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Dr Ruzilawati Abu Bakar

Jabatan Farmakologi

Mode of Drugs Action
(1)
Outline of the lecture
Overview - What is a drug?
- Route of drug administration
- PK - ADME

How do drugs work?
Target for drug actions
Drug-Receptor Bond
Overview
What is a drug?
 Drug is a chemical substance that
interacts with a biological system to
produce a physiologic effect.

 All drugs are chemicals but not all
chemicals are drugs.

 The goal of drug therapy is to prevent,
cure or control various disease states.

 To achieve this goal, adequate drug
doses must be delivered to the target
tissues so that therapeutic levels are
obtained.



Routes of drug administration
IV- intravenous
IM – intramuscular
SC - subcutaneous
- the way the drug enters the body and
reaches the bloodstream.

- where the drug goes in the body after
it has been absorbed.
- how it is changed by the body
- the route by which it, or its metabolites,
leave the body
Pharmacokinetics
Site of
Action
Dosage Effects
Plasma
Concen.
Pharmacokinetics Pharmacodynamics
what the body does
to the drug
what the drug
does to the body
ADME
Mechanisms of Drug Actions
How do drug works
 “Mechanism of drug action” refer to drug’s
effect at the site of action

 Drug molecules must be “bound” to particular
constituents of cells and tissues in order to
produce an effect/a pharmacological response

 A drug will not work unless it is bound

 It is important to be aware that not all drug
exert their effects by interacting with a
target site

Mode of drug action

Mode of drug action

 Most drugs exert their
effects, both beneficial
& harmful, by
interacting with
receptors

 Receptors present on
the cell surface or
intracellularly.

 Receptors bind drugs &
initiate events leading
to alterations in
biochemical activity of a
cell & consequently the
function of an organ.
Drug-Receptor complex
Drug + Receptor  {DR} complex







Biologic Response
The binding of a drug to its
receptor initiates a series of
cellular response reactions in
consequences which cause a
biologic response
• Drugs act in the body by 2 principles
of mechanisms

HOW DO DRUGS WORK?
1) Non-specific mechanism
of drug action

2) Specific mechanism of
drug action

1) Non-specific mechanism

• In this mechanism drugs do not bind
with any specific endogenous
substance within the body.

• The effects are produced due to
chemical and physical property of
the drugs.
Due to chemical property

Antacids (magnesium trisilicate)

•It is alkaline chemically &
reacts with gastric HCl
•There is acid-alkali reaction
and production of salt and
water.
•Acid + Alkali = Salt + Water
•Gastric acid neutralizes,
acidity reduced and pain
subsides.

Due to physical property

General anaesthetic agents (Halothane)


•This is highly lipid soluble
substance
•It dissolves into lipid membrane
of neurons
•There is disruption of normal
ionic exchanges within the nervous
tissue
•Loss of excitability of neurons
•Depression of CNS and
anesthesia produced.

 Mannitol – an osmotic diuretic
 Isphagula – a bulk laxative
 Dimercaprol – a chelating agent used in
heavy metal poisoning.
B) Specific mechanism


 drugs work by interacting with target
proteins.

 this interaction leads to change of
biochemical events within the cells

1. some activate target proteins
2. some antagonize, block or inhibit the
target proteins.



The protein targets for drug action

• Receptors
• Enzymes
• Ion channels
• Carrier molecules / transporter
Target for drug actions
Target for drug action
• some activate target proteins
• some antagonize, block or inhibit the target proteins.

Activator/
substrate
RECEPTOR
 Receptors are macromolecular substances,
 protein in nature
 present in the cell mainly on cell membrane
with which the drugs bind
 also present in the nucleus
 produce Drug-Receptor complex,
 induce changes in systems within cell
 produces drug responses

Definition of receptor
Cell membrane
 Most commonly receptors are present on cell
membrane.




 Example: -receptor of Adrenaline,
Muscarinic receptor of Ach

Nucleus
 Thyroxin receptor

Sites of Receptor
A receptor that is embedded in the cell membrane and functions
to receive chemical information from the extracellular
compartment and to transmit that information to
the intracellular compartment.
Types of receptors
4 types of major receptors:

Type 1: Ligand-gated ion channels
(ionotropic receptors)
Type 2: G-protein-coupled receptor
Type 3: Tyrosine Kinase-linked receptor
Type 4: Intracellular/nuclear receptor
Type 1: Ligand-gated ion channels
(ionotropic receptors)
 Cell Membrane receptor

 Coupled directly to an
ion channel



Ligand-gated ion channels
• Ligand-gated ion channels are activated after binding to specific ligands or
drugs.
• Many drugs activate membrane- bound ligand ion -gated channels.
• Eg. Benzodiazepines (psychoactive drug) enhance the stimulation of the
GABA receptor , resulting in increased chloride influx & hyperpolarization of
the cell - results in sedative, hypnotic (sleep-inducing), anxiolytic (anti-
anxiety),
Type 2: G-protein-coupled receptor
• Cell Membrane receptor

•Coupled with intracellular effector
systems via a G-protein (signaling
protein)(have 3 subunits)

•They are activated by hormones &
neurotransmitters

• A characteristic feature of these
receptors – they contain 7 membrane-
spanning domains

• The domain activation leads to the
subsequent synthesis of intracellular
second messenger

•This will activate numerous proteins
within cells.


•e.g. Beta Adrenergic Receptor
Muscarinic Receptor
INTRACELLULAR EFFECTS
G-protein activation
Generation of Second
Messenger
Activation of Cell signaling
-Unoccupied receptor
does not interact with
G-protein
- G-protein bound with
GDP
-Inactive adenylyl
cyclase

-Occupied receptor
changes shape and
interacts with G protein
-G protein releases GDP
& binds GTP

- subunit of G protein
dissociates & activates
adenylyl cyclase

-Biologic effect
GDP – guanosine diphosphate
GTP – guanosine triphosphate
Type 3: Tyrosine Kinase-linked receptor
• Cell Membrane
receptors

• Incorporate
intracellular protein
kinase within their
structure

•e.g.: Insulin receptor,
cytokines receptor
& receptor for growth
factors
-Ligand / drug binding to
the receptor on the
surface of the cell.

-formation of receptor
complexes (dimers &
tetramer)

- phosphorylation of
tyrosine residues on
numerous intracelullar
proteins.

-This triggers a cascade
of events leading to cell
activation (eg the
platelet-derived growth
factor initiates the
proliferation of smooth
muscle).

-These proteins are
involved in the regulation
of cell growth,
differentiation and
activity.

Type 4: Intracellular/nuclear
receptors
•Within nucleus


•Binding to receptor to form a
complex
Influence DNA
transcription

Result in mRNA encodes
for the synthesis of new
protein

Cellular / biologic effects

E.g.: oestrogen receptor
Steroid hormones
mRNA
A lipid soluble
substance drug/
hormone diffuse
across cell membrane
& moves to the nucleus
of the cell
Drug / hormone
binds to a nuclear
receptor
The drug- receptor
complex binds to
chromatin, activating
the transcription of
specific genes
Specific protein
Biologic effects
Receptors - summary
Receptor
1) Agonist of cell membrane receptors
2) Antagonist of cell membrane receptors
3) Agonist of nuclear receptors
4) Antagonist of nuclear receptors
Cell Membrane
Bound Endogenous Activator (Agonist) of Receptor
Active Cell Surface Receptor
Extracellular
Compartment
Intracellular
Compartment
Cellular Response
Agonist of cell membrane receptors

- Receptor agonists
- bind to cell surface
receptors & trigger a
response
-Eg. Morphine agonists
Cell Membrane
Displaced Endogenous Activator (Agonist) of Receptor
Inactive Cell Surface Receptor
Extracellular
Compartment
Intracellular
Compartment
Bound Antagonist of Receptor (Drug)
Antagonist of cell membrane receptors

-Receptor antagonist
-Block the receptor & cannot trigger a response
- eg. Angiotensin Receptor Blockers (ARBs) for
high blood pressure, heart failure, chronic renal
insufficiency
(losartan , valsartan)

Intracellular
Compartment
Nucleus
DNA
Modulation of
Transcription
Active Nuclear Receptor
Bound Endogenous Activator
(Agonist) of Nuclear Receptor
Agonist of nuclear receptors

e.g. HRT for menopause
steroids for inflammation
Displaced Endogenous Activator
(Agonist) of Nuclear Receptor
Intracellular
Compartment
Nucleus
DNA
Bound Antagonist
of Receptor (Drug)
Inactive Nuclear Receptor
In Cytosolic Compartment
Inactive Nuclear Receptor
In Nuclear Compartment
Antagonist of nuclear receptors

•Eg. Estrogen Receptor Antagonists for the prevention and treatment
of breast cancer (tamoxifen [Nolvadex®])
- tamoxifen competes with estrogen receptor in breast tissue

Enzymes
 Enzymes catalyze the biosynthesis of
products from substrates
 Drugs act by binding with enzymes
 Usually inhibit the enzymatic activity
 Bind reversibly or irreversibly to
enzyme

Enzymes
Binding


1) Aspirin (for pain relief) acts by binding with Cyclo-
oxygenase enzyme (COX)……irreversible binding
 Inhibits synthesis of prostaglandins


2) Physostigmine acts by binding with cholinesterase
enzyme (ChE)…….reversible binding
 Inhibits metabolism of Ach & thus increases the
concentration of Ach in the body

Enzymes
1) Enzyme inhibitors
- Angiotensin Converting Enzyme (ACE)
Inhibitors for high blood pressure, heart
failure, and chronic renal insufficiency
(captopril, ramipril)



2) Enzymes activators
- e.g. nitroglycerine (guanylyl cyclase)
Ion-channels
There are two general classes of
ion channels:

1) ligand gated – ionotropic receptors.
2) voltage gated

Ion-channels
Voltage-gated ion channels
 Voltage-gated ion channels are activated by alterations in membrane voltage.
 For example,
voltage-gated Calcium (Ca+) channels open when the membrane is depolarized to a
threshold potential and contribute to further membrane depolarization by
allowing Ca+ influx into the cell.

Ligand-gated ion channels

Blocker
Eg. Calcium Channel Blockers for angina and
high blood pressure
(amlodipine)

Opener
Eg. Alprazolam (for management of anxiety
disorder)

Ion-channels
Carrier molecules /
transporter
Carrier molecules/
Transporter
• The transport of ions & small organic molecules across cell
membranes generally requires a carrier protein, since the
permeating molecules are often too polar to penetrate lipid
membranes on their own.
• The carrier protein embody a recognition site that makes them
specific for a particular permeating species and these recognition
sites can also be targets for drugs that block the transport system.

 Some important example
1) Selective Serotonin Reuptake Inhibitors
(SSRIs) for the treatment of depression
(fluoxetine, fluvoxamine)

2) Inhibitors of Na-2Cl-K Symporter (Loop
Diuretics) in renal epithelial cells to increase
urine and sodium output for the treatment of
edema
(furosemide, bumetanide)

Carrier molecules/
Transporter
Drug-Receptor
Bonds
Drug-Receptor Bonds
 Drugs interact with receptors by means of
chemical forces & bonds

 any bond could be involved with the drug-
receptor interaction.

 There are 3 major types of chemical
forces/bonds
1) Covalent
2) Electrostatic
3) Hydrophobic


Covalent bonds
 Covalent bonds are very strong and
would be very tight.
 Frequently, a covalent bond is described
as essentially "irreversible" under
biological conditions.
 Since by definition the drug-receptor
interaction is reversible, covalent bond
formation is rather rare


 Involves mutual sharing of orbital electrons

Covalent bonds….con’t
 A covalent bond is formed between the activated
form of phenoxybenzamine (a receptor
antagonist)(antihypertensive drug) and the alpha
adrenergic-receptor.

 Results in blockade of the receptor
 The bonding is not readily broken
 The blocking effect of phenoxybenzamine
lasts long after the free drug has
disappeared from the bloodstream
 To overcome the alpha-adrenergic receptor
blockade, new alpha receptor protein must
be synthesized.
 This process may take 48 hours.

Covalent bonds….example
Electrostatic Bonding
 Electrostatic bonds are weaker than covalent
bonds

 Electrostatic interactions tend to be much more
common than the covalent bonding in drug-
receptor interactions

 The interaction strength is variable:
 Strong electrostatic interactions occur between
permanently charged ionic molecules (Ionic bonds)
 Weaker interactions all are due to hydrogen
bonding
 Very weak induced dipole interactions, e.g. van der
Waals forces

 Since many drugs contain acid or amine
functional groups which are ionized at
physiological pH, ionic bonds are formed by
the attraction of opposite charges in the
receptor site

 Electrostatic bonds that are formed between
two ions of opposite charge

 Ionic bonds is relatively high stability


Ionic bonds





Ionic bonds
 Positively charged drugs bind with negatively charged
receptors (between cations and anions)
 Complete transfer of electrons
Hydrogen bonds

 It is the electrostatic attraction
between opposite partial charges

 When a hydrogen atom bearing a partial
positive charge bridges 2 atoms bearing
partial negative charges, a hydrogen
bond is created.

 Weak bond
Hydrogen bonds…con’t

van der Waals bond

 Very weak induced dipole interactions.
 Bonding between two dipoles.
 non-specific attractions between two
atoms that are close to each other.



Hydrophobic Bonds

 Hydrophobic interactions referred to
interactions between molecules in
which the interactions are less driven
by molecule to molecule attraction and
more by the tendency of molecules to
wish to avoid the aqueous (water)
environments.


Hydrophobic Bonds


 Hydrophobic interactions are generally weak,
but important.

 Hydrophobic interactions are probably
significant in driving interactions:

 between lipid soluble drugs and the lipid
component of biological membranes
between non-polar hydrocarbon groups on the
drug and non-polar receptor regions

Hydrophobic Bonds
These bonds are not very specific but the
interactions do occur to exclude water molecules.
Outline of the lecture
 Drug-receptor binding
 Dose-response relationship
 Factors governing drug action
– affinity, potency, efficacy
 Effect of drugs on receptor
- agonist, antagonist
 Therapeutic Index
 Drug Reactions/Drug Interactions
 Factors influencing Drug Response
 Adverse Drug Reactions


Drug receptor binding
Drug-Receptor complex
Drug + Receptor  {DR} complex







Biologic Response
The binding of a drug to its
receptor initiates a series of
cellular response reactions in
consequences which cause a
biologic response
Drug-receptor binding
 When a drug (D) combines with a receptor (R), it
does so at a rate which is dependent on the
concentration of the drug and the concentration of
the receptor.

 This applies to the Law of Mass Action

k
1
[D] + [R]  [DR]
k
-1

D = drug
R = receptor,
DR = drug-receptor complex
k
1
= rate for association
K
-1
= rate for dissociation.
Effect
K
2
is a proportionality constant which relates to the maximal response or efficacy seen
when all receptors are occupied
k
2
Drug-response relationship
Drug-response relationship
 The relationship between dose of a drug
and response produced by that drug

 The concentration of the drug would be
plotted on the x-axis and the effect /
response of the drug would be presented
on the y-axis.

 A plot of drug concentration ([D]) versus
effect / response is a rectangular
hyperbola.

 The drug effect reaches a plateau or
maximum.

 This is because there are a finite number
of receptors. Hence, the response must
eventually reach a maximum - reaches an
equilibrium (the amount of drug bound to
the receptor is constant)

R
e
s
p
o
n
s
e

Drug-response relationship
 The hyperbolic plot is a
cumbersome graph because
drug concentrations often
vary over 100 to 1000-fold.

 This needs a long X-axis.

 To overcome this problem,
the log of the drug
concentration is plotted
versus the effect.

 A plot of the log of [D]
versus response is a sigmoid
curve.
R
e
s
p
o
n
s
e

Drug Concentration
SEMILOG DOSE-RESPONSE CURVE
EC50
50% Effect
Maximal Effect
E
f
f
e
c
t

o
r

Affinity

Potency

Intrinsic activity (efficacy)
Factors Governing Drug Action
 Factors that determine the effect of a
drug on physiologic processes are

1) Affinity

2) Potency

3) Intrinsic activity (efficacy)






Affinity
 Affinity is a measure of the tightness that a
drug binds to its receptor.

 The affinity of a drug for its receptor is
described by the equilibrium constant (K
D
)

 The higher the affinity (low K
D
value) the
more likely it is that the receptor will be
occupied by drug.

Potency
 A measure of the amount of drug
needed to produce an effect / a
response

 The concentration producing an effect
that is 50% of the maximum is used to
determine potency; it is commonly
designated as the EC
50

EC
50
 Half maximal effective
concentration (EC
50
) –
the concentration of
the drug that produces
a response equal to 50%
of the maximal
response.

 It is commonly used as a
measure of drug's
potency.

 The smaller the value of
EC
50
the more potent is
the drug.

25
100
50
75
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
Drug A
Muscle
Contraction
Response (mm)
Log [Drug] nM
Drug B
80
40
 Drug A is more potent
than Drug B because
less Drug A is needed to
obtain 50% effect

 Eg. Candesartan &
irbesartan –
angiotensin-receptor
blockers that are used
alone or in combination
to treat hypertension

 Candesartan is more
potent than irbesartan
because the dose range
for candesartan is 4 to
32 mg, as compared to a
dose range of 75 to 300
mg for irbesartan.

Potency…..con’t
SEMILOG DOSE-RESPONSE CURVE
RANK ORDER OF POTENCY: A > B > C > D
A B C D
Log [Dose]
Efficacy
 Efficacy or Intrinsic activity is a
measure of the ability of a drug-
receptor complex to produce a
functional response.

 Efficacy is dependent on the number of
drug-receptor complexes formed
POTENCY
EFFICACY
EC50
Maximal Effect
Log [Dose]
Potency & Efficacy
Potency & Efficacy
 Potency and
efficacy between
drugs can be
compared by using
dose-response
curve

Potency & Efficacy
RANK ORDER OF POTENCY: A > B > C > D
RANK ORDER OF EFFICACY: A = C > B > D
A
B
C
D
EC50
Agonist
Antagonist
Effect of drugs on receptors
Drug that act on a specific receptor can
be classified by their effect on the
receptor

1) Agonist

2) Antagonist


Agonist
 A drug that combines with receptors and
initiates a sequence of biochemical and
physiological changes
 Once bound to the receptor an agonist activates
or enhances cellular activity.
 Agonists have both affinity & intrinsic activity
 It has intrinsic activity = 1

- - -
+ + +
Depolarization
Agonist
 Examples of agonist action:-

Epinephrine – an agonist at beta
adrenergic receptor


Increase in force of contraction of the
heart
Agonists can be further divided into :


1) Full Agonists

2) Partial Agonists

Agonist
Full Agonist
 Compounds that are
able to elicit the
maximal response
of the tissue
following receptor
occupation and
activation.

 Full agonists have
high efficacy

Partial Agonist
 Compounds that
produce an agonist
action, but are
unable to elicit the
full response of the
tissue.

DRC – full & partial agonist
Antagonist

• Antagonists have the ability to bind to the
receptor but do not initiate a change in
cellular function.
• Because they occupy the receptor, they can
prevent the binding and the action of
agonists.
• Antagonists are also referred to as blockers.


Antagonist
 Antagonists, only have affinity for the
receptor. This property allows
antagonists to bind to the receptor.

 However, antagonists do not have
intrinsic activity at the receptor, NO
EFFECT is produced (zero efficacy)


Antagonist
Antagonists can be further divided into :


1) Competitive Antagonists

2) Noncompetitive Antagonists


Antagonist
Competitive Antagonist


 Agonists and antagonists
"compete" for the same
binding site on the
receptor.

 Once bound, an
antagonist will block
agonist binding.

 They bind in a reversible
manner
Competitive Antagonist


 Because competitive antagonists bind in a reversible
manner, agonists, if given in high concentrations, can
displace the antagonist from the receptor and the
agonist can then produce its effect.

 The antagonist can be completely displaced,
therefore, the agonist is still able to produce the
same maximal effect observed prior to antagonist
treatment.


Competitive Antagonist…con’t
 The presence of a competitive antagonist will shift
the dose response curve for an agonist to the right

 The maximum possible effect of the agonist does not
change
Competitive Antagonist…con’t
 Eg.
Prazosin – antihypertensive drug
competes with the endogenous ligand,
norephinephrine at 1-adrenoceptors

Decreasing vascular smooth muscle tone

Reducing blood pressure


Noncompetitive antagonist
 is referred to as an irreversible antagonist.

 They are chemically reactive compounds and
covalently binds with the receptor

 It remains attached to the receptor for a long period
of time.

 Because the antagonist is covalently bound to the
receptor, the binding of agonists & their
pharmacologic activity, are blocked.

 Unlike competitive antagonists, the blocking activity
of noncompetitive antagonists can not be overcome by
increasing the agonist concentration.
Noncompetitive antagonist…con’t
 Noncompetitive antagonist always decreases
the maximal response
Response
Noncompetitive antagonist…con’t
Noncompetitive antagonist…con’t
 Eg. Irreversible binding of antagonist

Aspirin inhibition of cyclooxygenase


Blocks production of prostaglandins from
arachidonic acid

 Requires synthesis of new protein to overcome
 This mechanism is important for the use of aspirin in
preventing recurrence of myocardial infarction

Therapeutic Index
Therapeutic Index
 therapeutic effect- desirable and beneficial
effect.
 toxic effect - harmful and undesired effect.

Therapeutic Index of a drug
 Is the ratio of the dose that produces
toxicity to the dose that produces a clinically
desire or effective response in a population


Therapeutic Index…con’t

TD
50
= the drug dose that produces a toxic
effect in half the population

ED
50
= the drug dose that produces a
therapeutic or desired response in half the
population
Log concentration drug
in plasma
Percentage of
patient
Therapeutic Index…con’t
Therapeutic index is a measure
of a drug’s safety, because a
larger value indicates a wide
margin between doses that are
effective & doses that are toxic




Narrow Therapeutic Index
Warfarin – oral anticoagulant
- When the therapeutic index is
small, it is possible to have range of
concentration where the effective &
toxic response overlap
•Warfarin
•Lithium
•Digoxin
•Phenytoin
•Gentamycin
•Amphotericin B
•5-fluorouracil
•AZT (zidovudine)
Large Therapeutic Index
Penicillin – antimicrobial drug
- It is safe & common to give doses in excess (often
about ten-fold excess) of that what which is minimally
required to achieve a desired response
Drug interactions
 A drug-drug interaction occurs
when one drug interacts with or
interferes with the action of
another drug.

 Drug-drug interactions can
produce effects that are:-
1. Additives
2. Synergistic
3. Antagonistic


Drug-drug interactions
Additive drug reactions
 Occurs when the combined effect of
two drugs is equal to the sum of each
drug given alone.

 Eg. taking drug heparin with alcohol will
increase bleeding

 The equation to illustrate the additive
effect of drugs 1 + 1 = 2
Synergistic drug reactions
 Occurs when drugs interact with each & produce an
effect that is greater than the sum of their separate
action.

 Eg. when a person takes both a hypnotic & alcohol

 When alcohol is taken simultaneously or shortly
before or after the hypnotic is taken, the action of
the hypnotic increase.

 The person experiences a drug effect that is greater
than if either drug was taken alone.

 The equation to illustrate the synergistic effect of
drugs 1 + 1 = 3
Antagonistic drug reactions
 Occurs when one drug interferes with the
action of another causing neutralization or a
decrease in the effect of one drug.

 Eg. Protamine sulfate is a heparin antagonist

 The administration of protamine sulfate
completely neutralizes the effects of heparin
in the body

 The equation to illustrate the antagonistic
effect of drugs 1 + 1 = 0

Drug-drug interactions
Factors influencing Drug Response
 Certain factors may influence drug
response


1. Body weight and size
2. Age and Sex
3. Genetics - pharmacogenetics
4. Condition of health / Disease


AGE
 The age of the patient may
influence the effects of a
drug.

 Infants & children usually
require smaller doses of a drug
than adults

 Immature organ function,
particularly of the liver &
kidneys, can affect the ability
of infants & young children to
metabolize drugs.

AGE…con’t
 Elderly patients may also require
smaller doses, although this may
depend on the type of drug
administered.

 Changes that occur with aging
affect the pharmacokinetics of a
drug – because of the physiologic
changes that occur with aging.


Weight
 In general, dosages are based on
a weight of approximately 150 lb
(~ 68 kg), which is calculated to
be the average weight of men
and women.

 A drug dose may sometimes be
increased or decreased because
the patient’s weight is
significantly higher or lower
than this average.


SEX
 The sex of an individual may
influence the action of some drugs

 Women may require a smaller dose of
some drugs than men.

 This is because many women are
smaller & have a different body fat-
to-water ratio than men.
Disease
 The presence of disease may influence the
action of some drugs.

 Sometimes disease is an indication for not
prescribing a drug or for reducing the dose of
a certain drug.

 Both hepatic (liver) & renal (kidney) disease
can greatly affect drug response
Disease…con’t
In liver disease

 The ability to metabolize or
detoxify a specific type of
drug may be impaired

 If the average or normal
dose of the drug is given, the
liver may be unable to
metabolize the drug at a
normal rate.

• The drug may be excreted from the body at much slower rate than normal – prescribe
a lower dose & lengthen the time between doses because liver function is abnormal.
Genetics
 Pharmacogenetic disorder – a genetically
determined abnormal response to normal
doses of a drug

 This abnormal response occurs because of
inherited traits that cause abnormal
metabolism of drugs.

 Eg. Individuals with G6PD deficiency- have
abnormal reactions to a number of drugs

 They exhibit varying degrees of hemolysis
when these drugs are administered
Adverse Drug Reactions
Adverse Drug Reactions
 Patients may experience one or more adverse
reactions when they are given a drug at a
normal dose
 Adverse reactions are undesirable drug
effects
 May be common or may occur infrequently
 May be mild, severe or life-threatening.
 May occur after the first dose, after several
doses or after many doses
Adverse Drug Reactions….con’t
 Often, an adverse reaction is unpredictable, although
some drugs are known to cause certain adverse
reactions in many patients

 Eg. drugs used in treating cancer are very toxic & are
known to produce adverse reactions in many patients
receiving them.

 Other drugs produce adverse reactions in fewer
patients

 Some adverse reactions are predictable, but many
adverse reactions occur without warning.
Adverse Drug Reactions…eg
Common adverse effects of oral iron therapy:-

 Black stools
 Nausea
 Constipation
 Diarrhea

References


1) Pharmacology, Rang & Dale, Churchill Livingstone, 5
th

ed., 2003

2) Introductory Clinical Pharmacology, Roach & Ford,
Lippincott Williams & Wilkins, 8
th
ed., 2008.

3) Pharmacology: Lippincott’s Illustrated Review, 4
th
ed.,
2009.