Drug efficacy and safety

• To achieve an effect, a drug must reach a critical concentration in the plasma (minimum effective concentration - MEC), but ideally be well below that causing significant unwanted effects (maximum tolerated concentration)

• ‘Safe’ drugs (high ratio) include penicillins and benzodiazepines
• ‘Unsafe’ drugs (low ratio) include cardiac glycosides and warfarin

The quantal dose response relationship

• Plots the fraction of the population that responds to a given dose of drug against the drug dose
• Response differs between individuals and occurs across a range of drug doses
• Response is quantal i.e. present or not present (not graded or scalar)
• Generalises the effect of a drug to a population, rather than the graded effect of different drug doses upon an individual
• Doses of drug that produce such responses in 50% of the population are, for example, the median effective dose (ED50), median toxic dose (TD50) and medial lethal dose (LD50)

Drug interactions

• Several drugs are often supplied simultaneously to patients (particularly the elderly) which can result in drug interactions where one drug modifies the response to the co-administered drug
• Adverse drug interactions can involve pharmacodyanamic, or pharmacokinetic, mechanisms - drugs with steep dose-response curves and serious dose-related toxicities are especially likely to be involved
  • Pharmacodynamic - drug A modifies the pharmacological effect of drug B without altering its concentration in tissue fluid
    • Usually predictable from a knowledge of the pharmacology of the interacting drugs
  • Pharmacokinetic - drug A modifies the concentration of drug B that reaches its site of action
    • Not easily predicted
    • Can involve changes in:
      • Absorption - may increase/decrease rate of emptying of stomach, enterohepatic recirculation of oral contraceptives may be reduced by antibiotics causing failure of contraception
      • Distribution - drugs bound to plasma protein may be displaced by a second drug increasing their concentration, generally of little importance as Cp drives the rate of elimination, which will increase
      • Metabolism - induction of hepatic enzymes by drug can decrease the efficacy of other drugs metabolised by the same enxyme, conversely enzyme inhibitors may potentiate the effect of other drugs metabolised by the same enzyme
      • Excretion - drugs may change a common transporter

Variability in drug response

Why does variability occur?

• Cp higher than desired - excessive dosage and/or decreased Cl
  • Normal variation
  • Saturable metabolism
  • Genetic enzyme deficiency
  • Renal failure
  • Liver failure
  • Old age
  • Very young age
  • Enzyme inhibition
    • Competitive: higher Km, same Vmax
    • Non-competitive: same Km, lower Vmax
• Cp lower than desired - dose too low, or increased Cl
  • Normal variation
  • Poor absorption
  • High first pass metabolism
  • Genetic hypermetabolism
  • Enzyme induction
    • Same Km, higher Vmax
  • Non-compliance

Drugs and liver disease