Pharmacodynamics Overview

Pharmacodynamics

• Clinically useful drugs are formulated for oral, intravenous, or other routes. Formulation choice depends on factors like drug passage barriers and the setting of drug use (e.g., surgery vs. home administration).
• The urgency of the situation often dictates the route of administration.
• Drug stability influences formulation; acid-sensitive drugs are not suitable for oral administration.
• First-pass effect: Drug metabolism in the liver can inactivate a drug before reaching other organs. This reduces the efficacy of orally administered drugs in some cases.
• Four processes in drug therapy: pharmaceutical, pharmacokinetic, pharmacodynamic, and therapeutic.

Pharmaceutical Process

• Ensuring the drug reaches the patient, focusing on the drug's formulation properties (e.g., tablet formulation, crystal size).

Pharmacokinetic Process

• How the drug reaches the site of action through absorption, distribution, and elimination.

Pharmacodynamic Process

• The drug's effect on the body; studying the biochemical, physiological, and molecular effects of drugs. Receptor binding, postreceptor effects, and chemical interactions are key components. Pharmacodynamics relates drug dose to response.

Therapeutic Process

• The translation of the pharmacologic effect into a suitable therapeutic effect.

Drug Receptors

• Receptors: Macromolecular structures for chemical signaling between and within cells (cell surface or cytoplasmic). Ligands (drugs, hormones, neurotransmitters) bind to receptors.
• Receptor binding can be specific and reversible or irreversible. Ligands can activate or inactivate a receptor, influencing cell function.
• Receptor binding site is related to a drug's affinity (probability of receptor occupation) and intrinsic efficacy (degree of receptor activation).
• Receptor binding causes intracellular effects through second messengers and other processes.
• Drug response depends on the density/number of receptors and their affinity.

Drug-Receptor Interactions

• Affinity: strength of binding between drug and receptor. High affinity means less drug is needed; it's also less likely to dissociate from the receptor.
• Dissociation constant (Kd): concentration required for 50% receptor occupation. Lower Kd indicates higher affinity.
• Agonist: Drug that binds to a receptor and triggers a response. Can be strong or weak; strong agonist produces maximal effects even at low receptor occupation. Weak agonists produce an effect only after binding to a larger number of receptors.
• Partial agonist: Drug that produces submaximal effects even when all receptors are occupied.
• Antagonist: Drug that blocks the action of an agonist by binding to the receptor. This can be competitive (agonist and antagonist compete for receptor binding) or non-competitive (antagonist blocks effects despite agonist binding). Irreversible antagonists bind permanently to the receptor.

Drug Responses

• Efficacy: degree to which a drug produces maximal effects. It is unrelated to affinity.
• Potency: Amount of drug needed to produce a particular effect. Lower dose means higher potency.
• Dose-response curves: Used for graphically depicting the effect of varying drug dosages on the body. Log dose (x-axis) and effect % (y-axis) will generate a sigmoidal curve.

Other Terminology

• Efficacy and potency are key concepts when comparing drug effectiveness and dose required.
• Drug action via inhibition of transport processes: example diuretics, calcium channel blockers, and insulin.
• Drug action via enzyme inhibition: examples include cholinesterase, xanthine oxidase, and MAO inhibitors.
• Drug action via other mechanisms: examples include chelating agents, osmotic diuretics, and volatile anesthetics.

Drug-Drug Interactions

• Drugs can interact with each other via several mechanisms
  • altering drug absorption
  • competing for metabolic enzyme sites
  • competing for protein binding sites
  • altering drug excretion.

Therapeutic Index and Safety

• Therapeutic index (TI): Comparing the toxic concentration of a drug to its effective concentration. High TI means wide margin of safety and low risk of toxicity. Low TI means narrow margin requiring greater care in dosing.

Tolerance, Dependence, and Withdrawal

• Tolerance: reduced responsiveness to a drug over time, requiring higher dosages to achieve the original effect.
• Dependence: physical or psychological need for a drug. Psychological dependence involves a desire to continue taking the drug.
• Factors influencing drug response (age, gender, disease, drug interactions).