DRUG-RECEPTOR INTERACTIONS Partial agonist: It an agonist that acts on the same

DRUG TYPES receptor as a full agonist but regardless of its dose it

terms cannot elicit the greatest response
Drug action: Biochemical or physiological A partial agonist has high affinity for the receptor,
mechanism(s) by which a drug produces a biological but possesses a low to moderate intrinsic activity
response (less than 1; 0-1)
Drug effect: Ultimate observable change in the A partial agonist when used alone acts as an
biological function of a cell or tissue brought about agonist (lower response than full agonist), but in
as a consequence of drug action presence of a full agonist/agonist, it acts as an
Action of NSAIDs is to inhibit cyclooxygenase antagonist (lowers effect of full agonist as it
enzyme and the effect is the analgesia competes with full agonist for receptor
Terms drug action and drug effect are used Antagonist: drug that interacts with a specific
interchangeably receptor(s) or other part of the effector mechanism
to inhibit action of an agonist
Affinity: Ability of a drug to combine with its Possess affinity, but have no intrinsic activity (IA = 0)
receptor Mediate their effects by binding to the active site or
High affinity drug will bind with greater to allosteric sites on receptors, or they may interact
intermolecular force with its receptor (a low at unique binding sites
concentration of a drug can maximally occupy a Receptor antagonists are called blockers
binding site) and vice versa for low affinity drug Inverse agonist
Intrinsic activity: or efficacy refers to the relative Drug that interacts with the same receptor, but
ability of a drug to evoke a pharmacological produces a response specifically opposite to that of
response (drug effect) on combining with the the agonist
receptor Inverse agonist has affinity but has intrinsic activity
High efficacy drugs can produce the maximal with a minus sign (IA = 0 to -1)
response while occupying a relatively low proportion Agonist-antagonist
of the receptors Acts simultaneously on a mixed group of receptors
Both properties depends on the chemical structure as an agonist on one set and as an antagonist on
of drug another set
TYPES OF DRUG For example, nalorphine, an opioid, activates K-
Agonist: Drug that interacts with a specific opioid receptor but blocks mu-opioid receptor
receptor(s) and elicits an observable positive Superagonist - agonist that produces a maximal
response response greater than the endogenous agonist for
The agonist resembles the endogenous ligands the target receptor, - efficacy of more than 100%.
such as a neurotransmitter or hormone. A co-agonist works with other agonists to produce
An agonist has both affinity and intrinsic activity the effect together e.g. NMDA receptor activation
Agonists may be further classified as full agonists requires the binding of both of its glutamate and
and partial agonists glycine co-agonists.
Full agonist: Binds to and activates a receptor to An irreversible agonist binds permanently to a
elicit the greatest possible response of the receptor -receptor is permanently activated; this
respective tissue causes a brief burst of agonist activity, followed by
For a full agonist, the intrinsic activity (IA) is equal to desensitization and internalization of the receptor
1 with long-term effect more like that of an antagonist
Generally, the terms full agonist and agonist are DOSE-RESPONSE RELATIONSHIP
used interchangeably The dose-response relationship is of two types:
Eg: isoprenaline - mimics the action of endogenous graded and quantal dose-response relationships
ligand epinephrine at beta-adrenoceptors
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1. Graded/Gradual Dose-Response drug under specified conditions. It is a characteristic
Relationship of the drug
A continual change in the effect with changing Effective dose-50 (ED50)/Median effective dose
dosages i.e. the response increases with increase in (MED): It is the dose that produces half (50%) of the
dose and decreases with decrease in dose. Most maximal response
drug responses fall in this category
2. Quantal / All-or-None Dose-Response
Relationship
Involving an all-or- none response i.e. on increasing
the dose of a drug, the response is either produced
or not. This type of relationship is seen with certain
responses which cannot be graded e.g. hypnosis,
blood coagulation and death
Quantal / All-or-None Dose-Response
Graded/Gradual Dose-Response Relationship
Relationship
Useful in measuring the incremental responses of
The graph - does not show the intensity of effect, but
drugs e.g. contraction or relaxation of smooth
the frequency with which any dose produces the all-
muscles, change in blood pressure, intensity of
or-none phenomenon
adverse effects,
This is always seen in a population
Presumptions:
the log-dose response curve is sigmoid in character
• The pharmacological effect is a result of the
which has a linear portion between 16 and 84 per
known drug
cent- used to determine the slope of the curve
• There is a molecular or receptor site(s) with which
A small proportion of population at left and right
the drug interacts to produce the response.
sides of the curve respond to low and high doses
• The production and the degree of response are
and constitute hyperreactive (hypersensitive) and
related to the concentration at receptor site
hypo-reactive (hypo-sensitive) groups
• The concentration of drug at receptor site, in turn,
is related to the administered dose.
• The effect of drug is proportional to the fractions
of receptor site occupied by the agent
Graded response versus dose on a simple graph
paper-the dose-response curve - shape of parabola
In case of response versus log- dose, the curve
becomes sigmoid (S-shaped)-it provides more linear
representation and facilitates visual and To make linear, the responses are converted into
mathematical comparisons between dose-response probits (probability units) from statistical table, and
curves log-dose probit response curve is plotted -useful for
From a graded dose-response curve-parameters calculating different lethal/effective doses-
obtained are: extensively used in toxicology for calculation of
Threshold dose: It is the minimal dose that lethal dose-50% (LD50)
produces the desired observable/recordable Lethal dose-50 (LD50) / Median lethal dose
pharmacological response (MLD): It is the dose that is lethal to 50 per cent of
Ceiling dose/Effective dose-100 (EDI00): It is the animals exposed under defined conditions
minimal dose that produces the maximal (100%) The mid-point of the graded or quantal dose
response (Emax) - Beyond that no increase response curve (ED50 or LD50) is usually taken -
Maximal response/Maximal effect (Emax)/Ceiling because it is a convenient description of average
effect: It is the maximal response produced by a response. Further there is least variability at 50%
level of response
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Variables of Dose-Response Curve slope -large proportion of population will be affected
4 characteristic variables: efficacy, potency, slope over a small range of doses
and variance Steeper curve also suggests that response of a
Efficacy compound in a population is more uniform and more
Efficacy (Maximal efficacy, Emax) is the maximal predictable
effect or response produced by a drug. Indicated by
the height (maximal response possible for the drug) Variance
of the dose-response curve. Efficacy is independent Variance (variation, biological variation) -
of the slope or position (potency) of dose-response appearance of differences in magnitude of response
curve among individuals in same population given same
Potency dose of a drug.
Potency is a measure of drug activity expressed in A range of effects will be produced by a given dose
terms of the amount or dose required to produce an in a population.
effect of given intensity Alternately, a range of doses is required to produce
Depends on its affinity for the receptor or target site a specified intensity of effect in all individuals.
and efficiency of drug-receptor interaction.
The position of dose-response curve on dose axis is MEASURES OF SAFETY
taken as index of the drug potency and the Therapeutic index
parameter that determines potency is the ED50 or The ratio between the lethal dose-50 (LD50) and the
LD50. -a drug producing the desired effect in a effective dose-50 (ED50)
smaller dose is called more potent Widely used for evaluating the safety and
usefulness of a drug. The higher the therapeutic
index, the safer is the drug
Also gives a rough idea of drug’s selectivity. A high
value indicates that drug is highly selective in its
action

Potency is independent of the efficacy - considered

important for selecting the drug dosage and not the
clinical action
Efficacy of a drug is -more important than its
potency in selecting drugs for a clinical situation
because it determines the intensity or magnitude of
response produced by a drug
In toxicology- extremely potent drugs require special
handling due to their low LD50 values

Slope
The slope of a dose-response curve reflects the
binding of a drug to its receptor and thus the affinity
between the receptor site and the drug. Steep slope
-more binding (affinity) of drug with its receptor -
only slight increase in dose will markedly increase
the response Therapeutic ratio
In a population, the slope indicates the range of Ratio between the lethal dose-25 (LD25) and the
doses over which the population is affected. A steep effective dose-75 (ED75). A better index of safety of
a drug as it includes slope of curve also. Shallow
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dose-response curves usually have low therapeutic drug, - potentiation and the effect - potentiative
ratios effect.
Certain safety factor Eab > Ea + Eb or 1 + 0 > 1
Ratio between the lethal dose-1 (LD1) and the This is seen mainly when one drug having no effect
effective dose-99 (ED99)-more convenient estimate of its own and enhances the concentration of other
of safety than the therapeutic index as the values drug at its site of action either by increasing its
are derived from extremes of the respective dose- absorption or by decreasing its elimination
response curves Probenecid enhances effect of penicillins by
Standardized safety margin: LD1- ED99/ED99 x decreasing their renal excretion
100% Synergism
Protective index: ratio between the toxic dose-50 When the combined effect of two drugs is greater in
(TD50) and the effective dose-50 (ED50) magnitude than sum of the effects of each drug
Risk-benefit ratio given alone, the interaction is called synergism and
term used to indicate a judgement on the estimated the effect - synergistic effect.
harm (e.g. adverse effect, etc.) vs. expected Eab> Ea+EB or 1 + 1 > 2
advantages (e.g. cure, relief of symptoms, etc.) Produced mainly when two drugs used together
DRUG INTERACTIONS have same or similar effects and they increase each
The interactions may occur between two drugs other’s action at the site of action. For example, both
(drug-drug interaction), between drug and food carbon tetrachloride and ethanol are
(drug-food interaction), as well as drug and herbs hepatotoxicants, but together they produce much
(drug-herb interaction) more injury to the liver
Drug interactions -number of mechanisms due to
pharmacokinetics or pharmacodynamics of one or Antagonism
both of the interacting drugs When the combined effect of two drugs is lesser in
Types of Drug Interaction magnitude than sum of the effects of each drug
Depending on the magnitude of pharmacological given alone, or when one drug having no effect of its
response produced by the combination of two drugs own decreases or inhibits the pharmacological effect
(irrespective of mechanisms), drug interactions are of other drug, the interaction is called antagonism
broadly divided into 4 types: addition, and the effect produced is called antagonistic effect.
potentiation, synergism and antagonism (i) EAB<EA+EB or 2+1 <3; (ii)Eab < Ea+Eb or 2 + 0
< 2 (True antagonism)
Addition: The combined effect of two drugs given when a partial agonist is combined with a full agonist
together is equal to sum of the effects of each drug (i) or when an antagonist and an agonist are
given alone (effect produced is called additive effect) combined together (ii, true antagonism).
Eab =EA+EB or 1 + 1 =2 Antagonism (Greek word antagonisma, from anti =
The additive effect is produced mainly when two against, nizomai = to fight)
drugs administered together have same/similar Types of antagonism
mechanism of action and /their effects are additive. Broadly of four types: chemical, functional,
For example, combination of two organophosphorus dispositional and receptor-mediated antagonisms
insecticides produces additive cholinesterase Chemical antagonism
inhibition and combination of two or more Chemical antagonism (inactivation antagonism)
sulphonamides (sulphadiazine + sulphamerazine + occurs when two or more drugs react chemically
sulphamethazine) produces additive antibacterial and form an inactive product
effect. Two agents have opposite chemical properties,
Potentiation which neutralize each other i.e. acid and base,
When one drug having no effect of its own, but cations and anions. For examples, sodium
increases the pharmacological effect of another bicarbonate neutralises acidic compounds and

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protamine (basic and cationic drug) neutralises
anticoagulant effect of heparin

Functional antagonism
Functional antagonism (Physiological antagonism)
occurs when two drugs counterbalance (neutralise)
each other by producing opposite effects on the
same physiological system.
For example, acetylcholine and epinephrine act on
muscarinic and adrenergic receptors on heart -
bradycardia and tachycardia, respectively
Effects of insulin and glucagon on blood sugar

Non-competitive antagonism: In non-competitive

Dispositional antagonism
(irreversible, un-surmountable) antagonism, the
Dispositional antagonism (pharmacokinetic
antagonist forms strong bonds (e.g. covalent bond)
antagonism) occurs when the disposition or
with its receptor and irreversibly blocks it.
pharmacokinetics (i.e. absorption, distribution,
Antagonist cannot be displaced by the agonist, even
metabolism and excretion) of a drug is altered so
at high concentrations The
that concentration and/or duration of the drug at the
Non-competitive antagonists generally bind to a
target site is diminished. Dispositional antagonism is
distinctly separate binding site (allosteric site) from
very common in therapeutics
the agonist, and may prevent conformational
changes in the receptor required for receptor
Receptor antagonism
activation
Receptor antagonism (Pharmacological antagonism)
The agonist can now act only on reserve receptors
-when two drugs act on the same receptor to
or receptor sites not influenced by the antagonist
produce less of an effect. Agonist increases the
effect and antagonist decreases or abolishes it
Receptor antagonism is of two subtypes:
competitive and noncompetitive antagonisms.

Competitive antagonism: In competitive

(reversible, surmountable) antagonism, the
antagonist and agonist compete with each other for
the occupancy of same binding site (active site) on
the receptor.
The interaction is due to formation of weak bonds,
so the effects of one drug can be easily overcome
by increasing the concentration of second drug.
Both agonist and antagonist have affinity for the
same receptor
In dose-response relationship, the competitive
antagonist causes a parallel shift of the log dose-
response curve to the right, but there is no change
in its shape, slope or maximal response

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