Pharmacodynamics relates to drugs binding to receptors and their effects.
Agonist: A drug is called an agonist when binding to the receptor results in a response.
Antagonist: A drug is called an antagonist when binding to the receptor is not associated
with a response. The drug has an effect only by preventing an agonist from binding to
• Affinity: ability of drug to bind to receptor, shown by the proximity of the curve to
the y axis (if the curves are parallel); the nearer the y axis, the greater the affinity
Potency: shows relative doses of two or more agonists to produce the same magnitude of
effect, again shown by the proximity of the respective curves to the y axis (if the curves do
Efficacy: a measure of how well a drug produces a response (effectiveness), shown by
the maximal height reached by the curve
It may be seen from the log dose-response curves in Figure 1-2-1 that:
1. When two drugs interact with the same receptor (same pharmacologic mechanism), the D-R
curves will have parallel slopes. Drugs A and B have the same mechanism; drugs X and Y do
2. Affinity can be compared only when two drugs bind to the same receptor. Drug A has a
greater affinity than drug B.
3. In terms of potency, drug A has greater potency than drug B, and X is more potent than Y.
4. In terms of efficacy, drugs A and B are equivalent. Drug X has greater efficacy than drug Y.
These include receptors for steroids. Binding of hormones or drugs to such receptors
releases regulatory proteins that permit activation and in some cases dimerization of
the hormone-receptor complex. Such complexes translocate to the nucleus, where they
interact with response elements in spacer DNA. This interaction leads to changes in
gene expression. For example, drugs interacting with glucocorticoid receptors lead to
gene expression of proteins that inhibit the production of inflammatory mediators.
Other examples include intracellular receptors for thyroid hormones, gonadal steroids,
and vitamin D.
Pharmacologic responses elicited via modification of gene expression are usually slow-
er in onset but longer in duration than many other drugs.
Membrane Receptors Directly Coupled to Ion Channels
Many drugs act by mimicking or antagonizing the actions of endogenous ligands that
regulate flow of ions through excitable membranes via their activation of receptors
that are directly coupled (no second messengers) to ion channels.
For example, the nicotinic receptor for ACh (present in autonomic nervous system
[ANS] ganglia, the skeletal myoneural junction, and the central nervous system
[CNS]) is coupled to a Na+/K+ ion channel. The receptor is a target for many drugs,
including nicotine, choline esters, ganglion blockers, and skeletal muscle relaxants.
Similarly, the GABAA
receptor in the CNS, which is coupled to a chloride ion channel,
can be modulated by anticonvulsants, benzodiazepines, and barbiturates.
Receptors Linked Via Coupling Proteins to Intracellular Effectors
Many receptor systems are coupled via GTP-binding proteins (G-proteins) to adenylyl
cyclase, the enzyme that converts ATP to cAMP, a second messenger that promotes
protein phosphorylation by activating protein kinase A. These receptors are typically
“serpentine,” with seven transmembrane spanning domains, the third of which is
coupled to the G-protein effector mechanism.
Protein kinase A serves to phosphorylate a set of tissue-specific substrate enzymes or
transcription factors (CREB), thereby affecting their activity.
Cyclic GMP and Nitric Oxide Signaling
• cGMP is a second messenger in vascular smooth muscle that facilitates dephosphory-
lation of myosin light chains, preventing their interaction with actin and thus causing
Nitric oxide (NO) is synthesized in endothelial cells and diffuses into smooth muscle.
NO activates guanylyl cyclase, thus increasing cGMP in smooth muscle.
Vasodilators t synthesis of NO by endothelial cells.
Receptors That Function as Enzymes or Transporters
There are multiple examples of drug action that depend on enzyme inhibition,
including inhibitors of acetylcholinesterase, angiotensin-converting enzyme, aspar-
tate protease, carbonic anhydrase, cyclooxygenases, dihydrofolate reductase, DNA/
RNA polymerases, monoamine oxidases, Na/K-ATPase, neuraminidase, and reverse
Examples of drug action on transporter systems include the inhibitors of reuptake of
several neurotransmitters, including dopamine, GABA, norepinephrine, and serotonin.
Receptors That Function as Transmembrane Enzymes
These receptors mediate the first steps in signaling by insulin and growth factors,
including epidermal growth factor (EGF) and platelet-derived growth factor (PDGF).
They are membrane-spanning macromolecules with recognition sites for the binding
of insulin and growth factors located externally and a cytoplasmic domain that usually
functions as a tyrosine kinase. Binding of the ligand causes conformational changes
(e.g., dimerization) so that the tyrosine kinase domains become activated, ultimately
leading to phosphorylation of tissue-specific substrate proteins.
Guanyl cyclase-associated receptors: stimulation of receptors to atrial natriuretic peptide
activates the guanyl cyclase and t cyclic GMP (cGMP)
Receptors for Cytokines
These include the receptors for erythropoietin, somatotropin, and interferons.
Their receptors are membrane spanning and on activation can activate a distinctive set
of cytoplasmic tyrosine kinases (Janus kinases [JAKs]).
JAKsphosphorylate signal transducers and activators of transcription (STAT)molecules.
STATsdimerize and then dissociate, cross the nuclear membrane, and modulate gene