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 Pharmacodynamics is the study of the biochemical and
physiological effects of drugs, in certain period.
 In brief, it can be described as what the drug does to the
body.
Drug receptors
Effects of drug
Responses to drugs
Toxicity and adverse effects of drugs

Drugs can act through:
1. Physical action:
Drug can produce a therapeutic response because of it’s physical properties. e.g: Mannitol as
diuretic because it increase osmalerity, Radio-isotopes : emit ionizing radiation
2. Simple chemical reaction:
Drug may act through a chemical reaction. e.g: Gastric antacids work by neutralizing the
stomach acidity with a base, Chelating agents that bind heavy metals in body.
3. Receptors:
A receptor is a specialized target macromolecule mostly protein, present on the cell surface
or intracellular, that binds a drug and mediates it’s pharmacological actions.
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
Receptors can either be enzymes, nucleic acids or structural proteins to
which drugs may interact.

A molecule that binds to a receptor is called a ligand, and can be a peptide
or another small molecule like a neurotransmitter, hormone, or drug.

Ligand binding changes the conformation (three-dimensional shape) of
the receptor molecule. This alters the shape at a different part of the
protein, changing the interaction of the receptor molecule with associated
biochemicals, leading in turn to a cellular response mediated by the
associated biochemical pathway.
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Not every ligand that binds to a receptor also activates the receptor. The following classes of ligands exist:
1. (Full) agonists are able to activate the receptor and result in a maximal biological response. The
natural endogenous ligand with greatest efficacy for a given receptor is by definition a full agonist (100% efficacy).
2. Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full
agonists (efficacy between 0 and 100%).
3. Antagonists bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of
agonists and inverse agonists.
`4. Reverse agonist
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Agonist
e.g. important
therapy
in asthma
Hormone
Antagonist
binds 2 receptor in lung 
bronchial relaxation
binds 1 receptor in heart muscle 
increased heart rate
control heart beat
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This is based on the type of the transduction mechanism that these receptors activate
when stimulated by their agonists:
1. Transmembrane ligand-gated ion channels: These
receptors are present in the walls of ion channels in cell
membranes. When activated by their specific agonist, they open
these ion channels & lead to movement of ions across cell
membrane.
 These mediate diverse functions, including neurotransmission,
cardiac conduction, and muscle contraction.
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Examples :
1. Nicotinic receptors for acetylcholine (Ach.) : when stimulated, they open receptoroperated Na+ channels, and thus increase influx of sodium ions across membranes of
neurons or NMJ(neuromuscular junction) in skeletal muscle and therefore activation
of contraction in muscle.
2. γ-aminobutyric acid (GABA) receptors:
Benzodiazepines enhance the stimulation of the GABA receptor by GABA, resulting
in increased chloride influx and hyperpolarization of the respective cell.
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2. Transmembrane G protein–coupled receptors:
 When these receptors are stimulated by their specific agonists, they will activate a
regulatory G-protein in cell membrane which in turn change activity of membrane
enzymes ( either adenyl cyclase or phospholipase C ) leading to a change in
intracellular level of a second messenger like cAMP (cyclic adenosine
monophosphate), or IP3 (inositol triphosphate), respectively, and this would lead
to cell response.

Examples : e.g. Receptors for transmitters : Stimulation of muscarinic receptors (M1 and M3)
for (Ach) will activate G and leads to increase intracellular level of IP3
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guanosine triphosphate (GTP), guanosine diphosphate (GDP)
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3. Enzyme-linked receptors:

These membrane receptors have an extra-cellular site that binds to specific agonists and an intracytoplasmic domain which contains tyrosine and other amino acids.

Binding to specific agonist and activation of these receptors usually lead to phosphorylation
of tyrosine in intra-cellular domain which then acquires kinase activity and leads to activation
of intracellular substrates or enzymes that finally leads to cell response.

Examples:
Receptors for insulin,
Receptors for growth factors like EGF or PDGF,
Receptors for immune cytokines
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4. Intracellular receptors:
 These receptors are located in cytoplasm (e.g. steroid receptors)
or nucleus
(receptors for thyroid hormones or vitamin D3) .
 The specific agonist must cross cell membrane to inside of cell, binds and
activates these receptors, which will then bind to DNA gene response
elements in nucleus and lead to change in gene transcription , and thus
synthesis of new proteins
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Drugs interact with receptors by means of chemical forces or bonds. These are of three major types:
1. Covalent: It is very strong and in many cases not reversible under biologic conditions. Thus, the
duration of drug action is frequently, but not necessarily, prolonged (irreversible)
2. Electrostatic: is much more common than covalent bonding in drug-receptor interactions. These vary
from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen
bonds and very weak induced dipole interactions such as van der Waals forces. Electrostatic
bonds are weaker than covalent bonds. (reversible)
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3. Hydrophobic: are usually quite weak and are probably important in the interactions of
highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction
of drugs with the internal walls of receptor "pockets.“

Drugs which bind through weak bonds to their receptors are generally more selective than
drugs which bind through very strong bonds.

This is because weak bonds require a very precise fit of the drug to its receptor if an
interaction is to occur
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Termination of drug action at the receptor level results from one of several processes:
1.
The effect lasts only as long as the drug occupies the receptor, so that dissociation of drug from the receptor
automatically terminates the effect.
2. The action may persist after the drug has dissociated, because, for example, some coupling molecule is still present in
activated form.
3. Drugs that bind covalently to the receptor, the effect may persist until the drug-receptor complex is destroyed and new
receptors are synthesized.
4. Many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when
agonist molecules continue to be present for long periods
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In order to make rational therapeutic decisions, the prescriber must understand how
drug-receptor interactions underlie
1. The relations between dose and response in patients
2. The nature and causes of variation in pharmacologic responsiveness
3. The clinical implications of selectivity of drug action.
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These relations are exhibited as following:
A. Graded dose–response relationships ( individual):
The response is a graded effect, meaning that the response is continuous and
gradual
B. Quantal dose–response relationships (population)
describes an all-or-no response
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The magnitude of the drug effect depends on the drug concentration at the receptor site, which in turn
is determined by the dose of drug administered and by factors characteristic of the drug pharmacokinetic
profile, such as rate of absorption, distribution, and metabolism.
As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases.
Plotting the magnitude of the response against increasing
doses of a drug produces a graph, the graded dose–response
curve.
 Two important properties of drugs, can be determined by
graded dose–response curves which are:
1. Potency
2. Efficacy
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 A measure of the amount of drug necessary to
produce an effect of a given magnitude.


The concentration of drug producing an effect that is 50
percent of the maximum is used to determine potency and is
commonly designated as the EC50
Drug A is more potent than Drug B, because a lesser
amount of Drug A is needed when compared to Drug B to
obtain 50-percent effect.
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Potency is affected by:
1. Receptor concentration or density in tissue,
2. Efficiency of stimulus-response coupling mechanism in tissue
3. Affinity: the strength of the interaction (binding) between a ligand and its receptor.
4. Efficacy
 Potent drugs are those which elicit a response by binding to a critical number of a
particular receptor type at low concentrations (high affinity) compared with other
drugs acting on the same system and having lower affinity and thus requiring more
drug to bind to the same number of receptors

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It is the ability of a drug to elicit a response when it interacts with a receptor.
 Efficacy is dependent on:
1. Number of drug–receptor complexes formed
2. the efficiency of the coupling of receptor activation to cellular responses.
 A drug with greater efficacy is more
therapeutically beneficial than one that is more potent.
 Maximal efficacy (Emax) of a drug assumes that all receptors are occupied by the
drug, and no increase in response will be observed if more drugs are added
 The height of maximal response is used to measure maximal efficacy of
agonist drug, and to compare efficacy of similar acting agonists
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The quantitative relationship between drug concentration and receptor occupancy is expressed as
follows:
Drug + Receptor ←→ Drug–receptor complex → Biologic effect

As the concentration of free drug increases, the ratio of the concentrations of bound receptors to total
receptors approaches unity
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A receptor can exist in at least two conformational states, active (Ra), and inactive
(Ri). These states are in equilibrium, & the inactive state Ri predominates in absence of
agonist drug, thus basal activity will be low or absent.
 If a drug that has a higher affinity for Ra than R i is given,
it will drive the equilibrium in favor of active state and thus activate more receptors.
Such drug will be an agonist.
A full or strong agonist is sufficiently selective for the active conformation that at
a high concentration it will drive the receptors completely to the active state.
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If a different but structurally similar compound binds to the same site on R
but with only slightly or moderately greater affinity for Ra than for Ri, its
effect will be less, even at high concentrations. Such a drug that has
intermediate or low efficacy is referred to as a partial agonist
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 If a drug binds with equal affinity to either conformation of receptor but
does not change the activation equilibrium, then it will act as a competitive
antagonist.
 A drug with preferential affinity for Ri actually will produce an effect
opposite to that of an agonist, and thus named inverse agonist. It further
reduces the resting level and effect of receptor activity.
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 They are of 3 main types :
1. Chemical antagonist :
This combines with agonist and inactivates it away from tissues or receptors
Examples:
a. Alkaline antacids neutralize HCl in stomach of peptic ulcer patients;
b. protamine (basic) neutralizes the anti-coagulant heparin (acidic) in plasma
c. Chelating agents bind with higher affinity to heavy metals (e.g. lead, mercury, arsenic
) in plasma and tissues, preventing their tissue toxicity
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2. Physiological antagonist :
 This is actually an agonist on the same tissue but produces opposite effect to that
of the specific agonist; it acts by mechanisms or receptors that are different from
those of the specific agonist .
 Physiological antagonists quickly reverse the action of the specific agonist on the
same tissue.
Examples:
Adrenaline, given IM, is a quick acting physiologic antagonist to histamine (that is
released from mast cells or basophils) in anaphylactic shock; it is a life-saving drug in this
condition
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3. Pharmacological antagonist :
Pharmacological receptor antagonists have affinity for the receptors but have no intrinsic activity or
efficacy
There are three main types :
A. Competitive reversible antagonist :
This antagonist , because of similarity in its chemical structure to agonist, competes with agonist for
binding to its specific receptors in tissue, and thus decreases or prevents binding of agonist and its
effect on tissue.
The antagonist molecules bind to the agonist receptors with reversible ionic bonds, so that it
can be displaced competitively from receptors by increasing the concentration or dose of
agonist , and thus response of tissue to agonist is restored.
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agonist (A) and antagonist (I)
The DR curve of agonist is shifted to the right, and the maximal response can be restored by
increasing dose of agonist. The more is the concentration of antagonist, the greater is this shift of
DR curve of agonist to the right.
Examples:
 atropine is a competitive reversible antagonist to Ach at muscarinic receptors;
 Beta-blockers are competitive antagonists to adrenaline at beta –adrenergic receptors.

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B. Non-competitive antagonist :
There are two subtypes:
1. Irreversible antagonist :
Here, the antagonist molecules either bind to agonist receptors by strong
irreversible covalent bonds or dissociate very slowly from the receptors,
so that the effect of antagonist can not be overcome fully by increasing
concentration of agonist.
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
The dose response curve of agonist is shifted slightly to the right , but the maximal
height or response of curve is depressed and can NOT be restored by increasing the
dose of agonist . This is due to decrease in number of receptors remaining available to bind
to agonist.

The more is the concentration of antagonist, the more is depression of maximal
response
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2. Allosteric antagonism :
Here, the antagonist binds to allosteric site on receptor that is different from the site that binds agonist
molecules, leading to change in receptor binding or affinity to agonist with subsequent antagonism.
The dose response curve of antagonist is similar to that of irreversible non-competitive antagonist.
Note : Allosteric enhancement : with some receptors, a drug can bind to another allosteric site on agonist
receptor leading to increase in binding of agonist to its receptor and thus allosteric enhancement of agonist
effect . e.g. Binding of benzodiazepines to GABA-A receptors can enhance the depressant GABA effect on
brain neurons.
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C. Uncompetitive antagonist:
Here antagonist bind to a receptor different from that of agonist, and is located more distally in the effector
mechanism so that the effect of agonist is blocked as well as that of other agonists that produce similar
effect by acting on a different receptor i.e. it lacks specificity. The dose-response curve is similar
to that of irreversible non-competitive antagonist.
A + RA
B + RU
Depolarization → Increases free
calcium
Y
Uncompetitive antagonist
Contraction
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1. Receptor up-regulation :
This means increase in number of receptors and/or affinity of specific receptors ( receptor
supersensitivity).
It may occur with :
A. Prolonged use of receptor antagonist : here, there is lack of binding of receptor
to agonist for long period of time
B. Disease : e.g. hyperthyroidism : here excess thyroxine hormone in blood stimulate
proliferation of beta-adrenergic receptors in heart which increases risk of cardiac
arrhythmia from adrenaline or use of beta-adrenoceptor agonists .
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B. Receptor down-regulation (Receptor tolerance):
This means a decrease in number and/or affinity of available specific receptors due to their prolonged
occupation by agonist .


It occurs with continued use (for days or weeks) of receptor agonist , and is evident as decrease in
response to agonist .
In order to restore the intensity of response, the dose of agonist must be increased.
Tachyphylaxis : it is a rapidly developing receptor tolerance
 It is not due to receptor down-regulation
 It is associated with repeated use of large doses
of direct receptor agonist, usually at short dose intervals , OR with continuous IV infusion of
agonist.
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It may be due to :
1. Desensitization of receptors :
Change in the receptor: where the agonist-induced changes in receptor conformation result in
receptor phosphorylation, which diminishes the ability of the receptor to interact with G proteins
2. Depletion of intra-cellular stores of transmitter
e.g. depletion of noradrenaline stores in vesicles inside sympathetic nerve ending resulting from
repeated use of indirect sympathomimetic amphetamine


In order to restore the response, the agonist drug must be stopped for short time to allow for
recovery of receptors or stores of transmitter.
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Individuals usually show variation in intensity of response to drugs due to :
1. Variation in concentration of drug that reaches the tissue receptors : due to
pharmacokinetic factors
2. Abnormality in receptor number or function : either genetically-determined or acquired
due to up-regulation or down-regulation
3. Post-receptor defect inside cells :
This is an important cause of response variation
4. Variation in Concentration of an Endogenous Receptor Ligand
contributes greatly to variability in responses to pharmacologic antagonists.
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1. Variation in concentration of drug that reaches the tissue receptors : due to pharmacokinetic
factors
2. Abnormality in receptor number or function : either genetically-determined or acquired due
to up-regulation or down-regulation
3. Post-receptor defect inside cells :
This is an important cause of response variation
4. Variation in Concentration of an Endogenous Receptor Ligand
contributes greatly to variability in responses to pharmacologic antagonists.
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the influence of the magnitude of the dose on the proportion of a population that responds.
 These responses are known as quantal responses, because, for any individual, the effect
either occurs or it does not.
The desired response is either :
A. Specified in amount or magnitude :
e.g. increase in heart rate of 20 beats/min by a drug that stimulates heart.
If the recorded response in any individual shows this amount or more, then this is
regarded as positive response; otherwise, the response is negative
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B. All-or-none response :
e.g. death; prevention of epileptic seizures; prevention of cardiac arrhythmias

For most drugs, the doses required to produce a specified quantal effect in individuals are
lognormally distributed; ie, a frequency distribution of such responses plotted against the log
of the dose produces a gaussian normal curve of variation
Determines minimum dose at which
each patient responded with the
desired outcome. The results have
been plotted as a histogram, and fit
with a gaussian curve. μ = mean
response; σ = standard deviation.
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 When these responses are summated, the resulting cumulative frequency
distribution constitutes a quantal dose-effect curve of the proportion or
percentage of individuals who exhibit the effect plotted as a function of log
dose
Example:
At 1.25mg/L, 2% respond,
and 2.5mg/L 3% respond,
 Then at 5mg/L plot 2%,
and at 7mg/L plot (2+3 =
5% etc.)
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 The quantal dose-effect curve is often characterized by:
1. median effective dose (ED50): the dose at which 50% of individuals exhibit the
specified quantal effect.
2. median toxic dose (TD50): the dose required to produce a particular toxic effect in
50% of Animals.
3. Median lethal dose (LD50): the dose required to produce a death in 50% of
Animals.
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Two common types of “agonistic” drug interactions are :
1. Summation: When two drugs with similar mechanisms are given together, they
typically produce additive effects.
2. Potentiation or synergism : if the effect of two drugs exceeds the sum of their
individual effects.
 Potentiation requires that the drugs act at different receptors or
effector systems.
Example of potentiation would be the increase in beneficial effects noted
in the treatment of AIDS by combination therapy with AZT (a nucleoside
analog that inhibits HIV reverse transcriptase) and a protease inhibitor
(protease activity is important for viral replication).
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 This may be obtained from knowledge of Therapeutic Index (TI) of drug.
the ratio of the dose that produces toxicity to the dose that produces a clinically desired or
effective response in a population of individuals
TI = TD50 / ED50
where :
TD50 = the drug dose that produces a toxic effect in half the population
ED50 = the drug dose that produces a therapeutic effect in half the population.
 A larger value indicates a wide margin between doses that are effective and doses that
are toxic.
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
TI is determined by measuring the frequency of desired response, and toxic response, at
various doses of drug.

In humans, the therapeutic index of a drug is determined using drug trials and
accumulated clinical experience. These usually reveal a range of effective doses and a
different (sometimes overlapping) range of toxic doses.

The concentration range over which a drug produces its therapeutic effect is known as its
therapeutic window
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 when the therapeutic index is low, it is
possible to have a range of concentrations where
the effective and toxic responses overlap
 Agents with a low therapeutic index are
those drugs for which bioavailability critically
alters the therapeutic effects
 When therapeutic index is large, it is safe and common to
give doses in excess (often about ten-fold excess) of that which is
minimally required to achieve a desired response. In this case,
bioavailability does not critically alter the therapeutic effects.
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
Specificity : If a drug has one effect, and only one effect on all biological systems it possesses the
property of specificity.
a drug that has a particular effect and not another.

Selectivity: refers to a drug's ability to preferentially produce a particular effect and is related to the
structural specificity of drug binding to receptors.
a drug that acts on a particular target (receptor) and not another

For example, a drug binds on a particular receptor-target (so its selective), but that target may be
expressed in different tissues and thus may exert different biological effects (so no-specific).
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These are unwanted and/or harmful effects
I. Predictable or dose-related or type A effects :
A. Side effects : These occur at therapeutic doses of a drug. They are usually
minor, and decrease or disappear on reducing dose or sometimes with continued use
of drug
B. Toxic effects : These are due to large toxic doses . They are usually serious,
and need stopping drug use, and sometimes supportive treatment to save life. They
may be :
1. Functional e.g. respiratory depression OR
2. Structural : causing tissue damage e.g.
damage to liver or kidney or heart or nerves
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II. Unpredictable or Type B reactions :
A. Allergy : This is due to activation of immunemechanisms by drug.
Drug acts as hapten to induce formation of antibodies by plasma cells or to sensitize T-lymphocytes .
Usually, allergic reactions have no dose-response relation ; they are of 4 main types :
Type 1 : Immediate type ; it is the commonest type ;
it is mediated by IgE antibodies that bind to membrane of mast cells in tissues or basophils in
blood.
After re-exposure and binding to their specific antigen,
they trigger release of histamine and other mediators from granules of these cells.
This causes urticaria or , in severe cases , anaphylactic shock which is a life threatening emergency
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Type 2 : Cyto-toxic reaction :
mediated by either IgM antibodies in plasma or IgG antibodies that causes tissue
damage by fixing complement and activating complement cascade
e.g. hemolysis ; liver or kidney damage .
Type 3 : Immune complex mediated reaction :
Circulating immune complexes form between antigen and IgG antibodies which
become deposited in capillaries of skin , joints , and kidney. Clinical features occur
after many days of exposure to drug e.g. serum sickness
Type 4 : Delayed cell-mediated reactions :
These are due to activation of sensitized T lymphocytes which release their cytokines and
attract macrophages to site that also release tissue damaging cytokines
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B. Idiosyncrasy :
abnormal drug reactions due usually to genetic factors affecting tissue enzymes or
receptors.
Examples:
a. Hemolysis by sulfonamides or the antimalarial drug primaquin in patients with
genetic deficiency of the enzyme glucose-6-phosphate dehydrogenase (G-6-PD) in
their RBC
b. Resistance to vitamin D or to the oral anti-coagulant warfarin
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III. Special toxicity including
1. Genotoxicity leading to Mutagenicity :
Alkylating agents
2. Teratogenicity :
Congenital disorder : drugs taken in pregnancy
3. Carcinogenicity : may take about 2 years .
- may be related to mutagenicity but less than
is the case with teratogenicity
4. Reproductive toxicity recording pregnancy
rate, number of live or stillbirths, & postnatal growth
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IV . Others
1. Delayed toxicity : occurs sometime after
stopping drug use e.g. idiosyncratic
aplastic anemia due to chloramphenicol
2. Chronic toxicity : occurs with prolonged use
of drug e.g. Cushing syndrome from
long-term use of steroids
3. Dependence : occurs with prolonged use
of CNS depressants e.g. alcohol ; opioids like morphine
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Adverse effects may be caused by :
1. Over-extension of same mechanism of action on same target tissue : e.g. sedative-hypnotics;
anticoagulants ; beta-adrenoceptor blockers
2. Effect on same receptor type but in another tissue :
e.g. anti-muscarinic drugs ; beta-blockers
3. Effect on different receptor or by different mechanism on target or other tissues
The following groups are more susceptible to adverse drug reactions : foetus during pregnancy;
elderly ; patients receiving many drugs (polypharmacy); patients with pre-existing disease ;
patients with genetic enzyme defects in liver (poor oxidizers or slow acetylators) or tissues
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