Drug Receptors and Pharmacodynamics

Question 1

1. Describe the drug-receptor concept and its consequences for pharmacotherapy.

Answer 1

• Receptor is specific to certain drugs and the fit induces conformational change and then transduction of a signal.
• Receptors mediate the actions of pharmacologic agonists and antagonists.
• Agonists bind the receptor and function as endogenous ligands.
• Antagonists may or may not bind receptor, but do not cause the characteristic response, blocking biologic action.
• Antagonist needs the presence of the agonist to work (function depends on ‘normal tone’ of the agonist).
• Receptors are also responsible for the selectivity of drug action (based on size, shape and charge of a drug to determine binding affinity).
• This increases the benefit: risk ratio.
• Specificity and proper fit required to elicit a response.
• DR binding allows quantitation of relation between drug dose/Co and pharmacological effects via dose-response curves.

Question 2

2. Explain the theoretical aspects and therapeutic consequences of the hyperbolic shape of the dose-response curve.

Answer 2

• Helps quantify the relationship between dose and effect, and is based on potency (EC50) of dose and therapeutic efficacy (Emax).
• Binding is reversible, interaction follows mass action relationships, and the RD complex is proportional to response.
• Dose vs. response curve is a hyperbola.
• If you increase dose, you increase effect until it eventually levels off.
• The curve starts linear at low doses, and response increases proportionally, but then the curve levels off, signifying that there’s a limit to the increase in response (eventually all the receptors are occupied is what it means).

Question 3

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

Answer 3

-The log dose vs. response sigmoid curve allows a wide range of doses to be plotted, and the line is still linear in the therapeutic range. (true)

Question 4

4. Explain the terminology of log dose-response curves and their use to compare potency and efficacy of different drugs, including: potency (affinity/Kd/EC50), efficacy (power/Emax), and agonist - partial agonist - antagonist.

Answer 4

• Potency: affinity / Kd / EC50 – is the concentration/dose required to produce 50% of one drug’s individual Emax (50% of the receptors are occupied).
• Depends on the affinity of the receptor for the drug (Kd) and the efficiency of the DR complex to produce a response.
• Potency determines dose needed to elicit effect (more potent = less needed).
• The lower the EC50 value, the higher the potency.

-Efficacy: power / Emax – Emax = maximal effect (power) –> reflects limit of dose-response relationship and indicates the ability of the DR complex to initiate a response. MOST IMPORTANT determinant of clinical utility (would rather have something more efficacious than potent).
-Higher on the y-axis = more efficient.
Agonist - Partial agonist – Antagonist –> Agonists act as endogenous ligand and promote the biological response.
-Full agonists occupy the receptor and produce full/maximal response (what most agonist drugs are). -Partial agonists occupy the same receptor as full agonist, but produces less than maximum response = less effective.

Question 5

5. Distinguish between characteristics of the different types of antagonism (pharmacological [competitive reversible and noncompetitive irreversible], physiological, chemical) and provide examples.

Answer 5

-Pharmacologic antagonists bind the same receptor as the agonist.
-They can be competitive, reversible, or noncompetitive irreversible.
-Competitive reversible binds active site and reduces affinity for agonist.
-EC50 increases and potency decreases (curve shifts right).
-Emax is unchanged, and can technically increase agonist concentration to outcompete antagonist.
This is surmountable because Emax is unchanged. (Ex: metoprolol blocks NOR from binding beta receptor and treats HTN).
-non-competitive irreversible binds to active or allosteric site irreversibly (or pseudo-irreversibly with high affinity-slow dissociation).
-Curve shifts downward and the Emax of the agonist is reduced (minimal effect on potency).
-Insurmountable because the receptor is ‘removed’ or unable to respond to the agonist.

• Non-receptor antagonists don’t bind the same receptor as the agonist (or a receptor at all) and can be physiological or chemical.
• physiologic antagonist blocks a different receptor that still mediates a physiologic response opposite that of the agonist (ex: epinephrine counters histamine but binds a different receptor).
• chemical antagonists don’t bind the receptor, but rather acts on the agonist (modifies or sequesters it) so it can’t act with its own receptor (ex: protamine and heparin).