Introduction to Clinical Pharmacology

A Study Guide for NATS2008

Introduction & Definitions

What is Pharmacology?

Pharmacology is the study of the properties of drugs and their interactions with living systems. It encompasses:

  • Clinical Pharmacology: The study of drugs in humans.
  • Pharmacotherapeutics: The use of drugs to diagnose, prevent, or treat disease or to prevent pregnancy.
  • Toxicology: The study of the adverse effects of chemicals on living organisms.

Key Terms:

  • Drug: Any chemical that affects living processes.
  • Medicine: A drug that is used to treat, cure, prevent, or diagnose a disease or to promote well-being.
  • Generic Name: The official, non-proprietary name of a drug (e.g., Paracetamol).
  • Trade (Brand) Name: The proprietary name given by a manufacturer (e.g., Panadol).

Pharmacokinetics: What the Body Does to the Drug

Pharmacokinetics describes the movement of drugs through the body. It consists of four main processes: Absorption, Distribution, Metabolism, and Excretion (ADME).

1. Absorption

The movement of a drug from its site of administration into the bloodstream. The rate and extent of absorption determine how soon effects will begin and how intense they will be.

  • Factors Affecting Absorption: Route of administration (IV, oral, IM, SC, etc.), drug formulation, blood flow to the administration site, lipid solubility, and pH.
  • Bioavailability: The fraction of the administered dose that reaches the systemic circulation unchanged. IV drugs have 100% bioavailability.

2. Distribution

The transport of a drug in body fluids from the bloodstream to various tissues and organs.

  • Factors Affecting Distribution: Blood flow to tissues, ability of the drug to exit the vascular system (capillary permeability), and ability of the drug to enter cells.
  • Protein Binding: Many drugs bind reversibly to plasma proteins (mainly albumin). Only unbound (free) drug can leave the bloodstream to exert an effect.
  • Blood-Brain Barrier (BBB): Tight junctions between capillary cells in the CNS that prevent many drugs from entering the brain. Only lipid-soluble drugs or those with specific transport systems can cross.

3. Metabolism (Biotransformation)

The chemical alteration of a drug structure, primarily occurring in the liver.

  • Hepatic Enzymes: Most drug metabolism is performed by the Cytochrome P450 (CYP450) system.
  • First-Pass Effect: Drugs absorbed from the GI tract are carried directly to the liver via the hepatic portal vein before entering systemic circulation. A significant amount of some drugs can be metabolized during this "first pass," greatly reducing bioavailability.
  • Outcomes of Metabolism: Accelerated renal excretion, drug inactivation, increased therapeutic action, activation of prodrugs, or increased/decreased toxicity.

4. Excretion

The removal of drugs from the body. The primary organ of excretion is the kidney. Other routes include bile, lungs, sweat, and breast milk.

  • Renal Excretion: Involves glomerular filtration, passive tubular reabsorption, and active tubular secretion.
  • Half-Life (t½): The time required for the amount of drug in the body to decrease by 50%. It determines the dosing interval. It typically takes about 4-5 half-lives to reach a steady state or to eliminate a drug from the body.

Pharmacodynamics: What the Drug Does to the Body

Mechanism of Action

Most drugs work by interacting with specific target molecules in the body, usually receptors.

  • Receptors: Macromolecules (usually proteins) on or in cells that endogenous signaling molecules (like hormones or neurotransmitters) bind to in order to produce an effect. Drugs can mimic or block these molecules.
  • Agonist: A drug that binds to a receptor and activates it to produce a biological response. It mimics the body's own regulatory molecules.
  • Antagonist: A drug that binds to a receptor but does NOT activate it. instead, it blocks the receptor and prevents endogenous agonists from binding.
  • Partial Agonist: A drug that binds to a receptor but produces a weaker response than a full agonist.

Dose-Response Relationships

The relationship between the size of an administered dose and the intensity of the response produced.

  • Therapeutic Index (TI): A measure of a drug's safety. It is the ratio of the drug's lethal dose (LD50) to its effective dose (ED50). A larger (or wider) TI indicates a safer drug.
  • ED50 (Effective Dose 50%): The dose required to produce a defined therapeutic response in 50% of the population.
  • LD50 (Lethal Dose 50%): The dose that is lethal to 50% of animals treated (used in preclinical testing).

Drug Development and Regulation

Stages of Drug Development

Bringing a new drug to market is a long, expensive, and risky process, often taking 10-15 years.

  1. Preclinical Testing (in animals): Evaluates toxicity, pharmacokinetics, and potential useful biologic effects. Takes 1-5 years.
  2. Clinical Testing (in humans):
    • Phase I: Testing in healthy volunteers to determine safety and pharmacokinetics.
    • Phase II: Testing in patients with the target disease to determine therapeutic efficacy and dose range.
    • Phase III: Large-scale clinical trials to confirm safety and efficacy in a larger patient population.
    • Phase IV: Post-marketing surveillance to monitor for long-term or rare adverse effects after the drug is released for general use.

Regulation in Australia

In Australia, the Therapeutic Goods Administration (TGA) is the regulatory body responsible for ensuring that therapeutic goods available for supply are safe and fit for their intended purpose.

Other relevant legislation includes:

  • Commonwealth: Therapeutic Goods Act 1989, National Health Act 1953.
  • State (e.g., NSW): Poisons and Therapeutic Goods Act 1966.