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.
2
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.
3
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
4
5
Agonist e.g. important
therapy
in asthma
Hormone binds 2 receptor in lung
bronchial relaxation
binds 1 receptor in heart muscle
increased heart rate
Antagonist control heart beat
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. 6
Examples :
1. Nicotinic receptors for acetylcholine (Ach.) :
when stimulated, they open receptor-operated
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.
7
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
8
guanosine triphosphate (GTP), guanosine diphosphate (GDP) 9
3. Enzyme-linked receptors:
These membrane receptors have an extra-cellular site that
binds to specific agonists and an intra-cytoplasmic 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
10
11
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
12
13
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)
14
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
15
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
16
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.
17
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
18
19
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
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.
20
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 21
It is the ability of a drug to elicit a response when it
interacts with a receptor.
22
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
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
23
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.
24
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
25
26
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.
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
27
28
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
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.
29
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.
30
agonist (A) and antagonist (I)
31
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.
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
32
33
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.
34
35
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 Depolarization → Increases free
calcium
B + RU
Y
Uncompetitive antagonist
Contraction
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 .
36
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.
37
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.
38
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. 39
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.
40
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
41
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
42
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.
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
43
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.)
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.
44
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.
45
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).
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.
46
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
47
48
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.
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).
49
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 50
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
51
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
52
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
53
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
54
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
55
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
56
