FRCA Notes

Excretion

  • Excretion describes the removal of a drug from the body
  • Sites of excretion include:
    • Biliary excretion via the GI tract
    • Renal excretion via the GU tract
    • The lungs (e.g. volatile agents)

  • Elimination describes the removal of a drug from the plasma
    • It consists of both distribution and metabolism

Filtration

  • Filtration occurs at the glomerulus
  • Low molecular weight, non-protein bound, water-soluble drugs are excreted at the glomerulus in ultrafiltrate
  • Drugs carrying a permanent charge (e.g. pancuronium, vecuronium) may have a large fraction excreted unchanged in the urine
  • Only the free drug present in the filtered fraction of plasma is removed - the remaining plasma has the same free drug concentration

Secretion

  • Tends to occur in the proximal convoluted tubule
  • A variety of molecules are secreted into the PCT against their concentration gradient i.e. active process
  • Different carrier systems exist for basic and acidic drugs
  • Drug secretion may be inhibited e.g. probenecid blocks penicillin

Diffusion

  • Tends to occur in the distal convoluted tubule
  • Passive diffusion down a concentration gradient occurs
  • Acidic drugs are preferentially excreted in alkali urine (as their ionised fraction increases in the urine and the ionised drug cannot be reabsorbed)

Renal disease

  • In renal disease, drugs that are normally renally excreted may accumulate
    • The effect of this depends on how much of a drug's excretion is via the renal route
    • If entirely dependent on renal excretion, a single drug dose may have a prolonged effect
    • E.g. the non-depolarising NMBA gallamine requires dialysis if given in renal failure as it is excreted unchanged by the kidneys
  • If required to give a drug that is renally excreted, a reduced dose ± increased dosing interval should be used, titrated according to creatinine clearance:

    • Reduced dose = usual dose x (impaired CrCl / normal CrCl)


  • High molecular weight compounds are excreted in bile e.g. aminosteroid NMBA
  • Secretion from the hepatocyte into the bile canaliculi is an active process and is subject to inhibition and competition for transporters
  • Drugs may be excreted unchanged (e.g. rifampicin) or after conjugation [Ph II metabolism] (e.g. morphine glucuronides)

Enterohepatic circulation

  • Drugs excreted in bile as glucuronide conjugates may be hydrolysed in the small bowel as glucuronidase is secreted by certain bacteria
  • The resulting lipid-soluble, active drug may be reabsorbed and pass back into systemic circulation via the portal system
  • E.g. the failure of the oral contraceptive pill with antibiotics is due to a reduction in these gut flora, reducing enterohepatic circulation

Hepatic disease

  • Alters many aspects of pharmacokinetics
    • Absorption: portocaval shunts may reduce hepatic blood flow and increase bioavailability
    • Distribution: reduced protein synthesis and binding, ascites may increase volume of distribution
    • Metabolism: reduced effects of both Phase I and Phase II metabolism
  • There is no hepatic surrogate of CrCl and there may be normal synthetic function in the face of markedly abnormal transaminase levels
  • The presence of symptomatic hepatic disease (e.g. encephalopathy, coagulopathy) should raise caution and lead to modified anaesthetic techniques