Drug Receptors and Pharmacodynamics

Question 1

Describe the drug-receptor concept

Answer 1

Drug–> recognition and binding to receptor–> Signal transduction via G proteins or other effectors–> Amplification (e.g. transport of ions/molecules; transcription factors, enzyme activation/deactivation; protein synthesis; release of neuroactive agents)–> Physiological effect.

Question 2

Consequences of drug receptor theory

Answer 2

Receptors mediate the actions of pharmacologic agonists and antagonists.

• Agonists bind to and regulate the function of receptor macromolecules in the same manner as the natural endogenous ligands, promoting receptor function.
• Pharmacologic antagonists bind to receptors but are unable to generate the characteristic response. This prevents the binding of endogenous agonist molecules to the receptor and blocking their biologic actions.

Receptors are responsible for selectivity of drug action.
- Changes in the chemical structure of a drug will significantly alter affinity for different classes of receptors with consequent alterations in its therapeutic and toxic effects.

Question 3

Describe the advantages of the log dose-response curve versus the dose-response curve.

Answer 3

The log dose-response curve plots a wider range of doses, allowing for an easier comparison of drugs. It also plots a straight line of the therapeutic range of doses.

Question 4

Potency

Answer 4

EC50/ED50 required to produce 50% of that individual drug’s Emax.

Potency depends on: Affinity (Kd) of receptors for binding the drug, and efficiency of drug-receptor complex to generate response.

Potency determines the dose required to produce a given effect.

• More potent a drug, less needed for any given effect.
• EC50 values compare potencies.

Question 5

Efficacy

Answer 5

Power/Emax reflects the limit of the dose-response relationship on the response axis (y); indicates relationship between receptor binding and ability to initiate response at molecular, cellular, tissue or system level.

Efficacy is the most important determinant of clinical utility.

Question 6

Full Agonist/Antagonist/Partial Agonist

Answer 6

Full agonist: Occupy receptor and produce full or maximal response

Partial agonist: Occupy same receptor as agonist, but produce less than maximal response

Antagonists: Binds to same receptor as agonist, does not elicit response

Question 7

Types of antagonism

Answer 7

Pharmacological antagonists:
Competitive reversible: Binds at active site, does not elicit response, prevents agonist response, allows block to be overcome by increasing agonist concentration.

Noncompetitive irreversible: can bind to active site or allosteric site, reduces Emax

Physiological antagonist: activates or blocks a distinct receptor that mediates a physiologic response opposite to agonist

Chemical antagonist: Does not involve receptor binding, antagonist acts to render agonist unable to interact with its receptor via modification or sequestrations of agonist