A summarized introduction to pharmacology for undergraduate students

1. 1
‫السعودية‬ ‫العربية‬ ‫المملكة‬
‫جامعة‬
‫عبد‬ ‫الملك‬
‫لعزي‬ ‫ا‬
‫ز‬
‫الطب‬ ‫كلية‬
‫األدويـــــة‬ ‫عــلم‬ ‫قســــم‬
Updated 2022
Ahmed S. Ali
Professor of Pharmacology
Profahmedali@gmail.com

2. 2
Introduction
What is the goal of studying pharmacology?
Studying pharmacology provide the basis for optimal use of drugs i.e to
provide maximum benefit with minimum harm All members of health care
team must cooperatefor achievement of this goal
What is Pharmacology ?
Is the since dealing with drugs. it is concerned with understanding the
interactions of chemical substances with living systems,
Clinical Pharmacology: study of drugs in humans (patient and volunteers)
Therapeutics: medical use of drugs i.e use of drugs to diagnose, prevent and
treat disease (and prevention of pregnancy)=
o Pharmacology has strong connections with other disciplines: Basis in Chemistry,
Physiology, Biochemistry, and Molecular Biology (See fig 1 )
o Toxicology is the study of the untoward effects of chemical agents on living
systems
What are the drugs ?
Drugs are chemicals that can be used for the diagnosis, prevention, and
treatment of disease.
Drugs are obtained from various sources.
Drugs may be inorganic or organic compounds from natural recourses; synthetic or
semithynthetic as well as biotechnology products few examples are given below
Drugs from plants :
-many drugs are obtained from medicinal plants. These drugs belong to different classes as :
alkaloids; glycosides ; flvainoids, etc
example of important drugs include atropine.; scopolamine; pilocarbin -. morphine ; digoxin;
caffeine and vincristine
Biotechnology products : - biological: Recombinant DNA technology (Insulin, growth
hormone).
Microorganisms: many Antibiotics e.g. penicillin, streptomycin.
Inorganic salts - Ferrous sulfate----potassium iodide ; magnesium sulfate;
Synthetic drugs:
-parcetamol, , indomethacin phenytoin etc : Aspirin.
Semi synthetic: Atropine N-acetyl bromide
Drugs vary in their physicochemical characteristics.

3. 3
Drugs vary in their physicochemical properties ( mol wt, size, shape, chemistry , ionization,
stability etc
Size. The great majority of drugs lie in the range from molecular weight 100 to 1,000.
Chemistry and reactivity. Drugs may be small, simple molecules (amino acids, simple amines,
organic acids, alcohols, esters, ions, etc.), or large molecules carbohydrates, lipids, or even
proteins.
Stereochemistry ( three dim national configuration ) . Chiral enantiomers often differ in their
ability to bind to and alter the function of receptors.
Drug Nomenclature.
1- Chemical name. : describe the chemical structure of the compound
2- Generic (Nonproprietary ; official or approved name).:: which is used in pharmacopoeias
and official authorities
3- Proprietary name (trade name): is the commercial property of a pharmaceutical company
ُExample Panadol etc ( a trade names ) of Acetaminophen ( generic name ); which has the
following the following chemical name : P- acetyl aminophenol
Good drugs & basis of drug selection
Criteria for good drugs include : Effectiveness: ; Safety: ; Selectivity:; Reversible action;
Predictability of action ; Ease of administration; Minimal drug interactions; Relatively Low
Cost ( availability );and Chemical Stability. All these cartelistic are rarely available in one
drug. The role of clinician is to compromise and make appropriate selection among the
available choices Basis of selection of drugs include:
o Characteristics of the drug (eg, efficacy, safety profile, route of administration, route of
elimination, dosing frequency, cost)
o The Patient demographic and clinical status (eg, age, sex, pregnancy, severity of disease
& other chronic illness )
o The Risks to Benefits of the drug should be assessed.
Factors that determine clinical response
Pharmacokinetic variables ( Lect 3 ) )
Pharmacodynamic variables ( lecture 2
Adverse Drug Reactions Toxicities and Side Effects
Drugs in general are poisons ( Pharmakon= poison in Greek)
Almost there is no drug which is free of toxic or adverse drug effects. Some
untoward effects of drugs are minor and can be tolerated or reduced by dose
adjustment , but others are serious or independent on the dose and may be fatal.
Side effects often are predictable from a knowledge of the pharmacology of a
particular drug. Examples of chemicals or drug-induced toxicities are given
below:
a) Allergic reactions - The number of serious allergic reactions to drugs involving
antigen-antibody reactions is low but when they occur the physician must have
sufficient knowledge to manage these problems.

4. 4
b) Blood dyscrasias - These are very serious and sometimes fatalcomplications of drug
therapy. They include: agranulocytosis, aplastic anemia, hemolytic anemia,
thrombocytopenia and defectsin clotting factors.
c) Hepatotoxicity and nephrotoxicity - Because many chemicalsand drugs are
eliminated and metabolized by the liver and kidney, damage to these organs is seen
commonly.
d) Teratogenic effects - The thalidomide tragedy dramaticallyemphasized that drugs
may adversely influence fetaldevelopment.
e) Behavioral toxicity - This is a term used to describe suppressionof normal anxiety,
reduction in motivation, impairment of memoryand learning, distortion of judgement,
impairment of reflexes, adverse effects on mood, etc.
f) Drug dependence and drug abuse - The repeated administration of some chemicals
may lead to drug dependence. Drugs likely to be abused and upon which drug
dependence may develop are the various psychopharmacological agents such as
opiates, barbiturates, amphetamines, nicotine and ethanol. Dependence on tobacco
(nicotine) is also well known.
g) Carcinogenesis - Carcinogenesis is a delayed type of toxicitywith a latency of many
years.
h) Pharmacogenetic toxicities - Certain genetically-predisposed individuals have a
markedly toxic reaction to certain otherwise safe drugs. Examples are prolonged apnea
after succinylcholine, or malignant hyperthermia associated with anesthetics.
The Drug Approval Process.
The approval process for new drugs, especially drugs that are new chemical class is
complex, time-consuming and expensive procedure ( assignment 1)
In the United States , the Food and Drug Administration( FDA) is responsible for creating
guidelines for the approval and use of drugs. The FDA requires that all approved drugs fulfill
two requirements :1- The drug must be found to be effective against the disease for which it is
seeking approval 2- The drug must meet safety criteria by being subject to extensive animal
and controlled human testing .
Gaining FDA approval usually takes several years to attain. Testing done on animals must be
extensive and must include several species to help in the evaluation of both the effectiveness
and toxicity of the drug.

5. 5
Simplified Pharmacodynamic principles
o WHAT IS PHARMACODYNAMIC (PD): (dynamic mean power). PD
is concerned with the mechanism of drug action and the relationship
between the concentration of the drug at the site of action and the
magnitude of the pharmacological response.
O MECHANISM OF DRUG ACTION:
1. Most drugs act by binding to specific receptors located on the cell
membrane (e.g., ligand-gated ionicchannels) or inside the cell (e.g., steroid
Receptors). Figure 1.
2. Variable strength of binding between receptors and drugs is recognized
(Van der Waals, Hydrogen, Ionic and covalent bonds)
3. Other non-receptor mechanisms:
o Physical: Adsorption e.g., Kaolin in diarrhoea.; Osmosis: Mannitol as osmotic diuretics.
o Chemical: Neutralization e.g., NaHCO3 in hyperacidity; Chelation e.g., dimercaprol (BAL) to
chelate mercury.
o Interfere with cell division e.g., cytotoxic agents.
o Interfere with metabolic pathway e.g., Sulfonamide competes with PABA in bacteria leading to
inhibition of synthesis of folic acid.
o Enzyme inhibition may be reversible as neostigmine or irreversible e.g., aspirin on cyclo-
oxygenase enzyme.
What are the receptors?
o Receptors are cellular molecules to which a drug (or endogenous chemical
substance) can bind to initiate a pharmacological response
o Drug receptor interaction is the fundamental event that initiates the action
of the drug
o Other macromolecules with which drugs interact are known as drug targets
o Specificity: individual classesof drugs bind only to certain targets, and individual targets can
recognize only certain classes of drugs. However, no drugs are completely specific in their
action.
o Some receptors are activated by endogenous transmitters & hormones.
o Many toxic chemicals produce their effect due to interaction with receptors
o NB: Drugs only modify already existing biochemical processes
o Drug act on receptors may be Agonist, Partial agonists or Antagonist
_______________________________
* This handout is not comprehensive, and students should consult textbooks of pharmacology for details

6. 6
What are the major receptor families?
A. Ligand-gated ion channels
B. G-Protein coupled receptors*
C. Enzyme-linked receptors**
D. Intracellular receptors (hormone receptors)
*Guanine nucleotide-binding protein ** Also named Tyrosine –kinase linked receptors
Fig. 1 Some Types of drug receptors
Effectors: (second messengers) are enzymes or macromolecules that translate the
drug-receptor interaction into a change in cellular activity. For example, the
interaction of certain drugs with G-protein coupled receptors leads to activation
of the enzymes adenylate cyclase. (Which results in the production of cAMP a second
messenger which regulates protein phosphorylation, the latter is responsible for altered cell
function or pharmacological response)
Spare receptors:
o The maximal response is obtained by a concentration of the agonist less than that
required for maximal occupation of the receptors.
Fig,1

7. 7
o For example, the maximal isotropic effect of heart muscles to catecholamine can be
attained even under conditions where 90 % of the adrenergic receptors are occupied by
an antagonist
DOSE-RESPONSE RELATIONSHIP
Generally, the intensity of pharmacological response increases as the drug
concentration increases until a certain limit after which no further increase in
response could be achieved. (See fig 2)
Types of Drug action:
Drug action can show several important properties: Specificity, Selectivity,
potency &efficacy
Efficacy:
o Is the maximal effect (Emax) a given drug can produce.
Note: It can be measured with a graded dose-response curve only.
Potency:
o It's the amount of the drug needed to produce a given effect.
o Potency is determined mainly by the affinity of the receptor for the drug.
o In a graded dose-response curve the dose causing 50% of the maximal effect (EC50) can
be obtained to describe the drug potency
 Drug A and drug B are more potent
than drug C,
 Drug A has the same efficacy as
drug C
 Drug A or drug C has higher
efficacy than drug B
Drug A
Drug B
Drug C
0
2
4
6
8
0 10 20 30
Ln concenteration
%
Response
o In Quantal Dose response measurements: ED50, TD50 and LD50 are typical potency
variables
CLASSIFICATION OF DRUG INTERACTION WITH RECEPTORS
Agonists:
 (Full agonist) are drugs (ligands) that bind to the receptors; lead to their
activation and produce effects of various types.
Fig 2

8. 8
 The magnitude of response for any given concentration of a drug is determined by
its "Efficacy " and "affinity " for the receptors
 Affinity is the ability of the drug to bind to a receptor and is equal to 1/Kd, where
kd is the equilibrium binding constant of a drug to its receptors.
Partial agonist:
Are drugs with efficacy lower than full
agonists? (i.e., don’t lead to a full
response as a full agonist.) (Fig 3)
They may antagonize the effects of full
agonists at sufficient concentration.
They may have a greater affinity for
certain receptors than full agonists
Fuall agonist vs partial agonist
0
0.2
0.4
0.6
0.8
1
1.2
1.00 1000.00
log Concentration
%
of
maximal
responses
full agonist
partial
agonist
Inverse agonists:
are drugs which produce an effect opposite to that of conventional agonists.; this action
can be inhibited by specific antagonists.
Antagonists: (Pharmacologic antagonists)
o These are drugs (ligands) that bind with the receptors (usually with high affinity)
without causing their activation. (Lack of efficacy or efficacy = 0).
o They block the effect of agonists on these receptors.
o There are two types of antagonists:
1-Reversible (Competitive) antagonists:

o Are drugs that bind to the receptor in a
reversible way
o Their effects can be overcome by
adding more agonists.
o It increases the ED50.
o The log dose-response curve for the
agonist is shifted to the right. (Fig 4)
Dose response curve of agonist alone (A)
and in presence of commettive
antagonis( B)
0.00
0.20
0.40
0.60
0.80
1.00
1.20
1.00 1000.00
log Concentration
%
of
maximal
responses
A
B

9. 9
2-Irreversible (non-competitive) antagonist:

Dose response curve of agonist alone (A)
and in presence of non commettive
antagonis( B)
0.00
0.20
0.40
0.60
0.80
1.00
1.20
0.10 100.00
log Concentration
%
of
maximal
responses
A
B
 They either prevent the agonists from
binding to the receptors or preventing
them from activating the receptors
 Their effect can not be overcome by
adding more agonists
 They cause a downward shift of the
Emax, with no shift of the curve on the
dose axis unless spare receptors are
present.


10. 10
PHARMACODYANMAIC QUANTIFICATION OF DRUG EFFECTS
Graded dose-response relationships
 When the response of a particular receptor-effector system is measured against
increasing concentration of f the drug.
 The efficacy (Emax) and potency (EC50) are derived from the curve.
 The smaller the EC50, the greater the potency of the drug.
 The concentration of the drug required to bind 50% of the receptor sites is the Kd
 Kd is a measure of the affinity of a drug for its binding site on the receptor
 The smaller the Kd the greater the affinity of the drug for its receptor
As the dose increases the response increases and the binding increases tell a
certain extent after which the response remains unchanged
Quantal dose-response relationship
 The fraction of the population that responds at each dose against the
log of the dose (sigmoid shape).
These curves allow the determination of the following parameters:
 The therapeutic effect, ED50
 The toxic effect, TD50
 The lethal effect, LD50
 Therapeutic index
Fig 5 Quantal dose-response curve (A); Therapeutic index (B)
Desensitization of receptors:
Repeated administration of drug results in diminished effect” “Tolerance”.
 Tachyphylaxis: is a type of tolerance which occurs very rapidly.

11. 11
 Desensitization: decreased response to the agonist after its repeated
injection in small doses. It may be due to
1- Changes in receptors: tight binding of agonist to receptors without opening
of channels.
2- Loss of receptors (down-regulation)
 Continuous administration of agonists results in molecular changes in
the membrane-bound receptors such that the receptor undergoes
endocytosis (down-regulation).
3- Exhaustion of mediators (depletion of catecholamine).
4- Enzyme induction (pharmacokinetic)
Therapeutic index (TI)
It is the ratio of the dose that produces toxicity to the dose that produces a
clinically desired pharmacological effect
TI = TD50/ ED50
Two examples are shown below; penicillin has a large therapeutic index and
warfare low therapeutic index.
However, in clinical practice therapeutic range is more important: it is the range between
the minimal effective level and the minimal level that is associated with adverse effects.
For example, therapeutic range of phenytoin (10-20 ug/ml). This means that most patients
will show adequate control of epilepsy with little incidence of dose-related adverse effects
when the blood level of the drug is attained within this range
Warfarin : small therapeutic index
0
0.2
0.4
0.6
0.8
1
1.2
1.00 100.00 10000.00 1000000.00
log Concentration of drug in plasma
%
of
patients
Effective level
toxic level
Penicillin : large therapeutic index
0
0.2
0.4
0.6
0.8
1
1.2
1.00 100.00 10000.00 1000000.00
log plasm drug level
%
of
patients
Desired
effect
Adverse
effects

12. 12
Simplified Pharmacokinetic Principles
Pharmacokinetics (PK) describes the action of the body on a drug. PK allows
prediction of the time of onset of effect, duration of effect, and potential drug interaction.
Proper utilization of PK principles supports the optimal selection of drugs and dosage
regimens on an individual basis. PK process include: ADME; A = Metabolism, D =
Distribution, M= Metabolism (biotransformation) & E= Excretion PK is clinically
important for design of optimal dosage regimen. {route, dose, dosing interval} Preventing
and management of many drug-drug or drug-food interactions
I-Absorption
Is a transfer of a drug from its site of administration to the
bloodstream.
1.1. Mechanism of the passage of drugs through biological
membranes include:
1.1.1. Passive diffusion: It is non-specific. It involves penetration of the lipid-soluble
along with the concentration gradient from high to low concentration.
1.1.2. Active transport: It is highly specific and requires a special carrier. The movement
of drug molecules can occur against the concentration gradient. It is energy dependent &
saturable.
1.1.3. Other mechanisms: Filtration or aqueous filtration, facilitated diffusion &
pinocytosis.
1.2. Factors affecting drug absorption:
1.2.1. Physicochemical properties of the drug: lipid solubility, chemical stability in GIT,
solubility in water etc.
1.2.2-Dosage form: (formulation, particle size, salt form,). This is particularly important
for drugs with poor bioavailability or a narrow therapeutic range
1.2.3-Physiological & pathological variables: Blood flow, the total surface area available
for absorption, GIT motility, pH, bile, and number of fluids. Examples include erratic
(variable) absorption of phenytoin in neonates. Reduced absorption of some drugs in
elderly (higher pH & low motility), reduced absorption of drugs after S.C injection in case
of shock. (Reduced blood flow). Diarrhoea significantly reduces drug absorption.
Increasing gastric emptying time usually increases the time to attain peak blood level
(maximum concentration) and may reduce its bioavailability

13. 13
Effect of pH on ionization & Lipid solubility of drugs
HA <==> H+ + A-
Unionized ionized
pH – pKa = log (A-/HA)
ASPIRIN pKa = 4.5 (weak acid)
99.9 = [ HA ] [ HA ]
Stomach
pH = 2
Blood
pH =
7.4
0.1 = [ A- ]
Aspirin is reasonably absorbed from stomach (fast action)
1.2.4-Interaction with food or other drugs. Certain food or drugs may delay the absorption
of concomitantly administered drugs. Through direct interaction or changing gastric
motility or emptying time: E.g., dairy products (milk, yoghurt) or Calcium containing anti-
acid form non-absorbable complex with tetracycline. Cholestyramine {non-absorbable
resin used to lower cholesterol levels) bind and reduce the absorption of many drugs such
as digoxin, warfarin, and thyroxine.
1.3. Bioavailability:the fraction of the administered drug that reaches
the systemic circulationin active form.
Oral bioavailability. Is estimated by
dividing the AUC (area under the
concentration vs. time curve) after oral
administration by AUC after IV
administration of the same dose
F = 0.9 means 90 % of the administered
dose is absorbed and reaches systemic
circulation ion Active form e.g.,
theophylline Bioav. Is clinically
important in the case of potent drugs with
narrow therapeutic ranges such as
Cyclosporine A (immunosuppressant.) &
When shifting from IV to oral
administration.
1.3.1. Factors affecting Bioavailability:
Most of the variables which affect drug absorption may influence its bioavailability.
There are many reasons for incomplete bioavailability, some of which include incomplete
dissolution, drug degradation or binding, and first-pass elimination
.
0
10
20
30
40
50
60
70
80
90
0 1 2 3 4 5 6 7 8
Plasma
concentration
Time (hours)
Bioavailability Factor (F) (AUC)o
(AUC)iv
=
AUC i.v. route
AUC oral route
Bioavailability :Fraction of administered drug
that reaches systemic circulation in active form.
(after a particular route of administration admin’)

14. 14
1.3.2. First-passelimination
Is the metabolism of orally administered
drugs by enzymes present in the gut or
liver. This is the result of drug passage
through the gut wall and portal circulation
before reaching the systemic circulation.
First-pass elimination primarily affects
drugs with high-extraction ratios. For
example, if the hepatic extraction ratio is
0.75, then only 25% of the dose enters the
systemic circulation. This can be avoided
by giving the drug via another route of
administration.
First Pass Metabolism Occurs
Primarily in the Liver and Gut
First pass clearance : the
extent to which a drug is
removed by the liver during
its first passage in the portal
blood through the liver
II- Distribution
Is the partitioning of drugs amongvarious bodily compartments?
I.e., the drug reversibly leaves the blood and enters the
intercellularfluids and or/ tissues.
2.1. Factors affecting distribution:
Drug characteristics: drugs having a low molecular weight and high lipid solubility readily
move across most biological membranes.
2.1.1- Blood flow: delivery of drugs to tissues such as muscles, skin, and fat is slow
compared to the will perused organs such as the heart, liver, kidney and brain
2.1.2-Capillary permeability: capillary structure varies widely in diffused organs
e.g., liver, and spleen, compared to those in the brain.
Blood-brain barrier: The structure of the
brain capillary prevents many polar drugs
from entering the brain. This is of clinical
importance e.g., modifying the structure
of the drug (making it more polar) to
reduce its CNS adverse effects
Example: [scopolamine butyl bromide,
quaternary semi-synthetic belladonna
alkaloid, used for the treatment of GIT
spasm]. Minimal CNS effects.
Physostigmine {tertiary amine alkaloid,
reversible anticholinesterase used to treat
toxicity of tricyclic antidepressants] good
penetration into CNS tissues.

..

Brain capillaries have a dense-
walled structure and are
surrounded by glial cells (lipid).
This prevents many drug
molecules from entering the
surrounding tissue
General body capillaries allow
drug molecules to pass freely into
the surrounding tissue
2.1.3-Bindingof drugs to plasma proteins:
Following absorption and entry into the vascular system, drug molecules frequently bind
to plasma proteins. In general, acidic drugs bind to albumin and basic drugs bind to α1-

15. 15
acid glycoprotein. This is reversible, and a state of equilibrium is maintained between
bound and unbound drugs. Drugs that are protein bound do not pass-through membranes;
only the unbound (free) fraction can distribute into the tissue compartment. i.e., the
pharmacological activity of the drug is due to its free fraction.
Clinical importance: The free level of the strongly bound drugs can be increased in
clinical conditions associated with low albumin levels or in the case of concomitant
administration of another strongly administered drug. An increase in free level may lead
to increased pharmacological activity and potential toxicity.
2.2 Volume of Distribution: (Vd)
It is a hypothetical volume that correlates the total amount of the drug in the body (dose)
to its concentration in the blood. Immediately after injection (CP: peak level or estimated
Co)
Vd = dose / Co
Volumes of distribution that are larger than the plasma compartment indicate that the drug
is distributed to tissues or fluids outside the plasma compartment.
2.2.1. Factors influencing volume of distribution includes extra-cellular fluid volume and
the lipid solubility and protein binding properties of the drug.
2.2.2. Clinical importance
1- Volume of distribution is used to calculate loading doses that will immediately achieve
the desired serum concentration. LD = Cp * Vd
Units: LD (mg), C (mg/L), Vd (L) Cp: peak plasma level (or steady-state plasma level
Css)
2-In case of overdose with a drug with very high Vd hemodialysis is inefficient to remove
the drug from the body
III- Drug Metabolism (biotransformation)
Is the enzymatic biotransformationof drugs to more polar and
less lipid-soluble forms by either catabolic and or anabolic
pathways.
3.1. General facts
o Effect of metabolism on lipid solubility: Metabolites are more polar and less lipid-
soluble than parent drugs. As a result, tissue penetration and renal tubular re-
absorption are decreased, and elimination is enhanced.
oEffect of metabolism on Pharmacological activity: Metabolites are usually inactive or
less active than the parent compound; however, many drugs are converted to active
derivatives. (In such cases the drug is called pro-drug. [ prednisone is a prodrug
converted in the body to the active form prednisolone, the enzymes responsible for its
activation are absent in the fetus, so the drug is suitable for pregnant women] In a few
cases metabolite(s) are more toxic than the parent drug. {paracetamol].

16. 16
oSite of metabolism liver is the primary site of biotransformation; however, drug
metabolism nay occurs in the intestinal wall, plasma and several sites throughout the
body,
3.2. Metabolic pathways of drugs: Hepatic metabolism occurs via phase I or II reactions.
Phase I reactions are classified as nonconjugative (catabolic) and can produce. These
include oxidation, hydrolysis, and reduction.
The cytochrome P450 enzymes are responsible for most oxidation reactions.
Phase II reactions are conjugative (anabolic) and produce water soluble, inactive
compounds that are renal eliminated. Some of the chemical compounds involved in
conjugation include glucuronic acid, sulfuric acid, and acetyl-CoA.
An Example of Phase I and II
Biotransformation:
-OC2H5
CH3CON-
H
-OH
CH3CON-
H
-O-
CH3CON-
H
-OH
OH
COOH
HO
O
PHASE I
PHASE II
Phenacetin
Paracetamol
Glucuronic Acid
Conjugate
Other (non-microsomal) reactions
Hydrolysis in plasma by esterases (suxamethonium by cholinesterase)
Alcohol and aldehyde dehydrogenase in the cytosolic fraction of the liver (ethanol)
Monoamine oxidase in mitochondria (tyramine, noradrenaline, dopamine, amines)
Xanthene oxidase (6-mercaptopurine, uric acid production)
enzymes for drugs (tyrosine hydroxylase, dopa-decarboxylase etc)
3.3. Variability in drug metabolism
o 3.3.1. Age: many drug-metabolizing enzymes are not well developed or absent
in neonates
o 3.3.2. Disease: advanced liver impairment associated with reduced ability to
metabolize many drugs

17. 17
o 3.3.3. Enzyme induction or inhibition due to other drugs, foods or
environmental factors.
*** Enzyme induction means the increased activity of certain CYP enzymes which are
responsible for the metabolism of certain drugs. this leads to lower serum drug levels and
potential lower pharmacological activity.
Example phenytoin (enzyme inducer) may lead to loss of activity of contraceptive pills
(Ethinyl estradiol + norethindrone)
Smoking causes enzyme induction for CYP responsible for the metabolism of
theophylline. So that smokers having severe bronchial asthma require a higher dose to
attain therapeutic theophylline level
Some drugs induce their own metabolism [ auto induction] such as carbamazepine.
**. Enzyme inhibition: means decreasing the activity of certain CYP enzymes this leads
to higher serum levels and potential toxicity
Some foods cause enzyme inhibitions e.g., grapefruits inhibit metabolizing enzymes of
cyclosporine A, such interactions may lead to serious toxicity.
*3.3.4. Genetic variability in drug metabolism
FOUR families of CYP have been identified CYP 1-4, SIX sub-families A-F up to
TWENTY isoenzymes 1-20. CYP3A4: CYP2D6: CYP2C9: CYP2C19: CYP2A6 are the
most important Genetic variability in drug metabolism represents a major source of
variation in serum drug level and clinical response after administration of similar doses by
different individuals. Genetic polymorphism has been identified for certain CYP. for
example, one variant of CYP2D6 leads to poor or extensive hydroxylation of
debrisoquine. Poor metabolizes may show toxicity with normal doses while fast
metabolism leads to suboptimal pharmacological response or even therapeutic failure with
normal doses. Some individuals show CYP2D6 with poor demethylation capacity so that
they obtain no or little benefit from codeine {because it must be O-demethylated to the
active form this reaction is catalyzed by CYP2D6.). The next figure shows the acetylation
polymorphism of isoniazid (Slow acetylators at the right show low serum level > 6 ug/ml).
The incidence of slow acetylators is different among different ethnic groups

18. 18
0
5
10
15
20
25
0 1 2 3 Isoniazid conc. ug/ml 9 10 11 12
No. of patients
Plasma conc. in 267 patients after
9.8 mg/kg ionized orally
Genetic
polymorphism
V- Excretion
Elimination of the drug or its metabolites from the body via any
route,the most importantbeing through the kidney into the urine
but some drugs are eliminated into the bile.
4.1 General facts.
o Although Small amounts of drugs or their metabolites may be excreted into other
body fluids, milk & saliva. This may be of significant clinical importance.
o volatile agents (general anaesthetics) are excreted via the lungs
o Some drugs are eliminated by the renal route
o Renal elimination is affected by age & gender.
o Some drugs are nephrotoxic
o Enterohepatic circulation: Some drugs are excreted into the intestine via the bile
as glucuronide conjugates. A significant amount may be hydrolysed by -
glucuronidase of the intestinal flora with subsequent re-absorption of the active
drug. This leads to extending the duration of the pharmacological effect or
appearance of the second peak level.

19. 19
Kidney
Filtration secretion Re-absorption
Acid Base 99% of H20 +
Lipid soluble
drugs
Plasma flow
650ml/min
Glomerular Filtration
Rate (GFR)
125ml/min
Urine
1ml/min
Active
4.3. Mechanism of renal elimination
4.3.1- Glomerular filtration: Passive process (Pressure driven)
20% of plasma volume is filtered, allowing passage of small molecules - Yes
But not allow large molecules - Most proteins are not filtered. Drugs which are
extensively protein bound will also not be filtered. Glomerular filtration allows drugs
<25K MW to pass into the urine.
4.3.2-Active Secretion: require Energy, can generate positive concentration
Gradients. It involves two separate mechanisms one for acids & one for bases
It is Saturable and there is a possibility for drug interaction
Probenecid and penicillin share the same mechanism. Probenecid competes with
penicillin. Penicillin clearance was reduced. Prolonged action of penicillin (required
4.3.3- Re-absorption 99% of water is reabsorbed, and Lipid soluble drugs are reabsorbed
along with the water. Only very water-soluble molecules can be efficiently excreted by the
kidneys. The extent of Re-absorption of these drugs depends on 1-urine flow & 2-PH of
urine

20. 20
4.4. Clinical importance of ion trapping: In case of toxicity of certain drugs ensure adequate
urine flow & appropriate PH that ensure ionization. This is called ion trapping
Ion trapping
Urine pH varies (4.5 - 8.0). Consider a barbiturate
overdose. Sodium bicarbonate may be given to make
the urine alkaline
Urine Rest of body
pH 8.0 pH 7.4
Non-ionised Non-ionised
Ionised Ionised
Barbiturate moves into urine - eliminated from body.
4.5. Assessmentof renal function (Clinically important)
4.5.1. Background: Creatinine is a waste product formed continuously by muscle.
Filtered by kidneys, almost no active secretion or re-absorption
Creatinine clearance (CLcr) equals filtration rate (G.F.R.)
The clearances of many renal-excreted drugs are closely linked to GFR. e.g., The clearance of
gentamicin equals GFR and therefore also approximates Clcr.
Creatinine production rate depends upon muscle mass, which in turn depends upon Body
weight Age (% muscle declines with age) Sex (Men have higher % muscle than women)
4.5.2. Estimation of Creatinine clearance rate for practical purposes
Can be done using reported equations e.g., Cockcroft & Gault equation & MDRD 4 variables
(or some clinicians still using urine collection method)
Cockcroft & Gault equation (modified)
CrCl ml/ min = Factor x (140 – Age (yr.)) x Wt (kg)
SrCr (umol/L)
For men, the factor is 1.23 for women the factor is 1.04
Many software & calculators which make such estimation simple and practical are available.