Pharmacodynamics Overview

Pharmacodynamics

• Drugs interact with specific receptors on cells.
• Receptors are biological molecules (proteins).
• Drug binding to receptors produces measurable responses, affecting biochemical and biophysical cell activity, and impacting organ function.
• Drugs act as signals; receptors act as signal detectors.

Major Receptor Types

• Ligand-gated ion channels:
  • Include calcium, sodium, and chloride channels.
  • Example: GABA reacting with chloride channels causing chloride influx into nerve cells (GABA is an inhibitory neurotransmitter).
• G protein-coupled receptors and second messengers:
  • Drugs activate G proteins, leading to intracellular enzyme activation (e.g., adenylyl cyclase)
  • This activates second messengers (e.g., cAMP), triggering protein phosphorylation and amplifying intracellular responses.

Enzyme-linked receptors

• Example: Receptors linked to tyrosine kinase (intracellular enzyme) which can be stimulated by insulin.

Intracellular receptors

• Example: DNA and RNA receptors interact with steroid hormones to produce proteins; the drug needs to be lipid-soluble to reach them.

Dose-Response Relationships

• Drug effect depends on receptor sensitivity and drug concentration at the receptor site.
• Concentration is determined by administered dose and pharmacokinetic factors (absorption, distribution, metabolism, and elimination).
• As drug concentration increases, the pharmacological effect also increases until all receptors are occupied (maximum effect).

Potency

• Potency is the amount of drug needed to produce an effect.
• EC50 (concentration producing 50% maximum effect) is used to determine potency.
• Example: Candesartan (32 mg) is more potent than irbesartan (300 mg) due to lower EC50 value.

Efficacy

• Efficacy is the magnitude of the response caused by a drug-receptor interaction.
• It depends on the number of drug-receptor complexes formed and the intrinsic activity of the drug (its ability to activate the receptor).
• Maximum efficacy (Emax) is the maximal response the drug can elicit.

Agonists

• Full agonists: Bind to a receptor and produce a maximal biological response that mimics the endogenous ligand (e.g., hormone or neurotransmitter).
• Partial agonists: Produce a submaximal response even with all receptors occupied, and cannot produce the same maximal effect as a full agonist.
• Inverse agonists: Produce effects opposite to those of agonists.

Antagonists

• Competitive antagonists: Bind to the same receptor site as the agonist, and can be overcome by increasing agonist concentration.
• Irreversible antagonists: Permanently bind to the receptor, and additional agonist cannot overcome the effect.
• Allosteric antagonists: Bind to a different site (allosteric site) on the receptor, preventing receptor activation.
• Functional antagonists: Act at a separate receptor to produce effects opposite to those of the agonist.

Desensitization and Down-regulation

• Desensitization: Prolonged agonist stimulation reduces receptor responsiveness.
• Down-regulation: Decreases the number of receptors on the cell surface.
• Up-regulation: Repeated exposure to an antagonist may increase the number of receptors, increasing sensitivity to agonists.

Therapeutic Index (TI)

• TI = TD50/ED50 (Toxic dose in 50% of test population/Effective dose in 50% of test population)
• Indicator of drug safety. A higher TI indicates greater safety.