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PHARMACOLOGY

SPRING TERM 2016


Dr LEONARDO DASSO

Lectures 2 & 3

PHARMACODYNAMICS
A FEW DEFINITIONS
Drug: any substance that when administered to a living organism produces a
biological effect.
Pharmacology the study of the manner in which the function of living systems is
affected by chemical agents. It involves the knowledge of the history, source,
physical and chemical properties, compounding, biochemical and physiological
effects, mechanisms of action, absorption, distribution, biotransformation and
excretion, and therapeutic and other uses of drugs.
The relationship between the dose of a drug and the utility of that drug in treating a
disease is described by two basic areas of pharmacology: pharmacokinetics and
pharmacodynamics.
These terms may be defined as what the body does to the drug (pharmacokinetics)
and what the drug does to the body (pharmacodynamics).
Pharmacokinetics deals with the absorption, distribution, metabolism and
excretion of drugs.
Pharmacodynamics is the study of biochemical and physiological effects of
drugs and their mechanisms of action.
Clinical pharmacology or Pharmacotherapeutics is the study of the use of drugs in
the prevention and treatment of disease.
Pharmacotherapy is the use of drugs to treat disease.
Toxicology is the aspect of pharmacology that deals with the adverse effects of drugs.

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DRUG ACTIONS
Drugs are chemicals that alter basic cellular processes. They can stimulate or inhibit
normal cellular functions. They cannot add functions.

MECHANISMS OF DRUG ACTION


The effects of most drugs result from their interaction with macromolecular
components of the organism. These interactions alter the function of the pertinent
component and thereby initiate the biochemical and physiological changes that are
characteristic of the response to the drug.
Drug molecules must be bound to particular constituents of cells and tissues in order to
produce an effect. The term receptor was coined to denote the component of the
organism with which the chemical agent interacts. A receptor is a component of a cell
or organism that interacts with a drug and initiates the chain of events that leads to
the drugs observed effects.
Most drugs produce their effects by binding to protein molecules.
The only important exception to proteins as drug receptors is DNA, on which a number
of antitumour and antimicrobial drugs act, as well as mutagenic and carcinogenic agents.
A NOTE ON TERMINOLOGY
Some pharmacologists prefer the term drug target to describe the molecule with which
a drug has to bind in order to elicit its effect, and reserve the term receptor to mean
only the physiological receptors, ie, the regulatory proteins which mediate the actions of
endogenous chemical signals such as hormones, growth factors, or neurotransmitters.

DRUG RECEPTORS
MAJOR TYPES OF DRUG RECEPTORS
Most drug receptors can be classified into the following major groups:
Ion channels
G protein-linked receptors
Ligand-regulated transmembrane enzymes
Cytokine receptors
Intracellular receptors
Nuclear Receptors
Enzymes
Structural proteins
Extracellular enzymes
Transporters

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ION CHANNELS
The functions of ion channels are diverse, including fundamental roles in
neurotransmission, cardiac conduction, muscle contraction, and secretion. Because of
this, drugs targeting ion channels can have a significant impact on major body functions.
Two major mechanisms regulate the activity of ion channels:
In voltage-gated ion channels, the conductance is regulated by changes in the
membrane potential.
In ligand-gated ion channels, the conductance is controlled by ligand binding to the
channel. The ligand can be either an extracellular mediator, specifically, a
neurotransmitter such as acetylcholine, GABA, aspartate or glutamate, or an
intracellular mediator, such as Ca2+, cAMP or cGMP.
Two examples of drug classes that act by altering the conductance of ion channels are the
local anesthetics and the benzodiazepines:
Local anesthetics block voltage-gated sodium channels in neurons that transmit pain
information from the periphery to the central nervous system, thereby preventing
action potential propagation and, hence, pain perception.
Benzodiazepines bind to the GABAA receptor in neuronal membranes in the CNS.
This receptor, which functions as a chloride ion channel, is activated by the inhibitory
neurotransmitter GABA. Binding of benzodiazepines to the receptor enhances the
ability of GABA to open the chloride channel, thereby hyperpolarizing the neuron.

G PROTEIN-LINKED RECEPTORS
Approximately 60 % of marketed prescription drugs act by selectively binding to G
protein linked receptors. Examples:
Albuterol, a 2-agonist, is used for asthma.
Propranolol, a -antagonist, is used for hypertension.
Bethanechol, a muscarinic agonist, is used for atonic bladder.
Ipratropium, a muscarinic antagonist, is used for asthma.
Signalling through G protein-linked receptors requires three separate membrane-bound
components:
1. A cell-surface receptor, which detects the extracellular ligand.
2. A G protein on the cytoplasmic face of the plasma membrane that is stimulated by
the activated receptor.
3. An effector: an enzyme or an ion channel whose activity is affected by the activated
G protein.

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G proteins
G proteins are composed of three polypeptide subunits: , and (that is why they are
called trimeric G proteins). The and subunits form a complex.

How G Proteins Work


In the unstimulated state the subunit has bound GDP. When a hormone binds to a G
protein-linked receptor, the receptor undergoes a conformational change that enables the
cytoplasmic domain of the receptor to interact with the G protein and activate it.
Receptor-binding induces a conformational change in the subunit, that exchanges its
GDP for GTP. This causes the subunit to dissociate from the subunit.
Both the subunit and the subunit can diffuse along membrane. Both the subunit
and the subunit can interact with targets located in plasma membrane.
The time for which the and subunits remain dissociated and available to act is
limited by the behavior of the subunit. The subunit is also a GTPase. After some
time it hydrolyzes GTP to GDP. The subunit then reassociates with a complex and
the signal is shut off. This happens a few seconds after the G protein has been activated.

Targets of G Protein Subunits


A. Ion Channels
G-protein-coupled receptors can control ion channel function by mechanisms that dont
involve any second messenger. The G protein interacts directly with the channel.
B. Membrane-Bound Enzymes
Interaction of G proteins with ion channels causes immediate change in state and
behavior of cell. Interactions with enzymes are more complex, leading to production of
further intracellular signaling molecules (second messengers).
The most frequent target enzymes for G proteins are:
Adenylyl cyclase, which catalyzes formation of cAMP
Phospholipase C, which catalyzes formation of IP3 and DAG
These two enzymes are activated by different types of G proteins. The coupling may be
stimulatory (ie, mediated by a stimulatory G protein) or inhibitory (ie, mediated by an
inhibitory G protein).
The intracellular signalling molecules cAMP , IP3 and DAG are called second
messengers (the first messengers being the extracellular signals)

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G PROTEINS AND THEIR EFFECTORS


G protein
Gs
Gi
Gq

Signalling pathway
Activates Adenylyl cyclase
Inhibits adenylyl cyclase
Opens K+ channels
Closes Ca2+ channels
Activates phospholipase C

G Protein-Coupled Second Messenger Systems


A. cAMP
A number of drugs, hormones and neurotransmitters produce their effects by increasing
or decreasing the catalytic activity of adenylyl cyclase and thus raising or lowering the
concentration of cAMP within the cell.
cAMP mediates such hormonal responses as:
Mobilization of stored energy (breakdown of carbohydrates in liver or
triacylglycerols in fat cells) (mediated by - and 3-adrenoceptors respectively)
Increased rate and contraction force of the heart muscle (mediated by 1adrenoceptors)
Relaxation of smooth muscle (mediated by 2-adrenoceptors)
cAMP exerts most of its effects by activating protein kinase A. This enzyme catalyzes the
phosphorylation of other cellular proteins thereby regulating their function. The
specificity of cAMP's regulatory effects lies on the distinct protein substrates of kinase
expressed in different cells.
When the hormonal stimulus stops, the actions of cAMP are terminated by a series of
enzymes. cAMP-stimulated phosphorylation of substrates is reversed by a group of
specific and nonspecific phosphatases. cAMP is degraded to 5'-AMP by
phosphodiesterases (PDE).
B. Inositol-1,4,5-trisphosphate (IP3)
A membrane-bound enzyme, phospholipase C- (PLC ) hydrolises a membrane
phospholipid, phosphatidylinositol-4,5-bisphosphate (PIP2), into diacylglycerol (DAG)
and inositol-1,4,5-trisphosphate (IP3), both of which function as second messengers.
The activation of PLC by various agonists is mediated through the G protein Gq.
DAG is confined to the membrane, where it (along with Ca2+) activates a membranebound protein kinase, protein kinase C (PKC). PKC causes phosphorylation of a variety
of intracellular proteins.

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IP3 triggers release of Ca2+ from the ER. Elevated Ca2+ promotes binding of Ca2+ to
calmodulin, which regulates activities of other enzymes, including calcium-dependent
protein kinases. The range of cellular responses mediated by intracellular Ca2+ extremely
broad. Examples of particular pharmacological importance include:
Smooth muscle contraction
Increased force of contraction of cardiac muscle
Secretion from exocrine glands
Neurotransmitter release from neurons
Hormone release
Termination of the signal: IP3 is inactivated by dephosphorylation. DAG is either
phosphorylated to give phosphatidic acid, which is then converted back into
phospholipids, or it is deacylated to give arachidonic acid. Ca2+ is removed from the
cytoplasm by Ca2+ pumps.

LIGAND-REGULATED TRANSMEMBRANE ENZYMES


These receptors are polypeptides consisting of an extracellular hormone-binding domain
and a cytoplasmic enzyme domain, which may be a tyrosine kinase, a serine/threonine
kinase, or a guanylyl cyclase.
RECEPTOR TYROSINE KINASES

The largest group of transmembrane receptors with enzymatic cytosolic domains is the
receptor tyrosine kinase family. This class of receptors includes the insulin receptor, the
epidermal growth factor receptor (EGFR), the platelet-derived growth factor
(PDGFR), the nerve growth factor receptor (NGFR), and others.
The receptor tyrosine kinase signalling pathway is as follows: The binding of the signal
molecules causes two receptor molecules to come together in the plasma membrane,
forming a dimer. Contact between the two intracellular receptor tails activates their
kinase: one phosphorylates the other. Phosphorylation triggers assembly of a signalling
complex on receptor tails. The phosphorylated tyrosines serve as binding sites for several
proteins, which become activated upon binding. These proteins lead to activation of
signal transduction pathways, such as the MAP kinase cascade, leading to regulation of
gene expression.
Receptor tyrosine kinases play an important role in cellular growth and differentiation.
Gain-of-function mutations in these receptors can lead to uncontrolled cell growth and
cancer.
In 2001, the FDA approved the tyrosine kinase inhibitor, imatinib, which has proven to
be an effective therapy for chronic myelogenous leukemia. Since then, many other
tyrosine kinase inhibitors have been approved.

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CYTOKINE RECEPTORS
Cytokine receptors respond to a heterogeneous group of peptide ligands, which include
growth hormone, prolactin, erythropoietin, and interferons.
These receptors use a mechanism resembling that of receptor tyrosine kinases, except that
in this case, the protein tyrosine kinase activity is not intrinsic to the receptor molecule.
Instead, the intracellular domain of the receptor binds an intracellular tyrosine kinase,
from the Janus-kinase (JAK) family.
Cytokine receptors dimerize upon binding to the activating ligand, leading to activation
of the bound JAKs which then phosphorylate tyrosine residues on the receptor.
JAKs also phosphorylate another set of proteins, called STATs (signal transducers and
activators of transcription). STAT molecules dimerize and the STAT/STAT dimers
translocate to the nucleus where they regulate transcription of specific genes. This
pathway is called the JAK/STAT pathway.

INTRACELLULAR RECEPTORS
Intracellular receptors generally are:
Nuclear Receptors
Enzymes
Structural proteins
NUCLEAR RECEPTORS
Nuclear receptors are ligand-activated transcription factors that contain binding sites
for the ligands and for DNA. Nuclear receptors regulate the expression of genes
controlling numerous physiological processes such as metabolism and development.
Members of the nuclear receptor superfamily include receptors for steroid hormones,
thyroid hormone, and vitamin D.
Some nuclear receptors (e.g. steroid receptors) reside in the cytoplasm, whereas others
(e.g. the thyroid receptor) reside in the nucleus.
Ligands for nuclear receptors (eg steroid hormones, vitamin D and thyroid hormones)
diffuse across the plasma membrane of target cells and once inside the cell, bind to the
nuclear receptors. The binding of the ligand to the receptor induces a conformational
change in the receptor, allowing it to bind to regulatory DNA sequences and thus affect
the transcription of target genes.
Because of the fundamental role played by control of transcription in many biologic
processes, transcription factors are the targets of some important drugs.

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The mechanism used by hormones that act by regulating gene expression has two
therapeutically important consequences:
All of these hormones produce their effects after a lag period of 30 minutes to several
hours -the time required for the synthesis of new proteins. E.g., glucocorticoids will
not immediately relieve the symptoms of acute asthma.
The effects of these agents can persist for hours or days after their plasma
concentration has dropped to zero. This persistence is primarily due to the relatively
slow turnover of most enzymes and proteins, which can remain active in cells for
hours or days after they have been synthesized. It means that the effects of a geneactive hormone will usually decrease slowly when administration of the hormone is
stopped.
ENZYMES
Enzymes are a common cytosolic target. Most drugs that target intracellular enzymes act
by inhibiting enzyme activity.
Statins are competitive inhibitors of HMG-CoA reductase, the enzyme that catalyzes
the first committed step of cholesterol biosynthesis. By inhibiting the de novo cholesterol
synthesis they deplete the intracellular supply of cholesterol. Depletion of intracellular
cholesterol leads to up-regulation of LDL receptors in hepatocytes; this results in
increased clearance of LDL from the blood.
STRUCTURAL PROTEINS
Structural proteins, such as tubulin, are important targets for antineoplastic drugs. For
example, the vinca alkaloids bind to tubulin monomers and prevent the polymerization
of this molecule into microtubules. As a consequence cells are arrested in metaphase.

EXTRACELLULAR ENZYMES
Many important drug receptors are enzymes with active sites located outside the plasma
membrane.
One example is angiotensin converting enzyme (ACE), which converts angiotensin I to
the potent vasoconstrictor angiotensin II. ACE inhibitors are drugs that inhibit this
enzymatic conversion, and thereby lower blood pressure.

TRANSPORTERS
Membrane transporters are the targets of many clinically used drugs.
For example, neurotransmitter transporters are the targets of several classes of drugs
used in the treatment of psychiatric or neurologic disorders.

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The selective serotonin-reuptake inhibitors (SSRIs), such as fluoxetine or


sertraline, are a group of antidepressant drugs that exert their pharmacological effect
by blocking the serotonin transporter (SET), thus blocking serotonin reuptake from
the synaptic cleft into the presynaptic neuron.

ACTIONS OF DRUGS NOT MEDIATED BY BINDING TO


RECEPTORS
Some drugs do not act by interacting with macromolecular components of the organism.
They interact specifically with small molecules or ions that are normally or abnormally
found in the body.
One example is the therapeutic neutralization of gastric acid by a base (antacid).
Another example is the use of the sulfhydryl compound mesma. Mesma reacts in the
bladder with acroleine, a reactive metabolite of the anticancer drug
cyclophosphamide and thus prevents hemorrhagic cystitis.
Some compounds, such as mannitol are administered to increase the osmolarity of
various body fluids. This effect can be exploited to promote diuresis, catharsis,
expansion of circulating volume in the vascular compartment or reduction of cerebral
edema.
Agents such as cholestyramine, colestipol and colesevelam bind bile acids in the
intestinal lumen and prevent their reabsorption. They are used to treat hyperlipidemia.
Drugs such as dimercaprol chelate heavy metals to decrease their toxicity.
Structural analogs of pyrimidines and purines can be incorporated into nucleic
acids and alter their function; such drugs have clinical utility in cancer and antiviral
chemotherapy.

QUANTITATIVE ASPECTS OF
DRUG-RECEPTOR INTERACTIONS
I often say that when you can measure what you are speaking about,
and express it in numbers, you know something about it; but when you
cannot express it in numbers, your knowledge is of a meagre and
unsatisfactory kind; it may be the beginning of knowledge, but you
have scarcely, in your thoughts, advanced to that stage of Science,
whatever the matter may be.
Lord Kelvin (1824-1907)

DOSE-RESPONSE CURVES
There are two major types of doseresponse curves: graded and quantal.
Graded doseresponse curves show the effect of various doses of a drug on an whole
animal or human subject, or in an in vitro tissue preparation.

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Quantal dose-response curves show the effect of various doses of a drug on a population
of animal or human subjects.

GRADED DOSERESPONSE CURVES


Responses to low doses of a drug usually increase in direct proportion to the dose. As
doses increase the response increment decreases. Finally, doses may be reached at which
no further increase in response is achieved. The relation between drug concentration and
effect is described by a hyperbolic curve according to the following equation:
Emax x C
E=
C + EC50
Where:
E is the effect observed at concentration C.
Emax is the maximal response that can be produced by the drug.
EC50 is the concentration of the drug that produces 50% of maximal effect.
DRUG-RECEPTOR BINDING
The relation between drug bound to receptors (B) and the concentration of free drug (C)
is described by the equation:
Bmax x C
B=
C + KD
Bmax is the total concentration of receptor sites.
KD (the equilibrium dissociation constant) is the concentration of free drug at which
half of the receptors are occupied. This constant characterizes the receptors affinity
for the drug. If the KD is low, binding affinity is high, and vice versa.
This equation shows that as the drug concentration increases the number of receptors
occupied by drug increases.
The shape of the dose-response curve is analagous to the drug-receptor binding curve
because the response to the drug is a consequence of the binding of the drug to the
receptor.
The magnitude of the response to the drug is a function of the number of receptors that
the drug occupies.
NOTE: Graphic representation of dose-response data is frequently improved by plotting
the drug effect against the logarithm of the dose or concentration. The effect of this
mathematical manoeuvre is to transform the hyperbolic curve into a sigmoid curve
with a linear midportion.

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SPARE RECEPTORS AND SIGNAL AMPLIFICATION


In most physiological systems the relationship between receptor occupancy and response
is not linear. All receptors do not have to be occupied to evoke a full response. Maximal
responses are elicited at less than maximal receptor occupancy (ie, EC50 is lower than
KD). Because of this a certain number of receptors are said to be "spare." Spare receptors
are receptors which exist in excess of those required to produce a full effect. It should be
noted taht there is nothing different about spare receptors.
The presence of spare receptors indicates signal amplification. For example, each beta 2
adrenergic receptor may activate several Gs protein molecules. Each Gs protein molecule
may activate several molecules of adenylyl cyclase, which can catalyze the synthesis of
many molecules of cAMP. Each molecule of activated protein kinase A can then
phosphorylate many molecules of phosphorylase kinase, which in turn can phosphorylate
many molecules of glycogen phosphorylase.
IN VITRO EXPERIMENTS VS WHOLE ANIMAL EXPERIMENTS
For in vitro experiments drug concentrations are plotted on the X axis. In this way the
drug concentration evoking 50% of the maximal effect (the EC50) is obtained.
On the other hand, if a drug is administered to an intact animal or patient, drug doses are
plotted. In this way the dose evoking 50% of the maximal effect (the ED50) is obtained.

EFFICACY AND POTENCY


Efficacy
Efficacy, often called maximal efficacy, is the maximal effect (Emax) a drug can produce.
Efficacy is determined mainly by the nature of the receptor and its associated effector
system.
Potency
The left-to-right position of the dose-response curve, indicating the magnitude of the
effects for a given dose is a measure of the drug's potency. Potency refers to the
concentration (EC50) of a drug required to produce 50% of that drugs maximal
effect. The potency of a drug depends in part on the affinity (KD) of receptors for
binding the drug, and in part on the efficiency with which drug-receptor interaction is
coupled to the response.
Two drugs that are qualitatively the same in producing a particular effect may differ in
either efficacy or potency, or both.
The clinical effectiveness of a drug depends not on its potency (EC50), but on its
maximal efficacy. However, the potency determines the dose of the drug. In general,
low potency is important only if the drug has to be administered in inconveniently
large amounts.

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Efficacy is a measure of the intrinsic ability of a drug to produce an effect and is


useful for therapeutic purposes. Potency is less important therapeutically since it usually
makes little difference whether the patient has to take 1 mg or 10 mg in order to achieve a
certain level of effect.

AGONISTS & ANTAGONISTS


An agonist is a drug that binds to and activates a receptor in some fashion that directly
or indirectly brings about an effect.
An antagonist is a drug that inhibits the action of an agonist but has no effect in the
absence of the agonist.

MECHANISMS OF DRUG ANTAGONISM


Receptor antagonism
Competitive
Noncompetitive
Nonreceptor antagonism
Functional antagonism
Chemical antagonism
RECEPTOR ANTAGONISM
A receptor antagonist binds to the same receptor to which the agonist binds. It may bind
to either the active site or to an allosteric site on the receptor. Receptor antagonism can be
competitive, noncompetitive or uncompetitive.
COMPETITIVE ANTAGONISM

Competitive antagonists bind to the agonist binding site on the receptor. Binding of
antagonist to the agonist binding site prevents the binding of agonist to the receptor.
Binding of antagonist to the receptor may be reversible or irreversible.
Reversible Competitive Antagonism
In the presence of a fixed concentration of agonist, increasing concentrations of a
reversible competitive antagonist progressively inhibit the agonist response. High
concentrations of antagonist prevent the response completely.
Reversible competitive antagonism is surmountable: sufficiently high concentrations
of agonist can completely surmount the effect of a given concentration of the
antagonist; ie, the Emax for the agonist remains the same for any fixed concentration of
antagonist.
Because the antagonist is competitive, its presence increases the agonist concentration
required for a given degree of response. So, the agonist concentration-effect curve
shifts to the right .
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Irreversible Competitive Antagonism


Occurs when the antagonist dissociates very slowly or not at all from the receptor,
with the result that no change in the antagonist occupancy takes place when agonist is
applied 1. The fractional occupancy by the agonist is thus reduced in proportion to the
fraction of receptors occupied by the antagonist. A receptor that is bound by an
irreversible antagonist can no longer respond to the binding of an agonist.
Therefore, the Emax of the agonist is reduced. This antagonism is insurmountable.
Irreversible competitive antagonism occurs with drugs that possess reactive groups
which form covalent bonds with the receptor. One example is phenoxybenzamine,
an irreversible -adrenoceptor blocker used in the treatment of pheochromocytoma.
Several irreversible enzyme inhibitors are clinically used, such as aspirin,
omeprazole and MAO inhibitors.
NONCOMPETITIVE ANTAGONISM

Noncompetitive antagonism is also called allosteric antagonism. Noncompetitive


antagonists bind to the receptor at a site different from the agonist binding site.
Antagonist binding reduces or prevents the action of the agonist with or without any
effect on the binding of the agonist. This type of antagonism is also insurmountable and
it evokes a decrease in Emax. Example: ketamine, a dissociative anesthetic, is a
noncompetitive antagonist at the NMDA receptor.
NONRECEPTOR ANTAGONISM
A nonreceptor antagonist does not bind to the receptor to which the agonist binds, but it
nonetheless inhibits the response to the agonist. Nonreceptor antagonists can be divided
into functional antagonists and chemical antagonists.
FUNCTIONAL ANTAGONISM

Indirect Antagonism
The antagonist does not bind to the receptor, but to an intermediate macromolecule
in the pathway that links the receptor to the physiological effect. For example, a
drug that inhibits protein kinase A blocks the effects of a -adrenoceptor agonist.
Physiological Antagonism
One agonist opposes another agonist, but through different receptors. Example,
epinephrine evokes an increase in blood pressure and bronchodilation, whereas
histamine evokes a decrese in blood pressure and bronchoconstriction. Epinephrine is
a physiological antagonist of histamine.
CHEMICAL ANTAGONISM

A drug that reacts chemically with an agonist to form a product that cannot activate a
receptor is referred to as a chemical antagonist. For example, protamine, a protein
1

Some authors refer to this type of antagonism as noncompetitive.

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which is positively charged at physiologic pH, can be used to counteract the effects of
heparin, an anticoagulant that is negatively charged.

FULL & PARTIAL AGONISTS


Agonists activate the receptor that they occupy. Antagonists cause no activation. But the
ability of a drug molecule to activate the receptor is a graded property.
Full agonists can produce a maximal response.
Partial agonists can only produce a submaximal response. Partial agonists produce a
lower response, at full receptor occupancy, than do full agonists. Even if all the receptors
are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of
a full agonist.
A partial agonist can act as a competitive antagonist in the presence of a full agonist,
by competing with the full agonist for receptor occupancy, thus reducing the response to
the full agonist. Many drugs used clinically as antagonists are actually weak partial
agonists.
Partial agonists can be used therapeutically to buffer a response by inhibiting untoward
stimulation without totally abolishing the stimulus from the receptor.
INVERSE AGONISTS
Inverse agonists reverse the constitutive (basal) activity of a receptor. In systems that are
not constitutively active, inverse agonists will behave like competitive antagonists. Many
drugs that were previously classified as antagonists are now known to be inverse
agonists. Examples of inverse agonists are famotidine, losartan, metoprolol and
risperidone.

DRUG SELECTIVITY
Drugs are classified according to their principal actions. However, no drug causes only
a single, specific effect. This is because drugs can interact with more than one single
type of receptor and thus can evoke different pharmacologic effects. Additionally, each
receptor type controls different biochemical processes that result in different effects.
Drugs are therefore selective rather than specific- in their actions. Selectivity is usually
assessed by separating effects into beneficial effects versus adverse effects.
Drug selectivity can be measured by comparing the binding affinities (Kd) of a drug to
different receptors or by comparing the EC50s or ED50s for the different effects of a drug.
For a drug to be useful as a therapeutic tool it must act selectively on particular types of
receptors, ie, it must show a high degree of binding selectivity.

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As a general rule, a drug is said to be selective if there is at least a 10-fold difference


between its binding affinity for its first target (the target which mediates the desired
effects) versus its second target (which mediates adverse effects). The greater the
difference, the more selective the drug is.
When a drug has a 10-fold difference in binding affinity for its first target versus its
second target, virtually complete occupancy of the first target can be achieved at a
concentration that produces only minimal occupancy of the second target.
When a drug has a 100-fold difference in affinity for the first versus the second target, no
detectable occupancy of the second target is achieved at a concentration that produces
full occupancy of the first target. Once that degree of separation has been achieved,
further increases in selectivity are of little clinical consequence.

DESENSITIZATION & TOLERANCE


Often, the effect of a drug gradually diminishes when it is given continuously or
repeatedly. Desensitisation and tachyphylaxis are synonymous terms used to describe
this phenomenon, which often develops in the course of a few minutes.
The term tolerance is describes a more gradual decrease in responsiveness to a drug,
taking days or weeks to develop.
The term refractoriness is also sometimes used, mainly in relation to a loss of therapeutic
efficacy.
Drug resistance is a term used to describe the loss of effectiveness of antimicrobial or
anticancer drugs.
Many different mechanisms can give rise to this type of phenomenon. They include:
Change in Receptors
Activation of ion channel receptors often leads to rapid desensitisation.
Most G-protein-coupled receptors also show desensitisation. The mechanism often
involves receptor phosphorylation. Phosphorylation of the receptor interferes with its
ability to activate the signalling cascade, although it can still bind the agonist molecule.
This type of desensitisation usually takes a few minutes to develop, and recovers at a
similar rate when the agonist is removed.
Internalization of Receptors
Prolonged exposure to agonists often results in a gradual decrease in the number of
receptors expressed on the cell surface, as a result of endocytosis of the receptors.

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Exhaustion of Mediators
Drugs such as amphetamine, which acts by releasing norepinephrine and other amines
from nerve terminals, show tachyphylaxis because the releasable stores of norepinephrine
become depleted.
Increased Metabolic Degradation of the Drug
Tolerance to some drugs, for example barbiturates and ethanol, occurs partly because
repeated administration produces lower plasma concentration.
Physiological Adaptation
Decrease of a drug's effect may occur because it is nullified by a homeostatic response.
For example, the blood pressure-lowering effect of thiazide diuretics is limited because of
a gradual activation of the renin-angiotensin system.

QUANTAL DOSE-EFFECT CURVES


An assay may be based on a graded response (as seen above) or on an all-or-nothing
(quantal) response. The quantal doseresponse relationship plots the fraction of the
population that responds to a given dose of drug as a function of the drug dose. Quantal
doseresponse relationships then show the concentrations of a drug that evoke a given
effect in a population. The responses are defined as either present or not present (i.e.,
quantal, not graded), such as prevention of convulsions, arrhythmia, or death.
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. When these responses
are summated, the resulting cumulative frequency distribution constitutes a quantal doseeffect curve (or dose-percent curve), displaying the percentage of individuals who
exhibit the effect plotted as a function of log dose.
This curve resembles the sigmoid shape of the graded concentration-effect curves
discussed above, but the slope of the quantal dose-effect curve is an expression of the
pharmacodynamic variability in the population rather than an expression of the
concentration range from a threshold to a maximal effect in an individual patient.
The quantal dose-effect curve is characterized by stating the median effective dose
(ED50): the dose at which 50% of individuals exhibit the specified quantal effect.
Note: the abbreviation ED50 has a different meaning in this context from its meaning in
relation to graded dose-effect curves.
Similarly, the dose required to produce a particular toxic effect in 50% of animals is
called the median toxic dose (TD50). If the toxic effect is death of the animal, a median
lethal dose (LD50) may be experimentally defined.
Such values provide a convenient way of comparing potencies of drugs in experimental
and clinical settings.
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NOTE: the quantal dose-effect curve and the graded dose-response curve summarize
different sets of information, although both appear sigmoid in shape on a semilog plot.
Critical information required for making rational therapeutic decisions can be obtained
from each type of curve:
Both curves provide information regarding the potency and selectivity of drugs.
Only the graded dose-response curve indicates the maximal efficacy of a drug.
The quantal dose-effect curve indicates the potential variability of responsiveness
among individuals.

THERAPEUTIC INDEX (TI)


Quantal dose-response curves may be used to generate information regarding the margin
of safety of a particular drug. In animal studies, the therapeutic index is defined as the
ratio of the TD50 to the ED50 for a therapeutically relevant effect.
TD50
TI =

LD50
Or

ED50

TI =
ED50

The TI represents an estimate of the safety of the drug.


The therapeutic index of a drug in humans is almost never known with real precision.
Instead, drug trials and accumulated clinical experience often reveal a range of usually
effective doses and a range of possibly toxic doses.
THE THERAPEUTIC WINDOW
The therapeutic window, a more clinically relevant index of safety, is the dosage range
between the minimum effective therapeutic concentration and the minimum toxic
concentration. For example, if the average minimum therapeutic plasma concentration
of theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the therapeutic
window is 8-18 mg/L.
SOURCES
Golan, DE, Tashjian, AH, Armstrong, EJ & Armstrong, AW. Principles of Pharmacology (2nd ed). LWW, 2007.
Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.) McGraw-Hill, 2010.
Katzung, BG, Masters, SB, Trevor, AJ. Basic & Clinical Pharmacology (13th Ed.). McGraw-Hill, 2015.
Harvey RA. Lippincotts Illustrated Reviews. Pharmacology (5th ed.). LWW, 2011.
Rang, HP et al. Rang and Dales Pharmacology (7th ed.) Churchill-Livingstone, 2011.
http://www.iuphar-db.org/termsAndSymbols.pdf
http://www.preskorn.com/columns/9907.html

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