Transcript dose-effect relationship

Section 2 Pharmacodynamics:
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Pharmacological effects, Basic concepts
(Drug-Receptor Interaction, );dose-effect
relationship; Cellular Sites of Action
(mechanism), adverse drug reaction (ADR)
Pharmacodynamics
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Pharmacodynamics is what drugs do to the body, including the study of the
biochemical and physiological effects of drugs and their mechanisms of action.
All of these contents are almost based on the principle of drug receptors.
Unit 1．Introduction on receptor
Unit 2. Drug Action
 1．Action and Effect
 2．Excitation and Inhibition
 3．Selectivity of Drug Action
 4. Therapeutic Effect and Adverse Reaction
Unit 3. Principles of Drug Action
 1． Dose-effect relationship
 2．Time-effect relationship
 3．Structure-activity relationship
Unit 4. Mechanisms of Drug Action
 1．Simple physical and chemical property
 2．Involving or interfering physiological and biochemical process of living
system
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(1) Receptors largely determine the quantitative
relations between dose or concentration of drug
and pharmacologic effects.
The receptor's affinity for binding a drug
determines the concentration of drug required to
form a significant number of drug-receptor
complexes, and the total number of receptors may
limit the maximal effect a drug may produce.
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(2) Receptors are responsible for selectivity of
drug action. The molecular size, shape, and
electrical charge of a drug determine whether-and with what affinity--it will bind to a
particular receptor among the vast array of
chemically different binding sites available in a
cell, tissue, or patient.
Accordingly, changes in the chemical structure
of a drug can dramatically increase or decrease
a new drug's affinities for different classes of
receptors, with resulting alterations in
therapeutic and toxic effects.
(3) Receptors mediate the actions of both pharmacologic
agonists and antagonists. Some drugs and many natural
ligands, such as hormones and neurotransmitters,
regulate the function of receptor macromolecules as
agonists; ie, they activate the receptor to signal as a
direct result of binding to it.
 Other drugs act as pharmacologic antagonists; ie, they
bind to receptors but do not activate generation of a
signal; consequently, they interfere with the ability of an
agonist to activate the receptor.
 Other antagonists, in addition to preventing agonist
binding, suppress the basal signaling ("constitutive")
activity of receptors. Some of the most useful drugs in
clinical medicine are pharmacologic antagonists.
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Macromolecular nature of drug receptor
Most receptors are proteins: e.g. regulatory
proteins(neurotransmitters) ; enzymes (dihydrofolate reductase, the
receptor for the antineoplastic drug methotrexate) ; transport proteins
(Na+/K* ATPase ) ; structural proteins (tubulin, the receptor for
colchicine, an anti-inflammatory agent).
Traditionally, drug binding was used to identify or purify receptors
from tissue extracts; However, advances in molecular biology and
genome sequencing have begun to reverse this order. Now receptors
are being discovered by predicted structure or sequence homology to
other (known) receptors, and drugs that bind to them are developed
later using chemical screening methods,.
a number of "orphan" receptors, so-called because their ligands are
presently unknown, which may prove to be useful targets for the
development of new drugs.
Three aspects of drug receptor
function
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(1) Receptors as determinants of the
quantitative relation between the concentration
of a drug and the pharmacologic response.
(2) Receptors as regulatory proteins and
components of chemical signaling mechanisms
that provide targets for important drugs.
(3) Receptors as key determinants of the
therapeutic and toxic effects of drugs in patients.
RELATION BETWEEN DRUG
CONCENTRATION & RESPONSE
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The relation between dose of a drug and the
clinically observed response may be complex.
This idealized relation underlies the more
complex relations between dose and effect that
occur when drugs are given to patients.
Unit 2. Drug Action
1．Drug Action and Effect
Action（作用）means the primary action of the
drug on the body；
Effect （效应）means the functional or
morphological alteration of the body induced by
drugs.
Pharmacology is defined as the study of substance that interact with
living systems through chemical processes, especially by binding to
regulatory molecules and activating or inhibiting normal body
processes.
1、The changes of physiological function:
e.g. Acetylcholine ：a brief decrease in heart rate and cardiac output.
e.g. Pilocarpine ：rapid miosis and contraction of the cillary muscle.
2、The changes of biochemical function:
e.g.Epinephrine
(or:Ad,Adrenaline)
initiates
a
significant
hyperglycemic effect through its increased glycogenolysis in liver
and a decreased release of insulin.
3、The morphological changes of tissue or cell：
e.g. The primary use of folic acid is in treating megaloblastic anemia,
caused by folic acid deficiency.
2．Excitation and Inhibition
The basic performances of drug action vary with
different organ, such as the increase or decrease of
heart rate, the contraction or dilation of skeletal
muscle, and the elevation or lower of blood glucose.
But all of drug action are basically subdivided
two major groups:
excitation or inhibition, which
strengthen or weaken the original function of the
living system, respectively.
Drug that strengthens the original function of the
body is defined as the stimulant, drug that weaken the
original function of the body is defined as the
depressant.
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Notice：
⑴Drug is only capable of altering the rate at which any
bodily function proceeds, but does not create effects.
⑵A drug is whether stimulant or depressant, depending
on different organs. Because it may excite some organ
and inhibit another one, even if the same tissue of
different organs.
e.g.Ad(Adrenaline) contracts the cardiac muscle and
relax the bronchiolar smooth muscle,effects of Ad on
the blood vessels are contractile in skin vessels and
relaxed in skeletal muscle vessels, respectively.
⑶ A drug is whether stimulant or depressant,
depending on the dosage of drug and the condition of
body.
3. Selectivity of Drug Action
The selectivity of drug action means that a drug has characteristic
effects on a tissue or an organ while does not on another one in the
given dose or concentration.
What is responsible for selectivity of drug action(why?):
 1．The existence of different receptors in the target tissues of
different cell or organism.
 2．The existence of different biochemical mechanisms in the
target tissues of different cell or organism.
 3．The existence of different micromolecular structures in the
target tissues of different cell or organism.
 4．The different distributions of drug in the target tissues of
different cell or organism.
 The selectivity of drug action is relative. No drug has a single
effect.
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The importance of understanding the selectivity:
1.
Theoretical importance: Inferring receptor concept-----Most drugs act by associating with specific macromolecules in ways that alter the molecules’ biochemical
and biophysical activities. The existence of receptors was
inferred from observations of the biochemical and
physiologic specificity of drug effects.
In addition to its usefulness for explaining biology, the
receptor concept has important practical consequences
for the development of drugs and for arriving at
therapeutic decision in clinical practice. Form the basis
for understanding the actions and clinical use of drugs.
2. Practical importance：
 ⑴The basis for classifying drugs
 ⑵The basis for arriving at therapeutic
decision
 ⑶The criterion for evaluating drugs
 The best approach is to learn drugs by
their class
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Clinical effects of drug action have the
dualism, The aim of drug therapy is to cure
or suppress disease, called therapeutic
action, but also bring about some harmful
effects, named untoward or adverse reaction.
4.Therapeutic Effect and Adverse Action
Therapeutic Effect
It implied the effects that conform the
goal of therapy, including etiological
treatment
and
symptomatic
treatment(e.g.fever,ache or pain).
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1 ． etiological treatment implies primary
therapy (e.g. in bacterial and parasitic
infections), when the disease is eliminated and
the drug is withdrawn; or auxiliary therapy, also
called supplement therapy or replacement
therapy.
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2．symptomatic treatment means suppression
of diseases or symptoms is used continuously
or intermittently to maintain health without
attaining cure (as in hypertension, diabetes,
epilepsy, asthma) or to control symptoms (such
as pain and cough) whilst awaiting recovery
from the causative disease.
Generally, etiological treatment is more
important than symptomatic treatment.
However, symptomatic treatment is not
necessarily trivial in emergency rescue, such as
heart failure, shock, epilepsy, asthma, etc.
Adverse Reaction (Untoward)
The term adverse reaction is defined as unwanted, seriously
unpleasant, or even harmful effects.
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Adverse Reaction including：
1. Side effects
2. Toxic reaction
3. Residual effect
4. Withdrawal reaction
5. Unusual reaction： ①Idiosyncrasy ②Allergy
1. Side effects is to be the undesired effects unrelated to therapeutic
aim and occurring at doses intended (unavoidable or inevitably) for
therapeutic effect.
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①It is often slight, recoverable functional alteration of the body.
②Some of side effects may make a quick recovery without
withdrawal of the drug, but others dose not disappear until
withdrawal of the drug.
③The pharmacological basis of side effect is lower selectivity
④Side effects vary with different therapeutic goals. For example,
atropine is used as an antisecretory agent to block secretions in the
upper and lower respiratory tracts prior to surgery .
⑤Usually drug in combination is the best way to prevent from side
effects.
2. Toxic reaction is the adverse reactions that occur frequently due to overdose
or longterm use(specially: sensitivity).
①Much of the serious drug toxicity in clinical practice represents a direct
pharmacological extension of the therapeutic action of the drug, thus they
are predictable.
②The severity of a toxicity is deteriorated with dose increase, so we cannot
rise the therapeutic effect by increasing doses of drug, which is very
dangerous.
③Toxicity can not automatically disappear because it often damages the
function or the morphology of organs, even inducing teratogenicity,
carcinogenicity and mutagenicity.
Toxicities include the acute toxicity, subacute toxicity and chronic toxicity
3. Residual effect implies the biological responses induced by residual drug
below effective concentration after cessation of administration, including a
short period, long term and permanent.
4. Withdrawal reaction implies a worsening of original diseases occurred after
suddenly cessation of administration, also called the rebound reaction.
5. Unusual reaction is the unpredictable adverse reaction which unrelated to
pharmacological action of the drug.
①Idiosyncrasy is defined as a genetically determined abnormal reactivity
to a drug. The observed response is qualitatively similar in all individuals,
but the idiosyncratic response may take the form of extreme sensitivity to
low doses or extreme insensitivity to high doses of the agent, which may
be explained, not by antibodies, but by a biochemical abnormality
present in an individual with a genetic defect. One example is a serious
hemolytic anemia when they receive primaquine (for malaria). Such
individuals have a deficiency of erythrocytic glucose-6-phosphate
dehydrogenase(G-6PD).
②Allergy is an adverse reaction that results from previous
sensitization to a particular drug or metabolite (a nondrug
element in the formulation) with subsequent re-exposure.
Such reactions are mediaed by the immune system. Lack
of previous exposure is not the same as lack of history of
previous exposure and exposure is not necessarily medical.
Drugs may elicit allergic reactions of all four types(?).
Features of allergy: A)no? correlation with known pharmacological
properties of the drug, thus it is easy to predict; B)no linear relation with drug
dose, very small doses may cause very severe effects; C)require an induction
period on primary exposure, but not on re-exposure; D)disappear on cessation
of administration and reappear on re-exposure.
Unit 3 Principles of Drug Action
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The knowledge of pharmacodynamics is essential to
the choice of drug therapy. But the well-chosen drug
may fail to produce benefit or may be poisonous
because too little or too much is present at the site of
action for too short or too long a time.
A. dose-effect/response relationship The magnitude of
the drug effect is proportional to the concentration or
dose of the drug, this is, if the concentration or dose of
a drug is increased or decreased, the magnitude of the
drug effect is also correspondingly increased or
decreased respectively. There are two basic types of
dose-response relationships: the graded or the quantal?
Concepts of dose involved
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Dose: a part of drug that is once used for therapy;
Threshold dose: a dose has exceeded a critical level；
Minimal toxic dose: a dosage regimen that is likely to
produce minimal toxicity;
Maximal effective dose (极量): a dosage regimen that is the
maximal dose used in patients limited by Pharmacopoeias;
Usual dose (therapeutic dose): a dosage regimen that is a
safe and effective for most of patients.
Concentration-effect curve &
receptor binding agonist
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As doses increase, however, the response increment diminishes;
finally, doses may be reached at which no further increase in
response can be achieved.
In idealized or in vitro systems, the relation between
drug concentration and effect is described by a hyperbolic curve
(Figure 2-1A p12) according to the following equation:
E=(Emax × C)/(C + EC50)
E: the effect observed at concentration C,
Emax: the maximal response
EC50: the concentration of drug that produces 50% of maximal
effect.
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drug bound to receptors (B) relates to the concentration of free
(unbound) drug (C) as depicted in Figure 2-1B and as described
by an analogous equation: (see above)
B=(Bmax x C)/(C+ Kd)
Bmax indicates the total concentration of
receptor sites (ie, sites bound to the drug at infinitely
high concentrations of free drug).
Kd (the equilibrium dissociation constant) represents the
concentration of free drug at which half-maximal binding is
observed
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If the Kd is low, binding affinity is high, and
vice versa.
Dose-response data are often presented as a plot
of the drug effect (ordinate) against the
logarithm of the dose or concentration
(abscissa). This mathematical maneuver
transforms the hyperbolic curve of Figure 21into a sigmoid curve with a linear midportion
(eg, Figure 2-2 p13 or next figure B).
1. Graded dose-response relations
Graded dose-response relation means the indicators showing drug effect,
such as high or low of blood pressure, could be increased or decreased on
the basis of the original amount, their determinants are the doses.
The effect of a drug is most easily analyzed by plotting the magnitude of the
response versus the drug dose, this is, a graded dose-response curve, which
is reflected by a rectangular hyperbolic curve (A), but it is frequently
convenient to plot the magnitude of effect versus log dose, because a wide
range of drug concentrations is easily displayed. In this case, the result is
the symmetric sigmoidal log dose-effect curve (B). This curve is steep in the
middle and even in both extremities.
Aim of plotting the dose-effect relation curve is to compare the
relative potencies and efficacies of different drugs,
obtaining two terms:
Potency (效价) also termed effective dose or concentration, is a
measure of how much drug is required to elicit a given
response. The lower the dose required for a given response,
the more potent the drug. Potency is most often expressed
as the dose of drug that gives 50% of the maximal response,
ED50 (dose) or EC50 (concentration).
Efficacy (效能) is the maximal response produced by a drug. It
depends on the number of drug-receptor complexes formed.
There is no connection between the potency and efficacy.
Potency is most often expressed as the dose of drug, however,
efficacy focuses on the effectiveness of the drug, which is more
important than potency. Drug A, B,and C have different
potencies, but similar efficacies, however,drug C, D, and E have
similar potencies but different efficacies.
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In the same figure above:
Logarithmic transformation of the dose axis and experimental
demonstration of spare receptors, using different concentrations of
an irreversible antagonist. Curve A shows agonist response in the
absence of antagonist. After treatment with a low concentration of
antagonist (curve B), the curve is shifted to the right; maximal
remonsiveness is preserved, however, because the remaining
available receptors are still in excess of the number required. In
curve C, produced after treatment with a larger concentration of
antagonist, the available receptors are no longer "spare"; instead,
they are just sufficient to mediate an undiminished maximal
response. Still higher concentrations of antagonist (curves D and E)
reduce the number of available receptors to the point that maximal
response is diminished. The apparent EC50 of the agonist in curves
D and E may approximate the Kd that characterizes the binding
affinity of the agonist for the receptor.
Receptor-effect coupling & spare receptors
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coupling
When a receptor is occupied by an agonist, the resulting conformational
change is only the first steps. The transduction process that links drug
occupancy of receptors and pharmacologic response is often termed coupling.
The effects of full agonists can be considered more efficiently coupled to
receptor occupancy than can the effects of partial agonists. Coupling
efficiency is also determined by the biochemical events that transduce
receptor occupancy into cellular response.
Sometimes the biologic effect of the drug is linearly related to the number of
receptors bound. This is often true for drug-regulated ion channels, eg, where
the ion current produced by the drug is directly proportional to the number
of receptors (ion channels) bound.
In other cases the biologic response is a more complex function of drug
binding to receptors. This is often true for receptors linked to enzymatic
signal transduction cascades, eg, where the biologic response often increases
disproportionately to the number of receptors occupied by drug.
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The concept of spare receptors is very useful clinically
because it allows one to think precisely about the
effects of drug dosage, without needing to consider
biochemical details of the signaling response.
The Kd of the agonist-receptor interaction determines
what fraction (B/Bmax) of total receptors will be
occupied at a given free concentration (C) of agonist
regardless of the receptor concentration:
Thus, it is possible to change the sensitivity of tissues
with spare receptors by changing the receptor
concentration
Competitive & irreversible
antagonist
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Antagonist:
1,Receptor antagonists bind to receptors but do
not activate them,at the same time ,to prevent
agonists (other drugs or endogenous regulatory
molecules) from activating receptors.
2, "inverse agonists", reduce receptor activity
below basal levels observed in the absence of
bound ligand.
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Antagonists are divided into two classes:
1, reversible competitive antagonist :
2, irreversible antagonists:
1, reversible competitive antagonist :
In the presence of a fixed concentration of agonist, increasing
concentrations of a eversible competitive antagonist
progressively inhibit the agonist response; high antagonist
concentrations prevent response completely. Conversely,
sufficiently high concentrations of agonist can completely
surmount the effect of a given concentration of the antagonist;
that is, the Emax for the agonist remains the same for any fixed
concentration of antagonist (Figure 2-3A). Because the
antagonism is competitive, the presence of antagonist increases
the agonist concentration required for a given degree of
response, and so the agonist concentration-effect curve is shifted
to the right.
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The concentration (C') of an agonist required to
produce a given effect in the presence of a fixed
concentration ([I]) of competitive antagonist is
greater than the agonist concentration (C)
required to produce the same effect in the
absence of the antagonist.
The relationship of ratio of these two agonist
concentrations (C, C') can be explained by the
Schild equation: c’/c=1+[I]/Ki
For the clinician, this mathematical relation
has two important therapeutic implications:
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1) The degree of inhibition produced by a
competitive antagonist depends on the
concentration of antagonist. Different patients
receiving a fixed dose of propranolol, for
example, exhibit a wide range of plasma
concentrations, owing to differences in clearance
of the drug. As a result, the effects of a fixed
dose of this competitive antagonist of
norepinephrine may widely in patients, and the
dose must be adjusted accordingly.
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2) Clinical response to a competitive antagonist depends on the
concentration of agonist that is competing for binding to
receptors. Here also propranolol provide a useful example:
When this competitive β-adrenoceptor antagonist is
administered in doses sufficient to block the effect of basal
levels of the neurotransmitter norepinephrine, resting heart rate
is decreased. However, the increase in release of norepinephrine
and epinephrine that occurs with exercise, postural changes, or
emotional stress may suffice to overcome competitive
antagonism by propranolol and increase heart rate, and thereby
can influence therapeutic response.
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2, irreversible antagonists:
Some receptor antagonists bind to the receptor in an
irreversible or nearly irreversible fashion, either by
forming a covalent bond with the receptor or by
binding so tightly that, for practical purposes, the
receptor is unavailable for binding of agonist.
After occupancy of some proportion of receptors by
such an antagonist, the number of remaining
unoccupied receptors may be too low for the agonist
(even at high concentrations) to elicit a response
comparable to the previous maximal response (Figure
2-3B).
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Therapeutically, irreversible antagonists present
distinctive advantages and disadvantages. Once
the irreversible antagonist has occupied the
receptor, it need not be present in unbound
form to inhibit agonist responses. Consequently,
the duration of action of such an irreversible
antagonist is relatively independent of its own
rate of elimination and more dependent on the
rate of turnover of receptor molecules.
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Good case:
Phenoxybenzamine, an irreversible α-adrenoceptor
antagonist, is used to control the hypertension caused
by catecholamines released from pheochromocytoma, a
tumor of the adrenal medulla. If administration of
phenoxybenzamine lowers blood pressure, blockade
will be maintained even when the tumor episodically
releases very large amounts of catecholamine. In this
case, the ability to prevent responses to varying and
high concentrations of agonist is a therapeutic
advantage. If over dose occurs, however, a real problem
may arise. If the α-adrenoceptor blockade cannot be
overcome, excess effects of the drug must be
antagonized "physiologically," ie, by using a pressor
agent that does not act viaαreceptors.
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Partial agonist:
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Drug A and B are said to be more potent than drug C and D because of the
relative position of their dose-response curves along the dose axis. Potency
refers to the concentration (EC50) or dose (ED50) of drug required to produce
50% of that drug’s maximal effect. Thus, the potency of drug A is less than that
of drug B, the EC50 of A is greater than the EC50 of B. However, some dose of
A can produce larger effects than any dose of B, because drug A has a larger
efficacy.
2. Quantal dose-response relations
A quantal response is defined as the defined effect is either present or
absent(all or none). Individual effective doses usually are lognormally
distributed.
A cumulative frequency distribution of individuals achieving the defined effect
as a function of drug dose is the quantal dose-effect curve or concentrationpercent curve. This curve resembles the sigmoid shape of the graded doseeffect curve,
but the slope of
this curve is an expression
of the pharmacodynamic
variability in the population
rather the an expression
of the dose
range from a threshold to
a maximal effect in the
individual patient.
e.g. An experiment was performed on 100 subjects,
and the effective plasma concentration that
produced a quantal response was determined for
each individual. The number of subjects who
required each dose is plotted, giving a lognormal
frequency distribution (colored bars). The gray
bars demonstrate that the normal frequency
distribution, when summated, yields the
cumulative frequency distribution—a sigmoidal
curve.
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The quantal dose-effect curve is often characterized by stating several
values, which provide a convenient way of comparing the potencies or
selectivity of drug.
ED50 (median effective dose ), the dose at which 50% of individuals
exhibit the specified quantal effect, which has a different meaning from the
graded one.
TD50 (median toxic dose), the dose required to produce a particular toxic
effect in 50% of animals.
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LD50 (median lethal dose), the dose required to
produce the death in 50% of animals.
Quantal dose-effect curve may also be used to
generate information regarding the margin of
safety to be expected from a particular drug used
to produce a specified effect.
TI (therapeutic index) is usually defined as the
ratio of the LD50 to the ED50 for some
therapeutically relevant effect. This is one measure,
which relates the dose of a drug required to
produce a desired effect to that which produces an
undesired effect.
2．Time-effect relationship
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Drug effects do not develop instantaneously or continue indefinitely, they change
with time, called time-effect relationship. Time-effect curve is plotted by effect as a
vertical coordinate and by time as a horizontal coordinate，There are three distinct
phases in all time-effect curves
1．Time for onset action （latent period）：a delay in time before the first signs of
drug effect are manifested following the administration of a drug, which reflects
the processes of drug absorption and distribution.
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2．Duration of action (persistent period)：the duration of action
of a drug extends from the moment of onset of perceptible effects
to the time when an action can no longer be measured.
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3．Residue period：the duration from the time when an action can
no longer be measured to the time when the drugs are eliminated.
Even after a primary action of drugs are terminated, it is possible
for a drug to exert a residual action.
Time to peak effect: The maximum response will occur when the
most resistant cell has been affected to its maximum or when the
drug has reached the most inaccessible cells of the response
tissue.(MEC:minimal effect concentration)
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The three phases of the temporal course of drug action are
closely dependent on the size of the dose administered. In
general, the larger the dose, the shorter the time to onset
and time to peak effect, and the longer the overall duration
of action.
The time-effect properties of drugs have considerable
importance in experimental pharmacology, where they are
used in the analysis of mechanism of action, and in
applied pharmacology, where they are form the basis for
selection of the best drug and the optimum dosage
schedule either for sustained therapeutic effect.
3．Structure-activity relationship
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Both the affinity of a drug for its receptor and its
intrinsic activity are determined by its chemical
structure, which is named the structure-activity
relationship.
Relatively minor modifications in the drug molecule
may result in major change in pharmacological
properties.
(1)The drugs having different structures produce
different effects.
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(2)The drugs having similar structures produce similar or opposite effect.
Generally, if both drugs having similar structures possess an intrinsic
activities or not, they may produce the similar effects; but if one
possesses the intrinsic activity and another one does not, they may
produce the contrary effects.
(3) Two enantiomers of a drug could produce different effects in
quantitative or qualitative aspects. In the great majority of cases, one of
these enantiomers will be much more potent than its mirror image
enantiomer. Generally, most of left-oriented drugs are effective, and
right-oriented drugs are not effective, such as morphine, chloramphenicol
and tubocurarine.
The understanding of drug’s structure-activity relationship is useful not
only for the design and synthesis of a new drug, but also for the
comprehension of its action mechanism. But as a Dr.?
Unit 4 Mechanism of drug action
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1. Simple physicochemical interaction
2. Interference with bodily physiological and
biochemical processes
3. Action on receptors: see followings
(1)Receptors
① Receptor concept; ②Receptor entity; ③ drugreceptor interaction
(2)Receptor theory
① Occupational theory; ②Rate theory; ③
Allostearic theory?
(3)Interaction between two drugs
① Synergistic effects; ②Dual effects ; ③
Antagonistic effects
1. Simple physicochemical interaction
Osmosis：as with purgatives, e.g. magnesium sulphate, and
diuretics, e.g. mannitol, which are active because neither
they are not the water in which they are dissolved are
absorbed by the cells lining the gut and kidney tubules
respectively.
Lipidsolubility ： e.g. general and local anaesthetics and
alcohol appear to act on the lipid, protein or water
constituents of nerve cell membranes. 。
pH: these are the direct chemical interaction, such as
antacids, and acidifiers, NaHCO3 or NH4Cl.
Chelating effects: this is also direct chemical interaction,
such as chelating agents.
2. Interference with physiological and biochemical
processes of the body
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Inhibition of membrane bound enzymes and pumps, e.g.
membrane bound ATPase by cardiac glycoside; tricyclic
antidepressants block the pump by which amines actively
taken up from the exterior to the interior of nerve cells.
Enzyme inhibition, e.g. monoamine oxidase by
phenelzine, cholinesterase by pyridostigmine, xanthine
oxidase by allopurinol, Cyclooxygenase by aspirin
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Interference with selective passage of ions across
membranes, e.g. calcium entry (channel) blocker.
Affecting release of
neurotransmitters or
hormones, e.g. Ad release by ephedrine, insulin
release by sulfonylureas.
Altering metabolic processes, e.g. penicillin
interferes with farmation of bacterial cell wall,
inhibition of folic acid synthesis by trimethoprim,
5-fluorouracil is incorporated into mRNA in place
of uracil.
3. Action on receptors
①A drug receptor is a specialized target macromolecule.
②Down-regulation or up-regulation.
③Endogenous ligands or exogenous ligands.
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We have to ask basic questions with important
clinical implications:
Why do some drugs produce effects that persist for minutes, hours, or even days
after the drug is no longer present?
Why do responses to other drugs diminish rapidly with prolonged or repeated
administration?
How do cellular mechanisms for amplifying external chemical signals explain the
phenomenon of spare receptors?
Why do chemically similar drugs often exhibit extraordinary selectivity in their
actions?
Do these mechanisms provide targets for developing new drugs?
How to carry chemical information across the plasma
membrane? What are key features of cytoplasmic second
messengers after activation of receptor?
Most transmembrane signaling is accomplished by a small
number of different molecular mechanisms as followings.
Five basic mechanisms of transmembrane signaling
are well understood (Figure 2-5, see above).
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Each uses a different strategy to circumvent the
barrier posed by the lipid bilayer of the plasma
membrane. These main strategies use:
(1) a lipid-soluble ligand that crosses the
membrane and acts on an intracellular receptor;
(2) a transmembrane receptor protein whose
intracellular enzymatic activity is allosterically
regulated by a ligand that binds to a site on the
protein's extracellular domain;
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(3) a transmembrane receptor that binds and
stimulates a protein tyrosine kinase;
(4) a ligand-gated transmembrane ion channel
that can be induced to open or close by the
binding of a ligand; or
(5) a transmembrane receptor protein that
stimulates a GTP-binding signal transducer
protein (G protein), which in turn modulates
production of an intracellular second messenger.
Intracellular receptor for lipid-soluble agents
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sufficiently lipid-soluble to cross the plasma membrane
and act on intracellular receptors.
One class of such ligands includes:
Steroids(corticosteroids, mineralocorticoids, sex
steroids, vitamin D), and thyroid hormone, whose
receptors stimulate the transcription of genes by
binding to specific DNA sequences near the gene
whose expression is to be regulated.
Many of the target DNA sequences (called response
elements) have been identified.
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For example, binding of glucocorticoid hormone to its normal
receptor protein relieves an inhibitory constraint on the
transcription-stimulating activity of the protein.
Figure 2-6 schematically depicts the molecular mechanism of
glucocorticoid action: In the absence of hormone, the receptor
is bound to hsp90, a protein that appears to prevent normal
folding of several structural domains of the receptor.
Binding of hormone to the ligand-binding domain triggers
release of hsp90.
This allows the DNA-binding and transcription activating
domains of the receptor to fold into their functionally active
conformations,
so that the activated receptor can initiate transcription of target
genes.
Ligand-receptor transmemberane enzyme
including receptor tyrosine kinase
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The class of receptor molecule mediates the first
steps in signaling by insulin, EGF,PDGF,TGFbeta and other trophic hormones.
The three characteristics of drug
receptor existence.
(1)High efficacy and High selectivity
(2)High structure specificity
(3)Competitive specific antagonist
Receptor Entity
Receptors have been isolated, purified,
and characterized.
Types of Receptors
G-Protein-Coupled Receptor
Ligand Gated Ion Channel Receptor
Receptors as Enzymes
Tyrosine kinase receptor
Cytokine receptor
Cytosolic Receptors
Interaction of drug and
receptor includes two steps:
(1) The formation of the
drug-receptor complex has
two characteristics - high
specificity and high affinity
(2) biochemical signal
amplifier.
The formation of the drug-receptor complex.
(2) biochemical signal amplifier
Types of Receptor drug
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Agonist: an agonist is a compound that binds to a receptor
and produces the biological response.
Partial agonist: a partial agonist produces the biological
response but cannot produce 100% of the biological
response even at very high doses.
Antagonist: antagonists block or reverse the effect of
agonists. They have no effect of their own.
Inverse agonist: inverse agonists have opposite effects from
those of full agonist. They are not the same as antagonists,
which block the effects of both agonists and inverse
agonists.?
Receptor Theory
① Occupational theory;
This is the classical receptor
theory developed by Clark. It
was assumed that the effect of
a drug is proportional to the
fraction of receptors occupied
by drug and that maximal
effect results when all receptors
are occupied
The occupational theory only
explains the effect of an
agonist, does not explain those
of partial agonist and
antagonist. .(just number)
Modified occupational theory
intrinsic activity affinity
②Rate Theory ：
This theory assumes that the effect of a drug
depends on the association rate and the dissociation
rate of drug binding receptor, particularly the latter.
Agonist
Antagonist
Partial Agonist
Association Rate
very rapid
very rapid
slow
Dissociation Rate
very rapid
very slow
slow
③Allostearic theory (Two model theory).
This theory considers that a receptor must exist in at
least two conformations: active state and inactive state,
which could interchange.
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agonists can be divided into two classes:
artial agonists produce a lower response, at full receptor occupancy, than do
full agonists.
Partial agonists produce concentration-effect curves that resemble those
observed with full agonists in the presence of an antagonist that irreversibly
blocks some of the receptor sites (compare Figures2-2 [curve D] and 2-4B). It
is important to emphasize that the failure of partial agonists to produce a
maximal response is not due to decreased affinity for binding to receptors.
Indeed, a partial agonist's inability to cause a maximal pharmacologic
response, even when present at high concentrations that saturate binding to
all receptors, is indicated by the fact that partial agonists competitively inhibit
the responses produced by full agonists (Figure 2-4C). Many drugs used
clinically as antagonists are in fact weak partial agonists.
Other Mechanisms of drug Antagonism
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1, chemical antagonist: some types of
antagonism do not involve a receptor at all. e.g.
Just by ionic binding that makes the other drug
unavailable for interactions with proteins
involved in blood clotting (For example,
protamine, positively charged at physiologic pH,
can be used clinically to counteract the effects
of heparin, an anticoagulant that is negatively
charged ).
physiologic antagonism:
 Between endogenous regulatory pathways
mediated by different receptors.
 For example, glucocorticoid ------insulin,
the clinician must sometimes administer insulin
to oppose the hyperglycemic effects of a
glucocorticoid hormone (eg, a tumor of the
adrenal cortex) or as a result of glucocorticoid
therapy.
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In general, use of a drug as a physiologic antagonist produces
effects that are less specific and less easy to control than are the
effects of a receptor-specific antagonist.
For example, to treat bradycardia caused by increased release of
acetylcholine from vagus nerve endings, the physician could use
isoproterenol, α β-adrenoceptor agonist that increases heart rate
by mimicking sympathetic stimulation of the heart.
However, use of this physiologic antagonist would be less
rational—and potentially more dangerous--than would use of a
receptor-specific antagonist such as atropine (a competitive
antagonist at the receptors at which acetylcholine slows heart
rate).
Antagonism
When in combination of an agonist and an antagonist, the antagonist
can block or reverse the effect of an agonist. Because antagonists have no
effect of their own, we need to consider their effect on the agonist.
（1）competitive antagonism
Antagonist competes with agonist for the same site on the
receptor. They bind reversibly at the receptor site. The
antagonist makes the dose-effect curves of agonist rightward
shift.
The competitive antagonistic index- PA2
①PA2 is an antagonistic index，the larger of
PA2, the more potent of antagonism.
②PA2 can be used to identify the subtypes of
receptors
③PA2 can be used to decide the property of an
agonist
（2）Noncompetitive antagonism
A noncompetitive antagonist binds to the receptor at a site different from the
agonist or irreversibly binds the receptor at the same site to prevent the
agonist binding on the receptor so as to prevent the agonist from producing a
maximal effect.