Overview of Pharmacodynamics

By Angela Cafiero Moroney, PharmD

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

Pharmacodynamics, sometimes described as what a drug does to the body, involves receptor
binding (including receptor sensitivity), postreceptor effects, and chemical interactions.
Pharmacodynamics,

with

pharmacokinetics

(what

the

body

does

to

drugsee

Pharmacokinetics), helps explain the relationship between the dose and response, ie, the drug's
effects. The pharmacologic response depends on the drug binding to its target. The concentration
of the drug at the receptor site influences the drugs effect.
A drugs pharmacodynamics can be affected by physiologic changes due to disorders, aging, or
other drugs. Disorders that affect pharmacodynamic responses include genetic mutations,
thyrotoxicosis, malnutrition, myasthenia gravis, Parkinson disease, and some forms of insulin resistant diabetes mellitus. These disorders can change receptor binding, alter the level of
binding proteins, or decrease receptor sensitivity. Aging tends to affect pharmacodynamic
responses through alterations in receptor binding or in postreceptor response sensitivity (see
Table: Effect of Aging on Drug Response). Pharmacodynamic drugdrug interactions result in
competition for receptor binding sites or alter postreceptor response.
Last full review/revision July 2013 by Angela Cafiero Moroney, PharmD

DrugReceptor Interactions
By Angela Cafiero Moroney, PharmD

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

Receptors are macromolecules involved in chemical signaling between and within cells; they
may be located on the cell surface membrane or within the cytoplasm (see Some Types of
Physiologic and Drug-Receptor Proteins). Activated receptors directly or indirectly regulate
cellular biochemical processes (eg, ion conductance, protein phosphorylation, DNA
transcription, enzymatic activity). Molecules (eg, drugs, hormones, neurotransmitters) that bind
to a receptor are called ligands. A ligand may activate or inactivate a receptor; activation may
increase or decrease a particular cell function. Each ligand may interact with multiple receptor
subtypes. Few if any drugs are absolutely specific for one receptor or subtype, but most have
relative selectivity. Selectivity is the degree to which a drug acts on a given site relative to other
sites; selectivity relates largely to physicochemical binding of the drug to cellular receptors.
Some Types of Physiologic and Drug-Receptor Proteins

Type

Structure

Cellular Location

Examples
Acetylcholine (nicotinic)

Multisubunit
channels

ion

Cell

surface

transmembrane

GABA A
Glutamate
Glycine

G-proteincoupled

Cell

surface

receptors

transmembrane

Acetylcholine
(muscarinic)

Type

Structure

Cellular Location

Examples
-

and

-adrenergic

receptor proteins
Eicosanoids
Growth factors
Protein kinases

Cell

surface

transmembrane

Insulin
Peptide hormones
Steroid hormones

Transcription factors

Cytoplasm

Thyroid hormone
Vitamin D

GABA =-aminobutyric acid; GDP = guanosine diphosphate; GTP = guanosine triphosphate.

A drugs ability to affect a given receptor is related to the drugs affinity (probability of the drug
occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activitydegree to
which a ligand activates receptors and leads to cellular response). A drugs affinity and activity
are determined by its chemical structure.
The pharmacologic effect is also determined by the duration of time that the drug-receptor
complex persists (residence time). The lifetime of the drug-receptor complex is affected by
dynamic processes (conformation changes) that control the rate of drug association and
dissociation from the target. A longer residence time explains a prolonged pharmacologic effect.
Drugs with long residence times include finasteride and darunavir. A longer residence time can
be a potential disadvantage when it prolongs a drug's toxicity. For some receptors, transient drug
occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes
toxicity.
Physiologic functions (eg, contraction, secretion) are usually regulated by multiple receptormediated mechanisms, and several steps (eg, receptor-coupling, multiple intracellular 2nd

messenger substances) may be interposed between the initial molecular drugreceptor interaction
and ultimate tissue or organ response. Thus, several dissimilar drug molecules can often be used
to produce the same desired response.
Ability to bind to a receptor is influenced by external factors as well as by intracellular
regulatory mechanisms. Baseline receptor density and the efficiency of stimulus-response
mechanisms vary from tissue to tissue. Drugs, aging, genetic mutations, and disorders can
increase (up-regulate) or decrease (down-regulate) the number and binding affinity of receptors.
For example, clonidine down-regulates

-receptors; thus, rapid withdrawal of clonidine can

cause hypertensive crisis. Chronic therapy with -blockers up-regulates -receptor density; thus,
severe hypertension or tachycardia can result from abrupt withdrawal. Receptor up-regulation
and down-regulation affect adaptation to drugs (eg, desensitization, tachyphylaxis, tolerance,
acquired resistance, postwithdrawal supersensitivity).
Ligands bind to precise molecular regions, called recognition sites, on receptor macromolecules.
The binding site for a drug may be the same as or different from that of an endogenous agonist
(hormone or neurotransmitter). Agonists that bind to an adjacent site or a different site on a
receptor are sometimes called allosteric agonists. Nonspecific drug binding also occursie, at
molecular sites not designated as receptors (eg, plasma proteins). Drug binding to such
nonspecific sites, such as binding to serum proteins, prohibits the drug from binding to the
receptor and thus inactivates the drug. Unbound drug is available to bind to receptors and thus
have an effect.

Agonists and antagonists

Agonists activate receptors to produce the desired response. Conventional agonists increase the
proportion of activated receptors. Inverse agonists stabilize the receptor in its inactive
conformation and act similarly to competitive antagonists (see Pharmacodynamics:Agonists and
antagonists). Many hormones, neurotransmitters (eg, acetylcholine, histamine, norepinephrine ),
and drugs (eg, morphine, phenylephrine, isoproterenol) act as agonists.
Antagonists prevent receptor activation. Preventing activation has many effects. Antagonists
increase cellular function if they block the action of a substance that normally decreases cellular

function. Antagonists decrease cellular function if they block the action of a substance that
normally increases cellular function.
Receptor antagonists can be classified as reversible or irreversible. Reversible antagonists readily
dissociate from their receptor; irreversible antagonists form a stable, permanent or nearly
permanent chemical bond with their receptor (eg, by alkylation). Pseudo-irreversible antagonists
slowly dissociate from their receptor.
In competitive antagonism, binding of the antagonist to the receptor prevents binding of the
agonist to the receptor. In noncompetitive antagonism, agonist and antagonist can be bound
simultaneously, but antagonist binding reduces or prevents the action of the agonist. In reversible
competitive antagonism, agonist and antagonist form short-lasting bonds with the receptor, and a
steady state among agonist, antagonist, and receptor is reached. Such antagonism can be
overcome by increasing the concentration of the agonist. For example, naloxone (an opioid
receptor antagonist that is structurally similar to morphine), when given shortly before or after
morphine, blocks morphines effects. However, competitive antagonism by naloxone can be
overcome by giving more morphine.
Structural analogs of agonist molecules frequently have agonist and antagonist properties; such
drugs are called partial (low-efficacy) agonists, or agonist-antagonists. For example, pentazocine
activates opioid receptors but blocks their activation by other opioids. Thus, pentazocine
provides opioid effects but blunts the effects of another opioid if the opioid is given while
pentazocine is still bound. A drug that acts as a partial agonist in one tissue may act as a full
agonist in another.
Last full review/revision July 2013 by Angela Cafiero Moroney, PharmD

Chemical Interactions
By Angela Cafiero Moroney, PharmD

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

Some drugs produce effects without altering cellular function and without binding to a receptor.
For example, most antacids decrease gastric acidity through simple chemical reactions; antacids
are bases that chemically interact with acids to produce neutral salts. The primary action of
cholestyramine, a bile acid sequestrant, is to bind bile acids in the GI tract.
Last full review/revision July 2013 by Angela Cafiero Moroney, PharmD

Dose-Response Relationships
By Angela Cafiero Moroney, PharmD

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

Regardless of how a drug effect occursthrough binding or chemical interactionthe

concentration of the drug at the site of action controls the effect. However, response to
concentration may be complex and is often nonlinear. The relationship between the drug dose,
regardless of route used, and the drug concentration at the cellular level is even more complex
(see Pharmacokinetics).
Dose-response data are typically graphed with the dose or dose function (eg, log

10

dose) on the

x-axis and the measured effect (response) on the y-axis. Because a drug effect is a function of
dose and time, such a graph depicts the dose-response relationship independent of time.
Measured effects are frequently recorded as maxima at time of peak effect or under steady-state
conditions (eg, during continuous IV infusion). Drug effects may be quantified at the level of
molecule, cell, tissue, organ, organ system, or organism.
A hypothetical dose-response curve has features that vary (see see Figure: Hypothetical doseresponse curve.): potency (location of curve along the dose axis), maximal efficacy or ceiling
effect (greatest attainable response), and slope (change in response per unit dose). Biologic
variation (variation in magnitude of response among test subjects in the same population given
the same dose of drug) also occurs. Graphing dose-response curves of drugs studied under
identical conditions can help compare the pharmacologic profiles of the drugs (see see Figure:
Comparison of dose-response curves.). This information helps determine the dose necessary to
achieve the desired effect. Dose-response, which involves the principles of pharmacokinetics and
pharmacodynamics, determines the required dose and frequency as well as the therapeutic index
for a drug in a population. The therapeutic index (ratio of the minimum toxic concentration to the

median effective concentration) helps determine the efficacy and safety of a drug. Increasing the
dose of a drug with a small therapeutic index increases the probability of toxicity or
ineffectiveness of the drug. However, these features differ by population and are affected by
patient-related factors (eg, pregnancy [see Drugs in Pregnancy], age [see Pharmacodynamics in
the Elderly], organ function [eg, estimated GFRsee Renal excretion]).
Hypothetical dose-response curve.

Comparison of dose-response curves.

Drug X has greater biologic activity per dosing equivalent and is thus more potent than drug Y or
Z. Drugs X and Z have equal efficacy, indicated by their maximal attainable response (ceiling
effect). Drug Y is more potent than drug Z, but its maximal efficacy is lower.

Last full review/revision July 2013 by Angela Cafiero Moroney, PharmD