1

PHARMACOLOGY
- came from the Greek word "Pharmakon" which means "Drug" and "Logos" which means "Discourse" / "Logia" (Latin) - "Study". - it is a science that deals with the chemical and physical properties of drugs, their sources, effects, biotransformation and excretion. - it is the study of the effects of chemical substances upon living tissues. HISTORY OF PHARMACOLOGY Pharmacologic thought had its beginning when early humans began to wonder why the chewing of certain plant roots or leaves altered their awareness or functions. As experience in root and leaf chewing progressed into therapeutic berry picking and smoke smelling, the experiences were spread and shared. As time progressed, some individuals became more astute in observing and remembering that plant products produced predictable effects. Thus, the first pharmacologist was born. Clearly this humble beginning has evolved through the years into a huge industrial and academic community that is concerned with the study and development of drugs. Drugs that evolved are then prescribed and dispensed through the practice of medicine, dentistry, and pharmacy. (for continuation - refer to Holroyd) The history of pharmacology can be divided into 2 periods: the early period dates back to antiquity and is characterized by empirical observations in the use of crude drugs. It is interesting that even primitive people could discover relationships between drugs and disease. The use of drugs has been so prevalent throughout history that Sir William Osler stated (1894) with some justification that man has an inborn craving for medicine. In contrast to this ancient period, modern pharmacology is based on experimental investigations concerning the site and mode of action of drugs. The application of the scientific method to studies on drugs was initiated in France by Francois Magendie and was expanded by Claude Bernard (1813-1878). The name of Oswald Schiemie Debug (1838 1921) is commonly associated with the development of Experimental Pharmacology - in Germany and John Jacob Abel (1857-1938) played a similar role in the U.S. The growth of pharmacology was greatly stimulated by the rise of synthetic organic chemistry which provided new tools and new therapeutic agents. More recently, pharmacology has benefited from developments of other basic sciences and in turn has contributed to their growth. Some of the greatest changes in medicine that have occurred during the last few decades are directly attributable to the discovery of new drugs. Claude Bernard - expanded application in scientific method. Alexander Fleming - discovered penicillin. Hippocrates - father of medicine John Jacob Abel - development of experiments in pharmacology Oswald Schieme Debug - development of experimental pharmacology Joseph Lister - antiseptic technique BRANCHES OF PHARMACOLOGY 1. Pharmacokinetics - concerned with the absorption, distribution, biotransformation, and excretion of drugs. - movement of drugs in the body. "How the body handles the drug?"

2 2. Pharmacodynamics - deals with the effects of drugs in the body; deals with the mechanism of action/effect of a drug in living organisms and their corresponding responses and the physiologic and biochemical effects of the drug. "How the drug produces its effect?" "What the drug does to the body?" 3. Pharmacognosy - identification and procurement of crude and naturally occurring drugs. Former name: "Materia Medica" 4. Pharmacy - procurement, preparation and dispensing of drugs. 5. Pharmacogenetics - effects of drug on people with congenital abnormalities of metabolism. e.q. Eskimos - hydrolyze isoniazid = faster than other races. barbiturates - geriatrics = stimulation instead of depression 6. Posology - study of dosage of drugs. 7. Toxicology - study of the adverse effects of drugs. 8. Biochemorphology - alteration of the chemical structure of drugs to produce a different effect. 9. Developmental pharmacology - effects of drugs in fetal development. e.q. Thalidomide babies - teratogenic. 10. Pharmacotherapeutics - "clinical pharmacology' - the uses/application of drugs in the treatment of disease; the art and science of using drugs in the diagnosis, treatment, and prevention of disease. 11. Descriptive pharmacology - qualitative effects of drugs in man. 12. Clinical Pharmacology the study of the effects of drugs in man. 13. Molecular pharmacology the study of drug effects at the molecular level. IMPORTANCE OF PHARMACOLOGY TO DENTISTRY 1. To be able to cure diseases 2. To be able to prescribe drugs to the patient appropriate for his condition. 3. To be able to communicate with the medical staff and practitioners. ***The dentist should be able to obtain the maximal advantage while producing the minimal disadvantages. ***The prescriber should be aware of how drugs may modify the physiology of the patient.

DRUGS - any chemical substance that affects / modifies the biologic system.
- chemical necessary for the maintenance of life processes by their ability to act selectively in biologic systems to accomplish a desired effect. - a single entity that may be one of the constituent of medicine. Medicine - may contain one or more active constituents (drugs) together with additives to facilitate administration. *** "All medicines are drugs, but not all drugs are medicine." SOURCES OF DRUGS 1. Natural a. Animals - glandular products are the chief medicinal currently obtained form animal sources. e.q. thyroid hormone, insulin from pancreas of cattle and pigs, epinephrine and ACTH.

3 b. Plants - crude drugs maybe obtained from any part of various plants used medicinally. E.q Leaves - Pito-pito, Alagaw, Banaba, etc.; digitalis from foxglove plant. c. Minerals - iron, commonly used in the form of ferrous sulphate 2. Synthetic/Chemical Substances - done in the laboratory by chemists. a. Pure drugs and other simple substances b. Products of complex synthesis (antibiotics, sulfonamides and adrenocorticosteroids). STAGES IN THE DEVELOPMENT OF A DRUG Evolution of a New Drug Drug development Strategies Experimental Pharmacology Toxicological Assessment Clinical Evaluation Marketing and Promotion STRATEGIES * Serendipity (luck and intuition) * Molecular Roulette (random clinical synthesis) * Program Basic Research with Synthesis of Specific Chemicals. * Clinical Observation of Drug Action in the Practice. PRINCIPAL INDIVIDUAL(S) CONCERNED Various Chemist Pharmacologists Biochemists Toxicologists Pharmacists Clinical Pharmacologists Normal Volunteers Dentist/Doctor/Patients Clinical Pharmacologists Nurse Patients Statistician Practicing Dentists/Doctors and their patients STAGES IN THE DEVELOPMENT OF A DRUG Ideas Natural or synthetic chemical compounds Pharmacological Tests Performs "biologic assays" Acute toxicity Chronic toxicity tests Mutagenicity Teratogenesis Carcinogenecity Pharmaceutical formulation / Clinical trials Phase 1: A pilot investigation made in a small number of normal volunteers Phase 2: An open clinical trial carried out in a small number of patients Phase 3: Large scale clinical trial Phase 4: Monitored release and post- marketing surveillance of new drug Accepted drug

CLINICAL EVALUATION Phase I * A pilot study that uses small numbers of human volunteers * Initially, low doses of drug that are gradually increased are used and the toxic or exaggerated effects are monitored Phase II * The drug is tested in limited numbers of hospitalized patients with the disease the drug is

4 intended to treat * The test drug is compared to established drugs and placebo Phase III * Testing is intended to large group of outpatients to permit evaluation of the drug under conditions that may exist if the drug is marketed. * If the drug is safe and effective for its intended use, the FDA may approve the drug for marketing. Phase IV * A new drug is usually marketed only after a few hundreds, or at most few thousand patients have been exposed to it for a relatively short period of time. * Post-marketing surveillance is necessary to assess efficacy and toxicity of a new drug on a larger scale. * 3 MAJOR PHASES IN A PRE-CLINICAL TESTS 1. Acute Toxicity Test 2. Sub-acute (prolonged) Toxicity Test 3. Chronic Toxicity Test PRINCIPLES OF DRUG ACTION 1. Cure disease 2. Alleviate symptoms 3. Replace deficiencies FUNDAMENTAL ACTION OF DRUGS 1. STIMULATION - drugs that increases the overall activity of specialized organs, tissue, or cell. e.q. caffeine (coffee - CNS stimulant; can cause tachycardia (inc. heart activity). 2. DEPRESSION - drugs that decreases the overall functional activity of cells, tissues, or organs. e.q. alcohol, barbiturates. 3. IRRITATION - either inc. or dec. but it is said that stimulation is pushed too far to the point of injuring the cell.; manifested as nausea, vomiting, itchiness, redness. 4. REPLACEMENT / SUPPLEMENT - drugs that can be used as substitutes for what is lacking in the body. e.q. vitamins. 5. ANTIMICROBIAL / ANTIBACTERIAL - when the action of the drug is directed towards the invading microorganism in the body. e.q. antibiotics. 6. ANESTHETIC - a solution that tends to produce a temporary block or nerve conduction. 7. PROPHYLACTIC - to prevent any untoward occurrences/illnesses in the body. e.q. DPT, polio vaccines, etc. *All drugs exert some effect on a biologic system * In most instances, a given effect can be related to drug dosage in a quantitative fashion. *Two important expressions of drug action can be demonstrated: POTENCY and EFFICACY. Potency - amount/strength of a drug required to produce the desired effect or action - is a measure of drug activity in terms of the amount required to produce an effect of given intensity. Efficacy - ability of the drug to elicit its maximum inherent physiologic effect. - the "Maximum Intensity of Effect" of a certain drug.

5 * For example, one drug (drug A) produces complete eradication of premature ventricular contractions (PVCs) at a dose of 10 mg. A second drug (drug B) produces complete eradication of PVCs at a dose of 20 mg. Therefore, both drugs have the same efficacy (complete eradication of PVCs), but drug A is more potent than drug B. It takes less of drug A to produce the same effect. A third drug (drug C) can reduce the PVCs by only 60%, and it takes a dose of 50 mg. to achieve the effect. Therefore, drug C has less efficacy and less potency in the reduction of PVCs compared with both drug A and drug B. CHARACTERISTICS OF DRUG ACTION 1. According to Biochemical Action E.q. Hypoglycemic agents; Hemostatic agents 2. According to Physiologic Effects E.q. Muscle relaxants; Anti-hypertensive agents 3. According to the Organ System on which they exert their Therapeutic Action E.q. CNS stimulants USES OF DRUGS 1. Diagnosis - e.q. barium enema 2. Prevention - e.q. DPT vaccine 3. Contraception - e.q. pills, deprovera, etc. 4. Treatment - e.q. analgesics, antibiotics MECHANISM OF DRUG ACTION 1. Action on a Receptor 2. Action on an Enzyme 3. Action on Membrane Ionic Channels 4. Cytotoxic action I. ACTION ON A RECEPTOR Receptor - a specific macromolecule usually a protein to which a specific group of drug or naturally occurring substances such as neurotransmitter or hormone can bind. RECEPTORS INVOLVED IN THE ACTION OF COMMONLY USED DRUGS RECEPTOR ADRENOCEPTOR 1 2 B1 B2 CHOLINERGIC Muscarinic MAIN ACTION OF NATURAL AGONISTS Vasoconstriction Hypotension ; Sedation Heart Rate Bronchodilation Vasodilation Uterine Relaxation Heart Rate Secretion

6 Gut Motility Bronchoconstriction Contraction of Striated Muscle Bronchoconstriction Capillary Dilation Increased Gastric Acid CNS Neurotransmitter CNS Neurotransmitter

Nicotinic HISTAMINE H1 H2 DOPAMINE OPIOD

II. ACTION ON ENZYME Enzyme - protein macromolecule with which substances interact to produce activation or inhibition. *Drugs in clinical use which exert their effect thru enzyme action generally do so by inhibition. E.q. Aspirin inhibits platelet cyclo-oxygenase; Allopurinol inhibits xanthene oxidase. III. ACTION ON MEMBRANE IONIC CHANNELS The conduction of impulse in nerve tissues and electrochemical coupling in muscles depends on the movement of ions particularly sodium, calcium, and potasium through membrane channels. *Several group of drugs that interfere with these processess: Antiarrythmic drugs, General and local anesthesia, Anticonvulsant. IV. CYTOTOXIC ACTIONS This mechanism have been defined in terms of effects on specific receptors or enzymes. But in other cases, chemical action (Alkylation) damages DNA or other macromolecules and results in cell death or failure of cell division. E.q. Drugs used in cancer or in treatment of infection may kill malignant cells or Microorganisms.

PUBLICATIONS IN PHARMACOLOGY
U.S.P. United States Pharmacopoeia - Representatives from school of medicine and pharmacy - American medical Association - American Pharmaceutical Association - State Medical Societies - American Chemical Society - Other scientific organization and federal agencies Purpose of U.S.P. : It sets the official chemical and physical standards that relate essentially to strength and purity of drug.

7 N.F. National Formulary - issued every 5 years - establishes official standards for drugs not described in the U.S.P. - described extent of drugs' use and therapeutic value British Pharmacopoeia - English equivalent of U.S.P. (Great Britain and Canada) Pharmacopoeia Internationalis - issued by W.H.O. A.D.T. Accepted Dental Therapeutics A.D.R. Accepted Dental Remedies - biennial publication of the Council on Dental Therapeutics (CDT) of the American Dental Association - drugs of recognized value that are labeled and advertised in accordance with CDT are included. - Primarily a handbook of dental pharmacotherapeutics and intended to assist the dental practitioner in the selection of drugs. P.D.R. Physician's Desk Reference - a handbook published annually by some 200 manufacturers Special Value: 1. Published annually and therefore includes relatively up to date information 2. It is cross-indexed to include the use of proprietary names Disadvantages: 1. Products or drugs are arranged by manufacturers rather than by pharmacologic class 2. Information may be "biased".

* REPUBLIC ACT 6675 - known as the GENERIC ACT OF 1988

- an act to Promote, Require and Ensure the production of an adequate supply, distribution, use and acceptance of drugs and medicines identified by their generic names. AIM: 1. To promote, encourage and require the use of generic terminology in the importation, manufacturing, distribution, marketing, advertising and promotion, prescription and dispensing of drugs. 2. To ensure the adequate supply of drug with generic names through a rational system of procurement and distribution. 3. To encourage the extensive use of drug with generic names through a national system of procurement and distribution. Importance of R.A. 6675 1. For health professionals to become more aware and cognizant of their therapeutic effectiveness. 2. To provide drugs to indigent patients at the lowest possible cost. 3. To have healthy competition among drug manufacturers

8 Who Shall Use Generic Terms? All government health agencies All medical, Dental and Veterinary practitioners All drug establishments All drug outlets Penalty for NOT complying to R.A. 6675 First Offense Reprimand which will be recorded in the Professional Regulation Commission Book. Second Offense Fine : Not less than P2,000.00 but not greater than P5,000.00. Third Offense Fine : Not less than P5,000.00 but not greater than P10,000.00. Fourth and Succeeding Fine : Not less than P10,000.00 and suspension of license to practice for one year.

DRUG NOMENCLATURE
1. CHEMICAL NAME "FIRST NAME" given to compound of known composition - conveys the chemical structure of the compound. E.q. N-Acetyl p-aminophenol CODE DESIGNATION - convenient means of referring to the compound before it has been assigned either a generic or trade name. 2 Types of Code Designation 1. A letter and number combination e.q. SH 567 letter/s - research laboratory involved number/s - arbitrarily assigned 2. Letter combination e.q. AZT - Azothymidine TPA - Tissue Plasminogen Activator ASA - Acetyl Salicylic Acid 2. TRADE NAME (Commercial Name; Proprietary Name; Brand Name) - name of the company who manufactured the drug - gives no or little information about the drug itself BRAND NAME - name of the company marketing the product - distinguishes its product from others. - E.q. Biogesic, Ponstan, Flanax, Amoxil, Two Important Disadvantages of Trade Name: 1. Makes the problem of drug identification more complex 2. Deprive the patient to avail of a less expensive generic preparations.

9 Advantages of Trade Names: 1. They are convenient and saves time when writing prescriptions for multiple-entity drugs 2. Trade names are usually shorter and easier to remember than generic names. 3. The use of trade names demands the product of a specific manufacturer in whose manufacturing practices the practitioner may have special confidence. 3. GENERIC NAME - "Official" name of the drug; "Non-Proprietary name. Advantages of using Generic Names 1. Healthy competition among drug manufacturers 2. Provides a wide selection of drugs 3. It is universally accepted. Disadvantages of using Generic Names 1. Not all preparations are prepared as they should be. 2. It is hard to remember. 3. It is inconvenient when written. E.g. Chemical : Generic : Trade Name : 2-diethylamino 2,6 acetoxylidide Lidocaine Xylocaine Dolicaine Octocaine L-caine : : : : : : N-acetyl p-aminophenol Acetaminophen Tylenol Tempra Valadol Datril

*** How to use the PIMS / MIMS PIMS - Philippine Index for Medical Specialties MIMS - Monthly Index for Medical Specialties. It is a global term for a therapeutic index. Brand Name /Manufacturer / Distributor Contents (C) Indication/s (I) Dosage (D) Contraindications ( C/I ) Special Precautions ( SP ) Adverse Reactions ( AR ) Drug Interactions ( DI ) Presentation / Price ( P/P ) Example: (Based from MIMS Dental Phils. 2002 page 68) ATMOSE Morishita-Seggs Rx (Metro Drug) C. Mefenamic Acid I. Relief of mild to moderate pain including (Atmose is the proprietary name of the drug; Morishita-Seggs is the name of the company who manufactured the drug

10 headache, dental pain, post-op and postpartum Metro Drug is the name of the pain, dysmenorrhea, osteoarthritis and RA. company marketing the product D. Adult and children > 14 yr. Initially 500 mg. Rx means this drug needs prescription then 250 mg 6 hrly. P/P. Atmose is available in capsule CI. Peptic ulceration or inflammatory bowel disease. form at a dosage of 500 mg.; SP. Hepatic or renal impairment; epilepsy. X100 means in one box there are AR. GI disturbances; peptic ulceration, GI bleeding; 100 capsules that costs drowsiness; dizziness; nervousness; visual Php357.63 disturbances; skin rash; urticaria; blood dyscrasias. DI. Enhances the effects of the coumarin anticoagulants. P/P. Cap 500 mg X 100s (P357.63) PHARMACOLOGICAL CLASSIFICATION INDEX Pharmacological Classes and Sub-classes (based on MIMS Dental Phils 2002) I. ALIMENTARY SYSTEM 1. Antacids and Antiulcerants 2. GIT regulators, Antiflatulents and Anti-Inflammatories 3. Antispasmodics 4. Antidiarrheals 5. Laxatives, Purgatives 6. Digestives 7. Cholagogues, Cholelitholytics and Hepatic Protectors

II. CARDIOVASCULAR AND HEMATOPOIETIC SYSTEM 1. Cardiac Drugs 2. Anti-anginal Drugs 3. ACE Inhibitors 4. Beta Blockers 5. Calcium Antagonists 6. Diuretics 7. Antidiuretics 8. Peripheral Vasodilators and Cerebral Activators 9. Vasoconstrictors 10. Migraine Drugs 11. Haemostatics 12. Anticoagulants, Antithrombotics and Fibrinolytics 13. Haemorrhoidal, Phlebitis and Varicose Preparations 14. Haemorrheologicals 15. Haematopoetic Agents 16. Other Cardiovascular Drugs III. RESPIRATORY SYSTEM 1. Respiratory Stimulants 2. Antiasthmatic Preparations

11 3. Cough and Cold Remedies 4. Decongestants and other Nasal Preparations 5. Other drugs acting on Respiratory System IV. NEUROMUSCULAR SYSTEM 1. Anti-inflammatory Enzymes 2. Analgesics and Antipyretics 3. Antirheumatic, Anti-inflammatory Analgesics 4. Gout Preparations 5. Minor Tranquilisers 6. Major Tranquilisers 7. Hypnotics and Sedatives 8. Anticonvulsants 9. Antidepressants 10. CNS Stimulants 11. Nootropics and Neurotonics 12. Antiemetics and Antivertigo Drugs 13. Neurodegenerative Disease Drugs 14. Antiparkinsonism Preparations 15. Neuromuscular Disorder Drugs 16. Muscle Relaxants V. HORMONES 1. Androgens and Related Synthetic Drugs 2. Oestrogens and Progesterones and Related Synthetic Drugs 3. Combined Sex Hormones 4. Corticosteroid Hormones 5. Trophic Hormones and Related Synthetic drugs 6. Anabolic Agents 7. Other Hormone Related Drugs VI. CONTRACEPTIVE AGENTS 1. Depot Contraceptives 2. Oral Contraceptives 3. Other Contraceptives VII. ANTIBIOTICS 1. Aminoglycosides 2. Cephalosphorins 3. Chloramphenicols 4. Macrolides 5. Penicillins 6. Quinolones 7. Tetracyclines 8. Antifungals 9. Antibacterial Combinations 10. Other Antibiotics

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VIII. OTHER CHEMOTHERAPEUTICS 1. Antituberculous Agents 2. Sulphonamides 3. Antiamoebics 4. Anthelmintics 5. Antileprotics 6. Antivirals 7. Antineoplastics 8. Antimalarials 9. Leishmaniacides, Trypanocides 10. Filaricides IX. GENITO-URINARY SYSTEM 1. Preparations for Vaginal Conditions 2. Urinary Antiseptics 3. Drug acting on Uterus 4. Other Drugs Acting on Genito-Urinary System X. METABOLISM 1. Insulins 2. Oral Antidiabetic Agents 3. Thyroid Preparations 4. Antithyroids 5. Antihyperlipidaemic Agents 6. Other Agents Affecting Metabolism XI. VITAMINS AND MINERALS 1. Vitamins A, D, E 2. Vitamin Bs / with C 3. Vitamin C 4. Calcium / with Vitamins 5. Multivitamins / with Minerals 6. Vitamins with Hormones / Geriatric Preparations 7. Pediatric Vitamins and Minerals 8. Electrolytes and Minerals 9. Antianemics / Pre and Post Natal Vitamins XII. NUTRITION 1. Infant / Follow-On Formulae 2. Enteral / Nutritional Products 3. Parenteral Nutrition 4. Tonics 5. Appetite Stimulants 6. Antiobesity Agents

13 EYE, EAR, MOUTH / THROAT *EYE 1. Eye Anti-infectives and Antiseptics 2. Eye corticosteroids 3. Eye Antiseptics with Corticosteroids 4. Mydriatic Drugs 5. Miotic Drugs 6. Glaucoma Preparations 7. Other Eye Preparations *EAR 1. Ear Anti-infectives and Antiseptics 2. Ear Corticosteroids 3. Ear Antiseptics with corticosteroids 4. Other Ear Preparations *Mouth / Throat 1. Mouth / Throat Preparations XIV. DERMATOLOGICALS 1. Topical Anti-infectives 2. Topical Anti-infectives with Corticosteroids 3. Topical Corticosteroids 4. Acne Treatment Preparations 5. Antiseptics and Disinfectants 6. Medicated Surgical Dressings 7. Topical Fungicides and Antiparasites 8. Psoriasis, Seborrhea and Ichthyosis Preparations 9. Topical Antivirals 10. Keratolytics 11. Skin Protectives 12. Topical Antihistamines / Antipruritics 13. Topical Analgesics and Anti-inflammatories 14. Other Dermatologicals XV. ANAESTHETICS 1. Local Anesthetics 2. General Anesthetics XVI. DIAGNOSTIC AGENTS 1. Urinalysis Agents XVII. ALLERGY AND IMMUNE SYSTEM 1. Antihistamines and Antiallergies 2. Vaccines, Antisera and Immunologicals 3. Immunosuppressants

14 ANTIDOTES AND DETOXIFYING AGENTS INTRAVENOUS AND OTHER STERILE SOLUTIONS XX. MISCELLANEOUS Different Factors Affecting Response: Routes of Drug Administration Passage of Drug Across Body Membranes Molecular Mechanism of Action Absorption Distribution Metabolism Excretion FATE of a DRUG

ROUTES OF DRUG ADMINISTRATION ENTERAL Oral Rectal PARENTERAL Hypodermic Routes Intravenous Intramuscular Subcutaneous Intradermal Intrathecal Intraperitoneal Additional Routes Topical Inhalation Sublingual Transdermal LOCAL ROUTE Topical Intradermal Intrathecal Intranasal Intraconjuctival Intra-oral Intra-articular Intra-arterial Other special routes

15 SYSTEMIC ROUTES Enteral Parenteral *** Locally administered drugs may be absorbed at a rate and to an extent sufficient to result in the production of systemic effects. ENTERAL ROUTES - drug is placed directly into the GIT from where absorption occurs. A. ORAL ROUTE - simplest and most convenient for self administration. Contraindication for Oral Route 1. Patients with gastrointestinal intolerance 2. Patients preparing for anesthesia 3. Patients with gastrointestinal surgery 4. Precluded in coma Disadvantages of Oral Route 1. Irritant drugs cannot always be given by mouth for it may cause sickness. 2. It is not feasible to give drugs by this route to patients who are vomiting or moribund. 3. Many drugs are destroyed by the action of the digestive ferments before they can be absorbed. 4. Intestinal absorption may be irregular due to other substances in the git. 5. Intestinal absorption may be affected by changes in gastric emptying which may increase or decrease the rate of absorption. "First Pass Effect" - refers to the metabolism of a drug en route from the gut lumen to the systemic circulation. - a process that rapidly deactivate some drugs in the liver that was given orally and was initially perfused into the hepatic portal circulation. Some drugs do not go directly into the systemic circulation following absorption but pass from the intestinal lumen to the liver, by the portal vein. In the liver, most of the drug is metabolized to an inactive drug form for excretion, reducing the amount of active drug. Importance of First Pass Metabolism 1. It is one of the reasons for the apparent differences in drug absorption between individuals. 2. In patients with severe liver disease, first-pass metabolism may be dramatically reduced leading to the absorption of greater amounts of parent drug. Drugs with High First Pass Metabolism Analgesics Aspirin Morphine Paracetamol Pentazocine

16 Pethidine Respiratory Drugs Salbutamol Terbutaline Drugs Acting on Central Nervous System Chlormethiazole Chlorpromazine Imipramine Levodopa Nortriptyline Oral Contraceptives Cardiovascular Drugs Glyceryl Trinitrate Isoprenaline Nifedipine Prazosin Propanolol Verapamil Lignocaine Metropolol RECTAL ROUTE - drugs are given via the rectum. E.q. solid form suppositories; liquid form enemata. - used when oral administration is impossible. - avoids the acidity and enzymes of the gastric juice and first pass metabolism. - Both local and systemic effects are obtained but absorption of many drugs are often irregular and incomplete. Indications: Pediatrics / Geriatrics PARENTERAL ROUTES - generally chosen when speed or reliability are specially desired. A. Injection essential if the drug is to be absorbed in active form. - absorption is usually more predictable and more rapid - requires special skill; drugs cannot be withdrawn easily. Disadvantages 1. Difficult for the patients to perform the injection by themselves. 2. Strict asepsis must be maintained to avoid infection 3. Usually more costly and less safe. 4. Can cause pain. TYPES OF INJECTION Intravenous (IV) - route of choice for emergency cases - Most rapid route / method to elicit drug response. Advantages 1. Rapid action 2. Can be used for drugs which are irritant by IM injection. 3. Useful for ill, hospitalized patients when a slow IV infusion provides a steady flow without disturbing the patient

17 Disadvantages 1. Tend to produce more immediate adverse reactions. 2. Too high concentration of the drug is readily obtained when injected rapidly. 3. The chance of penetration into an artery instead of a vein is a possibility. Complications: 1. Drug Shock 2. Acute, serious, allergic responses 3. Phlebitis 4. Necrosis around the injection site. Intradermal (cutaneous) - E.q. skin testing. Action: - local effect - small amount is injected into the epidermis of the skin so that volume does not interfere with wheal formation or cause a systemic reaction. - used for observation of an inflammatory (allergic) reaction to foreign proteins. - rarely employed except in certain Diagnostic and test procedures (screening for allergic or local irritant responses). - takes the longest time for drug absorption. Sites: - Locations are chosen so that inflammatory reaction can be observed. Preferred areas are lightly pigmented, thinly keratinized, and hairless such as ventral mid-forearm, clavicular area of chest, scapula area of back, and medial aspect of thighs. Equipment: Needle: 26 27 gauge Syringe: 1 ml. calibrated in 0.01 ml. increments Usually 0.01 0.1 ml. injected. Technique: Cleanse area using circular motion; observe sterile technique. Hold skin taut. Insert needle, bevel up, at a 15 degree angle; outline of needle under the skin should be visible. Inject medication slowly to form a wheal (blister or bleb). Remove needle slowly. Make a mark or encircle the bleb with a pen. Do not massage area; instruct client not to do so. Assess for allergic reaction in 24 72 hours; measure diameter of local reaction. Subcutaneous - for drugs which are not irritant to tissues. E.q. morphine sulphate, adrenaline, and insulin. - volume is usually 1 ml. or less; seldom exceeds 2 ml. - cutaneous blood flow is slower compared to IM

18 - sustained effect can be obtained by placing a pellet of drug subcutaneously; e.q. Estradiol plants. - drug is injected in the subcutaneous layer into the alveolar connective tissue just below the skin. Action: Systemic effect Sustained effect; absorbed mainly through capillaries; usually slower in onset than with intramuscular route. - Used for small doses of non-irritating water-soluble drugs. Sites: - Locations for subcutaneous injection are chosen for adequate fat pad size and include the abdomen, upper hips, upper back, lateral upper arms, and lateral hips. Equipment: Needle: 25 27 gauge - 5/8 in. in length Syringe: 1 3 ml. Usually 0.5 1.5 ml. injected. Insulin syringe measured in units for use with insulin only.

Technique: Cleanse area with circular motion using sterile technique Pinch the skin. Insert needle at angle appropriate to body size. 45 to 90 degrees. Release skin. Aspirate, except with heparin. Inject medication slowly. Remove needle quickly. Gently massage area, unless contraindicated with heparin. Apply plaster if needed. Advantages: 1. Spread the action out over a number of hours. 2. Avoid too intense or too short response 3. Avoid frequent injections. Layer of skin and site of injections: Epidermis Cutaneous Dermis Membrane Fascia Subcutaneous

19 Muscle Intramuscular (IM) - more dangerous than IV; better for irritant tissues. Action: systemic effect. Usually more rapid effect of drug than with subcutaneous. Used for irritating drugs, aqueous suspensions, and solutions in oils. indicated when an immediate effect is not required but a prompt effect is desirable.- 10 30 minutes absorption. Sites: Locations are chosen for adequate muscle size and minimal major nerves and blood vessels in the area. Preferred locations include ventrogluteal, dorsogluteal, deltoid, and vastus lateralis. Equipment: Needle: 18 21 gauge 1 1.5 in. in length Syringe: 1 3 ml. Usually 0.5 1.5 ml. injected

Technique: Same as for subcutaneous injection except that needle is inserted at 90 degree angle into the muscle.

Figure:

Angles for injections. (A) IM 90 (B) (C) (D) SC 90 , 60 , 45

(E) ID 10=15 .

Intraperitoneal injected into the peritoneal cavity by absorption of messenteric veins

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Intrapleural - introduce into the pleural cavity; for aspiration of fluids. Intrathecal / Intraspinal - for spinal analgesia into the spinal subarachnoid space. - administered into the cerebrospinal fluid at any level of the cerebrospinal axis. Intraneural - used in trigeminal neuralgia. Intrasternal - drugs which normally do not cross the blood brain barrier. BUCCAL and SUBLINGUAL route - an enteral route infrequently used but useful in drugs with first pass hepatic metabolism. E.q. glyceryl trinitrate for angina attack but ineffective when swallowed as its first pass metabolism approaches 100 per cent - drugs that are susceptible to degradation by the GIT and even the liver are safely administered sublingually. INHALATION - E.q. inhalation anesthetics, aerosol inhalation for asthma. inhalation is via the mouth; absorption occurs in the small bronchioles. E.q. disodium cromoglycate via a Spinhaler. - drug is absorbed through the pulmonary endothelium at the alveoli to gain rapid access to the general circulation. Reasons for rapid absorption 1. Alveolar and vascular epithelial membranes of the lungs are quite permeable. 2. Blood flow is abundant. 3. There is al large surface for absorption. Particle Size 1. Particles greater than I um in diameter - tend to settle in the bronchi. 2. Particles less than 0.5 um - fail to settle; mainly are exhaled. TOPICAL - least effective. - drug is applied to the skin and other epithelial surfaces with glove, tongue blade, or cotton-tipped applicator. - utilized for local drug effect. - Use appropriate technique to remove medication form container and apply to clean, dry skin, when possible. Do not contaminate medication in container, use gloves or an applicator. Methods of enhancing drug absorption via the Topical route Ionotophresis - uses galvanic current Inunction - mechanical rubbing of drug into the skin. TRANSDERMAL - stored in a patch placed on the skin and absorbed through skin, having systemic effect

21 Transdermal drugs provide more consistent blood levels and avoid GI absorption associated with oral products.

PHARMACEUTICAL PREPARATIONS AND DOSAGE FORMS

Pharmaceutical preparations are the forms in which drugs are prepared by the pharmacist or pharmaceutical chemist for administration in the treatment of the sick. SOLID PREPARATIONS Aerosols - packed with compressed gas under pressure for topical application. Upon release, the aerosol takes the form of a fine mist, foam, semisolid fluid or solid. Ampules - are hermetically sealed glass containers for medicinal substances containing a sterile solution for parenteral use. Capsules - small gelatin receptacles of various sizes for oral administration. Generally dissolve in the stomach except the enteric capsules which dissolves in the intestines. They maybe of firm or flexible consistency. Carpules - are glass tubes enclosed on both ends with rubber stoppers, one acting as a plunger, the other as a diaphragm. Contain a drug in solution and designed for parenteral medication Confections - medicinal substances formed into a mass with sugar, honey, and water as confection of rose. Effervescent Salts - powdered drug which give off CO2 gas and go into solution when added to water. Konseals - (rice flour capsules) or wafers (thin sheets of dried flour paste) sometimes used to enclose drug powders. Papers - paper impregnated with medicinal substances. E.q. mustard paper Pills - small spherical masses of drugs intended for swallowing covered with various substances as gelatin, salol, sugar, chocolate, etc. and generally colored; powdered drugs mixed with adhesive substances like glucose or honey and molded in spherical or ovoid forms. Suppositories - solid bodies of various weights and shapes adapted for introduction into orifices (vagina, rectum, urethra, etc.) of the human body and usually melting, softening, or dissolving at body temperature. For urethral use, they are called bougies. Rectal Suppositories - conical or bullet-shaped, usually weigh about 2 grams. Used to produce local and systemic effects and to produce catharsis. Vaginal Suppositories - conical or spherical in shape and weigh from 4 10 grams. Used to confer antisepsis, to combat various infections, and as spermatocides. Urethral Suppositories - pencil-shaped and weigh for 2 4 grams. Used mainly for local treatment of the female urethra Tablets - solid dosage forms containing granulated or powdered drugs that are compressed or molded into round or discoid shapes.contains medicinal substances with or without suitable diluents. They vary in shape, size and weight. It may be classed according to the method of manufacture, as molded tablets or compressed tablets. Troches - lozenges intended to be dissolved in the mouth for local effect on the mucous membrane of the mouth and throat.

22 SEMI-SOLID PREPARATIONS Cerates - unctuous preparations having for their bases the simple cerate. Similar to ointments in consistency but do not melt at body temperature. E.q. Cantharides cerate. Creams - semi-solid emulsions of either the oil-water or the water in oil type for topical application. Extracts - concentrated preparation of vegetable or animal drugs. Made in 3 forms: 1) Semi liquids or liquids of syrupy consistency 2) Plastic masses (pilular or solid extracts) and 3) Dry powders (powdered extracts. Ointments - for external application. Medicinal substances are combined with a base of sufficient softness which tend to fall into two groups: hydrophilic such as the lanolin and the lipophilic, such as the petrolatum. E.q. ZOE ointment Pastes - comprise two classes of ointment-like preparations intended for external application: 1)Hydrogels such as hydrated pectin; and 2) Fatty pastes such as ZOE paste, which consist of thick, stiff ointments which do not ordinarily flow at body temperature and therefore serve as protective coatings over the areas they are applied. Plasters - adhesive, fatty or resinous compounds spread on textile fibers, leather, muslin, etc., Either soft or dry and intended for local application. E.q. Belladone plaster, etc.. Poultices (Cataplasma) - semi-liquid mixtures of such substances as flaxseed, elm bark, or bread, etc., with hot water or milk, spread upon cloth and used as a means for applying heat and moisture or stimulation to the body surfaces. E.q. Cataplasma Kaolini. Triturations - powders consisting of an active remedy triturated with sugar or milk, usually of 10% strength. E.q. Triturations of Elaterin. LIQUID PREPARATIONS Aromatic waters - saturated (0.2%) aqueous solutions of volatile substances, usually volatile oils. Generally used as vehicle for water-soluble drugs. E.q. peppermint water. Collodions - liquid preparations having for their base a solution of guncotton (pyroxylin) in a mixture of ether and alcohol. E.q. Flexible collodion. Collyria - Medicinal eyewashes. Decoctions - solutions of vegetable substances prepared by boiling with water in a closed container for 15 minutes and strained as decoction of coffee and sarsaparilla. Elixirs - clear, sweetened, hydroalcoholic liquids intended for oral use. Contains flavoring substances. Because of alcoholic content, they are miscible with tinctures. Two types: 1. Aromatic elixir - used mainly for diluting other liquid preparations 2. Medicated elixirs - include Phenobarbital elixir, Diphenhydramine Hydrochloride Elixir, and Terpin Hydrate and Codeine elixir. Emulsions - aqueous preparations in which oils, oleoresins, balsams, resins, or other substances which are insoluble in water are suspended by means of gum or other viscid excipients. E.q. Cod liver oil emulsion, milk and eggyolk. Fluid extracts - liquid extractions of drugs prepared by percolation. Concentrated tinctures in which 1 g. of the drug corresponds to 1 ml. of the finished product. E.q. Ergot fluid extract. Gargles - mixtures or hydroalcoholic solutions for application to the pharynx and mouth. Gels - suspension in a water medium, of insoluble drugs in hydrated form wherein particle size approaches or attains colloidal dimensions. Glycerites - mixtures or solutions of medicinal substances with or in glycerin. E.q. Tannic acid

23 glycerite. Honeys - solutions of drug in clarified honey. E.q. Honey of rose. Injections - sterile preparations for parenteral use. Comprise of 1) Solutions for injection 2) Dry solids, which upon the addition of suitable solvents yield solutions conforming in all respects to the requirements for injections 3) Solids suspended in a suitable fluid medium which are not to be injected IV or into the spinal canal 4) dry solids, which upon the addition of suitable vehicles, yield preparations conforming to the requirements for sterile suspensions and 5) emulsions of fluids in fluid media, suitable for parenteral administration, but are not to be injected in the spinal canal. Liniments - liquid ointments applied with friction to the skin. Lotions - mixtures or solutions of medicinal agents intended for external application with soothing and protective effect. Milks - suspension of poorly soluble drugs in water medium and distinguished from gels mainly in that the suspended particles are larger. They tend to separate on standing and must be shaken well before use. E.q. Milk of magnesia. Mixtures - suspension of drugs in an aqueous vehicle. E.q. Brown mixture. Oleates - solutions of metallic salts or alkaloids in oleic acid. E.q. Oleate of Mercury. Solutions - liquid preparations that contain one or several soluble chemical substances (non volatile) in water. Spirits or Essences - volatile substances dissolved in alcoholic solution. Many are flavoring agents. E.q. Peppermint spirit also used as a carminative. Aromatic Ammonia Spirit a medicated spirit used as a reflex stimulant. Suspensions - finely divided drugs either intended for suspension in some suitable liquid vehicle prior to use or already in suspension in a liquid vehicle. Syrups - highly concentrated solutions of sugar such as sucrose in water, carrying flavors or medicinal substances as syrup of Orange, Syrup of Wild cherry. Syrups serves as vehicle or preservatives. Some contain active therapeutic agents. 2 Classes of Syrups: 1. Flavored syrups - employed to mask the taste of unpleasant tasting drugs and to add stability to preparations. E.q Acacia syrup, Cocoa syrup. 2. Medicated syrups - E.q Ipecac syrup (emetic, expectorant); Chloral Hydrate syrup (hypnotic), contain some added medicinal substances. Tinctures - hydroalcoholic solutions of medicinal substances usually obtained by extractin of vegetable drugs; generally alcoholic extracts of vegetable or animal drugs obtained by percolation. E.q. Belladona tincture; Vanilla tincture (used as flavoring agents); Iodine tincture (used as antiseptic). Waters - may be a natural product, as tap water, or distilled and de-ionized to form a more purified and sterile product. E.q. Water for injection. SYSTEMS OF MEASUREMENT Three systems of measurement (metric, apothecary, and household) are used in measuring drugs and solutions. The metric system developed in the late eighteenth century, is the internationally accepted system of measure. It is replacing the apothecary system, which dates back to the middle ages and had been used in England since the 17th century. It is proposed that the apothecary system will phase out by the end of this century. Household measurement is commonly used in community and home settings.

24

I. METRIC - to measure based on decimals and Arabic numbers; the official system used in the USP. Units: Meter (m) = for length Liter (l) = for capacity Gram (gm.) = for weight Table of Capacity = 1,000 l. = 100 l. = 10 l. = 0.1 l. = 0.01 l. = 0.001 l. Table of Weight = 1,000 gm. = 100 gm. = 10 gm. = 0.1 gm. = 0.01 gm. = 0.001 gm.

Metric Tables: Table of Length 1 km. = 1,000 m. 1 hm. = 100 m. 1 dkm = 10 m. 1 dm. = 0.1 m. 1 cm. = 0.01 m. 1mm. = 0.001 m.

1 kl. 1 hl. 1 dkl 1 dl. 1 cl. 1ml.

1 kg. 1 hg. 1 dkg 1 dg. 1 cg. 1mg.

Procedure for Conversion Between Units of the Metric System: 1. To change milligrams to grams, milliliters to liters, or grams to kilograms, divide by 1000. 2. To change liters to milliliters, grams to milligrams, kilograms to grams, multiply by 1000. Examples: a. 64 mg. = ? gm. 1000 mg. : 1 gm. = 64 mg. : x gm. 1000 x = 64 x = . 64 . 1000 = 0.064 gm. b. 325 ml. = ?L 1000 ml. : 1L. = 325 ml. : x L. 1000 x = 325 x = . 325 . 1000 = 0.325 L II. APOTHECARIES OR ENGLISH SYSTEM - In this older system, Roman numerals and common fractions are used to designate units. Also, the units of measure precede the numeral in correct form. e.q the correct way to signify 20 grains would be gr.xx. A line is often written above the numerals, and a dot is placed above the numeral I to distinguish more clearly between the two Is and a V or X hastily written. When using the apothecary system in calculations, however, the Arabic numbers are used.

25 Procedure for Conversion Within the apothecary System 1. Write the equivalent between the terms to be converted as the first two terms of the proportion. 2. Being careful to keep the units in the last two terms in the same order as they occur in the first, write the known quantity and the unknown equivalent as the third and fourth terms of the proportion. Examples: a. 6 drams = ? ounces 8 drams : 1 ounce = 6 drams : X ounces 8x = 6 x = . 6 . = . 3 . ounce 8 4 b. 2 drams = ? minims 60 minims : 1 dram = x minims : 2 drams 1 x = 120 x = 120 minims TABLE OF WEIGHT 60 grains = 1 dram 8 drams = 1 ounce 12 ounces = 1 lb. TABLE OF CAPACITY 60 minims = 1 fluidram 480 minims or 8 fluidrams = 1 fluid ounce 7680 minims or 16 fluid ounces = 1 pint 2 pints = 1 quart 4 quarts = 1 gallon III. HOUSEHOLD SYSTEM - The household system of measurement is not as accurate as the metric system because of the lack of standardization of spoons, cups, and glasses. The measurements are approximate. HOUSEHOLD UNITS OF MEASUREMENT 60 drops (gtt) = 1 teaspoon 3 teaspoon = 1 tablespoon (tbs) 6 teaspoon = 1 ounce 2 tbs = 1 oz. 6 oz. = 1 tea cup 8 oz. = 1 glass 8 oz. = 1 measuring cup OTHER EQUIVALENTS 1,000 cc. = 1 L = 1 quart 500 cc. = 1 pint 30 cc. = 1 fluidounce = 2 tbsp.

26 5 cc. = 1 fluidram = 60 minims = 1 tsp. 1 cc. = 15 minims 1 kg. = 1000 gms. = 2.2. lbs. 4 gms. = 1 dram = 60 grains TEMPERATURE CONVERSION Celsius to Farenheit: ( C ) (9/5) + 32 Farenheit to Celsius: ( F 32 ) (5/9)

METRIC DOSES with APPROXIMATE APOTHECARY EQUIVALENTS ( by Musser/ONeil * reprinted from USP XVI) LIQUID MEASURE Approximate APOTHECARY METRIC equivalents 1 quart 3 ml. 1 pints 2 ml. 1 pint 1 ml. 8 fluid ounces 0.75 ml. 7 fluid ounces 0.6 ml. 3 fluid ounces 0.5 ml. 1 fluid ounces 0.3 ml. 1 fluid ounce 0.25 ml. 4 fluid drams 0.2 ml. 2 fluid drams 0.1 ml. 2 fluid drams 0.06 ml. 1 fluid drams 0.05 ml. 1 fluid drams 0.03 ml. WEIGHT Approximate APOTHECARY METRIC Equivalents 1 ounce 30 mg. 4 drams 25 mg. 2 drams 20 mg. 2 drams 15 mg. 90 grains 12 mg. 75 grains 10 mg. 60 grains (1 dram) 8 mg. 45 grains 6 mg. 30 grains 5 mg. 22 grains 4 mg. 15 grains 3 mg. Approximate APOTHECARY equivalents 45 minims 30 minims 15 minims 12 minims 10 minims 8 minims 5 minims 4 minims 3 minims 1 minims 1 minim minim minim Approximate APOTHECARY equivalents grain 3/8 grain 1/3 grain grain 1/5 grain 1/6 grain 1/8 grain 1/10 grain 1/12 grain 1/15 grain 1/20 grain

METRIC 1000 ml. 750 ml. 500 ml. 250 ml. 200 ml. 100 ml. 50 ml. 30 ml. 15 ml. 10 ml. 8 ml. 5 ml. 4 ml.

METRIC 30 Gm. 15 Gm. 10 Gm. 7.5 Gm. 6 Gm. 5 Gm. 4 Gm. 3 Gm. 2 Gm. 1.5 Gm. 1 Gm.

27 0.75 Gm. 0.6 Gm. 0.5 Gm. 0.4 Gm. 0.3 Gm. 0.25 Gm. 0.2 Gm. 0.15 Gm. 0.12 Gm. 0.1 Gm. 75 mg. 50 mg. 60 mg. 40 mg. 12 grains 10 grains 7 grains 6 grains 5 grains 4 grains 3 grains 2 grains 2 grains 1 grains 1 grains 1 grains grain 2/3 grains 2 mg. 1.5 mg. 1.2 mg. 1 mg. 0.8 mg. 0.6 mg. 0.5 mg. 0.4 mg. 0.3 mg. 0.25 mg. 0.2 mg. 0.15 mg. 0.12 mg. 0.1 mg. 1/30 grain 1/40 grain 1/50 grain 1/60 grain 1/80 grain 1/100 grain 1/120 grain 1/150 grain 1/200 grain 1/250 grain 1/300 grain 1/400 grain 1/500 grain 1/600 grain

APPROXIMATE HOUSEHOLD EQUIVALENTS HOUSEHOLD APOTHECARY METRIC 1 drop (gt) 1 minim (m or min) 0.06 milliliter (ml.) 15 drops (gtt) 15 min 1 ml. (cc.) 1 teaspoon (tsp) 1 fluidram (60 minims) 5 or 4 ml. * 1 tablespoon (tbsp) 4 fluid dram 15 ml. 2 Tbs. 1 fluid ounce 30 ml. 1 ounce 1 fluid ounce 30 ml. 1 tea cup 6 fluid ounce 180 ml. 1 glass 8 fluid ounce 240 ml. 1 measuring cup 8 fluid ounce 240 ml. 2 measuring cups 1 pint (pt) 500 ml.

DOSE CALCULATIONS
Children are not able to tolerate adult doses of drugs. There are several formulas for graduating dosage according to age and weight. The recommended dosage for kg. or lb. of body weight is more accurate than calculating dosage according to age. Other factors beside age and weight enter into dosage for children. For this reason, some physicians, use the :body surface area method to estimate the dosage for children. Charts are available to determine the body surface area in square meters according to height and weight. For Infants and Preschool children Clarks Rule

28

Weight (lbs.) X Adult dose ---------------------------------- = Infant dose 150 Frieds Rule - sometimes used in calculating dosages for infants less than 2 years old. Age (mos.) X Adult dose --------------------------------- = Infant dose 15 For Preschool to Adolescent years: Youngs Rule - not valid after 12 years of age. If the child is small enough to warrant a reduced dose after 12 years of age, the reduction should be calculated on the basis of Clarks rule. Age (yr.) X Adult dose ---------------------------------- = Child dose Age (yr.) + 12 Cowlings Rule Age (at next b-day) X Adult dose ------------------------------------------- = Child dose 24 Calculation based on Body Surface Area (BSA) : - considered to be the most accurate way to calculate the drug dose for infants, children, older adults, and clients who are on antineoplastic agents or whose body weight is low. The BSA, in square meters is determined by where the persons height and weight intersect the nomogram scale. Surface area X Adult dose ----------------------------------- = Child dose 2.00 OR Multiply the drug dose ordered by the number of square meters. Example: Order: Cyclophosphamide (Cytoxan) 100 mg. / m2 / day, PO

29 Patient is 5 ft. 10 in. (70 in.) tall and weighs 160 lbs. a. 70 in. and 160 lbs. intersect the nomogram at 1.97 m2 (BSA) b. 100 mg. x 1.97 = 197 mg. Answer: Administer Cyclophosphamide 197 mg. or 200 mg./day.

30

31

PRESENTLY USED DOSE CALCULATION: Weight: (Ideal Body Weight) At Birth: 3000 Grams Less than 6 months: Weight In Grams Age in Months X 600 + Birth Weight 6 12 Months: Weight in Grams Age in Months X 500 + Birth Weight 1 6 Years: Weight in Kilograms Age in Years X 2 + 8 7 12 Years: Weight in Kilograms Age in Years X 7 - 5 2 Suggested Dose: Age 13 18 years = 250 mg. 19 above = 500 mg. Example: Given: Age of child = 2 years old Recommended dose = 10 mg. Available dose: 250mg./5ml. x 30 ml.

Formula: Age in years X 2 + 8 Solution: 2 X 2 + 8 = 12 kg. 10 mg. X 12 Kg. = 120 mg. (dose needed by a 2-year old child) What part of 250 mg. is 120 mg.? To compute for the exact dose/ml., multiply 120 mg. to 5ml. and 250mg. to X(ml.) then divide to 250mg. 250mg. / 5ml. = 120mg / X(ml.)

5ml. X 120mg. = 600mg./ml. 250mg. X ?ml = 250mg. Then divide:

32 600mg./ml. 250 mg. = 2.4 ml. *120mg. computed dose of the child is 2.4ml. in a 250mg./5ml. preparation of the drug. DOSE CALCULATION ACCORDING TO KEE AND HAYES Basic Formula: D -----X V = A H Where: D = is the desired dose; drug dose ordered by the physician H = is the on hand dose; drug dose on label of container (bottle, vial). V = is the vehicle; drug form in which the drug comes (tablet, capsule, liquid) A = is the amount calculated to be given to the client. Example: Order: Ampicillin (Polycillin) 0.5 g., PO, bid Available (drug label): Polycilin 250 mg./capsule Solution: The unit of measure that is ordered, grams, and the unit on the bottle, milligrams, are from the same system of measurement, the metric system. Conversion to the same unit is necessary to work the problem. Since the bottles is in milligrams, convert grams to milligrams. To convert grams (large value) to milligrams (small value), move the decimal point three spaces to the right. 0.5 G. = 0.500 mg. or 500 mg.

D ------ x V H

500 mg. 500 --------- x 1 capsule = ------- = 2 capsules 250 mg. 250

RATIO AND PROPORTION: - the oldest method currently used in calculating drug dosage. H Known : V : : means extremes x = D Desired : x

33

Example: Order: Ampicillin 100 mg., PO, qid Available: Ampicillin (Polycillin) 250 mg./5ml. Solution: Conversion is not needed since both are expressed in the same unit of measure. H : V :: D : x 250 mg. : 5 ml. :: 100 mg. : x ml. means extremes 250x = 500 x = 2 ml. Answer: Ampicillin 100 mg. = 2 ml.

DRUG LIST:
NARCOTIC ANALGESICS 1. MEPERIDINE HCL (DEMEROL) Elixir: 50mg/5ml. Tablet 50,100 mg. Injection 100 mg./ml. Dose: 6mg./kg./Day or 0.5 1.0 mg./Kg./Dose 2. NALBUPHINE (NUBAIN) Injection 10 mg./ml. Dose: 0.1 0.2 mg./Kg./Dose NON-NARCOTIC ANALGESIC 1. ASA (ASPIRIN) 60, 81, 200, 300, 600, mg. Tablet Dose: 6.5 mg./Kg./Day 2. ACETAMINOPHEN Afebrin, Tempra, Tylenol, Calpol, Rexidol, Naprex, Panadol 100 mg./5ml., 120mg./5ml., 250mg./5ml. Syrup 60mg./0.6 ml. Drops Dose: 10 20 mg./Kg./Dose

34 3. MEFENAMIC ACID Ponstan, Dolfenal 50 mg./5ml. Suspension 250, 500 mg. Tablet, Capsule Dose: 6.5 mg./Kg./Dose (Pedia) BETA-LACTAM ANTIBIOTICS PENICILLIN G 1. PENICILLIN G BENZATHINE Usual Dose: Newborn(NB), Infants (IN): 50,000 units/kg/single dose IM Children (CH) (>60 lbs.) and Adults (A): 600000-1200000 units IM q 3 weeks for rheumatic fever prophylaxis 2.4 million units IM once (divided into 2 injection sites at one visit) for three treatment of early syphilis, weekly X 3 doses for syphilis of more than one year duration. Preparation: (Penadur L-A): 1.2 M units and 2.4 M units/vial. 2. CRYSTALLINE PEN G (BENZYLPENICILLIN) Usual dose: NB - 25,000 U/Kg. q 6, 8, 12 IN, CH - 100,000 250,000 U/Kg. div. q4h. Preparation: Pen G: 1 M units/vial and 5 M units/vial 3. PHENOXYMETHYLPENICILLIN (PENICILLIN V) Usual Dose: IN, CH - 25-50 mg./Kg./Day or 25,000-100,000 U/Kg./Day div.q6-8 h, PO 1-2 g/d or 1.6-3.2 million u/d div.q6h, PO Preparation: Oral - 250, 500, 625 mg. capsule 125 mg./5ml; 25mg./5ml, suspension 60 ml. Note: Administer on empty stomach (1-2 hours after meal) BROAD SPECTRUM PENICILLINS 1. AMOXICILLIN Usual Dose: IN, CH- 20-40 mg./kg./day div.by 3 doses (q8h) PO Adults- 750-1500 mg./day div. q8h, PO Preparations: Drops - 100mg./ml. Granules/Powder for suspension, 10ml. drops 125, 250 mg./5ml. 60-70 ml. Capsule- 250, 500 mg. Injection- 250,500mg./vial 2. AMPICILLIN Usual Dose: NB- 25-50 mg./kg. Q6-12 IV IN, CH- 100-200 mg./kg./day div.q4-6 h. A- 2-12 Grams infusion div. q6h. (Ampicin, Amopen drops: 100 mg/ml.; suspension 125, 250 mg./5ml.; capsule- 250,500mg.; Injection- 100, 250, 500 mg./vial) COMBINATION OF A PENICILLIN AND BETA-LACTAMASE INHIBITOR

35 1. BACAMPICILLIN Usual Dose: IN, CH - 25-50 mg./kg./day div.by 2 doses (q12) PO A- 800-1600 mg. bid (Penglobe susp. 200mg./5ml.; Tablet- 200, 400, 800 mg. 2. CO-AMOXICLAV Usual Dose: NB- not recommended IN, CH- 40 mg./kg./day div. q8h PO and IV. A- 750 1.5 Grams/d div.q8 PO and IV. Preparations: 156.25 mg./5ml (30-60 ml) 375, 625 mg. tablet 600,1200 mg./vial PENICILLINASE RESISTANT PENICILLIN 1. CLOXACILLIN Usual Dose: IN, CH - 50-100 mg./kg./day div.q6h (4 doses) PO Adults - 2-4 Grams/day div.q6 PO Preparations: Suspension - 125 mg./5ml x 60 ml. Capsule - 250 mg., 500 mg. Injection - 250, 500 mg./ vial CEPHALOSPORINS First Generation A. CEPHALEXIN Usual Dose: IN, CH - 25-50 mg./kg./day div.q6h, PO Adults - 1-4 Grams/day div.q6h, PO Preparations: 125 mg./ 5ml. Granules/Powder for Suspension (50-70 ml). 100 mg./ 5 ml. Granules/Powder for drops (10 ml.) Capsule - 250, 500 mg. B. CEPHAZOLIN Usual Dose: NB - 20 mg./kg. q12h IN, CH - 50-100 mg./kg./day div. q8h, IM or IV Adults - 1-6 Grams/day div.q8h, IM or IV. Preparation: 1 Gram vial Second Generation A. CEFACLOR Usual Dose: IN, CH - 20-40 mg./kg./day q8-12h, PO Adults - 750 1500 mg./day div.q8-12 h, PO Preparations: Suspension 125mg./5ml. Granules/ Powder for suspension Puvule 250, 500 mg. 50 mg./ml. Granules/Powder for drops (20ml.) B. CEFUROXIME Usual dose - 30-50 mg./kg./day Injection 250-750 mg./vial

36

Third Generation A. CEFTRIAZONE Usual Dose: 50-100 mg./kg./day Injection 250, 500 mg., 1 G / vial B. CEFTAZIDIME Usual Dose: 30-50 mg./kg./day Injection 250, 500 mg., 1 G./ vial AMINOGLYCOSIDES 1. GENTAMYCIN SULFATE Usual Dose: IN, CH, A - 3.5-8 mg./kg./day div.q8 IM or IV Preparation: Injection - 20, 40, 80 mg./ml. (vial) 2. AMIKACIN SULFATE Usual Dose: IN,CH,A - 15mg./kg./day loading, 10mg./kg./day maintenance Preparation: Injection - 50, 125, 250 mg./ml. (vial) DRUGS THAT ACT ON 30 S RIBOSOMAL SUBUNIT TETRACYCLINE Usual Dose: CH(>8years) - 25-50 mg./kg./day div. q6h, PO Adults - 1-2 Grams / day div.q6h, PO Preparations: Oral - 250, 500 mg. capsules Other preparations: Doxycycline - 2-4 mg./kg./day Doxin capsule - 100 mg. Minocycline (Minocin) - capsule: 50 mg., 100 mg. DRUGS THAT ACT ON 50 S SUBUNIT CHLORAMPHENICOL Usual Dose: IN, CH - 50-100 mg./kg./day div.q6h, PO, IM, IV Adults - 50-100 mg./kg./day div.q6h, PO, IM, IV Preparations: Oral - 125 mg./5 ml., 60 ml. suspension 250, 500 mg. capsules Injection - 1 Gram vials ERYTHROMYCIN Usual Dose: IN, CH - 30-50 mg./kg./day, div. q6h PO, IV Adults - 1-2 Grams/day div. q6 PO, IV Preparations: 250, 500 mg. tablet; 500 mg. capsules; 100mg./2.5 ml. (30 ml. drops); 200, 400 mg./5ml. (60 ml. suspension) CLINDAMYCIN Usual Dose: IN, CH - 10-25 mg./kg./day, div. q6h PO, IV Adults - 600-1800 mg./day div. q6 PO Preparations: Oral - 150, 300 mg. capsule; 75 mg./5 ml. x 30 ml. suspension

37 TRIMETHOPRIM - SULFAMETHOXAZOLE (COTRIMOXAZOLE) Usual Dose: IN, CH - 8 mg. TMP and 40 mg. SMX/kg./d div.q12h PO Adults - 320 mg. TMP and 1600 SMX/d div.q12h PO Preparations: Oral - 100,000 units/ml. 30 ml. suspension; 500,000 units per tablet Vaginal - 100,000 units tablets KETOCONAZOLE Usual Dose: CH - 5-10 mg./kg./day div. q12-24 h, PO Adults - 200 400 mg. qd PO Preparations: Oral - 200 mg. tablets ISONIAZID Usual Dose: 10-20 mg./kg./day Preparation: Syrup - 150 mg./5ml. Tablet - 400 mg. METRONIDAZOLE Usual Dose: For amoebiasis and Anaerobic Infections: IN, CH - 35-50 mg./kg./d div. q8h, PO Adults - 750 mg. tid, PO Preparations: Oral - 250, 500 mg. tablets; 125 mg./5ml. (60 ml. suspension) Injection - 5mg./ml. 100 ml. vial Rectal - 1 G Suppository QUINOLONES Usual Dose: Adults - 400-800 mg./day divq12h, PO, IV Preparations: Ofloxacin (Inoflax), Ciprofloxacin (Coprobay) - 200, 400 mg. tablets RIFAMPICIN Usual Dose: 10-20 mg./kg./day PO Preparations: Syrup - 100 mg./ml. and 200 mg./5ml. (50-60 ml. suspension) Capsule - 150, 300, 450, 600 mg. ANTIFUNGALS AMPHOTERECIN B Usual Dose: IN, CH - 0.1-0.25 mg./kg./day (single IV dose) Adults - 0.25-1 mg./kg./day Preparation: Injection - 5 mg./ml. (10 ml. vial) NYSTATIN Usual Dose: NB - 400,000 units/day div.q4-6 h PO IN, CH - 400,000-800,000 units / day div.q4-6 h PO Adults - 800,000 2,000000 units/day div. q4-6 h PO

38 PRINCIPLES OF PRESCRIPTION ORDER WRITING Prescription - a written order for medicines written by a qualified Medical, Dental or Veterinary practitioner to the pharmacist for a patient. Simple - if containing only one ingredient. Compound - if containing more than one ingredient. Drugs may be combined in prescriptions for the following reasons: 1. To obtain the conjoint effect of two or more active substances. 2. To diminish or annul undesirable effects produced by one or more of the active ingredients. 3. To increase the solubility or aid in the dispensing of the active substances. 4. Occasionally, to produce a new compound.

PARTS OF AN IDEAL PRESCRIPTION

________Doctors Name_________ _____________Address______________ ________Tel. No.________ ---------------------------------------------------------------------------------------------------------------------Patients name: __________________________________ Date:_____________ Address:________________________________________________________________________ Tel. No. __________________ Age: ______ Sex: ______

Rx
Generic name of drug, dosage form and amount . (Brand name of drug) Direction to the pharmacist Direction to the patient . .

__________________ D.M.D. Prescribers Signature PRC License Number P.T.R. Number .

39 Narcotic License Number ( S-2) T.I.N. Tax Identification Number ____________________ Refill Information Parts of the Prescription Superscription : Patients name, address, and age; date and the symbol Rx. Inscription : Name of drug, dosage form, and amount. Subscription : Directions to the pharmacist Transcription / Signature : Direction to the patient HEADING Name, address and phone number of the prescriber. Name, address, age, and phone number of the patient, and date BODY The symbol Rx Name and dosage unit or concentration (liquids) of the drug. Amount to be dispensed Directions to the patient CLOSING Prescribers signature Space for DEA number Refill instructions Please place name of drug on label Importance of placing the name of the drug on label: 1. In case of overdose or adverse reactions, the drugs identity can be quickly obtained. 2. Other practitioners can identify drugs the patient is taking. 3. In most cases, the patient has the right to know what drug he or she is taking. Hints for Prescription Writing 1. Write legibly in ink or have it typewritten 2. Use the metric system 3. Avoid abbreviations 4. Keep a copy of each prescription or transcribe the information to the patients record. 5. Include complete information for the patient. a. Never use take as directed unless a written instruction sheet is provided. b. Include the intended purpose. c. Use precautions to remind a patient of a drugs side effects. E.q. Caution: Sedation or drowsiness. d. Add reminder phrases to increase the patients compliance. E.q. Take until all are gone. 6. It must contain the following particulars: a. The address and usual signature of the practitioner giving it.

40 b. The date on which it was signed by the practitioner. c. An indication of whether the practitioner is a dentist, doctor, or veterinary surgeon. d. The name, address, age (if under 12) of the person whose treatment is given. 7. The prescription shall not be dispensed not later than six months after the date of signature. Considerations in Drug Administration / Prescribing Tolerance the ability of a client to respond to a particular dose of a certain drug may diminish after days or weeks of repeated administration. A combination of drugs may be given to decrease or delay the development of tolerance for a specific drug. 1. Pathologic State / Pre-existing Disease State - Liver, kidney, heart, circulatory and gastrointestinal disorders are examples of preexisting states that can affect a response to a drug. For instance, diabetics should not be given elixirs or syrups than contain sugar. Age - The age of a patient will affect his or her response to drugs. Children and elderly persons are more sensitive to drugs; they require less than the usual adult dose. 2. Weight - the more a person weighs, the more dilute the drug will become and a smaller amount will accumulate in the tissues. On the other hand, the less a person weighs, the greater accumulation in the tissues and a more powerful drug effect is produced. 3. Sex - Women are more susceptible to the action of certain drugs and are usually given smaller doses. 4. Drug-Drug Interaction - the effects of a combination of drugs may be greater then, equal to, or less than the effects of a single drug. Some drugs may compete for the same receptor sites. An adverse reaction may lead to toxicity or complication such as anaphylaxis. 5. Psychological factors / Emotional factors - A persons personality often plays an important part in his response to drugs; comments about the drug and its side effects may influence its effects. 6. Genetic factors - drug idiosyncrasy is an abnormal susceptibility of some individuals that causes them to react differently than most people. This intolerance to small amounts of some drugs is thought to be due to genetic factors. If your mother or father has an adverse reaction to a drug, you may also. 7. Environmental factors - the setting in which the drugs are given and the attitude of the person giving the medication may influence the effects of drugs. 8. Method of administration - generally, larger doses are ordered when a medication is given by mouth or by rectum and smaller doses when the parenteral route is used. Blood level curves and dosing regimens Pregnant and breastfeeding mothers - Administration of medication in the early weeks of pregnancy may cause damage to the fetus. During the third trimester, there is the possibility of premature labor caused by drugs that may stimulate muscular contractions.

LATIN PHRASES and ABBREVIATIONS Used in PRESCRIPTION WRITING Abbreviations a. aa a.c. ad ass. ad lib. acq. agit. aq. aq. dest. amp. b. bene b.i.d. c c. cap. co. ; comp. coch. mag. coch. med. coch. parv. cong. d. da d. in p. acq. d.t.d. dieb alt. dil disp. div. dos. E.C. elix. Et Ex Ext ex aq. e.m.p. f. Fac fl. or fld. Ft. gm. gr. gtt. h h.s. hypo Latin ante ana ante cibum ad adde, addantur ad libitum acqualis agita aqua aqua distilata --bis bene bis in die cibum cum capsula compositus cochleare magnum cochleare medium cochleare parvum congium dies da dividatur in partes acquales dentus tales doses diebus alternis dilitus dispensa, dispensetur divide dosis --elixir et ex extractum ex aqua ex modo prescripto fiat, fiant face fluidus fiat ----gutta, guttae hora hora somni --English before of each before meals to, up to add, let them be added at pleasure equal shake water distilled water ampule twice well twice a day meal with capsule compound a tablespoonful a dessertspoonful a teaspoonful a gallon a day give let it be divided into equal parts give such doses every other day dilute dispense divide a dose enteric coated elixir and out of extract with water after the manner prescribed make, let be made make fluid make gram grain a drop, drops hour at bedtime(hour of sleep) hypodermically

41

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DRUG THERAPY
Pharmaceutical Process Pharmacokinetics Process Pharmacodynamics Process Therapeutic Process PHARMACEUTICAL PROCESS Is the drug getting into the patient? Approximately 80% of drugs are taken by mouth; therefore, the pharmaceutic phase is the first phase of drug action. In the gastrointestinal tract, drugs need to be in solution to be absorbed. A drug in solid form (tablet or pill) must disintegrate into smaller particles in order for it to dissolve into a liquid. Disintegration is the breakdown of the tablet or pill into smaller particles. Dissolution is the dissolving of smaller particles in gastrointestinal fluid for absorption. Rate Limiting is the time it takes for the drug to disintegrate and become available for the body to absorb it. Factors to consider 1. Particle size - the smaller the particle size, the faster it can be absorbed in the body. 2. Excipients of drug - fillers and inert substances are used in drug preparation to allow the drug to take on a particular size and shape and to enhance dissolution of the drug. Some additives such as K and Na in penicillin K and penicillin Na, increase the absorbability of the drug. 3. Coating material - Enteric-coated (EC) drugs resist disintegration in the gastric acid in the stomach, so disintegration does not occur until the drug reaches the alkaline environment in the small intestine. PHARMACOKINETIC PROCESS Is the drug getting into its site of action? - is the process of drug movement to achieve drug action. - concerned with the absorption, distribution and elimination (metabolism and excretion) of drugs. ABSORPTION - process by which drug molecules are transferred form the site of administration in the body to the circulating fluids Factors Affecting Absorption 1. Physico-chemical factors 2. Site of absorption / Blood flow at the site 3. Drug Solubility 4. Effects of food a. Blood flow b. Gastric emptying

43

the non-ionized portion behaves as a non-polar lipid soluble compound which readily traverses body membranes. The amount of ionization that any weak electrolytes undergoes depend on the pH at the drug site in the tissues and its dissociation characteristics. Increase pH (weak acids) - the greater the degree of ionization Decrease pH (weak bases) the greater the degree of ionization.

Oral absorption depends on the dosage form of drugs. Absorption on injection sites - depends on the solubility of drug and the blood flow at the site; also affected by dosage form. E.q. drugs in suspension are absorbed much ore slowly than those in solution. Effects of food on drug absorption - by affecting the blood flow and gastric emptying. E.q. liquid glucose meal decreases flow and a meal rich in protein increases flow. - some drugs are irritating to the stomach mucosa, so fluids or food are necessary to dilute drug concentration - there are drugs that are absorbed easily in the presence of food. Factors that Modify the Rate of Absorption 1. Drug Concentration at the Site 2. Circulation to the Site of Absorption 3. Area of Absorptive surface FACTORS GOVERNING THE FATE OF A DRUG 1. Molecular Weight - substances with high molecular weight are not usually absorbed intact except in minute quantities. - they are absorbed by enzymatic actions. E.q. insulin is a protein it undergoes enzymatic breakdown in the git and is not absorbed. 2. Chemical Stability - unstable drugs maybe inactivated in the git. E.q. Benzylpenicillin in unstable in acid medium and cannot be effective if given by mouth. Phenoxymethylpenicillin is more stable in acid medium. 3. Lipid Solubility - if the drug is lipid soluble, it can easily pass through the membrane. 4. Degree of Ionization - the unionized portion of a drug is lipid soluble and so is readily absorbed; ionized portion is lipid insoluble. THE CELL MEMBRANE Composition: Lipids (40%) phospholipids - makes membrane relatively impermeable to ions and polar molecules Proteins (50-60%) - make up the structural components of the membrane

44 - acts as enzyme during transport Carbohydrates (remainder) Oligosaccharide - linked covalently to form complexes of glycoproteins and glycolipids *PRINCIPAL MECHANISMS INVOLVED IN THE PASSAGE OF DRUGS ACROSS CELL MEMBRANE Lipid Diffusion (Simple Diffusion) - drug molecules dissolves in the membrane to penetrate through the other side. Can take place either via: Lipoprotein membrane Paracellular spaces 2. Aqueous Diffusion (Filtration through Pores) - the size of the drug molecule is relative to the size of the pores. - water soluble drugs with molecular weight less than 100 Daltons are able to cross the cell membrane by passing through the polar pores. E.q. Ethanol (46); Urea (60) 3. Specific Carrier Mediated Transport System Active Transport - process by which a substance is transported against a concentration gradient. Drug molecules are mediated by transport carrier that furnish energy for the transportation of drug from lower concentration through higher concentrations. E.q. Na, K, Ca, Fe, amino acids, and glucose.
1.

3 Features 1. Ability to work against concentration gradient, osmotic, electrical, or hydrostatic gradient 2. Specificity ability to concentrate a selected substance on one side of the cell membrane. 3. Each system require an energy source (ATP), to which it is directly coupled. Facilitated Diffusion - a passive process whereby drugs can move across cell membranes more rapidly than simple diffusion. - involves the action of a specific but saturable carrier system - can only work in the presence of an appropriate concentration gradient. DISTRIBUTION - the passage of drug into various body fluids compartments such as plasma, intestinal fluids and intracellular fluids; process by which the drug becomes available to body fluids and body tissues. Factors affecting Distribution 1. Blood flow 2. Affinity to the tissue 3. Protein binding Forms of Drug inside the Body

45 1. Free / Unbound state - free active drug 2. Bound - inactive drug Binding to Plasma Proteins - e.q. salicylic acid and warfarin bind to Albumin Basic drugs bind to acid glycoproteins and lipoproteins Binding to Cells - drugs become bound onto the surface or inside the cells. *Only free drugs or drugs not bound to protein are active and can cause a pharmacologic response. As the free drug in the tissues decreases, more bound drug is released from the protein to maintain the balance of free drug. Checking the protein-binding percentage of all drugs administered is important in order to avoid possible drug toxicity. E.q. Drug accumulation and toxicity can result if two highly protein-bound drugs are given concurrently because they will compete for protein binding sites causing more free drug to be released into the circulation; Also, a low protein level decreases the number of protein binding sites, causing an increase in the amount of free drug in the plasma. Drug overdose may result because drug dosage is prescribed according to the percentage in which the drug binds to protein. STORAGE DEPOT (Non-specific Site) - helps prevent prolong the action or areas for transient storage. AFFINITY TISSUES - maybe sites of action or areas for transient storage; some drugs accumulate in particular tissues such as fat, bone, liver, eye, and muscle. E.g. Guanethidine - binds to heart and skeletal muscle Quinacrine - binds to liver and skeletal muscles Tetracycline - bone and enamel Thiopental - adipose tissue METABOLISM - Liver main organ of metabolism - most drugs are inactivated by liver enzymes and are then converted by hepatic enzymes to an inactive metabolite or water soluble substance for excretion. However, some drugs are transformed into active metabolites causing an increased pharmacologic response. Example of liver disease that affects metabolism - cirrhosis and hepatitis. 1. 2. Excretion in the original form e.q. Hexamethonium a highly ionized antihypertensive compound excreted in the urine unchanged. Transformation into one or more Metabolites Other organs: G.I.T., Lung, kidney, skin and placenta.

BIOTRANSFORMATION - a process wherein parent drug is converted by enzymes into drug metabolites ready to perform its action. Biotransformation of Drugs has Two Effects 1. It alters the pharmacological activity, usually decreasing it but sometimes converting the drug to a compound similar or greater activity (potency) than the original. 2. Results in metabolites that are more water-soluble and less lipid soluble than the parent compounds and therefore more readily excreted in the urine.

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* Two General Types of Chemical Reaction Phase 1 (Non-Synthetic reaction) 1. Oxidation - Diazepam 2. Reduction - Nitrazepam, Cortisone 3. Hydrolysis - Suxamethonium, Amethocaine Phase 2 (Synthetic (Conjugation) Reaction) -It involves conjugation to form one or more of the following: 1. Glucoronide e.g. Morphine, Paracetamol 2. Sulphate e.g. Isoprenaline 3. Acetate e.g. Isoniazid, Hydralazine 4. Glutathione e.g. Paracetamol BIOLOGIC HALF-LIFE (t1/2) - is the time it takes for one half of the drug concentration to be eliminated. - a drug goes through several half-lives before more than 90% is eliminated. Example: 650 mg. of Aspirin Number (t1/2) 1 2 3 4 5 6 Time of Elimination(h) 3 6 9 12 15 18 t1/2 = 3 hours Dosage Remaining (mg) 325 162 81 40.5 20 10 %left 50 25 12.5 6.25 3.1 1.55

- it takes three hours for the first half-life to eliminate 325 mg and the second half-life (6h) for an additional 162 mg. to be eliminated, and so until the 6th half-life (18h) when 10 mg. of aspirin is left in the body. - a short half-life is 4-8 hours. - a long half-life is 24 hours or longer (e.q Digoxin 36 hours); it takes several days until the body completely eliminates the drug. Factors Affecting Drug Metabolism 1. Age 2. Sex 3. Liver Disease 4. Environmental Factors 5. Genetic Factors 6. Route of Administration MICROSOMAL DRUG METABOLIZING SYSTEM - the most important of the many biochemical system in the body involved in biotransformation. - located primarily in the smooth Endoplasmic Reticulum of hepatic cells.

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CYTOCHROME P450 - the most important enzyme in the microsomal enzyme system involved in the oxidative transport processes. EXCRETION - major way by which the activity of the drug is terminated - mainly in the Kidney; some via the (Extra Renal Route) .Bile, Skin (sweat), Lungs (expired air), Saliva, Feces and Breast Milk - expressed in terms of Renal Plasma Clearance the volume of plasma effectively cleared of the drug by the kidney in unit time. RENAL EXCRETION - most important route of drug elimination *3 Processes Implicated in Renal Excretion 1. Glomerular Filtration - depends upon the plasma concentration of drugs and molecular weight. - 125 ml./min. 2. Tubular Reabsorption / Active Secretion in the Proximal tubule 3. Tubular Secretion / Passive Re-absorption in the distal tubule PHARMACODYNAMICS Is the Drug producing the required Pharmacological Effect? - study of a drugs effect on cellular physiology and biocehmistry and the drugs mechanism of action. I. Drugs which act via Pharmacological Receptors: 1. Act at low concentration 2. React with specific receptors 3. Show structure activity relation 4. Can be antagonized by specific antagonist e.q. acetylcholine; adrenaline; noraduraline and histamine e f g h i II. Drugs which DO NOT act via Pharmacological Receptors: 1. Act at higher concentrations 2. Do not react with specific receptors 3. Tend to show structure-activity relationships 4. Do not have specific antagonists e.q. General anesthetics and non-specific destructants of cell membranes such as detergents.

DRUG-RECEPTOR INTERACTION Receptor - a macromolecule with special sites to which specific substances binds. (Drug/Ligands Receptor). SITES OF RECEPTORS 1. On or within Cell Membranes 2. Inside Cells

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Most receptors, protein in structure, are found on cell membranes. Drugs act through receptors by binding to the receptor to produce (initiate) a response or block (prevent) a response. The activity of many drug is determined by the ability of the drug to bind to a specific receptor. The better the drug fits at the receptor site, the more biologically active the drug is. It is similar to the fit of the right key in a lock.

Figure: Two drug agonists attach to the receptor site. The drug agonist that has an exact fit is a strong agonist and is more biologically active than the weak agonist. Agonist - a drug (hormone or neurotransmitter) which combines with its specific receptor, activates it and initiates a sequence of effects. E.q. Isoproterenol stimulates the beta1 receptor. Antagonist - a drug which interferes with the action of an agonist but does not have any effect itself unless it possess partial agonist activity. E.q. Cimetidine blocks the H2 receptor thus preventing excessive gastric secretion. Partial Agonist - a drug that act on a receptor with an intrinsic activity or efficacy of < 1. Mixed Agonist-Antagonist - a drug that act simultaneously on a mixed group of receptor with an agonist action on one set and an antagonist action on another. ***DRUG ANTAGONISM - occurs when their biological effect is less than the expected sum of their individual effects. Pharmacological Antagonism: 1. Reversible Competitive / Equilibrium Antagonism - substances are competing dynamically for the same pharmacological receptor 2. Irreversible Competitive / Non-Equilibrium Antagonism - drugs form very strong bonds Non-Competitive Antagonism - block action of an agonist not at the receptor level but at some point between receptor and effector that leads to the action of the agonist. Physiological Antagonism - occurs when two drugs that act on different receptors produce opposite effects. E.q. Adrenaline antagonizes the effects of histamine on bronchial smooth muscle. Chemical Antagonism - occurs when one drug combines chemically with another to

49 produce inactive product. Pharmacokinetic Antagonism - occurs when one drug effectively reduces the concentration of another at its site of action by altering its absorption, distribution or elimination. ***Relationship Between the Dose of Drug and the Effect it produces: Two Types of Relationship: 1. Quantitative (Graded) responses or effects - the effect increases as the dose is increased until the maximum is reached. Beyond this point, any increase in the dose is not accompanied by an increase in effect or response. Graded - refers to that characteristic of an effect which begins at some low level and increase through progressive stages until it reaches some higher level. 2. Quantal responses or effects - All or None response. E.q. In toxicity test, a dose could either kill or not.

Definition of Terms: Onset of Action - begins when the drug enters the plasma and lasts until it reaches minimum effective concentration (MEC). Peak Action - occurs when the drug reaches its highest blood or plasma concentration. Duration of Action - is the length of time the drug has a pharmacologic effect. Time-response-curve - evaluates three parameters of drug action: the onset of drug, peak action, and duration of action. Biologic Variation - connotes the sum total of all the sources of variation that combine to cause one biologic unit to vary from one another. Threshold Dose - lowest case of a drug that will produce a measurable response. Plateau - endpoint/terminal point in a graded dose response curve. Therapeutic Index - the difference between the dose which will produce the desired effect and that which will cause adverse effect. - estimates the margin of safety of a drug by using a ration that measures the effective therapeutic dose in 50% of animals (ED50) and lethal dose in 50% of animals (LD50). The closer the ratio is to 1, the greater the danger of toxicity. - a figure that gives measure as to the amount by which therapeutic dose made exceeded before eliciting a toxic effect. For clinical situation, a better measure would be adverse effect dose ED50 in which a specific adverse effect is considered, rather than the lethal median dose. Median Effective Dose (ED 50) - smallest dose causing the given pharmacologic effect in 50% of the individuals of a sample. Relative Safety - dose of the drug required to produce the desired therapeutic effect relative to the dose of the drug required to produce toxic or lethal effects. Therapeutic Effects - desirable clinical action of a drug. "Risk - Benefit Ratio" - toxicity taken into consideration --- "the risk of treatment weighed against the risk of disease" e.q. the use of known highly toxic drugs such as those used in the treatment of cancer applies this principle.

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THERAPEUTIC PROCESS Is the Pharmacological effect being translated into a desired therapeutic effect? Factors which Determine the Relationship Between Prescribed Drug Dosage and DRUG Effect Dosage Pathway Prescribed dose Administered dose Influences on Drug Effect Patient compliance Medication errors Rate and extent of absorption Body size and composition Distribution in body fluids Binding in plasma and tissues Rate of elimination Physiological variables Pathological factors Genetic factors Interaction with other drugs Development of tolerance Drug receptor interaction Functional state Placebo effects

Concentration at locus of action

Intensity of effect

PHARMACOLOGY OF INFLAMMATION
- a reaction of the vascular and supporting elements of a tissue to injury which results in a protein-rich exudate, provided the injury has not been so severe as to destroy the area. CLINICAL SIGNS OF INFLAMMATION 1 Rubor - Redness 2. Tumor - Swelling 3. Calor - Hotness 4. Dolor - Pain 5. Functio Laesa - Loss of function CLINICAL MEDIATORS HISTAMINE a vasoactive amine found in most tissues of the body formed by the decarboxylation of the amino acid histidine. PHARMACOLOGICAL PROPERTIES OF HISTAMINE - relaxation of the vascular smooth muscle - contraction of the bronchi and gut wall - secretion of exocrine glands - production of pain and itch - acts as neurotransmitter in the CNS (control of thirst, secretion of antidiuretic hormone,

51 control of blood pressure, and pain perception). TYPES OF HISTAMINE RECEPTORS H1 = primarily related to smooth m. activity H2 = primarily involved with the stimulation of gastric secretions H3 = mediates CNS effects of histamine on histaminergic nerve terminals Effects of Histamine: Heart - increase heart rate & force of contraction which results in an increase in cardiac output - increase histamine may cause arrhytmias due to slowing of A-V conduction - dilation of small b.v leads to flushing, lowered peripheral resistance, and a drop in blood pressure. Smooth muscles - Bronchial muscle - activation of H1 receptor results to bronchoconstriction. - Patients who suffer from asthma are particularly sensitive to the action of histamine on the bronchial musculature however, antihistamines are of no value in the treatment of asthma. Gastric secretion - even a slow concentration can cause copious secretion of the gastric juices mediated by H2 receptor. Pain and Itch - caused by direct stimulation of free nerve endings when injected. - Subcutaneous injection of histamine causes sharp pain of short duration like a wasps sting but when injected into a more superficial layer of the skin, causes itching. ANAPHYLAXIS AND ALLERGY Anaphylactic reaction most dangerous acute allergic reaction occurring hour after drug administration. - histamine will be released due to an antigen combining with specific antibody attached to the surface of mast cells (DEGRANULATION) causing the extrusion of histamine from the secretory granules in the mast cells. - e.q. of substances that can cause anaphylaxis and allergy: Penicillin, animal fur, pollen. Adverse Effects - undesirable clinical action of a drug; a range of untoward effects (unintended and occurring at normal doses) of drugs that cause mild to severe side effects, including anaphylaxis; Always undesirable. Side Effects - are physiologic effect not related to desired rug effects; Maybe desirable or undesirable and are predicted. Toxic Effects - adverse effects of an unexpected nature resulting from the direct action of a drug. Allergy - altered capacity of the body to react to various antigens. Idiosyncracies - covers unusual or bizarre drug effects that cannot readily be explained in an individual recipient.

52 AUTOCOIDS derived from the Greek word autos (self) and akas (remedy). It refers substances which have local hormone-like activity at or near the site of production. EICOSANOIDS a term that denotes the metabolites of certain 20-carbon polyunsaturated fatty acids, mainly arachidonic acid. - products of arachidonic acid metabolism are divided into two main groups on the basis that they are ultimately derived from the action of one of the two enzymes systems (cyclo-oxygenase or lipoxygenase) on arachidonic acid. ARACHIDONIC ACID - a 20 - polyunsaturated fatty acid Two sources : 1. Metabolic pool - endogenous synthesis of arachidonic acid 2. Cell membrane pool - stimulated synthesis such as trauma; major source of the eicosanoid precursor in inflammation. Arachidonic acid -----metabolized------ results to metabolites (eicosanoids - a term) by the action of the 2 enzyme (cyclo-oxygenase and lipoxygenase) *In most cells and tissues, phospolipids are thought to be the major source of arachidonic acid. 1. The first step in eicosanoid synthesis: liberation of the Arach. Acid from cell membrane phospolipids by the action of a group of enzymes known as the phospolipases particularly phospolipase A2 responsible for its bulk. 2. The second step : formation of cyclo-oxygenase on free arachidonic acid ( results in the insertion of 2 oxygen molecules into the fatty acid carbon chain to form PGG2 which is rapidly transformed by the peroxydase-like activity of cyclo-oxygenase into the hydroxyperoxide, PGH2). This is followed by the formation of one of the three groups depending on the particular cell and circumstances involved, the prostaglandins, thromboxane, and prostacyclin. CYCLO-OXYGENASE PRODUCTS: PROSTAGLANDIN - 1st identified in 1930 but their structure and function were elucidated until 1960. - occur in every tissue and body fluid. vasodilators = fall in blood pressure 2 Types: PGE and PGF series THROMBOXANE AND PROSTACYCLIN THROMBOXANE A2 - Main synthesis in platelets plays an important role in platelet aggregation PROSTACYCLIN - a potent vasodilator and acts as an antagonist of platelet aggregation; main synthesis in vessel walls. *T and P are biologically opposite poles of the mechanism for regulating the platelet vessel wall interaction and the formation of hemostatic plug. Both are unstable, with very short half lives.

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LIPOXYGENASE PRODUCTS: LEUKOTRIENES - has potent chemotactic properties; probably involved in the process of cellular infiltration that accompanies inflammation. Types: LTA4; LTB4; LTC4; LTD4; LTE4 PLATELET ACTIVATING FACTOR - a lipid autocoid synthesized mainly by platelets, leukocytes, and endothelial cells. - action includes vasodilation, inc. in vascular permeability, white blood chemotaxis, and the release of lysosomal enzymes. - a potent stimulator of platelet aggregation. - may also be important in the pathogenesis of asthma.

Arachidonic Acid Metabolism Product Cyclo-oxygenase product Lipoxygenase product

Prostaglandins Thromboxanes Prostacyclin

Leukotrienes Compounds based on eicosatetraenoic acid

BRADYKININ AND KALLIDIN - Polypeptides formed from the plasma alpha globulins by a complex series of proteolytic reactions. - Potent vasodilators - Increase capillary permeability = oedema - Cause bronchoconstriction - Bradykinin: 10X active than histamine; effects are brought by: Kinin Receptors : B1 and B2
j k

5-HYDROXYTRYPTAMINE (5-HT) - amine formed by the hydroxylation of tryptophan stored in gastric mucosa - dilatation of arteries and constriction of veins via receptors 5HT1 ; 5HT2 ; 5HT3 - high concentrations are found in platelets. - pharmacologic properties: role in inflammation is uncertain and maybe insignificant; dilation of arteries and constriction of veins. CYTOKINES - Proteins secreted by cells that have effects on other cells LYMPHOKINES - cytokines produced by sensitized T lymphocytes and to a lesser

54 extent by B lymphocytes in response to antigenic challenge Actions of Lymphokines: 1. Chemotactic for macrophages 2. Macrophage activation 3. Macrophage inhibition 4. Chemotactic for other mononuclear WBC 5. Mutagenic for other lymphocytes 6. Increased vascular permeability 7. Activation of osteoclasts. INTERLEUKINS - cytokines from macrophages and lymphocytes during inflammation and immune response. - exerts a number of inflammatory actions which include the stimulation of PG and collagenase production, chemoattraction for WBC and enhancement of the hepatic synthesis of acute phase proteins. - Has 8 types: Interleukins 1 8. COMPLEMENT - consist of a series of protein that react in a cascade fashion ANTIHISTAMINES - antagonize histamine at the receptor sites; do not alter the formation or release of histamine from tissues or mast cells. - classified as H1 or H2 receptor blockers (antagonists) H1 Receptor Antagonists - interact with H1 receptor on cell membranes - results in a decrease in the availability of these receptors for the action of histamine; well absorbed from the git; therapeutic effects can be observed within 15-30 min. after dosage; widely distributed in the body and broken down in the liver. - Therapeutic uses: Treatment and prevention of a variety of allergic conditions (e.q. rhinitis, hay fever, and certain allergic dermatoses such as acute urticaria). Topical application is useful in relieving the itching associated with insect bites; widely used as common cold remedies usually combined with decongestants (e.q. Actifed). - no effect on bronchospasm or severe hypotension associated with anaphylactic shock; no value in the treatment of asthma. Unwanted effects: Sedation; may cause stimulation; dryness of the mouth; variety of g.i disturbances. *** Alcohol should be avoided while taking H1 blockers as it enhances the sedative effect. H2 Receptor Antagonists antagonizes the action of histamine at H2 receptor. commonly used are Cimetidine and Ranitidine. reduce gastric secretion; Treatment of duodenal ulcers and gastric hypersecretion.

55 Unwanted effects: slight such as headache, dizziness, constipation or diarrhea, and skin rashes 5-HT ANTAGONISTS - Ergot alkaloids are a group of compounds that are antagonists for 5-HT, Ergotamine. CORTICOSTEROIDS - have potent anti-inflammatory properties; widely used in the treatment of recurrent oral ulceration and other oral mucosal lesion such as erosive lichen planus, erythema multiforme, and pemphigus. E.q. 0.1% Triamcinolone (topical) ; hydrocortisone sodium succinate 2.5 mg. ; Bethamethasone 17-valerate (topical spray) ; etc. - pulpal inflammation; TMJ pain; Bells palsy; post-operative pain and swelling after dental surgery; Anaphylactic and allergic reactions.

PHARMACOLOGY OF PAIN
Pain - an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Analgesia - absence of pain in response to stimulation which would normally be painful. Hyperalgesia - an increased response to a stimulus which is normally painful Neuralgia - pain in the distribution of a nerve. Neuritis - inflammation of a nerve or nerves. Nociception - activity in a nerve fiber which arises as the result of stimulation of nociceptors. If nociception reaches consciousness, it is perceived as pain. Nociceptor - a receptor preferentially sensitive to a noxious stimulus or to a stimulus which would become noxious if prolonged. Pain threshold - the least stimulus intensity at which a subject perceives pain. Pain tolerance level - the greatest stimulus intensity causing pain that a subject is prepared to tolerate. Allodynia - pain due to a stimulus which does not normally provoke pain. Causalgia - a syndrome of sustained burning pain, allodynia and hyperpathia after a traumatic nerve lesion, often combined with vasomotor dysfunction and later trophic changes. Hyperaesthesia - increased sensitivity to stimulation excluding special senses. Hyperpathia - a painful syndrome characterized by increased reaction to a stimulus, especially repetitive stimulus, as well as an increased threshold. Neuropathy - a disturbance of function or pathological change in a nerve; in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy. Two Main Types of NOCICEPTORS 1. High Threshold Mechanoreceptor 2. Polymodal Nociceptor THEORIES OF PAIN 1. SPECIFICITY Theory - concerned primarily with the sensory discriminative aspects of pain and its quality, location on the skin, intensity and duration. 2. CENTRAL SUMMATION (PATTERN) Theory pain is not a separate entity, but results from over stimulation of other primary sensations.

56 3. SENSORY INTERACTION Theory stresses inhibition as an important physiological mechanism in pain transmission. 4. GATE CONTROL Theory - stressed the importance of both descending control mechanism and activity in large sensory fiber in modulating the pain experience. PERIPHERAL MEDIATORS OF PAIN 1. BRADYKININ 2. HISTAMINE 3. EICOSANOIDS Four Main Groups of Eicosanoids 1. Prostaglandin 2. Prostacyclin 3. Thromboxane 4. Leukotrienes CENTRAL MEDIATORS OF PAIN 1. Amino Acids 2. Peptides METHODS TO RELIEVE PAIN 1. Remove peripheral stimulus 2. Interrupt nociceptive input 3. Stimulate nociceptive inhibitory mechanism 4. Modulate central appreciation of pain and/or emotional concomitants 5. Block or remove secondary factors maintaining pain.

I. NON NARCOTIC ANALGESICS

General Characteristics 1. Relieves pain without altering consciousness. 2. Safer than narcotics. 3. Produce fewer side effects. 4. Not addicting. 5. Act principally on peripheral nerve endings. 6. Inhibits the synthesis of prostaglandins. PharmacologicAction 1. Analgesia 2. Antipyresis 3. Antiinflammatory SALICYLATES extracts of willow bark containing the bitter glycoside salicin. Therapeutically Useful SALICYLATES 1. Salicylic Acid - parent compound., toxic internally, topical fungicide, keratolytic agent. 2. Sodium Salicylate - internal use as an analgesic, less effective than aspirin, may be used in patients allergic to aspirin.

57 Methyl Salicylate (oil of wintergreen) external use as a counterirritant, flavoring in cooking. 4. Acetylsalicylic acid - widespread use as an analgesic, antipyretic and antirheumatic 5. Salicylamide internal use as an analgesic; less effective than aspirin; less G.I. irritation. 6. Difflunisal an investigational salicylate; possibly better tolerated , effective at lower doses; apparent therapeutic advantage over aspirin and perhaps other inflammatory agents.
3.

ASPIRIN - absorbed from the git; partly from stomach but mainly in the upper small intestine Pharmacological Properties - Analgesic (mild analgesic) due to inhibition of the synthesis of PGE. Suitable regimen: 600-1200mg. every 4-6 hours. - Anti-inflammatory inhibit synthesis of eicosanoids; High concentrations can inhibit the function and activity of PMN leukocytes - Antipyretic lowers an elevated body temp. (pyrexia) due to infection, tissue damage, malignancy or other disease states; due to inhibition of prostaglandin production in the hypothalamus. - Antithrombotic effect Unwanted effects - Gastrointestinal epigastric pain, nausea, gastric erosions leading to blood loss - Haemostatic effects prolongs bleeding time; inhibiting the synthesis of platelet thromboxane. - Tinnitus hearing loss due to rise in labyrinth pressure - Uricosuric effect increase plasma uric acid. Should Not be given to patients with gout(a disorder of uric acid metabolism). - Effects on kidney decrease renal blood flow; also enhances sodium and water retention. Aspirin Hypersensitivity from rhinitis to life threatening laryngeal edema. Aspirin Overdose 10-30 gm. can be fatal. Aspirin and Reyes Syndrome an acute encephalopathic illness and fatty degeneration of the viscera, especially the liver that arises after an infectious illness such as chickenpox or influenza. - interaction between aspirin and the viral infection leads to damage of cell mitochondria in genetically susceptible individuals. PARA-AMINOPHENOLS A. Acetaminophen (paracetamol, N-acetyl) B. Phenacetin (acetophenetidin) ACETAMINOPHEN Pharmacologic Properties 1. Analgesic 2. Antipyretic

58 3. 4. 5. 6. 7. 8. Antiinflammatory (not clinically significant) Do not produce gastric bleeding Do not affect platelet adhesiveness Do not affect uric acid excretion Enhances water transport in the kidney. Peak plasma concentration usually occur 30 minutes. After dosage, and the half life is usually 2 hours. 9. Conjugated in the liver and excreted in the urine. Adverse Effect: 1. Methemoglobinemia (Phenacetin) - condition that results from conversion of the iron in hemoglobin to an oxidized state that cannot effectively carry oxygen. Signs: 1. Cyanosis 2. Dyspnea on exertion 3. Anemia 2. Hemolytic Anemia - Hemolysis is caused by minor metabolites that oxidize glutathione in the RBC and thereby labilize the erythrocyte membrane to oxidative destruction. Signs: 1. Abdominal or lower back pain 2. Jaundice 3. Hemoglobinuria 4. Anemia 3. Hepatic Necrosis - may occur after ingestion of a single dose of 10 to 15 Grams. 4. Nephrotoxicity Adult dose: 325 to 500 mg. or 2 tablets or capsules; not more than 4 Grams in 24 hours. Unwanted effects: few; most serious is hepatoxicity Paracetamol Overdose: 10-15 gm. acute liver damage manifests between 2-6 days after overdose 25 gm. fatal Treatment: Gastric lavage provided it is in the first hour after dosage; <12 hrs. N acetylcysteine; after 24 hrs. the success of treatment depends on the magnitude of the initial dose. (px will suffer a slow and distressing death). - In postoperative dental pain, efficacy is NOT dose-related. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) - share many of aspirins pharmacological properties. - anti-inflammatory and analgesic because they can inhibit the synthesis of eicosanoids. - produce unwanted effects similar to those of aspirin.
A.

PHENYLPROPIONIC ACID DERIVATIVES Ibuprofen, Naproxen, Flurbiprofen and Fenoprofen

59 Pharmacologic Properties 1. The mechanism of action appears to be related to inhibition of prostaglandin synthetase. 2. Analgesic, antipyretic, and anti-inflammatory. 3. Indicated for the symptomatic treatment of rheumatoid arthritis. Adverse Reaction 1. Gastointestinal upset 2. CNS effects such as dizziness, headaches, drowsiness and tinnitus. Naproxen: t1/2 13 hours. Ibuprofen peak plasma concentration 1.5 hrs. after dosage and the plasma half life is 2 hours; broken down in the liver; excreted in the urine; has similar unwanted effects as aspirin. B. INDOLEACETIC ACID 1. Indomethacin - most potent inhibitors of cycloxygenase - analgesic, antipyretic, powerful anti-inflammatory agent. - used in rheumatoid arthritis. - first drug of choice to treat gout. Adverse reaction: - GI complaints - CNS - dizziness, headache, tinnitus, vertigo, confusion unknown, but may be due to PG inhibition 2. Sulindac - has analgesic, antipyretic effect. - treatment of rheumatoid arthritis. C. PYRROLACETIC ACID Tolmentin Zomepirac
D.

FENAMIC ACID DERVIATIVES (FENAMATES) 1. Mefenamic acid - treatment of pain, dysmenorrhea - sedation can occur - absorbed after oral dose; peak plasma concentrations after 2 hrs.; half-life is 3-4 hours. - metabolized in liver, half of metabolites excreted in the urine, half in the feces. - Diarrhea occurs in 25% of patients - as active as aspirin; - incidence of unwanted effects esp. GI disturbance is high. 2. Meclofenamate - treatment of arthritis - dose: initial 500 mg. followed by 250 mg. every six hours.

60 E. PYRAZOLONES Phenylbutazone Oxyphenbutazone

F.

DIFFLUNISAL - a difluorophenyl derivative of salicylic acid; has similar pharmacologic properties as aspirin - long plasma half-life 8 hrs. (only b.i.d.)

II. NARCOTIC ANALGESIC

Similarities: They all produce: 1. Potent analgesia 2. Addiction 3. Respiratory depression 4. Sedation 5. Emesis 6. Constipation CLASSIFICATION 1. OPIUM ALKALOIDS 2. SEMISYNTHETIC DERIVATIVES 3. SYNTHETIC DERIVATIVES I. OPIUM ALKALOIDS - opium is the dried juice obtained from the unripe seed capsules of the poppy plant (Papaver somniferum) A. Morphine most potent analgesic in use named after Morpheus (Greek God of Dreams) undergoes extensive first pass metabolism in the liver. Parenteral solutions of morphine sulfate and oral preparations are available. t1/2 = 3 hours Dosage: Adult 10 to 15 mg. subcutaneously every 4-6 hours. Children 0.1 to 0.2 mg/kg/dose Maximum dose: 15 mg. Pharmacological Properties 1. Analgesia - effective against continuous dull pain. 2. GIT used to treat diarrhea and dysentery; produce degree a degree of constipation. 3. Cough suppression - effective antitussive. 4. Cardiovascular - cause the release of histamine. Unwanted Effects 1. Respiratory depression 2. Dependence

61 3. Nausea and Emetic effect 4. Cause constriction of the pupil (MIOSIS) 5. Actions on the bladder. B. Codeine or Methyl Morphine - Dose: Adult 15-60 mg (1/4 to 1 grain) Pharmacological Properties 1. Effective when taken by mouth 2. Use in treating mild to moderate pain 3. Very effective antitussive. Unwanted Effects 1. Nausea, vomiting, sedation, dizziness 2. Can depress respiration 3. Can cause constipation C. Heroin - produced by acetylation of morphine - 2 to 5X as potent as morphine as an analgesic. - highly euphoric and addicting drug II. SEMISYNTHETIC DERIVATIVE OF MORPHINE OR CODEINE A. Hydromorphone - more potent than morphine. - principal use is for acute pain. B. Hydrocodone (Codone, Dicodid) C. Oxymorphone - extremely addicting and a potent respiratory depressant. - Dose: Adult - 1mg. subcutaneously. - Available only for parenteral use. III. SYNTHETIC NARCOTICS A. Meperidine (Demerol) - most common narcotic abused by professionals. - Dose: Adult 50 to 100 mg. orally, subcutaneously, or intramuscularly. - Preparation: Tablets, elixir, and solutions for injections. - available in combination with acetaminophen or promethazine. Adverse Effect 1. Sedation 2. Respiratory depression 3. Increased tone and secretions of GIT 4. Produces addiction 5. Tolerance develops.

62 B. Alpaprodine C. D. Anileridine - Dose: usual Adult dose 25 to 50 mg. every six hours. - can be give orally, intramuscularly or subcutaneously. - available in tablets and injection. OPIOID ANTAGONIST Naloxone - mainly used to treat opioid overdose, particularly the effects on respiration. - must be given intravenously. - 0.4 to 0.8 mg for immediate effect - t1/2 1 hour COMPREHENSIVE DRUG ABUSE PREVENTION and CONTROL ACT OF 1970 SCHEDULE 1 SUBSTANCES Drugs with a high potential for abuse and no currently accepted medical use. Not for prescription use but may be obtained for research purposes. E.q. Heroin Ketobemidone Marijuana Benzylmorphine Peyote Nicomorphine Mescaline Methaqualone LSD Dihydromorphine Nicodeine Racemoramide Morphine methylsulfonate Levomoramide SCHEDULE II SUBSTANCES Drugs with a high potential for abuse with severe liability to cause psychic or physical dependence. Consists of certain opioid drugs and drug containing amphetamines or metaamphetamines as the single active ingredient or in combination with each other. Categorized as Class A Narcotic Drugs. E.g. Opium Morphine Codeine Hydromorphone Amobarbital Methadone Meperidine Cocaine Oxycodone Pentobarbital Diphenoxylate Phemetrazine Methylphenidate Secobarbital Methamphetamine Dextroamphetamine Etorphine hydrochloride

63 SCHEDULE III SUBSTANCES Drugs with a potential for abuse that is less than those in schedules I and II substances. Their abuse may lead to moderate or low physical dependence or high psychological dependence. Drugs included was formerly known as Class B Narcotic drugs plus a number of nonnarcotic agents. E.q. Chlorhexadol Gluthethimide Methylprylon Sulfodiethylmethane Sulfonmethane Nalorphine Benzphetamine Chlorphentermine Phendimetrazine Certain barbiturates except those listed in another schedule. SCHEDULE IV SUBSTANCES Drugs with low potential for abuse that leads only to limited physical or psychological dependence relative to drugs in Schedule III. E.q. Barbital Phenobarbital Ethinamate Paraldehyde Phentermine Methohexital Fenfluramine Methylphenobarbital Chloral betaine Chloral hydrate Meprobamate Propoxyphene Benzodiazepines Mebutamate Ethchlorvynol SCHEDULE V SUBSTANCES Drugs have a lower potential for abuse than those in Schedule IV for which there is currently accepted medical use in the U.S. Drugs are categorized as Exempt Narcotics.

HEMOSTATICS
Locally applied substances that are employed to arrest excessive bleeding or hemorrhage. Sympathomimetics - reduce bleeding by local vasoconstriction. E.q. Epinephrine Styptics and Astringents - precipitates the tissue proteins in the immediate area. E.q. Zinc Chloride, Aluminum Chloride, Ferric Sulfate Mechanical Agents - acts as matrices in which blood cells / fibrin can be entrapped. E.q. Gel foam, Oxidized Cellulose, Oxidized Regenerated Cellulose. Thrombin - normal constituent of the blood coagulation scheme, combines with fibrinogen.

64

HEMOSTASIS AND HEMOSTATIC AGENTS Factors in the Arrest of Hemorrhage 1. Vessel wall contraction - of short duration (5-20 minutes) - can be prolonged by topical or local infiltration of Adrenaline. 2. Adhesion and Aggregation of Platelets - Platelets are non-nuclear cells with a cytoplasm rich in granules. - normal count: 150,000 4000,000 cells/ml. - half life is 7 to 10 days - releases Adenosine Diphosphate (ADP) and Thromboxane A2 - forms Platelet PLUG 3. Ability of blood to coagulate Stage I - Activation of Factor X --- Xa Stage II Prothrombin (II) --- Thrombin Stage III - Fibrinogen (I) --- Fibrin --- Clot Stage IV - Fibrin Clot - Lysed fibrin and fibrin peptides. 4. Fibrinolysis (The breakdown of blood clot) - can be influenced by age, sex, diet, smoking, altitude, exercise. VITAMIN K - fat soluble vitamin that is essential for the normal hepatic biosynthesis of several factors required for blood clotting. (II, VII, IX, X) ANTICOAGULANTS - they directly or indirectly interfere with the normal clotting mechanism of blood. - patients receiving are those with a history of myocardial infarction, cerebrovascular thrombosis, venous thrombosis, and pulmonary embolism. A. Heparin - enhances the activity of antithrombin III (neutralizes several of the activated clotting factors Ixa, Xa, Xia, and XIIa. It also inactivates prothrombin by forming an irreversible complex with it). - must be administered parenterally. - half life is between 1 to 5 hours (the higher the dose, the higher the half life) - Unwanted effects: Heamorrhage and Thrombocytopenia. - the effect can be reversed by the specific antagonist (Protamine Sulphate) at eh dose regimen of 1 mg. of protamine for every 100 units of heparin. B. Coumarin Anticoagulants - Oral anticoagulants - includes Warfarin Sodium and Phenindione. - antagonist to vitamin k - reduces synthesis of vitamin K dependent clotting factors (II, VII, IX, X). - affected by diet, bowel disease, pyrexia, age, pregnancy, liver disease.

65 ANTIPLATELET DRUGS - Antithrombotic - decrease thrombin formation E.q. Aspirin, Diprydamole, Sulphin Pyrazone. FIBRINOLYTIC DRUGS - promotes the breakdown of thrombi by activation of plasminogen to form plasmin. E.q. Streptokinase, Urokinase, Tissue Plasminogen Activator. ANTIFIBRINOLYTIC DRUGS - these encourage the stabilization of fibrin by inhibiting plasminogen activator. E.q. Tranexamic acid - effects: Nausea, diarrhea, hypotension. DENTAL MANAGEMENT OF PATIENTS WITH HEMOSTATIC PROBLEMS 1. Impaired Platelet Function - due to reduction in platelet count or impaired aggregation due to drug therapy. - Treatment: Low platelet count Platelet transfusion before surgery. Thrombocytopenia due to immune destruction of platelet Administration of corticosteroid - it is a wise precaution to suture and pack the socket to minimize the risk of post extraction hemorrhage. - drugs that impair platelet aggregation and increase bleeding time includes Aspirin, NSAIDs, Sodium Valproate, and Phenytoin. 2. Vascular Defects - associated with vitamin C deficiency and long term corticosteroid therapy. - patients have increased capillary fragility which can cause bleeding problems after surgery. - can be controlled by pressure, suturing, and packing. 3. Impaired Coagulation A. Haemophilia - sex-linked; affects only males. - patients have reduced factor VIII activity. - can be corrected by replacement therapy of freeze-dried factor VIII (cryoprecipitate). - drugs used in conjunction with factor VIII include anti-fibrinolytic agents, epsilon aminocaproic acid which should be started pre-operatively. B. Christmas Disease - associated with a deficiency of factor IX (derived from plasma but not present in cryoprecipitate). - Replacement therapy. C. Von Willebrands disease - inherited disorder associated with both prolonged bleeding time and deficiency of factor VIII.

66 - replacement therapy is necessary.

LOCAL ANESTHETICS
- reversible Blockade of Peripheral Nerve Conduction; drugs that have little or no irritating effects when injected into the tissues and that will temporarily interrupt conduction when absorbed into the nerve. Autonomic Losses in the usual order 1. Sense of Cold 2. Warmth 3. Pain 4. Touch 5. Pressure 6. Vibration 7. Proprioception 8. Motor function Components of Local Anesthetics A. Anesthetic Drug B. Vasoconstrictor e.g. epinephrine, levonordefrin Role of Vasoconstrictor in Local Anesthetics Prolong Local Block Delay Systemic Absorption Limit Toxicity C. Antioxidant e.g. Sodium Bisulfite or Sodium Pyrosulfite D. Antiseptics methylparaben Ideal Properties of Local Anesthetics 1. Potent Local Anesthesia 2. Reversible Local Anesthesia 3. Absence of Local Reactions 4. Absence of Systemic Reactions 5. Absence of Allergic Reactions 6. Rapid Onset 7. Satisfactory Duration 8. Adequate Tissue Penetration 9. Low Cost 10. Stability in Solution (long shelf life) 11. Sterilization by Autoclave 12. Ease of Metabolism and Excretion

m n

67 Two Groups: ESTER group and AMIDE group CHEMISTRY OF LOCAL ANESTHETICS Aromatic Nucleus Linkage ESTER O R1 ------- C O R2 ------- N Amino Group R3

R4 ____________________ o r ____________________________ AMIDE H O R1 ------- N C R2 -- ------ N R4 R3

Absorption: Increase vasodilation = Increase speed of circulation Distribution: Brain, liver, kidneys, lungs, spleen. Metabolism: Ester hydrolyzed in plasma by plasma cholinesterase. Amide Liver Prilocaine Lungs Excretion: Kidney Pharmacologic Effects 1. Reversible peripheral nerve conduction 2. Smooth muscle effects relaxation of smooth muscle because sensory receptors are depressed. 3. Analgesic effect 4. Anticonvulsant effects. Most Local Anesthetics are Synthetic except Cocaine 1. An Aromatic, Lipophilic Group 2. An Intermediate Chain (Ester or Amide Linkage) 3. A Hydrophilic 2 or 3 amino group, which forms water soluble salts when combined with acids. Generally almost without exception, Drugs thus formed are: White and Odorless Viscid Liquids or Amorphous Solids Fat Soluble but relatively Insoluble in water All are Bases and form Water Soluble Salts with Acids

68

Toxicity of Local Anesthetics: Descending stimulation of the C.N.S. followed by DEPRESSION of certain areas of the brain Classic Progression: 1. Restlessness, Apprehension and Tremors progressing to Excitement and Convulsions 2. Increase Blood Pressure and Pulse Rate 3. Increase Respiratory Rate 4. Respiratory and cardiovascular depression with Loss of reflexes and consciousness. Characteristics of Lidocaine Toxicity: DEPRESSION, generally the cause of Death, may appear without initial stimulation.

GENERAL ANESTHESIA
- the drug induced absence of the perception of all sensation allowing surgery or other painful procedures to be carried out. - depresses the CNS; alleviate pain and cause a loss of consciousness. HISTORY Nitrous Oxide laughing Gas described by john Priest Horace Wells observed its effects as anesthetics. Ether by T.G. Morton and C.T. Jackson Highly flammable, volatile, pungent odor. Chloroform - volatile liquid; by J.Y. Simpson THEORIES ON MECHANISM OF ACTION OF G.A. 1. Lipid or Meyer Overton Theory 2. Inhibition of biochemical Action 3. Molecular theories Pharmacologic Effects 1. CNS depressants 2. CVS depression 3. Urine output is reduced 4. May produce liver damage. 5. Release of ACTH, antidiuretic hormone, sympathetic neurotransmitters. STAGES OF ANESTHESIA (Guedels Classification) Stage I : ANALGESIA - from administration of anesthesia loss of consciousness Analgesia Euphoria Perceptual distortions Amnesia Stage II : DELIRIUM - loss of consciousness beginning of surgical anesthesia Excitement

69 Involuntary muscular activity (Increase muscle tone) Irregular breathing Hypertension Tachycardia Stage III : SURGICAL ANESTHESIA - state of analgesia associated with majority of surgical procedures - spontaneous respiration ceases * 4 Planes based on: Respiration Size of pupils Reflex characteristics Eyeball movement Stage IV : MEDULLARY DEPRESSION / RESPIRATORY PARALYSIS begins with cessation of respiration circulatory collapse Pupils fixed and dilated No lid or corneal reflexes If not reverse immediately, Death occurs.

PHASES OF ANESTHESIA (Flagg) INDUCTION - encompasses all the preparation and medication necessary for a patient up to the time the surgeon is ready to begin. MAINTENANCE - begins with the patient at a depth of anesthesia sufficient to allow surgical manipulation and continues until completion of procedure. RECOVERY - begins with the termination of the surgical procedure and continues through the post operative period until the patient is fully responsive to the environment. CLASSIFICATION OF G.A. BY ROUTE OF ADMINISTRATION Inhalation Gases Nitrous Oxide Volatile liquids Halogenated Hydrocarbon Chloroform Neuroleptics Fentanyl with Droperidol Intravenous Agents

70 Ethyl Chloride Trichloroethylene (Trilene, Trimar) Halothane (Fluothane) Halogenated Ether Methoxyflurane (Penthrane) Enflurane (Enthrane) Isoflurane (Forane) Ether Diethyl Ether (Ether) Vinyl Ether (Vinethene) (Innovar) Dissociative Ketamine (Ketalar, Ketaject) Barbiturates Methohexital (Brevital) Thiamylal Sodium (Surital) Thiopental Sodium (Pentothal) Narcotics Fentanyl (Sublimaze) Morphine

Cyclopropane Ethylene

BALANCED ANESTHESIA - PRE-ANESTHETIC MEDICATION- INDUCTION- NEUROMUSCULAR BLOCKING -AGENT - ANESTHETICSGOAL: ANALGESIA SLEEP MUSCLE RELAXATION ABOLITION OF REFLEXES PREMEDICATION Features Required of PREMEDICATION Agents 1. Alleviate pre-operative anxiety. 2. Provide some degree of post-operative amnesia esp. in children. 3. Make the induction and maintenance anaesthesia easier. 4. Reduce the amount of anaesthetic agents required by enhancing their effects 5. Provide additional analgesia. 6. Reduce salivary and bronchial secretions. 7. Reduce activity in the parasympathetic nervous system. PREMEDICATION AGENTS OPIOIDS - e.q. Morphine, Pethidine, Papaverum

71 Therapeutic Effects: Analgesic, Sedative, Euphoriant, Respiratory depression, Suppression of cough reflex Unwanted Effects: Nausea, Vomiting ANXIOLYTICS - e.q. Benzodiazepines - used orally to provide post-operative sedation. ANTIPSYCHOTICS (Neuroleptics) e.q. Penothiazines derivatives promethazine and Trimeprazine. - pre-anaesthetic sedatives; anti-emetic; for patients who fear or has predisposition to post-operative vomiting; depresses respiration: cause varying amount of hypotension. ANTICHOLINERGIC Atropine Sulphate; Hyoscine; Glycopyrrolate - reduce secretions; prevent overactivity of the parasympathetic nervous system. Atropine Sulphate - commonly used to reduce salivary and bronchial secretions during anesthesia by antagonizing the actions of acetylcholine at muscarinic receptors. Hyoscine - antagonizes the effect of endogenous acetylcholine at muscarinic receptors; given IM 30-60 minutes before induction anesthesia; a CNS depressant causes drowsiness and depression of the vomiting center -anti-emetic. Athigh doses, it may act as stimulant of the CNS. Both atropine and hyoscine block the action of acetylcholine released from the vagal nerve endings which gives some protection against vagal stimulation. Glycopyrrolate - a quarternary ammonium; produces prolonged and good control of salivary and pharyngeal secretions; less effect on the cardiovascular system; used as preoperative or intraoperative antimuscarinic to attenuate or prevent the intra-operative bradycardia sometimes associated with the use of suxamethonium or due to cardiac vagal reflexes.. NEUROMUSCULAR BLOCKING AGENTS - by specific blockage of the neuromuscular junction, they enable light levels of anesthesia to be used with adequate relaxation of the muscles of the abdomen and diaphragm; produce relaxation of the abdominal muscles, and paralysis of the respiratory muscles; relaxes the vocal cords allowing the passage of a tracheal tube. Two Types of Neuromuscular Blocking Agents I. NON DEPOLARIZING MUSCLE RELAXANTS(competitive) Tubocurarine - highly ionized; given IV ; produce paralysis of all voluntary muscles; action commences 3-4 mins. and lasts up to 40 mins.; used as an adjunct to G.A.; action may be reversed by administration of neostigmine ; a weak ganglion blocker causes the release of histamine -- peripheral vasodilation - - will lower the b.p. ; may also cause flushing and bronchospasm due to the release of histamine; does not cross the blood brain barrier or the placenta.

72 Pancuronium - more potent than Tubocurarine but has a shorter action; acts by competitive block but does not normally block transmission in autonomic ganglia and so does not significantly alter the blood pressure. However, if rapidly injected IV, it may cause a rise in bp due to vagal blocking and tachycardia; does not cause histamine to be released; may also be used to produce relaxation in a number of pathological conditions such as tetanus; also used extensively in ICU. Atracurium and Vecoronium - most often used at the present time; have little effect on the cardiovascular system; may release little of histamine; more advantageous to patients with renal or hepatic impairment. II. DEPOLARIZING MUSCLE RELAXANTS Suxamethonium - depolarizes the postsynaptic membreane and maintains this state so that the adjacent m. fibers are electrically inexcitable; injected IV; produces complete muscular relaxation in half a minute; has a number of muscarinic action including increase in salivary secretion, muscle injury occasionally due to direct action on the muscle or may follow K depletion from muscles.; may cause malignant hyperpyrexia maybe treated by rapid cooling, inhalation of 100% oxygen and IV of Dantrolene 1 mg/kg of body weight. * MUSCLE CONTRACTION action potential ---- travels down the motor nerve---- release of packets of acth (quantamillions of acth molecules) ----- acth crosses the synaptic cleft and interacts with the cholinergic receptors on the end plate of a muscle fiber ---- surge of acth brings a massive increase in the permeability of the post-synaptic membrane to Na ions and to a < extent to K ions (Na ions enter and generate a local end plate potential (depolarization) until it reaches a critical threshold --- triggers off a muscle action potential propagated along the muscle fiber causing it to contract. Acth is then broken down by cholinesterase in the neuromuscular junction; the motor end plate polarizes and is then ready to be stimulated again. INDUCTION AGENTS (IV ANESTHETIC AGENTS) - widely used to induce anaesthesia Sodium Thiopentone - an ultra short acting barbiturate; given IV; produces loss of consciousness in 10-20 seconds. Max. depth occurs 40 secs. ; px becomes conscious 2-3 mins. after dosage; provide anes. for short operative procedures; induce unconsciousness prior to inhalation anaesthesia; rapidly enters the brain; 85% bound to plasma protein; metabolized in the liver; excreted in the kidney; depresses many of the functions of CNS; no analgesic properties; low doses may increase sensitivity to pain; an anticonvulsant; often associated with laryngospasm; bronshospasm; cough; extravascular injection may cause pain and necrosis when the concentration is > 2.5%; endothelial and deeper layer may be damaged when inadvertently injected into an artery; must not be given to patients with porphyria no effect on the uterus but can cross the placenta and depress the fetal cardiovascular system; there is transient drop in blood pressure. Methohexitone - an ultra short acting barbiturate; Pharmacological properties same with Thiopentone Unwanted effects - pain on injection, involuntary movements, cough, and laryngospasm;

73 has convulsant properties Etomidate - a carboxylated imidazole derivative; rapid recovery and lack of hangover effect may be due to short plasma half life; does not release histamine; painful, cause involuntary movements; prolonged use may cause adrenocortical suppression in ICU; has little or no effect on the cardiovascular system. Ketamine - given IV but can be given IM; associated with profound sedation and analgesia; produces dissociation but not sedation and so airway reflexes are maintained; vivid hallucinations and nightmares; raises b.p. and pulse rate; useful in management of mass casualties. Propofol - a new phenolic IV induction agent and maintenance anaesthesia provided the surgical procedure does not exceed 1 hour.; recovery is usu. rapid and often accompanied by euphoria; sexual fantasies can also occur; highly lipophilic; More expensive. Unwanted effects - cardiac respiratory depression; apnea and marked hypotensive effect; pain on injection. INHALATION ANAESTHESIA - most widely used form of maintenance anaesthesia INHALATION ANAESTHETIC AGENTS Nitrous Oxide - E.q. Entonox colorless, odorless gas; weak anaesthetic; an adjunct to other inhalation agents; may produce severe hypoxia when used alone; an excellent analgesic agent; a direct myocardial depressant; stimulates sympathetic nervous system; may cause nausea, vomiting, (megaloblastic anemia and neuropathy in animals); suppresses spermatogenesis and production of WBC and RBC in bone marrow; Uses: changing painful dressing, an aid to post-operative physiotherapy and emergency ambulances. Halothane - a halogenated hydrocarbon; colorless at room temperature; has pleasant smell;not inflammable; non explosive; causes dose-related reduction in b.p.,slowing of heart rate; severe dysrhythmia; bronchodilation ; depresses respiration; no analgesic property and does not produce a degree of relaxation; may cause hepatic necrosis. Enflurane - a halogenated ether; colorless at room temperature; non flammable with a mild sweet odor; alters electrical activity in the brain; 80% excreted unchanged in expired gases, 2.5 % metabolized in the liver and excreted in the kidney; produces a dose-related reduction in b.p.; causes respiratory depression; twitching of the limbs, jaws, face and neck but self limiting; no significant effect on the liver Isoflurane - isomer of enflurane; a halogenated methylethyl ether; physical properties similar to enflurane; reduction in b.p. but has little or no effect on cardiac output; increase in heart rate but no arrythmias; depresses respiration and stimulates airway reflexes causing increased secretion, coughing and laryngospasm. Ether - one of the earliest and safest volatile liquids irritating to the mucus membrane; inflammable and explosive; often associated with nausea and vomiting; now rarely used. ANAESTHETIC EMERGENCIES 1. Respiratory Obstruction

74 2. Hypersensitivity reaction

ANTISEPTICS AND DISINFECTANTS

- substance that kill or prevent the growth of microorganism Antiseptics - used on living tissues. Disinfectants applied on inanimate objects. 1. ALCOHOLS A. Ethyl Alcohol and Isopropyl Alcohol B. Chlorhexidine and Iodine C. Surgical Spirits mixture of ethyl/methyl alcohol 2. ALDEHYDES A. Formaldehyde bactericidal activity on bacteria, fungi, and viruses; action is very slow 0.5% will take 12 hrs.; 2-8% concentrations to disinfect inanimate objects. B. Glutaraldehydes acts against all microorganisms; less viruses, odor; 2% concentration; for cold sterilization; for articles contaminated by hepatitis B virus that cannot be heat sterilized; 1 12 hour exposure. C. Chlorhexidine (Hibitane) antiseptic and disinfectant 1. Hibiscrub ICI pre-operative preparation of skin and hand disinfection. 2. Hibisol ICI disinfection of sin and hands. 3. Corsodyl ICI in dental gel; mouthwash 0.2% solution. Hibitane Obstetric cream (ICI) pre-operative preparation of hands and skin of midwife/doctor. Hibitane Concentrate general purpose antiseptic 3. DYES complex organic substances from coal tar e.q. aniline dyes, gentian violet, brilliant green, acnidine dyes, acriflavin and proflavine. 4. HALOGENS reacts with bacterial proteins. 5. CHLORINE has a rapid, potent and brief action; effective against most bacteria, some fungi, yeast, and viruses; in the form of hypochlorites, organic chloramines, chlorinated isocyanurates; inactivated by organic matter. 6. IODINE acts as much the same way as chlorine but not readily inactivated by organic matter; bactericidal and fungicide; present in weak solution of 2.5% iodine in potassium iodine, water and alcohol; stains skin. 7. IODOFORM mild antiseptic E.q. whiteheads varnish incorporated into ribbon gauze for infected sockets and dressing for surgical removal; contains iodoform with benzoin, storax, and balsam of tolu in solvent ether; Kri-paste- used as root canal filler; Kri liquid - sterilize root canals. 8. IODOPHORS combination of iodine and surface active detergents; effective against

p q r

s t u
v

75 gram + - organisms after 15 secs.; doesnt stains skin. E.q. Povidone Iodine 9. OXIDIZING AGENTS liberates oxygen which oxidizes proteins of bacteria and tissue proteins. Hydrogen Peroxide mild antiseptic; 30% aqueous solution to bleach discolored root filled teeth; mouthwash in acute ulcerative gingivitis. Sodium Perborate treatment of acute ulcerative gingivitis; liberates oxygen when in contact with organic matter. 10. PHENOLS, CREOSOLS and their derivatives Phenol - 80% in water; irritant and caustic producing a burning pain; produces feeling of anesthesia CMCP (Camphorated para-aminophenol) 35% in camphor; medicament in root canals. Cresol 3x bacteridal potency of phenol; also toxic E.q. Metacrsyl acetate (Cresatin) irrigation of root canals; not irritant to periapical tissues. Chloroxylenols less effective than phenolic agents; activity reduced in the presence of organic matter. E.q. Dettol (5% chloroxylenol). Hexachloropane excellent disinfectant; for gram + cocci; not very irritant to tissues but has neurotoxic effects on babies (dusting powders). 11. SURFACE ACTIVE AGENTS Classification according to ionic charge: CATIONIC - positive charge; includes quarternary ammonium compounds such as: 1. Benzalkonium chloride (Zepiran) 2. Cetylpyridinium (Ceepryn) 3. Cetrimide (Cetavlon) - bactericidal against some gram + and some gram negative bacteria; little effect on tubercle bacilli, spore forming microbes and psuedomonas aeruginosa; ANIONIC - negative charge; not bactericidal, only enhances physical removal of bacteria; effective against gram + microorganism; E.q. Sodium lauryl sulfate and green soap. DENTAL USES OF ANTISEPTICS 1. Skin preparation before surgery or injection 2. Pre-operative preparation of the oral mucosa 3. Sometimes as an ingredient of dentrifices 4. Inhibition of dental plaque 5. Cleaning of operating areas 6. Cold sterilization of instruments and equipment 7. Storage of sterilized surgical equipment 8. Preparation of surgeons hand 9. Irrigation of root canals in endodontics.

76

DEFINITION OF TERMS Antimicrobial Agents substances that kill or suppress the growth or multiplication or prevent the action of microorganisms Anti-infective Agents substances that act against or tend to destroy infection. Antibacterial Agents substances that destroy or suppress the growth or multiplication of bacteria. Antiviral Agents substances that destroy or suppress the growth or multiplication of viruses. Anti-fungal Agents substances that destroy or suppress the growth or multiplication of fungi. Antibiotic Agents chemical substances produced by microorganisms that have the capacity, in dilute solutions, to destroy or suppress the growth or multiplication of organisms or prevent their action. Antibacterial (Antimicrobials) are obtained from natural sources or are manufactured Antibiotic chemicals that are produced by one kind of microorganism that inhibit or kill another kind of organism. * The difference between antibiotic and synthetic antibacterial agents is that antibiotics are produced by microorganisms and the antibacterial agents are made in the laboratory. Classification of Antibacterials According to its ACTION 1. Bacteriostatic inhibit or retard the multiplication or growth of bacteria but does not kill them. E.q. Tetracyclines, sulfonamides, chloramphenicol - bacteria can grow again when drug is withdrawn. - Host defense mechanism (e.q. phagocytosis) are required to kill the microorganism. 2. Bactericidal drugs that kill bacteria. E.q. Penicillin, Cephalosphorins, Aminoglycosides, Vancomycin, Metronidazole, Imipenem. - best choice in treatment especially in life threatening infections, endocarditis and in patients whose leukocyte count is <500/L * some drugs may be bacteriostatic at low concentrations and bactericidal at high concentrations against the same or different microorganisms; In patients with impaired defense mechanism, a bactericidal is preferred over a bacteriostatic agent because the bodys ability to fight infection is compromised. Classification According to RANGE OF ACTIVITY Spectrum the range of activity of a drug. 1. Narrow Spectrum acts against either gram positive or gram negative organisms. one type of organism; only selective. E.q. Penicillin and erythromycin gram + bacteria. 2. Broad Spectrum acts against a wide variety of organisms effective on both gram + and gram bacteria as well as some viruses; treats infection not

77 identified by culture and sensitivity test. E.q. Tetracylcine and Cephalosphorins. INFECTION invasion of the body by pathogenic microorganism and the reaction of the tissues to their presence and to the toxins generated by them. Principal factors that determine a microorganism causing an infection 1. Virulence of the microorganism 2. Number of organisms present 3. Resistance of the host How do Microorganism cause an infection? 1. Infectivity (must enter the right portal of entry) 2. It must be able to multiply on the body of the susceptible host. 3. Invasiveness (effective mechanism for transmission) 4. It must be able to produce toxins, enzymes and other metabolites that affect the cell or toxigenecity. Two Goals to be achieved to prevent infection 1. Reduce the number of bacteria in the surgical wound. 2. Enhance the hosts defenses so as to prevent the bacteria that entered the wound from causing clinically evident infection. INDICATION FOR ANTIMICROBIAL AGENTS A. Prophylactic Indications - used for high risk patients whose immune system are weak. E.q. in rheumatic or congenital heart disease, Renal dialysis patients, or the presence of a heart prosthesis. Any dental procedure may precipitate a bacteremia, therefore, prophylactic antibiotics must be given to prevent bacterial endocarditis. B. Therapeutic Indication - for the treatment of infection. Does this particular patient need the assistance of antimicrobial agents to resolve this particular infection?" * NOT ALL INFECTIONS REQUIRE ANTIBIOTIC THERAPY, it all depends on: 1. The patient. host responses - Defense mechanism is considered. - The presence or absence of systemic manifestation such as fever, malaise, and lymphadenopathy are indicators of how well the patient is doing without antimicrobial therapy. 2. The Infection. - The virulence and invasiveness of the etiologic microorganism are important in determining the acuteness, severity, and spreading tendency of the infection which is obviously need to be treated with antimicrobial agents. Five Basic Principles in the Use of Antibiotics / Antimicrobials 1. Infection must be present or imminent - consider the signs of inflammation. 2. Identify the organism - accomplished through culturing, gram stain or educated guesses. Purpose: To determine the specific type of antimicrobial sensitive to the specific type of

78 microorganism. 3. Choose the specific type of antibiotic --------------------------------------------------------------------------------------------------------Antibiotics G- & G+ G-------------------------------------------------------------------------------------------------------Phenoxymethyl Penicillin ++++ + Penicillin G ++++ + Ampicillin +++ Erythromycin +++ ++ Clindamycin +++ + Cephalosporins +++ + Tetracycline ++ +++ Aminohlycoside + ++++ ---------------------------------------------------------------------------------------------------------4. Administer antibiotics properly 5. Prevent and minimize toxicity and hypersensitivity. a. right dose b. right dose interval c. right dose form d. right duration of therapy Duration of dosage: - An antimicrobial agent should be continued long enough to prohibit a regrowth of the causative microorganism, but not so long to induce toxic drug symptoms or alter the normal flora to the extent that superinfection results ** It should continue 48 hours after the symptoms of infection are absent. If beta hemolytic streptococci are the causative organisms, usually penicillin should be continued for at least 10 days. For osteomyelitis, it should be continued for 14 days after fever and tenderness are absent and drainage has ceased. In patients with a depressed immune system or history of prolonged healing, coverage usually needs to be continued longer than in normal patient. MECHANISM OF ACTION OF ANTIBACTERIALS 1. Inhibition of cell wall synthesis a. Inhibition of cross linking (transpeptidation) of peptidoglycan. e.q. Penicillins; Cephalosporins. b. Inhibition of other steps in peptidoglycan synthesis. e.q. Vancomycin, Cycloserin, Bacitracin. 2. Inhibition of protein synthesis x a. Action on 50S ribosomal subunit e.g. Chloramphenicol, Erythromycin, y Clindamycin. z b. Action on 30S ribosomal subunit. e.q. Tetracyclines and Aminoglycosides. 3. Inhibition of nucleic acid synthesis aa a. Inhibition of nucleotide synthesis e.q. Sulfonamides and trimethoprim bb b. Inhibition of DNA synthesis e.q. Quinolones (Ofloxacin) cc 4. Alteration of cell membrane function a. Antibacterial activity e.q. Polymyxin

79 b. Antifungal activity e.q. Amphotericin B, Nystatin, ketoconazole. 5. Uncertain mechanisms E.g. Isoniazid, Metronidazole. Resistance ability of a microorganism to be unaffected by an antimicrobial agent. Natural resistance occurs when an organism has always been resistant to the antimicrobial Agent; occurs without previous exposure to the drug. Acquired resistance occurs when the organism that was previously sensitive to an antimicrobial agent develops resistance/ caused by prior exposure to the drug. Cross Resistance - occurs with antibacterials that have similar actions. E.q. Penicillin; Cephalosporins. Genetic recombination including conjugation, transformation , and transduction, can result in the passing on of resistance from one bacterial strain to another. The second strain becomes resistant to the same antibiotics as the first strain without having been exposed to the antibiotic. **Action depends on depends on several variables: 1. Usual therapeutic concentration of that agent 2. Type of organism 3. The mechanism of action of that agent. GENERAL ADVERSE REACTIONS TO ANTIBACTERIALS 1. Allergy / Hypersensitivity - may be mild to severe. E.q rash, pruritus, hives-treated with antihistamine. 2. Anaphylactic Shock - shortness of breath is the first symptom; treatment is epinephrine bronchodilators and antihistamines. 3. Superinfection, Suprainfection - infection caused by proliferation of microorganisms that are different than those causing the original infection. - a secondary infection that occurs when the normal microbial flora of the body are disturbed during antibiotic therapy. E.q. Fungal infections. - often caused by broad spectrum antibiotics such as tetracycline CULTURE AND SENSITIVITY TESTS - only way in which one can reasonably ensure that a particular drug will kill or inhibit the growth of an infecting microorganism. However, it will not show the potency of the drug nor differentiate between bactericidal and bacteriostatic effects, they will only show which drug adversely affect the growth of the microorganism on the culture plate. Culture a sample from the infected site is taken and grown on culture media. After the pathogen is grown, sensitivity test can be conducted. Sensitivity after the organism is identified, it is again grown on culture media and the effect of different antimicrobial agents on the organism is tested. One to two days are required before the result of this test are available Advantages of Culture and Sensitivity tests 1. An early correction of therapy is possible if the drug selected is ineffective against the

80 microorganism causing the infection Pathogens grown on culture before antibiotic therapy is begun can be more easily identified than after a therapeutic failure has occurred.

2.

Blood level the concentration of the antibacterial agent present in the blood or serum; an important index to drug dosage, since certain concentration of the drug is required in the body fluids to inhibit or kill the microorganism. Synergism effect when a combination of two antibiotics is more rapidly bactericidal than either drug used alone. Combinations of antibiotic that are bactericidal generally are synergistic. Combinations of those that are bacteriostatic are merely additive. Antagonism effect when the bactericidal rate for the combination of two drugs is less than that for either drug used alone; often exhibited when a bateriostatic and a bactericidal agent are used in combination. DENTALLY USEFUL ANTI-INFECTIVE AGENTS 1. PENICILLINS - can be divided into three groups A. Penicillin G and V B. Penicillinase-resistant penicillins (Methacillin, Cloxacillin, Nafcillin, Floxacillin, Dicloxacillin) C. Extended-Spectrum penicillins (Ampicillin-like agents, carbenicillin-like agents and amino-penicillin group. Administration and Body handling - can be administered orally or parenterally. - should not be applied topically because of its allergenecity. - Penicillin V is better absorbed orally than penicillin G - degraded by the gastric fluid-it should be administered one hour before meals or 2 hours after meals. - crosses placental barrier and a small amount appears to be excreted in the milk and saliva. Spectrum: - very potent bactericidal agent that acts by interfering with the synthesis of the bacterial cell wall. - its narrow spectrum of activity includes gram positive aerobic and facultative organism(cocci: Streptococcus,and Staphylococcus; rods: Bacillus, Corynebacterium and Clostridium; Spirochetes:Treponema pallidium; and certain gram negative aerobic cocci: Neisseria gonorrhea and N. meningitidis) Adverse reactions : - most common cause of drug allergies. 1. Toxicity - large doses of penicillin G have been associated with renal damage manifested as fever, eosinophilia, rashes, albuminuria. - gastrointestinal irritation can manifest itself as nausea with or without vomiting.

81 2. Allergy and Hypersensitivity Immediate - less than 30 minutes includes anaphylaxis. Accelerated - 2 to 48 hours includes serum sickness and laryngeal edema. Late - 3 or more days includes rashes, oral lesions, and other symptoms. Uses: - for dental infections a. ANUG penicillin V b. Periodontal abscess - penicillin V c. Abscess, cellulitis, pericoronitis penicillin V d. Osteomyelitis - penicillin V e. Rheumatic heart disease - penicillin V. 2. ERYTHROMYCIN - administered orally; available in tablets and capsules, oral suspensions and IV and IM forms. - formulated as enteric-coated tablet, capsule or insoluble ester to reduce degradation by the stomach acid. - it should be administered 2 hours before meals or several hours after meals. Activity and Spectrum: - usually bacteriostatic but may be bactericidal at normal therapeutic doses. - used against gram positive bacteria. - also a drug of choice for whooping cough, diphteria, syphilis, and gonorrhea. - cross-resistance has been reported between erythromycin and clindamycin. - poor second choice to treat dental infections. Adverse Effect: 1. Gastrointestinal Effects - include stomatitis, abdominal cramps, nausea, vomiting and diarrhea. 2. Cholestatic Jaundice - symptoms include nausea, vomiting and abdominal cramps followed by jaundice and elevated liver enzyme levels. 3. Allergy - very uncommon. Drug Interaction: - patients taking Theophylline chronically for asthma or acutely for bronchitis may exhibit a drug interaction with erythromycin. - has been implicated in the failure of oral contraceptive efficacy. Uses: - drug of first choice in patients allergic to penicillin. - indicated certain situations for the prophylaxis of rheumatic heart disease. - usual adult dose is between 250 and 500 mg qid. - for bacterial prophylaxis- 1 gm 1 hour before the dental appointment 3. TETRACYCLINE

82 broad spectrum antibiotics affecting a wide range of microorganisms. most commonly given by mouth. secreted in the saliva and milk of lactating mothers. stored in the dentin and enamel of unerupted teeth. also concentrated in the gingival crevicular fluid.

dd

Types: 1. Doxycycline - excreted in the feces 2. Tetracycline eliminated by glomerular filtration, - oral absorption is decreased by administration of food with high calcium content, dairy products, oral iron supplements or antacids. 3. Minocycline - metabolized in the liver and excreted in urine. - may be given to patients with renal dysfunction Spectrum: Bacteriostatic and interfere with the synthesis of bacterial protein Broad spectrum Adverse Reactions: 1. Gastrointestinal effects - anorexia, nausea, vomiting, diarrhea, gastroenteritis, glossitis, stomatitis, xerostomia, and superinfection (moniliasis) 2. Hepatoxicity - large dose of parenteral tetracycline 3. Renal toxicity 4. Hematologic effects - hemolytic anemia, leukocytosis, thrombocytopenic purpura 5. Effects on teeth and bones 6. Superinfection 7. Photosensitivity exaggerated sunburn 8. Allergy Uses:
1. 2.

3. 4. 5. 6.

Alternative drug to treat chlamydial and rickettsial infections Used to treat cholera, acne, and pulmonary infections Doxycycline is used to treat travelers diarrhea Indicated for the treatment of periodontitis Mixture of equal parts of tetracycline syrup and lidocaine viscous for the management of recurrent aphthous stomatitis ANUG may also be treated with tetracycline

4. CLINDAMYCIN - bacteriostatic antibiotic effective primarily against gram-positive organisms. - administered orally, intramuscularly, or intravenously. ee - food does not interfere with absorption ff - cross-resistance between Clindamycin and tetracycline (competition for binding site) Adverse Reaction: 1. Gastrointestinal effects (Pseudo Membranous Colitis- PMC ) -severe, persistent diarrhea and the passage of blood and mucus in the stool

83 2. Superinfection 3. Allergy Uses: Should be used only when specifically indicated 2. Mixed infections insensitive to penicillin- anaerobes
1.

5. METRONIDAZOLE - taken orally - bactericidal and penetrates all bacterial cells. Adverse Reactions: 1. Gastrointestinal effects - nausea, anorexia, diarrhea and vomiting, epigastric distress and abdominal cramping 2. Oral effects - unpleasant metallic taste; altered taste of alcohol; glossitis, stomatitis and a black furred tongue; dryness of the mouth 3. Effects on CNS - headache, dizziness, vertigo, ataxia, confusion, depression, weakness, insomnia, and convulsive seizures 4. Renal toxicity - cystitis, polyuria, dysuria, incontinence 5. Disulfiram-like reaction - alcohol should be avoided; symptoms include nausea, abdominal cramps, flushing, vomiting or headache Uses:
1. 2. 3.

Treatment of trichomoniasis, amebiasis Not the drug of choice for any dental infections (alternative drug) Shown to be effective for the treatment of B. fragilis infections following mandibular fracture

6. CEPHALOSPHORINS - chemically related to penicillin - bactericidal agents - can be administered orally, intramuscularly, or intravenously. Adverse Reactions: 1. Gastrointestinal effects 2. Nephrotoxicity 3. Superinfection 4. Local reaction 5. Allergy 6. Cross sensitivity with penicillin Uses: 1. For infections that are sensitive to these agents but resistant to penicillin 7. VANCOMYCIN - administered only intravenously - bactericidal - narrow spectrum of action against many gram positive cocci.

84

Adverse Reactions: 1. Ototoxicity 2. Nephrotoxicity 3. Anaphylaxis 4. Superinfection Uses: 1. Useful in the prophylaxis of infective endocarditis for patients with prosthetic heart valves who are allergic to penicillin. 2. Used orally to treat PMC. 8. AMINOGLYCOSIDES (Neomycin, Streptomycin, Kanamycin, Gentamycin, Tobramycin, Amikacin, Netilmicin) - bactericidal - have a broad antibacterial spectrum - poorly absorbed after oral administration & so must be administered by IM or IV injection for a systemic effect - used for the treatment of aerobic gram-negative infections Adverse Reaction: 1. Ototoxicity - toxic to the 8th cranial nerve, which can lead to auditory and vestibular disturbances. Patients may have difficulty in maintaining equilibrium and can develop vertigo. 2. Nephrotoxicity - can cause kidney damage 3. Neuromuscular blockade - act as weak neuromuscular blocking agents, potentially producing apnea Uses: - reserved for hospitalized patients with the serious gram-negative infections Gentamicin is used in dentistry to prophylaxis patients with prosthetic heart valves 9. CHLORAMPHENICOL - broad spectrum gg - bacteriostatic - active against a large number of gram-positive and gram negative organisms, rickettsiae, and some chlamydiae. Particularly active against Salmonella typhi. - has serious side effects like fatal blood dyscracias (aplastic anemia, and thrombocytopenia) - Grey baby syndrome occurs when infants given cannot conjugate it. - Antibiotic of first choice in the treatment of life-threatening influenza and typhoid fever. SULFONAMIDES - cannot be classified as an antibiotic because they are not produced by living organisms. - bacteriostatic against many gram positive and gram negative bacteria.

85 Adverse Reaction: 1. Allergic reaction (rash, urticaria, pruritus, fever, fatal exfoliative dermatitis). 2. Nausea, vomiting, abdominal discomfort, headache and dizziness. 3. Liver damage, depressed renal function, blood dyscrasias. Uses: - used when antibiotics are ineffective or cannot be used. - should not be used topically for oral lesions ANTIFUNGAL DRUGS 1. NYSTATIN - effective against candida albicans - not absorbed from the skin or mucuos membranes. - used for local effects in the treatment of candidiasis on the skin or any part of the alimentary tract. - has a very unpleasant taste. Uses: a. b. c. d. Thrush Denture stomatitis Antibiotic stomatitis Some forms of mucocutaneous candidiasis.

2. AMPHOTERICIN B - poorly absorbed from the GIT and probably not all from the unbroken skin. - used locally to treat conditions for which nystatin could be used. - available in intravenous injection. 3. IMIDAZOLE AGENTS (Miconazole, Ketoconazole) - used in the treatment of systemic fungal infections and candidiasis

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GENERAL

REFERENCES

Ansel, H.C., Popovich, N.G., and Allen, L.V.: Pharmaceutical Dosage forms and Drug Delivery Systems, Sixth edition, William and Wilkins, USA, 1995. Asperheim, M. K.: Pharmacology AN INTRODUCTORY TEXT, Seventh Edition W.B. Saunders Company, Philadelphia, Pennsylvania, USA, 1992. Grajeda-Higley, L.: Understanding Pharmacology: A Physiologic Approach, Appleton and

86 Lange, Stanford, USA 2000. Kee, J.L. and Hayes, E.R.: Pharmacology: A Nursing Process Approach, 1st edition, W.B. Saunders Company, Philadelphia, Pennsylvania, USA. Musser, R. D. and ONeil, J. J.: Pharmacology and Therapeutics, 4th edition. The McMillan Company, London, 1969. Mycek , M. J., Harvey, R. A., and Champe, P. C.: Lippincotts Illustrated Reviews: Pharmacology, 2nd edition, Lippincott-Raven Publishers, Inc. New York 1997 Olson, J.: Clinical Pharmacology Made Ridiculously Simple, international editions 2000, McGraw-Hill Book Company, Singapore, 1997. Stringer, J.L.: Basic Concepts in Pharmacology, A Students Survival Guide, 2nd edition, McGraw-Hill Companies, Inc., Singapore, 2001. Walton, J. G., Thompson J. W., and Seymour, R. A.: Textbook of Dental Pharmacology and Therapeutics, Second edition, Oxford University Press, New York, 1994 ---------------------------------------------------------------------------------------------------------------------CENTRO ESCOLAR UNIVERSITY College of Dentistry

Course Title: PHARMACOLOGY Course Number: PHA100/PHA100L Units: Lecture 2 Laboratory 1 Pre-requisites: Anesthesiology Course Description: The course presents the principles in the use of drugs for the diagnosis, prevention, and treatment of diseases. Each drug is considered according to its indication, mechanism of action, pharmacokinetics, contraindications and precautions, unwanted effects and drug interactions. The course deals more on the commonly prescribed drugs used and related in the practice of Dentistry. General Objectives: 1. To explain the basic and clinical pharmacology upon which drug therapy is based with particular emphasis on drugs used in Dentistry. 2. To demonstrate the physical and biological behavior of some drugs in order to familiarize students with the actual effects of drugs. Hours / Week: Lecture 2 hours/week Laboratory 3 hours/week

87 3. To expose students to the type of questions they will encounter in the licensure examinations. COURSE PLAN: Course Content Introduction to Pharmacology Drug Nomenclature Drug Therapy
Suggested Teaching Methodology/ Strategy and Materials Time Allotment (no. of hours)

Specific Objectives To introduce the general principles of pharmacology To identify drugs according to their generic, chemical, and trade names To know and understand the different processes involved in drug therapy. To effectively apply drugs according to its route of administration

Evaluative Measures and Requirements Recitation/Quizzes Laboratory Manual Recitation/Quizzes Laboratory Manual MIMS Recitation/Quizzes

Lecture Lecture

Lec. = 4 Lab. = 3 Lec. = 2 Lab. = 3 Lec. = 4

Lecture

Route of Drug
Administration

Lecture
demonstration

A. IM/ Subcutaneous B. Cutaneous Dosage Forms

method

Lab. = 3 Lab. = 3

Practical exercise Quizzes

Drug Literature Systems of Measurement Conversion Computation of a childs dose Prescription Writing and Prescription Orders

To familiarize students Show and Lab. = 6 on the different dosage Tell Method forms of drugs; differentiating one from the other To interpret different Lecture Lab. = 3 drug literature To know how to convert units and doses of drugs To know how to properly compute for a childs dose. To equip students with the knowledge of prescription writing. To learn how to interpret prescription order. Lecture Board exercises Lecture Board exercises Lecture Board exercises Lec. = 2 Lab. = 3 Lec. = 2 Lab. = 3 Lec. = 2 Lab. = 6

Written Report Oral Report Laboratory Manual Practical/Written Quiz Interpretation of literatures Laboratory Manual Exercise/Quizzes Laboratory Manual Exercise/Quizzes Laboratory Manual Quizzes Laboratory Manual

88 Pharmacology of Pain and Inflammation To know the different processes involved with pain. To know the different mediators of inflammation. To know the mechanism of action and application of the different groups of analgesics. To know the pharmacokinetics and pharmacodynamics of antihistamines To know the mechanism of action of hemostatic agents and its importance in Dentistry. Lecture Lec. = 2 Recitation Quizzes

Analgesics

Lecture Prescription Writing exercises Lecture

Lec. = 4

Recitation Quizzes

Antihistamines

Lec. = 2

Recitation Quizzes Recitation Quizzes Laboratory Manual

Hemostasis / Hemostatic agents

Lecture Test for bleeding time/clotting time of white mice Anesthetic To describe the Lecture agents pharmacokinetics and Tests the pharmacodynamics of effects on these drugs. white mice Antimicrobials To know the different Lecture types of antimicrobials Inoculation and its corresponding of bacteria mechanism of action. Culture and To apply through sensitivity prescription writing Test the antimicrobials learned. Antiseptics and To know the Lecture Disinfectants pharmacokinetics and pharmacodynamics of these drugs. Drugs acting on To describe the Lecture the Central mechanism of action Nervous of sedative-hypnotics
System Therapeutic Measures of Common Dental Conditions and Emergency Drugs.

Lec. = 2 Lab. = 3

Lec. = 2 Lab. = 3 Lec. = 4 Lab. = 3

Recitation Quizzes Laboratory Manual Recitation Quizzes Practical exercises Laboratory manual

Lec. = 2 Lab. = 3 Lec. = 2 Lab. = 3 Lec. = 6 Lab. = 9

Recitation Quizzes Laboratory manual Recitation Quizzes Laboratory manual Research papers Recitation Quizzes Laboratory manual

To familiarize students Lecture with common dental diseases and its therapeutic measures. To understand the proper management of

89 some dental office emergencies. To understand the pharmacologic orientation of AIDS and Hepatitis.

Suggested References: Textbook of Dental Pharmacology and Therapeutics by: John G. Walton Pharmacology by: Goodman and Gillman Pharmacology by: Katzung Clinical Pharmacology in Dental Practice by: Sam V. Holroyd

LABORATORY TOPICS

MANUAL TOPICS

LECTURE TOPICS 1. Introduction and definition of terms 2. Drug Nomenclature 3. Drug Therapy 4. Routes of Drug Administration 5. Dosage Forms 6. Drug Literatures 7. System of Measurements 8. Prescription Writing / Orders 9. Analgesics 10. General Anesthetics 11. Local Anesthetics

1. Introduction and definition 1. Introduction to of terms Pharmacology 2. Demonstration of Routes of 2. Drug Nomenclature Administration 3. Skin Testing 3. Routes of Drug Administration 4. Interpretation of Drug 4. Skin Testing Inserts 5. Conversion of doses and 5. Drug Dosage Forms measurements 6. Prescription Writing 6. Drug Literatures 7. Prescription Orders 7. System of measurements PRELIM EXAM 8. Conversions 8. Narcotics and NonNarcotics Analgesics 9. Histamine and Antihistamines 10. Hemostasis and Hemostatic Agents 9. Prescription Writing 10. Prescription Orders 11. Analgesics

90 11. General Anesthetics 12. Local Anesthetics 13. Antimicrobials culture and Sensitivity 14. Sedative Hypnotics 15. Antiseptics and Disinfectants 16. Common Oral Diseases 17. Office Emergencies 18. AIDS and Hepatitis 12. Antihistamines 13. Hemostasis and Hemostatics Agents 14. General Anesthetics 15. Local Anesthetics 16. Antimicrobials 17. Sedative-Hypnotic Drugs 18. Antiseptics / Disinfectants 19. Common Dental Diseases 20. Office Emergencies 21. AIDS and Hepatitis 12. Histamines and Antihistamines 13. Hemostasis and hemostatic Agents 14. Antimicrobials 15. Antiseptics / Disinfectants 16. Sedative-Hypnotic Drugs 17. Office Emergencies 18. Common Oral diseases 19. AIDS / Hepatitis

OUTLINE OF TOPICS IN PHARMACOLOGY PRELIM LECTURE 1st Meeting Orientation 2nd Meeting Definition of terms Introduction History of pharmacology Branches of Pharmacology Importance of Pharmacology to dentistry Fundamental action of drugs Uses of Drugs Drug Nomenclature

91 Drug Publications Quiz 3rd Meeting Stages in the development of a drug Introduction to Drug Therapy Quiz 4th meeting Process of Drug Therapy Quiz 5th meeting Continuation of Drug Therapy Quiz LECTURE PRELIM EXAM LABORATORY 1st Meeting Orientation 2nd Meeting Exercise 2 & 3 *Exercise 1 will be given as a quiz How to use MIMS Quiz 3rd Meeting Exercise 4 Routes of Drug administration Quiz 4th meeting Exercise 5 Quiz LABORATORY PRELIM EXAM

General Principles / Factors / Terminologies 1. Factors affecting Patient's Reaction to Drugs A. Routes of Drug Administration 1. Enteral 2. Parenteral B. Passage of Drug Across Body Membrane

92 1. Active Transfer 2. Passive Transport C. Fate of Drug 1. Absorption 2. Distribution 3. Metabolism / Biotransformation 4. Excretion / Elimination 2. Considerations in Drug Administration A. Tolerance B. Pathologic State C. Age and Weight 3. Action vs. Effect Anaphylaxis Placebo Immunity Idiosyncrasy Tolerance Tachyphylaxis Drug Resistance Refractory Hyporeaction Hyper-reaction Hypersensitivity Supersensitivity
88888888888888888888

3rd Meeting General Anesthetics Local Anesthetics Locally Acting Medication: Antimicrobials, Hemostatics and Protectives 4th Meeting Diuretics and Antihypertensive Sedative Hypnotics Psychotherapeutic 5th Meeting Central Nervous System Stimulants Anticonvulsant Antineoplastic Adrenocorticosteroids

93

FINALS * SPECIAL TOPICS 1st Meeting Emergency Drugs 2nd Meeting Pharmacologic Considerations 3rd Meeting Disease Status of Common Interest 4th Meeting Pharmacologic Management of Certain Common Oral Disease Entities 5th Meeting Drug Interactions Predictable Reaction: 1. Excess pharmacological activity 2. Rebound response upon discontinuation Excessive Pharmacological Effects: 1. Respiratory depression in severe bronchitic patients given morphine or benzodiazepine hypnotics 2. Hypotension resulting in stroke, myocardial infarction or renal failure in patients receiving excessive doses of antihypertensive drugs. 3. Bradycardia in patients receiving excessive DIGOXIN Withdrawal Symptoms: 1. Extreme agitation, tachycardia, confusion, delirium and convulsions may occur following the discontinuation of long-term CNS depressants such as barbiturates, benzodiazepine and alcohol. 2. Acute Addisonian crisis may be precipitated by the abrupt cessation of corticosteroid therapy. 3. Severe hypertension and symptoms of sympathetic overactivity may arise shortly after discontinuing clonidine therapy. 4. Withdrawal symptoms after narcotic analgesics. Allergic Responses:

94 Allergy - altered capacity of the body to react to various antigens with which it comes in contact. * 2 Types of Hypersensitivity: 1. Immediate - antibody is circulating or fixed to certain tissues. - Antigen reacts to antibody. 2. Delayed - a reaction of T-cells that have been stimulated by antigen to react against targets such as infectious agents. - Antibody is not involved. Genetically Determined effects - major toxicity of some drugs is restricted to individuals with particular genotype or genetic make-up. DEFECT Pseudocholinesterase Deficiency Glucose-6-Phosphate Dehydrogenase deficiency Acetylator-Polymorphism Hepatic Porphyria TOXIC DRUG Succinylcholine Sulfonamides Quinidines Primaquine Procainamide Hydralazine Isoniazid Barbiturates SYMPTOMS Paralysis Apnea Hemolysis Systemic Lupus Neuropathy Symptomatic prophyria

Idiosyncratic Drug Reaction: Idiosyncracy - used primarily to cover unusual, unexpected, bizarre drug effects that cannot readily explained or predicted in individual recipients. *DRUG INDUCED MALIGNANT DISEASE IS FORTUNATELY RARE... PHARMACOLOGY OF THE AUTONOMIC NERVOUS SYSTEM: - generally, all drugs influence blood pressure, heart rate, potassium pump Diversity of ANS on Body functions specific to Dentistry: 1. Practical application of vasoconstrictors in local anesthetic solutions. 2. Agents that reduces salivary flow 3. Alterations of the ANS mechanism both centrally and peripherally antihypertensive drug. 4. Significant peripheral changes in ANS activity produced by antipsychotic phenothiazines and antidepressants.

95 5. Entire concept of chemical neurotransmitters and receptors are founded on the principles of the ANS. *2 Divisions of the ANS 1. Sympathetic 2. Parasympathetic * Both are regarded as peripheral in modes of action and drug reactions even though these cell bodies are located within the CNS and receive considerable CNS input. Autonomic Nervous System - concerned with the maintenance of a constant internal environment to provide for optimal cellular function and survival. Functions: Reflex vasodilation Regulates Body temperature Blood glucose level Cardiac Rate Water Balance SYMPATHETIC DIVISION - designed to cope with sudden emergencies. E.q. Fright and flight phenomenon PARASYMPATHETIC DIVISION - conservation of bodily processes E.q. Reflex slowing of the heart Action Potential - bioelectric signals / self propagated impulses along the nerves. Neurotransmitters - chemical mediators that transmit signals across nerve to nerve, or nerve to effector tissue. Acetylcholine - specific chemical mediator at all autonomic ganglia and parasympathetic post ganglionic synapses. - transmitter substance of the neuromuscualr junction in skeletal muscle. Norepinephrine - principal chemical mediator of the sympathetic postganglionic neuron. Epinephrine - major mediator released by the adrenal medulla. Cholinergic - nerves releasing acetylcholine. Adrenergic - nerves releasing norepinephrine.

96