Drug-Receptor Binding and Dose-Response

Drug-Receptor Binding

• Pharmacodynamics relies on drug-binding dynamics, where sufficient receptor binding leads to cellular effects.
• Cellular responses aggregate to produce clinical responses in organs and patients.
• Drug affinity is notably influenced by changes in the "off" rate (Koff).
• The relationship between free and bound receptors is described by the law of mass action: [L]*[R]*Kon= [LR]Koff, rearranged as [L][R]/[LR]= Kd.
• If Ro is the total receptor number, Ro = [R] + [LR].
• When [L] = Kd, 50% of receptors are bound; when [LR]/Ro = 1, 100% of ligands are bound.

Dose-Response (D-R) Relationships

• D-R relationships are closely related to drug-receptor binding.
• Graded D-R applies to individuals, while quantal D-R applies to populations.
• Graded D-R relationships are scalar.
• Quantal D-R plots show the percentage of a population responding to a drug dose.
• Biological variation causes individuals to respond over a range of doses.
• Responses are defined as present or absent (e.g., sleep/no sleep).

Population-Based Dosing

• Quantal D-R relationships are useful for predicting drug effects in a population.
• Population-based median effective dose (ED50), toxic dose (TD50), and lethal dose (LD50) are key metrics.
• The therapeutic index (TD50/ED50) estimates a drug's relative safety margin.

Agonism

• Agonists bind to a receptor and stabilize it in a specific conformation, often the active one.
• Unbound active receptor (R*) and bound inactive receptor (DR) are generally unstable and transient.
• More potent drugs have a greater affinity (lower Kd) for their receptors.
• More efficacious drugs (larger Emax) usually activate a greater proportion of their receptors.

Full vs. Partial Agonists

• Full agonists elicit maximal responses at a receptor.
• Partial agonists cannot achieve the same maximal response as full agonists, even with increasing concentration.
• Partial agonists can exhibit greater potency than full agonists (e.g., buprenorphine vs. morphine).
• A receptor may have multiple DR configurations with differing activity depending on the agonist bound.

Receptor Antagonists

• Receptor antagonists:
  • Bind to the active site,
  • Have affinity for the receptor,
  • Inhibit agonist action by preventing binding,
  • And have no effect without the agonist.
• Antagonists can bind reversibly or irreversibly.

Competitive Receptor Antagonists

• Competitive antagonists bind reversibly to the receptor active site.
• Antagonist binding does not stabilize the active receptor conformation.
• Antagonists increase the Kd for the agonist, decreasing agonist potency.
• Antagonists do not affect receptor efficacy, as higher agonist concentrations can overcome the antagonist.
• The ED50 shifts rightward with the antagonist.

Noncompetitive Receptor Antagonists

• Noncompetitive antagonists bind to the active site, sometimes irreversibly (e.g., acetylsalicylic acid).
• Irreversible binding cannot be "washed out" or outcompeted by the agonist.
• Noncompetitive antagonists reduce maximal efficacy (Emax).
• In some systems, they can also decrease potency, shifting ED50 rightward.

Non-Receptor Antagonists

• Chemical antagonists inactivate the agonist by modification or sequestration (e.g., protamine inactivates heparin).
• Physiological antagonists bind to different receptors, producing opposite effects (e.g., drugs affecting blood pressure).

Allosteric Modulators

• Allosteric modulators indirectly influence agonist effects by binding to sites distinct from the agonist.
• Binding to an allosteric site:
  • Alters the Kd for agonist binding or
  • Alters the conformational change needed for activation.
• Positive allosteric modulators enhance agonist effects (e.g., benzodiazepines enhance GABAa receptor activity).
• Negative allosteric modulators act similarly to noncompetitive antagonists.

Spare Receptors

• Maximal agonist effects can be achieved with less than 100% receptor occupancy.
• The dose-receptor curve shows that the EC50 value is less than the Kd value.
• Receptors remain active after the agonist departs, allowing one molecule to activate many receptors and receptor signal pathway amplification allows this.

Explore drug-receptor binding dynamics and dose-response relationships. Understand the impact of drug affinity, receptor occupancy, and the law of mass action. Learn about graded and quantal dose-response curves and how biological variation affects drug response in populations.