The nature of drugs

* Drugs can only modify (increase or decrease)

an existing cell functions but do not create new
one.
*Most of the drugs are weak acids or weak
bases. Could a drug be strong acid or
strong base? WHY?
Sources of drugs
1-Plant e.g. atropine, cardiac glycosides
2-Animal e.g. insulin from pancreas of animals
3-Microorganisms e.g. penicillin
4-Synthetic e.g. acetylsalicylic acid (aspirin)
5-Recombinant DNA technology (Human insulin)
Uses of drugs
1-Cure of diseases e.g. antibacterial for
microbial infection
2-Symptomatic e.g. Aspirin for fever
3-Replacement therapy e.g. insulin in
diabetes
4- Prophylaxis of diseases e.g. hyoscine
in motion sickness, vaccines
5-Prevention of normal biological
function e.g. contraceptives
6-Diagnosis of diseases e.g. dye in
radiotherapy 2
Methods (routes) of drug administration
Oral administration is the preferred method of
administering drugs, but it is also the most
depending on the drug.
Drugs administered by methods other than oral
route avoid the first pass effect
Inhalation
Oral
Sublingual Injection
Rectal Intravenous

Epithelial Subcutaneous

Topical Intramuscular

Nasal spray Intrathecal

Eyedrops Implants
3
 Pharmacokinetics
Pharmacokinetics is the study of how a
drug reaches its target in the body and how
it is affected on that journey, i.e; effect of
the body on the drug.
Pharmacokinetics is the study of how
is the drug absorbed, distributed,
metabolized and excreted in the body
(ADME)
This process is important in order to
design the proper dosage schedule (Dose,
route, frequency of administration) as
well as the drug's bioavailability4
Pharmacokinetics: absorption
the passage of the drug from its site of
administration through body barriers or cell
membranes in order to reach its site of
action. The most common and preferred method of
administration is the oral route But has variable
bioavailability
Bioavailability is the fraction of unchanged
drug reaching the systemic circulation
following administration by any route. For an
IV dose of a drug, bioavailability is 100%, but,
after oral administration, bioavailability is
variable due to several factors
(factors affecting absorption + 1st
5
pass metabolism)
First pass metabolism
=pre-systemic metabolism Bioavailability
A-Gut first pass effect:
Gastric acidity #
benzyl penicillin
Digestive enzymes # insulin
B-Hepatic first pass effect
Complete metabolism e.g.
nitroglycerine or partial e.g. propranolol
How to overcome hepatic 1st pass
metabolism?
*Increase the oral dose e.g. propranolol
*Use other routes e.g. SL. nitroglycerine.
6
Passage of drugs across membranes
1- By simple diffusion
Occurs through the lipid portion of the cell
membrane, depends on:
a- lipid solubility: direct relationship.
b- Ionization: most of drugs are weak base or weak
acid that exist partly unionized (lipid soluble) and
partly ionized (lipid insoluble)

7
Passage of drugs across membranes
ionization, process by which electrically neutral
molecules are converted to electrically charged
molecules (ions) by gaining electron to be (-ve) or
loosing electrone to be (+ve).
Ionization of drugs depends on:
*PH of its environment,
*PKa of the drug=ionization constant of the
drug or the PH at which 50% of the drug is
ionized and 50% is unionized.
So, factors which increase the
unionized lipid soluble fraction will also
increase the rate of diffusion and vice
versa. 8
 Clinical significance of PKa
1- GIT :- aspirin is mostly non-ionized in
the stomach and well absorbed from
the stomach mucosa while a weak base
is absorbed mostly from the intestine
2- renal:- alkalinization of urine in acidic
drug poisoning and acidification of
urine in basic drug poisoning.

Acidic drugs are absorbed from acidic medium

and basic drugs are absorbed from basic medium
9
Passage of drugs across membranes
2-By Filtration or aqueous diffusion:
*Occurs through large water filled
pores of capillary endothelium and
glomeruli.
*Through these pores all drugs can be
filtered except protein and protein
bound drugs. This process takes place
with no energy, no carrier and along
concentration gradient.

10
Passage of drugs across membranes
3-By Facilitated diffusion
*Substances which are lipid
insoluble and too large to pass
through pores pass by facilitated
diffusion e.g. glucose.
*Specific carrier transport system
is needed to make them more lipid
soluble and easily diffused.
*No energy and along
concentration gradient. 11
Passage of drugs across membranes
4- By Active transport
Able to work against concentration gradient.
*Needs energy source and carrier.
*This process is saturable and site for
competition.
e.g. Na+/K+ pump & active tubular excretion of
penicillin.
5- By Pinocytosis
*substances are engulfed by
local invagination of the cell
membrane e.g. absorption of
vitamin B12 in terminal ileum. 12
Factors affecting drug absorption
1. Factors related to the drug
1-Water solubility
2-Lipid solubility
3-Pharmaceutical preparation:
-Dosage form: solution is better
absorbed than suspension
-Rate of disintegration and dissolution:
The smaller the particle size, the greater
is its absorption

13
Factors Affecting Drug Absorption

1. Factors related to the drug cont..

4-Stability:
Oral drugs have to be chemically stable
to survive the stomach HCl and
metabolically stable to survive the
digestive enzymes in GIT and metabolic
enzymes in liver (mainly cytochrome
P450 ).
-Insulin, local anaesthetics and first
penicillins are acid labile , so they can't
be taken orally but are given parentrally.
14
Factors affecting drug absorption
2- Factors related to the patient
1-Route of administration: Skin Oral S.C.
I.M. Inhalation I.V.
2-Area health sate and vascularity of the
absorbing surface: direct relationship
3-Rate of the general circulation: in case of
shock, peripheral circulation is reduced, so,
the rate of transport of the drug to the
site of action is reduced.
4-Presence of other drugs: Adrenaline VC
so delay absorption of other drugs.
15
Factors affecting Drug oral absorption
Factors related to the drug (see before)
Factors related to the patient:
1- State of health of the G.I.T. mucosa:
2-Specific factors e.g. Intrinsic factor for vit B12
absorption
3-Gastric emptying:
-Atropine decrease gastric emptying time, so,
inhibit absorption of concomitantly given drugs
-Metoclopramide increase emptying, so, increase
absorption of drugs with rapid rate of
disintegration and dissolution and vice versa.
4-PH
5- Gastric contents: Food, tetracycline
6-First pass effect 16
Distribution
After the drug is absorbed, it is
distributed among body compartments.

17
Distribution: body compartments
1. Intravascular "one compartment"
Drugs with high MW are retained in the
blood as they cannot be filtrated
through capillary endothelium e.g.
Polysaccharides" dextran.
2. Intravascular + Interstitial "two
compartment" = extracellular
Drugs can pass capillary wall but
cannot pass across cell membranes e.g.
mannitol
Distribution cont..
3. Extracellular + Intracellular "All
over the body"
These are drugs which are lipid
soluble and have a low molecular
weight e.g. alcohol, salicylates and
sulphonamides.
4. Some drugs have special affinity
for certain tissues
These tissues act as reservoirs for
these drugs e.g. calcium in bones,
iodine in thyroid gland. 19
Binding to plasma proteins
- A fraction of most drugs bind to plasma
proteins reversibly.
- Albumin is the major plasma binding protein
Bound portion is inactive , non diffusible ,
and can not be metabolized or excreted
it acts as a reservoir for the free part

Drugs with high affinity to plasma proteins

displace drugs of lower affinity. Aspirin displaces
the oral anticoagulant warfarin bleeding
Volume of distribution (Vd)
It is defined as the apparent volume that
would accommodate the entire amount of the
drug in the body if its concentration in
tissues was the same as that in plasma.

Importance
dialysis is
not useful
for drugs
with high
vd
Biotransformation= metabolism
- Chemical alterations in a drug aiming to
convert it from non-polar, lipid soluble, non-
ionized to polar, water soluble and ionized
form in order to be easily excreted

*The liver is the main metabolizing organ;

however, a number of other tissues
including the kidney, gut mucosa, lung & skin
may contribute.
Types of metabolism
A. Phase I, non-synthetic :
(Oxidation, Reduction, Hydrolysis)
Results of phase I metabolism:
1. Conversion of active drug to inactive
metabolite (most of drugs)
2. Conversion of inactive drug (prodrug)
active drug e. g. Imipramine desipramine
3. Conversion of active drug to active
metabolite e. g. phenacetin paracetamol
4. Conversion of drug to toxic metabolite
. e. g. Methanol oxidation Formaldehyde
Types of metabolism
B. Phase II or synthetic reaction
Usually, it results in inactivation of the
parent drug. The conjugated product is
usually more water soluble.
Glucuronic acid (GA): Aspirin,
paracetamol, chloramphenicol
Acetic acid: sulphonamides
Methylation: Noradrenalin
Glycine: Aspirin
24
 Sites of biotransformation:

1. Microsomal enzymes:
Their activity is low in: neonates, premature
babies, old age, cancer and liver diseases.
The activity of the enzymes is induced and
inhibited by drugs:
Enzyme inducers e.g. phenobarbitone, smoking,
Enzyme inhibitors e.g. cimetidine, estrogen,
25
Sites of biotransformation:
2. Non-microsomal enzymes
Located in liver, digestive juices, plasma, and
flora.
Responsible for some conjugation reactions,
oxidation, reduction, and hydrolysis.
The drugs are mostly lipid insoluble.
The activity of such enzymes is not affected
by drugs (neither induction nor inhibition).
How you can manage a drug dose,
when given with another enzyme
inducer or inhibitor drug?
2
6
 Excretion
Drugs are eliminated through:
A) Renal
-Renal excretion is a
result of passive
glomerular filtration
(e.g. water soluble
non bound drugs with
MW < 500 and active
tubular secretion and
reabsorption e.g. weak acids (penicillin), weak
bases (Quinidine)..\
27
 Excretion cont..
A) Renal cont..
Factors affecting renal clearance:
a. Changes in urinary PH affect excretion of
weak acid and weak bases.
e.g. alkalinization of urine increases excretion
of acetylsalicylic acid, acidification of urine
increase excretion of ephedrine.
b. Blood flow to clearing organ
c. Binding of drug to plasma proteins
 Excretion cont..
B) Lungs
Excretes gases and volatile drugs (general
anesthetics)
C) Alimentary tract
Saliva: Iodides, morphine, salicylates.
Bile: excreted in stools or undergoes
enterohepatic circulation e.g. rifampicin
D) Skin glands
Excreted in sweat e.g. rifampicin red
discoloration of sweat.
E) Mammary glands Excreted in breast
milk e.g. chloramphenicol, affect suckling baby.
2
9
 Plasma half life
a- It is the time required to reduce the plasma
concentration of a drug to half the initial
concentration.
b-It depends on kinetics of drug clearance e.g.
metabolism & excretion.
c-The drug will
disappear
after about 4-5
t1/2
Plasma half-life
d-Drugs reach a plateau after continuous
administration for 4-5 t1/2
e-It is useful to determine the frequency of
drug administration.

31
Types of elimination kinetics

The t1/2 is constant e.g. The t1/2 is NOT constant and

small dose of aspirin and increases proportional to drug
alcohol. dose e.g. Large dose of
aspirin and alcohol
Metabolizing enzymes can Metabolizing enzymes can not
32
be induced (unlimited) be induced (limited)
Pharmacokinetic drug interactions
a. Absorption
-Atropine motility and so delays
absorption of most of the drugs
-Gastric acid PH enhance absorption of
acidic drugs e.g. acetylsalicylic acid
-Gastric contents e.g. milk inhibits
absorption of tetracycline
b. Distribution
Occur when highly P.P. bound drugs are
given together (aspirin, warfarin).
33
Pharmacokinetic drug interactions
c. Metabolism
- Hepatic microsomal enzymes inducers e.g.
barbiturates increase their own metabolism as
well as metabolism of other co-administrated
drugs short duration of action. The reverse
is true for hepatic enzyme inhibitors.
d. Excretion
- Drugs sharing the same tubular active
transport system can compete with each other
for tubular secretion e.g. Probenecid renal
tubular secretion of penicillin
-Alkalinization of urine increases excretion of
acidic drugs 34