either diminish or eliminate the dentine alone and in combination with chloroform
sensitivity to make the excavation painless. But and olive oil in a 2:4:10 ratio. It acts rapidly
due to the availability of local anaesthetics e.g. but does not penetrate deeply and due to
xylocaine for painless excavation, the use of its protoplasmic poisonous nature it
obtundents is very limited. produces its obtundent action.
An ideal obtundent should possess the CREOSOTE
following characteristics
Its characteristics and action is same as
(i) It should remove dentive sensitivity that of phenol, in addition its penetrability
and penetrate the dentine sufficiently. is relatively more.
(ii) It should not stain the dentine.
BENZYL ALCOHOL
(iii) It should be free from any local
Due to its local anaesthetic property it is
irritation or pain.
used as obtundent agent. It can be used
Obtundents may be classified into three
either alone or in combination of chloroform
main categories according to their and ethyl alcohol in a 5:3:2 ratio.
mechanism of action.
I Act by destroying the nervous tissue CAMPHOR, THYMOL, MENTHOL
– Absolute alcohol All three are volatile oils and are used in
II Act by paralysing the sensory nerve a mixture in a ratio of 1:2:1 for rapid action.
endings The mixture acts initially stimulating and
– Phenol creosote then paralysing the sensory nerve endings.
– Benzyl alcohol EUGENOL (CLOVE OIL)
– Camphor Clove oil is used due to the presence of
– Thymol eugenol as its main constituent. It acts by
– Menthol paralysing the sensory never endings. It is
– Eugenol (clove oil) non-irritating but stains the dentine yellow.
a p
p tte r
e r Styptics (Local
CChh Pharmacodynamics
Haemostatics) and
12.4
1.4 (Mode of Action of Drugs)
Disclosing Agents
app t
t eerr
CChha Dentifrices and
Pharmacodynamics
12.5
1.4 Mouth Washes
(Mode of Action of Drugs)
er Pharmacotherapy of
apt
Ch Common Oral
12.7 Conditions & Dental
Emergencies
The most common oral condition and irreversible pulpitis, root canal therapy
dental emergency is dental caries, which is (RCT) becomes necessary. The contents of
a destructive disease of the hard tissues of the pulp chamber and root canals are
the teeth due to bacterial infection with removed, followed by thorough cleaning,
Streptococcus mutans and other bacteria. It antisepsis and filling. Alternatively,
is characterized by destruction of enamel extraction may be indicated.
and dentine. Dental decay presents as Apical peridontitis- A severely
opaque white areas of enamel with grey inflammed pulp will eventually necrose,
undertones and in more advanced cases, causing apical peridontitis, which is the
brownish discoloured cavitations. Dental inflammation around the apex of the
caries is initially asymptomatic and pain tooth. It is characterised by severe
does not occur until the decay impinges on spontaneous and persistent pain and
the pulp, and an inflammation develops. regional lymphadenopathy can be present.
Treatment of caries involves removal of the Management is root canal treatment or
softened and infected hard tissues, sealing extraction. Antibiotics are generally not
of exposed dentines and restoration of the necessary but patients should be advised
lost tooth structure with porcelain, silver, to report back to dentist/physician, if
amalgam, composite plastic, gold etc. swelling or other evidence of infection
occurs.
The common dental emergencies are:
Periapical abscess- It is pulpal
Pulpitis- If the caries lesion progresses, inflammation characterized by localized
infection of the dental pulp may occur, pain and swelling. If the pulpitis is not
causing acute pulpitis (Pulpal treated successfully, infection may spread
inflammation). The tooth become sensitive beyond the tooth apex into the peridontal
to hot or cold, and then severe continuous ligament. This infection causes acute
throbbing pain ensues. In reversible inflammation with pain on chewing or on
pulpitis, filling is an option but in case of percussion is present. The treatment of
426 Section 12/ Dental Pharmacology
abscess is incision and drainage or RCT or untreated, the abscess may rupture or less
extraction supported by antimicrobial and commonly, progress to cellulitis.
NSAlD’s. The treatment is drainage and debride-
Cellulitis- Proliferation of epithelial cell ment of the infected perdontal area sup-
cysts may convert the granuloma into a ported with antibiotics.
periapical cyst. The pus in the periapical Pericoronitis- It is the inflammation of
abscess may track through the alveolar soft tissues surrounding the crown of a
bone into soft tissues, causing cellulitis and partially erupted tooth and most
bacteremia, or may discharge into the oral commonly, a wisdom tooth. It generally
cavity, into the maxillary sinus, or through occurs when bacterial plaque and food
the skin of the face or submandibular area. debris accumulate beneath the flap of gum
Maxillary infection also may spread to the covering the partially erupted tooth. It is
periorbital area, increasing the risk of other characterized by inflammation, often
serious complications including loss of complicated by trauma from the opposing
vision, carvernous sinus thrombosis and tooth, leads to swelling of the flap,
CNS involvement. tenderness, pain and a bad taste due to pus
Outpatient with localized cellulitis oozing from beneath the flap.
should be treated by the physician with In localized pericoronitis, hot saline
antistreptococcal oral antibiotics e.g. oral mouthwashes and irrigation under the flap
penicillin and in case of penicillin allergy, can resolve symptoms in most of the cases.
macrolide antibiotics may be substituted Severe disseminated cases with spreading
with appropriate pain medication. cellulitis should be treated with penicillin
Definitive theraphy is root canal treatment and appropriate medication for pain.
or extraction. Dental trauma- Dental trauma is
In severe infection, patients be extremely common in children with injuries
hospitalized under the direct supervision to their primary or permanent teeth.
of physician and treatment should be Examination of any injury should focus on
started immediately with intravenous related soft tissue injuries and the need for
broad- spectrum antibiotics and surgical suturing, signs of tooth loosening,
drainage if abscess formation is detected. displacement or fracture or any other
Peridontal disease- It is an inflammatory disturbance in the bite or other signs of
destruction of the periodontal ligament and alveolar fracture. The complete diagnosis
supporting alveolar bone and the main require dental radiograph (x-rays) and
etiologic agent is bacterial plaque. Multiple need follow up with the dentist for
bacteria are implicated but after progressing complete diagnosis, treatment and long-
the disease, gram negative anaerobes term care.
predominate. It is characterized by Tooth fracture may involve the crown,
throbbing pain with erythema and swelling root or both and with or without the
over the affected tissue. At this stage, if left exposure of the pulp. Fracture exposing the
Pharmacotherapy of Common Oral Conditions and Dental Emergencies 427
pulp are often painful and immediately often coupled with root canal
require referral to a dentist and definitive treatment.
treatment may involve root canal treatment (iii) Avulsion (complete displacement of
or extraction depending on the exact nature the tooth out of its socket- It is a true
of the root fracture. dental emergency. Primary teeth are
Injuries to teeth and their supporting never implanted. Permanent teeth
structures can be classified as fractures. that are avulsed should be
reimplanted as soon as possible and
(i) Lateral or extrusive (loosening and care should be taken not to touch or
displacement of the tooth)- It requires clean the root, which could remove
immediate referral to dentist. Luxated periodontal ligament fibres and
permanent teeth require repositioning, which ultimately reduce the chance
splinting or root canal treatment and of successful re-implantation. The
long term follow up. Any luxated patient should be immediately
tooth that interferes with normal referred to dentist for splinting and
occlusion requires immediate dental antibiotic prophylaxis. Antibiotic
evaluation and treatment for pain and prophylaxis with penicillin should be
other complications. given and tetanus toxoid vaccine
(ii) Instrusion (displacement of the tooth should be administered
vertically into the alveolar bone)- Dental caries and peridontal disease
Teeth subject to intrusive luxation which can lead to certain dental
have been intruded into the alveolar emergencies can be minimised by regular
bone, which may occur at the point dental care i.e. regular tooth brushing,
that the teeth are not visible. Dental appropriate fluoride use, decreasing
referral is required for monitoring to ingestion of sugar containing confectionery
determine if the teeth will re-erupt. For items and regular dental examination.
permanent teeth, monitoring and Dental trauma especially in children and
treatment is required to promote re- sport persons can be avoided by using
eruption (surgical or orthodontic) and certain mouth guards and face shields.
This page
intentionally left
blank
Section 13
Miscellaneous
This page
intentionally left
blank
a p
p tte r
e r Vaccines, Sera and
CChh Pharmacodynamics
Other Immunological
13.1
1.4 (Mode of Action of Drugs)
Agents
The immunological agents are the agents The active immunity may be acquired
which produce active or passive immunity following clinical infection (chicken pox,
and are used to prevent or to modify certain rubella, measles), following subclinical
infectious disease. Immunity can be infection (polio and diphtheria) and
defined as the ability of the body to following immunization with an antigen
neutralize and eliminate the pathogens and which may be killed vaccine, live
their toxic products. attenuated vaccine or a toxoid.
The immunity can be divided into two When an antigen is administered for
sub-groups: the first time in human body, the antibodies
I. Active immunity: that is elicited first is entirely of the IgM
Humoral immunity. type. The IgM antibody titres rise steadily
Cellular immunity. during the next three to four days, reaches
Combination of these two. a peak and then declines. Meanwhile if the
antigenic stimulus was sufficient, IgG
II. Passive immunity:
antibody appears in a few days, reaches a
Normal human Ig.
peak in a week time and gradually falls over
Specific human Ig. a period of weeks or months, this is called
Animal antitoxins or antisera. as primary response.
Active Immunity The secondary response is also known
Active immunity depends upon the as booster response. It differs from primary
humoral and cellular responses of the host. response and has a shorter latent period,
It is the immunity which an individual production of antibodies is more rapid,
develops as a result of infection and antibodies are more abundant, antibody
production of antibodies or cells having a response is maintained at a higher level for
specific action on the microorganisms a longer period and antibodies elicited tend
concerned with a particular infectious to have a greater capacity to bind to the
disease or on its toxin. antigen.
432 Section 13/ Miscellaneous
INACTIVATED VIRUS
Polio virus vaccine Inactivated Subcutaneous Two doses, 4 to 8 weeks apart and a third
inactivated (IPV) viruses of all 3 dose 6 to 12 months after the second and
serotypes one-time booster dose for travellers.
Rabies Inactivated virus Intramuscular or Preexposure: 3 doses (IM or ID) at days 0, 7,
intradermal and 21 or 28.
Postexposure: 5 doses (IM only) at days 0, 3, 7,
14, and 28 and serologic testing every 6 months
to 2 years in persons at high risk.
Influenza Inactivated Intramuscular One dose (children ≤12 years of age should
virus or viral receive split virus vaccine only; children < 9 yrs
components who are receiving influenza vaccine for the first
time should receive 2 doses, administered at
least 1 month apart) and booster yearly with
current vaccine.
Hepatitis A Inactivated virus Intramuscular One dose (administer at least 2 to 4 weeks
before travel to endemic areas) and booster at
6 to 12 months for long-term immunity.
Hepatitis B Inactive viral Intramuscular Three doses at 0, 1, and 6 months.
antigen
BACTERIA
Typhoid, Ty 21a Live bacteria Oral Four doses given 2 days apart and booster 4
oral doses every 5 years.
Typhoid, heat-phe- Inactivated Subcutaneous Two doses ≥ 4 weeks apart & booster every
nol inactivated bacteria or intradermal 3 years.
Cholera Inactivated Subcutaneous, Two doses given at least 1 week apart, prefer-
bacteria intramuscular, ably 1 month apart & booster every 6 months.
or intradermal
Contd.…
Vaccines, Sera and Other Immunological Agents 435
…Contd.
BACTERIAL POLYSACCHARIDES
Typhoid, Vi-capsular Bacterial Intramuscular One dose and booster at every 2 years.
polysaccharide polysaccharide
Haemophilus, Bacterial Intramuscular One dose
influenzae type b polysaccharide
conjugate (Hib) conjugated
to protein
Pneumococcal Bacterial poly- Intramuscular or One dose & booster after 6 years in patients
saccharides subcutaneous at high risk.
of 23 serotypes
Meningococcal Bacterial poly- Subcutaneous One dose
saccharides
of serotypes
A/C/Y/W-135
TOXOIDS
Tetanus-diphth- Toxoid Intramuscular Two doses at least 4 weeks apart and a third
eria (Td or DT) dose 6 to 12 months after the second and
booster at every 10 years or at age 50.
Diphtheria-tetanus- Toxoids and Intramuscular DTP at 2 months, 4 months, 6 months and at
pertussis (DTP) inactivated 12 to 18 months then at 4 to 6 years.
whole bacteria
Diphtheria-tetanus- Toxoids and Intramuscular Same as DTP vaccine.
acellular inactivated
pertussis (DTaP) bacterial
components
DTP-Haemo- Toxoids, inac- Intramuscular Same as DTP vaccine.
philus influenzae tivated whole
type b conjugate bacteria and
(DTP-Hib) bacterial poly-
saccharide
conjugated to
protein.
humans. The virus usually spreads by Polio is a highly contagious disease. By the
contact with infected individuals via the time first case is detected in a family, all family
water borne route, though mouth-to-mouth members may have probably been infected
transmission is also possible. The disease due to the rapidity of viral spread. Viral spread
typically affects very young children, with is enhanced by crowding and poor sanitation.
80 to 90 percent of cases occurring in The most prominent example of the
children under three years of age. effectiveness of OPV is the success of the
…Contd.
Tetanus immune Postexposure prophylaxis: 250 units IM. Tetanus
globulin Treatment: 3,000 to 6,000 units IM.
Varicella-zoster 125 units/10 kg IM, up to 625 units. Higher doses may be Varicella
immune globulin required.
Immune globulin Initial dose of 400 mg/kg IV every 3 weeks. Dosage should Chronic lymphocytic
(intravenous) be adjusted upward if bacterial infections occur. leukemia
Cytomegalovirus Bone marrow transplantation: 1 g/kg weekly. Cytomegalovirus
immune globulin Kidney transplantation: 150 mg/kg then 50 to 100 mg/kg
(intravenous) every 2 weeks.
Diphtheria 20,000 to 120,000 units IV or IM depending on the severity Diphtheria
antitoxin, equine and duration of illness.
Anti gas gangrene Prophylactic: 10, 000 IU; Gas gangrene
serum Therapeutic: 30-75,000 IV SC/IM/IV
prevention of invasive infections such as infectious than HIV which causes AIDS.
meningitis, septicaemia, epiglottitis etc. Hepatitis B kills more people in a day than
caused by Haemophilus influenzae type b, AIDS kills in a whole year.
diphtheria, tetanus and pertussis. Blood is the most important vehicle for
Dosage: Three injections of 0.5 ml at transmission but other body fluids have
one or two months interval followed by a also been implicated including semen,
booster injection administered one year vaginal secretions and saliva.
after the primary vaccination. HBV can spread in three ways: From
mother to child (MTC), at birth and from
DUAL ANTIGEN
person to person.
It is a uniform suspension of diphtheria
Hepatitis B vaccine is used for active
and tetanus toxoid adsorbed on aluminium
phosphate and suspended in isotonic saline immunisation against hepatitis B infection.
solution. Immunisation should be considered in
persons at high risk of contracting hepatitis
Adverse effects include mild local B.
reactions like pain, redness, tenderness at
the site of injection. Mild to moderate Adverse effects include mild transient
transient fever and irritability. soreness and induration at injection site.
Occasionally low grade fever, malaise,
It is used for active immunisation of
fatigue, headache, nausea and dizziness.
children against diphtheria and tetanus in
cases where it is decided not to immunize It is used for active immunization
against pertussis also. against hepatitis B virus infection.
Dosage: 3 IM injections of 0.5 ml to be Dosage:
administered with an interval of four to
• Adults: 1 ml by IM injection into the
eight weeks between doses. A fourth
deltoid muscle; repeated one month
injection of 0.5 ml should be administered
and six months later.
one year after initial injection.
• Children: 0.5 ml by IM injection into the
HEPATITIS B (BEVAC) anterolateral aspect of thigh; repeated
Hepatitis B is a worldwide disease one month and six months later.
caused by the hepatitis B virus (HBV). HBV Administration: This is for IM use only.
primarily affects the liver inducing an In adults the injection should be given in
inflammatory reaction that destroys liver the deltoid region; in neonates and infants
cells and often hinders liver function. The the injection should be given in
consequences of infection are variable and anterolateral thigh. Dose for adults and
unpredictable. They depend on the age and children above 10 years is 20 mcg and for
immunity status of the patient. neonates, infants and children below 10
The hepatitis B virus is highly infectious. years the dose is 10 mcg. Three doses are
It is estimated to be 100 times more given as above. For rapid immunization the
440 Section 13/ Miscellaneous
third dose can be given two months after hepatitis A is an occupational hazard or in
the first dose and a fourth booster dose at whom there is an increased risk of
12 months. transmission (persons working in a day care
centre, nursing, medical and paramedical
HEPATITIS A (AVAXIM) personnel especially gastroenterology and
Hepatitis A is one of the most paediatric unit, sewage workers,
widespread infectious diseases worldwide. homosexuals, haemophilia patients, abusers
It is caused by the hepatitis A virus and is of injectable drug and persons with multiple
common in places with poor standards of sexual partners.
hygiene and sanitation. The virus attacks Adverse effects include injection site
the liver and causes varying degrees of soreness, redness and swelling; mild
illness in patients. headache, malaise, fatigue, fever, nausea
The hepatitis A virus is excreted in the and loss of appetite.
faeces. Direct contact with an infected
person’s faeces or indirect contamination of Dosage:
food, water, hands and cooking utensils may • Adults (19 years onwards): A single
result in the virus being ingested, causing dose of hepatitis A adults vaccine (1
infection. ml suspension containing not less than
1,440 ELISA units of viral antigen) is
Symptoms include nausea, vomiting,
used for primary immunization.
jaundice (yellowness of eyes, skin and
urine), diarrhoea, pale stools, abdominal • Children and adolescents (from 1 year
up to 18 years of age): A single dose
pain, malaise, fatigue, fever, chills, lack of
of hepatitis A junior vaccine (0.5 ml
appetite, sore throat, etc.
suspension containing not less than
Hepatitis A is often confused with 720 ELISA units of viral antigen) is
hepatitis B. What is important to remember used for primary immunization.
is that hepatitis A is the single largest cause In both a booster dose is recommended
of jaundice. Also vaccination against hepatitis any time between 6 to 12 months later to
B does not protect from hepatitis A. ensure long time protection from hepatitis A.
A vaccine is now available and is the Administration: By IM route only, in
most practical means of protection against deltoid muscle.
hepatitis A. A complete course of vaccine
should be taken to get long term protection. TYPHOID (TYPHIVAX)
Hepatitis A vaccination is indicated for Typhoid fever is a disease which starts
active immunisation against hepatitis A virus as an infection of the gastrointestinal tract.
(HAV) infection in subjects at risk of exposure It is caused by the bacterium Salmonella
to HAV such as travellers to high prevalence typhi. It spreads by ingestion of
areas, armed force personnel travelling to contaminated food or drink. Normally
high endemic areas, person in whom Salmonella typhi bacterium is inactivated by
Vaccines, Sera and Other Immunological Agents 441
MMR (MEASLES, MUMPS & Rubella soon after birth is a disease which
RUBELLA; TRESIVAC) is usually trivial and of short duration. Its
most obvious sign is a mild rash. Rubella
Measles virus infection during pregnancy can
In developing countries, measles can be disrupt fetal growth and cause birth defects.
a very severe disease, with mortality rates Approximately 25 to 50% of rubella in-
as high as 10 percent. Hence, vaccination fections may go undetected. When symp-
is recommended for all children at the toms do present, they are usually quite mild.
earliest possible age. Currently, the WHO
recommended nine months as the age for Adults who contract rubella present
measles vaccination, taking into account with fever and loss of appetite for two days
maternal antibody levels and vaccine intake, prior to the onset of the rash.
as well as disease incidence.
MMR Vaccination
The signs and symptoms of measles Live attenuated virus vaccines for
include fever, common cold-like symptoms, measles, mumps and rubella (MMR) have
conjunctivitis, cough, spots inside the mouth been combined into a single vaccine known
and a skin rash. Diarrhoea, stomach pain as MMR vaccine. The MMR vaccine is
and loss of appetite may also be present. effective as the single-virus vaccine
The severity of the symptoms of measles composed of the respective strains and has
is greater in adolescents and adults than in been shown to be highly effective. The
children. The incubation period is 10 to 12 immunity induced by MMR is long lasting
days and during this period there is virtually and may be lifelong.
no outward sign of illness. During this Adverse effects include hyperthermia,
period the virus first causes a local infection rhinopharyngeal or respiratory symptoms of
of the upper respiratory tract then spreads short duration. Hyperthermia convulsions
to other parts of the body. The virus is then are rarely observed. Lymphadenopathies or
disseminated throughout by bloodstream parotitis may be observed.
causing a primary disease.
It is indicated for joint prevention of
Mumps measles, mumps and rubella, normally, given
Mumps or infective parotitis is an acute from the age of 12 months, in infants of both
infectious disease usually marked by a sexes.
painful enlargement of one or both salivary
CHICKENPOX (VARICELLA; OKAVAX)
glands around the jaw. In addition,
dryness of the mouth may often occur. Chickenpox or varicella is caused by the
varicella zoster virus (VZV). Varicella
Rubella vaccine is indicated for active immunisation
Rubella or German measles, is a highly against varicella in healthy subjects and
infectious disease, which mostly affects their susceptible healthy close contacts
children, adolescents and young adults. from the age of 12 months onwards.
Vaccines, Sera and Other Immunological Agents 443
a p
p tte r
e r
CChh Drugs Used in Skin
Pharmacodynamics
13.2
1.4 Disorders
(Mode of Action of Drugs)
For the treatment of various skin disorders, positive aerobic bacteria including methicil-
local application of drugs in the form of lin resistant S. aureus are sensitive to
cream, ointment, gel etc., appears to be the mupirocin. It inhibits in-vivo synthesis of
ideal and convenient form of management. bacterial proteins by specific and reversible
However, in severe conditions different binding to isoleucyl transfer-RNA syn-
drugs can also be given by oral routes. The thetase bacterial enzyme. It is indicated in
different agents used in various skin the treatment of impetigo (which is a com-
disorders are classified as in table 13.2.1. mon skin disease, characterized by superfi-
The detailed pharmacology of various cial bacterial infection caused by S. aureus
agents listed in table are discussed in or streptococci. The primary lesion is a su-
different chapters and only remaining perficial pustule crust, which may occur on
agents are covered in this section. normal skin or superimposed upon another
skin disease).
ANTIBACTERIAL AGENTS
Topical Antibiotics Used in Acne
Topical antibacterial agents are used to Clindamycin is active against
prevent infection and in the early treatment Propionibacterium acnes. Erythromycin alone
of infected dermatoses and wounds. Various and in combination with benzoyl peroxide
preparations contain corticosteroids in is used in the treatment of acne vulgaris.
addition to antibacterial agents. Topical metronidazole is effective in the
Detailed pharmacology of various treatment of acne rosacea.
antibacterial agents is discussed in chapter
Tetracycline hydrochloride and
‘Chemotherapeutic agents’.
minocycline sulfosalicylate are used in the
MUPIROCIN treatment of acne vulgaris.
It is structurally unrelated to other topi- Topical sodium sulfacetamide is used in
cal anti-bacterial agents. Most of the gram the form of lotion and in combination of
450 Section 13/ Miscellaneous
This page
intentionally left
blank
Appendices
This page
intentionally left
blank
tderix List of Recently Approved
h a p
n
ACpphaepter New Drugs and
Pharmacodynamics
C
I
1.4
Combinations
Pharmacodynamics inDrugs)
(Mode of Action of
(During 1999-July
of 1999-
ActionJuly
India
2006)
1.4
(Mode of Drugs)
…Contd.
27. Fluvoxamine maleate Antidepressant
28. Celecoxib NSAID
29. Nevirapine Anti HIV
30. Repaglinide Antidiabetic
31. Ganciclovir Antiviral
32. Trapidil Adjunct in angioplasty
33. Cerivastatin Lipid lowering agent
34. Rofecoxib NSAID
35. Irbesartan Antihypertensive
36. Rosiglitazone maleate Antidiabetic
37. Granisetron Antiemetic
38. Rituximab Antineoplastic
39. Trastuzumab Antineoplastic
40. Rosiglitazone Antidiabetic
41. Moclobemide Antidepressant
42. Candesartan Antihypertensive
43. Venlafaxine hydrochloride Antidepressant
44. Paroxetine hydrochloride Antidepressant
45. Iomeprol Contrast medium
46. Capecitabine Antineoplastic
47. Daclizumab Immunosuppressive agent
48. Pioglitazone hydrochloride Antidiabetic
49. Didanosine Anti-HIV
50. OctyIonium bromide For irritable bowel syndrome
51. Pravastatin Lipid lowering agent
52. Sildenafil citrate Male erectile dysfunction
53. Triflusal Platelet aggregation inhibitor
54. Thymosin Alfa-1 inj Immunomodulator (for chronic hepatitis-B)
55. Vinorelbin tartrate inj Antineoplastic aggregation inhibitor
56. Broncho-Vaxom Antiasthmatic, immune boosting drug
57. Indinavir sulphate Antiviral (Anti-HIV)
58. Butenafine hydrochloride cream Antifungal
59. Mirtazapine Antidepressant
60. Clopidogrel Antithrombotic; platelet aggregation inhibitor
61. Mosapride Prokinetic agent
62. Donepezil hydrochloride For Alzheimer’s dementia
63. Bupropion SR Smoking cessation adjunct
64. Raloxifene hydrochloride Menopausal osteoporosis
65. Efavirenz Anti-HIV
66. Moxifloxacin Antibacterial
67. Misoprostol Antiulcer agent
Contd.…
Appendix-I List of Recently Approved New Drugs and Combinations... 461
…Contd.
Contd.…
462 Appendices
…Contd.
108. Miltefosine For Kalaazar
109. Ziprasidone hydrochloride For Schizophrenia
110. Abacavir Anti-HIV
111. Nadifloxacin cream Antibacterial; antiacne
112. Meloxicam inj (vet) NSAID
113. Mesalazine SR For bowel disease (inflammatory)
114. Tamsulosin hydrochloride For BPH (benign prostate hypertrophy)
115. Famciclovir Antiviral
116. Nateglinide Antidiabetic
117. Lercanidine hydrochloride Antihypertensive
118. Itopiride capsule Gastroprokinetic agent
119. Alprostadil inj For erectile dysfunction
120. Vimpocetine Vasodilator
121. Quetiapine fumarate Antipsychotic
122. Isotretinoin soft gel cap For Acne vulgaris
123. Nebivolol hydrochloride Antihypertensive
124. Sirolimus Immunosuppressant
125. Drotrecogin alpha For severe sepsis
126. Pygenum africum For BPH (benign prostate hypertrophy)
127. Valdecoxib NSAID
128. Thalidomide For leprosy
129. S (–) Amlodipine besylate Antihypertensive
130. Cabergoline For hyperproloactemia
131. Butarphenol tartarate Opoid analgesic
132. Gemtuzumab For myeloid leukemia
133. Quinapril antihypertensive
134. Valacyclovir Antiviral
135. Fosphenytoin sodium Anti-Epileptic
136. Ceftiofur sodium and hydrochloride Antibiotic (For veterinary use)
137. Metaxalone Muscle relaxant
138. Meglumine gadoteric Contrast media
139. Cafepine hydrochloride Antibiotic
140. Acamprosate calcium For alcohol dependency
141. Aztreonam Antibacterial
142. Tegasserod maleate For irritable bowel syndrome
143. Parecoxib inj NSAID
144. Balsalezide disodium For ulcerative colitis
145. Cefetemet-piroxil Antibacterial
146. Telmisartan Antihypertensive
147. Levocetrizine Antihistaminic
148. Poractant α For respiratory distress in preterm babies
Contd.…
Appendix-I List of Recently Approved New Drugs and Combinations... 463
…Contd.
…Contd.
Contd.…
Appendix-I List of Recently Approved New Drugs and Combinations... 465
…Contd.
…Contd.
Contd.…
Appendix-I List of Recently Approved New Drugs and Combinations... 467
…Contd.
…Contd.
336. Tobramycin Inhalation solution For chronic pulmonary infection cystic fibrosis.
337. Propionyl-L-Carnitine HCl Tablet & injection Chronic congestive heart failure
338. Eflornithine HCl Cream For reduction of unwanted facial hair in women.
339. Lactulose Enema For constipation & hepatic encephalopathy
340. Doxofylline Syrup For bronchial asthma & COPD.
341. Cholestyramine Powder for oral suspension For hypercholesterolaemia
342. Haloperidol As approved earlier (Antipsychotic)
343. Resperidone Tablet & Syrup Acute mania & mixed episode in bipolar-I disorder.
344. D-trans Fentantyl Transdermal patches For pain
345. Oseltamivir formulation (additional indication) For Prophylaxis of influenzae in adult and children
> 14 years of age
346. Atazanavir Anti-HIV in adults.
347. Nicorandil E.R. Tablet Angina Pectoris
348. Nadifloxacin Gel 1% Acne vulgaris
349. Midazolam (as maleate) For insomnia
350. Olmesartan (as Medoxomil) 10 mg Anti-hypertensive
(Addl. Strength)
351. Pregabalin capsule 25/50/100/200 mg Same as approved
(Addl. Strength)
352. Oxcarbazepine S.R 450 mg/900 mg Anti-epileptic
(Addl. Strength)
353. Ciclesonide rotacaps For Asthma
354. Itopride capsule (S.R) For GERD
355. Ibandronic Acid Tablet (150 mg) Same as approved.
(Addl. Strength)
356. Zonisamide capsule 25/50 mg Same as approved
(Addl. Strength)
357. Perflutren liquid microsphere injectable For diagnostic use
suspension
358. Cyclosporin Eye drops (0.1%) (Addl. Strength) For Ophthalmic use
359. Bemiparin Sodium Solution For deep vein thrombosis
360. Icodextrin peritoneal dialysis solution For peritoneal dialysis
361. Lamotrigin 200 mg tablet (Addl. Strength) Anti-epileptic
dispersible tablet
362. Olopathadine Ophthalmic solution For allergic conjunctivitis
363. Methyl Prednisolone Aceponate Cream For atopic dermatitis
364. Levofloxacin Ear drops For otitis media
365. Buclizine HCl tablet & syrup As appetite stimulant
366. Solifenacin Succinate Tablet For overactive bladder with urge urinary incontinence
urgency & urinary frequency
367. Zolpidem Tartrate E.R. tablet For insomnia
368. Deferasirox dispersible tablet For chronic iron overload due to blood transfusion
369. Sodium Hyaluronate Injection For OA
370. Forskolin Eye drop For open angle glaucoma
Appendix-I List of Recently Approved New Drugs and Combinations... 469
Contd.…
470 Appendices
…Contd.
…Contd.
Contd.…
472 Appendices
…Contd.
List of recently approved new drugs and combinations in Indian Market by Directorate
General of Health Services, Min. of Health & Family Welfare, Govt. of India.
e rix List of Banned Drugs
a
hn p td
ACppe and Fixed Dose
Pharmacodynamics
Combinations
(Mode of Action ofin India
II
1.4 Drugs)
(Updated till January 2007)
1. Amidopyrine
2. Fixed dose combinations of vitamins with antiinflammatory agents and tranquilizers.
3. Fixed dose combinations of atropine and analgesics and antipyretics.
4. Fixed dose combinations of strychnine and caffeine in tonics.
5. Fixed dose combinations of yohimbine and strychnine with testosterone and vitamins.
6. Fixed dose combinations of iron with strychnine, arsenic and yohimbine.
7. Fixed dose combinations of sodium bromide/chloral-hydrate with other drugs.
8. Phenacetin.
9. Fixed dose combinations of antihistaminics with antidiarrhoeals.
10. Fixed dose combinations of penicillin with sulphonamides.
11. Fixed dose combinations of vitamins with analgesics.
12. Fixed dose combinations of tetracyclines with vitamin C.
13. Fixed dose combinations of hydroxyquinoline group of drugs with any other drug except for preparations
meant for external use only.
14. Fixed dose combinations of corticosteroids with any other drug for internal use.
15. Fixed dose combinations of chloramphenicol with any other drug for internal use.
16. Fixed dose combinations of crude ergot preparations except those containing ergotamine, caffeine,
analgesics, antihistamines for the treatment of migraine, headache.
17. Fixed dose combinations of vitamins with anti TB drugs except combination of isoniazid with pyridoxine
hydrochloride (vitamin B6).
18. Penicillin skin/eye ointment.
19. Tetracycline liquid oral preparations.
20. Nialamide.
21. Practolol.
22. Methapyrilene, its salts.
23. Methaqualone.
24. Oxytetracycline liquid oral preparations.
25. Demeclocycline liquid oral preparations.
Contd.…
474 Appendices
…Contd.
26. Combinations of anabolic steroids with other drugs.
27. Fixed dose combinations of estrogen and progestin (other than oral contraceptive) containing per
tablet estrogen content of more than 50 mcg (equivalent to ethinyl estradiol) and of progestin content
of more than 3 mg (equivalent to norethisterone acetate) and all fixed dose combination injectable
preparations containing synthetic estrogen and progesterone.
28. Fixed dose combination of sedatives/hypnotics/ anxiolytics with analgesics-antipyretics.
29. Fixed dose combination of pyrazinamide with other antitubercular drugs except combination of
pyrazinamide with rifampicin and INH as per recommended daily dose given below:
Drugs Minimum Maximum
Rifampicin 450 mg 600 mg
INH 300 mg 400 mg
Pyrazinamide 1000 mg 1500 mg
30. Fixed dose combination of histamine H2-receptor antagonists with antacids except for those
combinations approved by the Drugs Controller, India.
31. The patent and proprietary medicines of fixed dose combinations of essential oils with alcohol having
percentage higher than 20% proof except preparations given in the Indian Pharmacopoeia.
32. All pharmaceutical preparations containing chloroform exceeding 0.5%, w/w or v/v whichever is
appropriate.
33. Fixed dose combination of ethambutol with INH other than the following:
INH Ethambutol
200 mg 600 mg
300 mg 800 mg
34. Fixed dose combination containing more than one antihistaminic.
35. Fixed dose combination of any anthelmintic with cathartic/purgative except piperazine.
36. Fixed dose combination of salbutamol or any other bronchodialator with centrally acting antitussive
and/or antihistaminics.
37. Fixed dose combination of laxatives and/or anti-spasmodic drugs in enzyme preparations.
38. Fixed dose combination of metoclopramide with systemically absorbed drugs except fixed dose
combination of metoclopramide with aspirin/paracetamol.
39. Fixed dose combination or centrally acting antitussive with antihistaminics having atropine like activity
in expectorants.
40. Preparations claiming to combat cough associated with asthma containing centrally acting antitussive
and/or antihistaminics.
41. Liquid oral tonic preparations containing glycerophosphates and/or other phosphates and/or central
nervous system stimulant and such preparations containing alchohol more than 20 proof.
42. Fixed dose combination containing pectin and/or kaolin with any drug which is systemically absorbed
from GI tract except for combination of pectin and/or kaolin with drugs not systemically absorbed.
43. Chloral Hydrate as a drug
44. Dover’s powder IP
45. Dover’s powder tablets IP
46. Antidiarrhoeal formulations containing kaolin or pectin or attapulgite or activated charcoal.
47. Antidiarrhoeal formulations containing phthalyl sulfathiazole or sulfaguanidine or succinyl
sulphathiazole.
Contd.…
Appendix-II List of Banned Drugs and Fixed Dose Combinations in India 475
…Contd.
48. Antidiarrhoeal formulations containing neomycin or streptomycin or dihydrostreptomycin including
their respective salts or esters.
49. Liquid oral antidiarrhoeals or any other dosage form for paediatric use containing diphenoxylate or
atropine or belladonna including their salts and esters or metabolites, hyoscyamine or their extracts
or their alkaloids.
50. Liquid oral antidiarrhoeals of any other dosage form for paediatric use containing halogenated
hydroxyquinolines.
51. Fixed dose combination of anti-diarrhoeals with electrolytes.
52. Patent and proprietary oral rehydration salts other than those conforming to the specified parameters.
53. Fixed dose combination of oxphenbutazone or phenylbutazone with any other drug.
54. Fixed dose combination of analgin with any other drug.
55. Fixed dose combination of dextropropoxyphene with any other drug other than anti-spasmodics and/
or non-steroidal antiinflammatory drugs (NSAIDs).
56. Fixed dose combination of a drug, standards of which are prescribed in the Second Schedule to the
said Act with an Ayurvedic, Siddha or Unani drug.
57. Mepacrine hydrochloride (Quinacrine and its salts) in any dosage form for female sterilization or
contraception.
58. Fenfluramine and dexfenfluramine.
59. Fixed dose combination of diazepam and diphenhydramine hydrochloride.
60. Cosmetics licensed as toothpaste/tooth powder containing tobacco.
61. Parenteral preparations containing fixed dose combination of streptomycin with penicillin.
62. Fixed dose combination of vitamin B1, vitamin B6, and vitamin B12 for human use.
63. Fixed dose combination of haemoglobin in any form (natural or synthetic).
64. Fixed dose combination of pancreatin or pancrelipase containing amylase, protease and lipase with
any other enzyme.
65. Fixed dose combination of nitrofurantoin and trimethoprim.
66. Fixed dose combination of phenobarbitone with any anti-asthamatic drugs.
67. Fixed dose combination of phenobarbitone with hyoscine and/or hyoscyamine.
68. Fixed dose combination of phenobarbitone with ergotamine and/or belladona.
69. Fixed dose combination of haloperidol with any anti-cholinergic agent including propantheline bromide.
70. Fixed dose combination of nalidixic acid with any anti-amoebics including metronidazole.
71. Fixed dose combination of loperamide hydrochloride with furazolidone.
72. Fixed dose combination of cyproheptadine with lysine or peptone.
73. Astemizole
74. Terfenadine
75. Phenformin
76. Rofecoxib.
77. Valdecoxib & its formulation.
List of drugs and fixed dose combination prohibited for manufacturing and sale through
Govt. of India (Ministry of Health & Family Welfare) Gazette notification GSR 578 (E)
Dated 23-7-83 Amended from time to time.
(Published in the Gazette of India, Extraordinary Part-II; Section 3 Subsection (i), Ministry
or Health & Family Welfare, Govt. of India notification).
This page
intentionally left
blank
Index
Index
B Bougies 7, 12
Bretylium 190, 193
Carbonic anhydrase
inhibitors 204 ,207
British National Formulary 4 Carcinogenicity 47, 49
Bacillus subtilis 5 British Pharmaceutical Codex Cardiac arrhythmias 189
Bacitracin 335 4 Cardiac glycosides 169
Baclofen 111, 113 Broad spectrum penicillins Carisoprodol 111, 113
Bacterial 30S ribosomes 327 319 Carminative 4
Balsams 5 Bromhexine 231 Carvedilol 148, 152, 176, 179
Bambuterol 133, 232, 233 Bromocriptine 125, 273 Castor oil 4, 253
Index 479
Ethoheptazine 76, 79 Folic acid 383, 384, 389 Good Manufacturing Practice
Ethosuximide 106, 108 Follicle stimulating hormone (GMP) 21
Etidocaine 114 (FSH) 269, 272 Gossypol 299
Etomidate 66 Fosfestrol 372, 377 Gout 93
Expectorant 229 Fosphenytoin 107 G-protein 43
Extrinsic pathway 240 Fosracetam 121 Granistetron 258
Eye applicaps 10 Framycetin 327, 329 Granules 10
Furazolidone 307, 356, 358 Graves’ disease 295
Furosemide 71, 204, 304 Grey baby syndrome 40
F Griseofulvin 345
Growth hormone 269
5-Fluorouracil 371
G Growth hormone- releasing
factor (GHRF) 270
Famciclovir 338, 339 Guaiphenesin 231
Famotidine 263, 264 G-6-PD deficiency 351
Gabapentin 109 Guanethidine 176, 178
Fat soluble vitamins 383 Gugulipid 195, 198
Felbamate 106 Galantamine 122
Ganciclovir 338, 340 Gumresins 5
Feminism 271
Fenoterol 133 Gargles 6, 11, 13
Fentanyl 62, 76, 79 Gastric ulcer 262
Feracrylum 241, 242
Ferric ammonium citrate 248
Gatifloxacin 308, 310
Gels 10, 12
H
Ferric glycerophosphate 248 Gemfibrozil 195, 197
Gentamicin 327, 328 5-HT blockers 222
Ferritin 248
Giardiasis 359 5-Hydroxytryptamine 221
Ferrous amionate 248
Gigantism 270 Haemodialysis 50
Ferrous gluconate 248
Ginkgo biloba 122 Haemoglobin 248
Ferrous glycine sulphate 248
Ferrous succinate 248 Glibenclamide 277, 278 Haemolytic anaemia 247
Ferrous sulphate 248 Gliclazide 277, 279 Haemoperfusion 50
Fexofenadine 216, 219 Glimepiride 277, 279 Haemostasis 239
Fibrin stabilizing factor 240 Glipizide 277, 278 Haloperidol 68, 95, 97
Fibrinogen 240 Globin zinc insulin 276 Halothane 62, 63
Fibrinolysis 242 Glomerular filtration rate Hamycin 345
Fibrinolytics 245 (GFR) 34 Hard capsules 10
First order kinetics 36 Glucocorticoids 271, 281, 282 Hegeman factor 240
Fixed oils 4 Glucuronide conjugation 32 Hemosiderin 248
Flavouring agent 4 Glutathione conjugation 32 Heparin 243, 244
Flavoxate 163, 165 Gluthemide 67 Heparin antagonists 245
Fluconazole 345, 346 Glycerinated haemoglobin Heparinoids 244
Flucytosine 345 248 Hexaethyl tetraphosphate 154
Fluocinolone 282 Glycerine 231 Hexobaritone 62
Fluoroquinolones 308 Glycerol suppositories 253 High density lipoproteins
Fluorouracil 374 Glyceryl trinitrate 185 (HDL) 195
Fluoxetine 101, 104 Glycine conjugation 33 Histamine 215
Flurbiprofen 84, 88 Glycopyrrolate 163, 165 HMG CoA reductase
Flurdocortisone 282 Glycosides 4 inhibitors 196
Flutamide 290, 291 Gold compounds 84, 92 Homatropine 163, 164
482 Index
Mood stabilizers 104 Nicotinic acid 195, 196, 198 Olsalazine 256
Morphine 75, 76 Nicotinyl xanthinate 186 Omeprazole 263, 264
Mosapride 258, 259 NIDDM 275 Ondansetron 258, 259
Motion sickness 218 Nifedipine 176, 182, 186 Opioid agonists/antagonists
Moulded passaries 12 Nifurtimox 359 80
Mouth washes 6, 14 Night blindness 385 Opioids 67, 75, 231
Multiple drug therapy 51 Nikethamide 119 Opium 4
Mycophenolate mofetil 379 Nimesulide 84, 91 Oral anticoagulants 245
Myxoedema 293 Nimodipine 119, 121 Oral contraceptives 297
Nitrates 294 Orciprenaline 133, 138, 190,
Nitrazepam 70 232
Nitrofurans 307 Organic iodide 294
N Nitrofurantoin 307, 314
Nitrofurazone 307
Organic mercurials 209
Ornidazole 356
Nitroreductase 34
Nabumetone 84, 92 Orphenadrine 111, 113, 125
Nitrous oxide 62
N-acetyltransferases 32 Osmotic diuretic 204, 209
Nadolol 148, 151 Nocturia 211
OTC (over the counter) 47
Nadroparin 244 Non-competitive antagonism
45 Oxazepam 70, 72, 99
Nafarelin acetate 273 Oxcarbazepine 106, 107
Nalbuphine 80 Non-steroidal
antiinflammatory drugs Oxethazaine 114, 118
Nalidixic acid 308 Oxiracetam 121
Nalmefene 80 (NSAIDs) 83
Noradrenaline 133 Oxprenolol 151
Nalorphine 80 Oxycodone 76
Naloxone 80, 81 Norethindrone 297, 298
Norethindrone enanthate Oxymetazoline 133, 137
Naltrexone 80, 81 Oxymorphone 76
Nandrolone 290, 291 298
Norethisterone 289 Oxyphenbutazone 84, 87
Naphazoline 133
Norfloxacin 308, 309 Oxyphenonium 165
Naproxen 84, 88, 93
Norgestrel 297, 298 Oxytetracycline 311
Nateglinide 277, 280
Normal saline 201 Oxytocin 274
National Formulary 4
Nebivolol 153 Nortriptyline 101, 102
Nebracetam 121 Noscapine 231
Nebulizers 14 N-oxidation 31
Nylidrin 133
P
Nefiracetam 121
Negative antagonists 43 Nystatin 345
Paclitaxel 372, 377
Neomycin 327, 329 Paediatric drops 13
Neostigmine 154, 159
Paints 14
Nephron 34
Neuroleptics 67
O Pamparin 244
Pancuronium 111, 112
Neutral Protamine Hagedorn
Octerotride 270 Panthienate 165
(NPH) insulin 276
Nevirapine 338, 341 Ofloxacin 308, 310, 365, 369 Pantoprazole 263, 265
New Drug Policy 24 Oils 4 Para-amino benzoic acid
Nicergoline 119, 121 Ointments 6, 14 (PABA) 305
Nickel 390 Oleogum resin 5 Para-amino salicylic acid 365
Niclosamide 362 Oleoresins 5 Paracetamol 84, 90
Nicorandil 186 Olive oil 4 Paraldehyde 67
Index 485
Propranolol 99, 148, 150, 172, Rauwolfia serpentina 4 Secnidazole 356, 359
176, 178, 186, 190 Recombinant human Secobarbitone 67, 70
Propyl thiouracil 294 erythropoietin 249 Secondary hypertension 175
Proscillaridin-A 171 Reflex expectorant 229 Sedative 67
Regular (soluble) insulin 276 Selective serotonin reuptake
Prostacyclin I2 (PGI2) 239
Rehydrating solutions 254 inhibitors (SSRI) 103
Prostaglandin analogues 226,
Renin angiotensin system
265 Selegiline 125, 126
175
Prostaglandins 83, 215, 225 Selenium 345, 347, 391
Renzapride 260
Protamine sulfate 245 Senna 4, 253, 255
Repaglinide 277, 279
Protamine zinc insulin 276 Reserpine 176, 177 Serotonin 221
Prothrombin 240 Resins 5 Sertindole 95
Prothrombinase 240 Retinoids 385 Sertraline 101, 103
Proton pump inhibitor 264 Reversible anticholinesterase Sevoflurane 65
Pseudocholinesterase 156 159 Sex hormones 285
Pseudoephedrine 133, 136 Reviparin 244 Shark liver oil 6
Psychostimulants 120 Rheumatoid arthritis 92 Sildenafil 148
Psyllium 253 Ribavarin 338, 342 Silver sulfadiazine 304
Purgative 11 Rifabutin 365, 368 Simmond’s disease 270
Pyrantel pamoate 362 Rifampicin 365, 366, 369, 370 Simvastatin 195, 196
Pyrazinamide 365, 366 Rifapantine 365, 368 Skeletal muscle relaxants 111
Pyridostigmine 154, 160 Rimeterol 133 Sodium biocarbonate 263
Pyridoxine 125 Ringer Lactate 201 Sodium channel blockers 189
Pyrilamine maleate 216 Rioprostil 226 Sodium cromoglycate 232,
Pyrimethamine 350, 352 Ritodrine 133 234
Pyritinol 119, 120 Ritonavir 338, 342 Sodium nitroprusside 176,
Pysllium 254 Rivastigmine 122, 154 183
Ropinirole 125, 126 Sodium phosphate 253
Ropivacaine 114, 118 Sodium picosulphate 253,
Rosiglitazone 277, 280 254
Q Roxatidine 263, 264
Roxithromycin 331, 332
Sodium salicylate 84
Sodium stibogluconate 358
Quinidine 189, 190 Sodium thiosulfate 345, 347
Quinine 350, 352 Sodium valproate 108
Quiniodochlor 345, 347
Quinolones 308
S Soft capsules 10
Solid dosage form 12
Salbutamol 133, 232 Soluble tablets 11
Salicylamide 84 Solutions 10, 13
R Salicylate poisoning 86 Somatostatin 270
Sometrem 270
Salicylates 83
Rabeprazole 263, 265 Salicylism 86 Sotalol 148, 151, 176
Radioactive gold (198AU) Saline expectorants 230 Sparfloxacin 308, 310, 369
372 Salmeterol 133, 232, 233 Spironolactone 204, 208
Radioactive iodine 294, 372 Salt Form 27 Sprays 6, 10, 14
Radioactive phosphorus 372 Scopolamine 68 Stanozolol 290, 291
Ramipril 176, 181 Scored Tablets 11 Status asthmaticus 235
Ranitidine 263, 264 Scurvy 389 Stavudine 338, 340
Index 487
Tripelennamine 216 Verapamil 176, 182, 186, 190 Water soluble vitamins 383
Triphala 5 Very low density lipoproteins
Triprolidine 216 (VLDL) 195
Tropicamide 163, 164
True cholinesterase 156
Vigabatrin 110
Vinblastine 372, 376 X
Trypanosomiasis 358 Vinca rosea 4
Turpentine oil 4 Vincristine 372, 376 Xipamide 204
Tyramine 100 Vinorelbine 372, 376 Xylometazoline 133
Tyrothricin 335 Virilism 271
Viscosity 27
Vitamin A 384 Y
U Vitamin B 383
Vitamin C (Ascorbic acid)
384, 389 Yohimbine 145, 148
United States Pharmacopoeia Vitamin D 383, 384, 385
4 Vitamin E 383, 384, 386
Urea 204, 209
Urinary antiseptics 314
Vitamin K 240, 241, 384 Z
Vitrellae 14
Urokinase 244, 246 Volatile oil 4 Zafirlukast 232, 235
Volume of distribution (Vd) Zaleplon 70, 74
36 Zero order kinetics 36
V Zidovudine 338, 340
Zolliger-Ellison syndrome
Valacyclovir 338, 339 W (ZES) 263
Valproic acid 106 Zolpidem 70, 74
Vancomycin 331, 334 Warfarin 244, 245 Zopiclone 70, 74
Vasopressin 210, 211, 274 Water partition coefficient 25 Zuclopenthixol 95, 98