Pharmacodynamics and Receptor Interactions

Pharmacodynamics

• The effects of drugs on biologic systems are studied in pharmacodynamics.
• Drugs often interact with macromolecules within the organism, leading to biochemical and physiological changes.
• Drug-receptor interactions are central to drug actions, and the response is proportional to the number of drug-receptor complexes formed.

Receptors and Ligands

• Receptors are specific molecules that drugs interact with to alter biological system function.
• Receptors must be selective for specific drugs and modifiable by drug binding.
• Agonists are drugs that bind to receptors and mimic endogenous regulatory effects.
• Antagonists block the effects of agonists without producing any regulatory effect of their own.
• Partial agonists are less effective than full agonists at any dose.

Receptor Families

• Ligand-gated ion channels regulate ion flow across plasma membranes.
  • Examples of natural ligands include acetylcholine, serotonin, GABA and glutamate.
  • These receptors alter membrane potential by altering ion conductance.
  • The response is very rapid.
• G Protein-Coupled Receptors (GPCRs): Initiate intracellular signaling through second messenger pathways.
  • Extracellular ligands bind to a cell-surface receptor.
  • The receptor activates a G protein on the inner face of the membrane.
  • The activated G protein alters the activity of an effector element, usually an enzyme or ion channel.
  • Examples of second messengers include adenylyl cyclase and phospholipase C.
• Enzyme-Linked Receptors: Ligand binding to an extracellular domain activates or inhibits intracellular enzyme activity.
• Intracellular Receptors: Receptors are entirely located within the cell.

Graded Dose-Response Relationship

• As drug concentration increases, the magnitude of its pharmacological effect also increases.
• The relationship between dose and response is continuous.
• The graded dose-response curve plots the response against increasing drug concentration or dose.
• The curve is typically sigmoidal when plotted on a semi-logarithmic concentration axis.
• Efficacy (Emax) represents the maximum effect an agonist can produce.
• Potency (EC50 or ED50) is the concentration or dose required to produce 50% of the drug's maximal effect.
  • Potency is influenced by the affinity of receptors for the drug (Kd).

Graded Dose-Binding Relationship and Binding Affinity

• The relationship between drug concentration and the fraction of receptors bound can be plotted similarly to a dose-response curve.
• Kd is the concentration required to bind 50% of the receptor sites.
• Kd measures the affinity of a drug molecule for its binding site on the receptor.
  • Lower Kd indicates higher affinity.

Quantal Dose-Response Relationships

• These curves plot the fraction of a population exhibiting a specific response at progressively increasing doses.

Inert Binding Sites

• These are components of endogenous molecules that bind drugs without triggering any effects.
• Inert binding sites buffer drug concentrations by reducing the free drug available.
• Most important plasma proteins for drug binding are albumin and orosomucoid.

Agonists and Partial Agonists

• Full agonists fully activate the effector system when bound to the receptor.
• Partial agonists produce less than the full effect even when saturating the receptors.
  • They have lower intrinsic activity than full agonists.

Antagonists

• Competitive Antagonists: Bind reversibly to the receptor site, preventing agonist binding without activating the effector system.
  • Shift the dose-response curve to higher doses but don't alter the maximum effect.
• Irreversible Antagonists: Bind irreversibly to the receptor, causing a downward shift in the maximum effect and a potential shift in the dose axis if spare receptors are present.
  • Effects cannot be overcome by increasing agonist concentration.
• Functional/Physiological Antagonists: Act on different receptors, producing effects opposite to the agonist.
• Chemical Antagonists: Directly interact with a drug, removing it or preventing it from reaching its target.

Therapeutic Index and Therapeutic Window

• Therapeutic Index (TI) is the ratio of the dose causing toxicity (LD50) to the dose producing a desired effect (ED50).
  • TI reflects drug safety.
• Therapeutic Window is the dosage range between the minimum effective dose and the minimum toxic dose.