Medical Science In The Clinical Context (How Drugs Work)

28.9.05

"Pharmacodynamics" - how drugs work.
"Pharmacokinetics" - how drugs get about and where they go.

Therapeutics:
• Concept of benefit versus risk.
• The disease
-Causation.
-Natural history and prognosis.
-The aims of treatment.
• The evidence base for 'therapeutic strategy' (which drug do I choose first?)
• How to monitor progress.

What is a drug?
• Any molecule used to alter a disease process.
-Smallest = ions.
-Largest = polypeptides.
• All drugs are also poisons - it's just a matter of dose - also idiosyncratically eg. allergy.

Where do drugs come from?
• Origins:
-synthetic
-biological
-semisynthetic.
• Discovery:
-serendipity
-systematic search of vast numbers of molecules
-by design (human/pathogen genomes will help)

• How do drugs work?
Receptors 1
• Regulatory molecules for endogeneous ligands.
• Proteins or glycoproteins.
• Drug-receptor bonds are usually reversible.
• Activation [leads to] structural alteration.
• Activation changes cellular activity [leads to] response.
• Speed of response varies from milliseconds to hours.
• Receptor numbers may increase or decrease.

Receptors 2
• Transmembrane ion channels eg. Na+, lignocaine.
• Transmembrane protein linked to G-protein eg. adrenaline, salbutamol.
• Transmembrane pro-enzymes eg. insulin.
• Intracellular receptor eg. steroids.

Other macromolecule targets
• Enzymes: competition for active site eg. methotrexate (cancer therapy) inhibits enzyme of folate pathway.
• Membrane-bound ion pumps.
• Transport proteins.
• Structural proteins.
• Ribosomes.

Physiochemical activity
• pH: antacids.
• Osmolality: mannitol.
• Resins: cholestyramine.

Stimulates receptor = agonist.
• Agonists
-bind to a receptor and stimulate it
-full agonists
-partial agonists.
• Antagonists
-bind to a receptor without stimulating it
-competitive antagonists: can be overcome by increasing agonist concentration
-non-competitive antagonists: cannot be overcome.

Therapeutic window
• Terms 'therapeutic' and 'toxic' are arbitrary - are simply two ends of a continuity.
• Inter-subject variability in:
-dose needed for benefit
-dose needed for harm.
• Drugs differ in 'gap' between benefit and harm