Excretion

Question 1

Excretion vs elimination

Answer 1

Elimination = process of removal of drug from plasma, includes distribution and metabolism
Excretion = removal of drug from body

Question 2

Excretion

Routes

Answer 2

= removal of drug from the body

• Mostly occurs in urine and bile
• Traces of drug in tears and breast milk
• Lungs: volatile anaesthetic agents (although metabolites detectable in urine)

Relative contributions from different routes of excretion depend on structure and molecular weight of drug
* High molecular weight compounts (>30,000 Da) are not filtered or secreted by the kidney: preferentially excreted in the bile. E.g. steroid-based muscle relaxants
* Drugs with permanent charge (e.g. pancuronium) may be excreted unchanged in the urine

Question 3

Renal excretion

Mechanisms at different sites

Answer 3

Glomerulus
* Small, non-protein bound, water soluble (therefore poorly lipid-soluble) drugs are excreted into the glomerular ultrafiltrate
* Note only free drug present in the fraction of plasma that is filtered is removed at the glomerulus. Remaining plasma will have same concentration of free drug as that fraction filtered, so there is no change in the extent of plasma protein binding

Proximal convuluted tubules
* Drugs are secreted via **active energy-requiring processes against their concentration gradient **
* Different carreir systems exist for acidic and basic drugs that are each capcity limited for their respective drug type (maximal clearance of one acidic drug -> reduced clearance of another acidic drug, but not of a basic drug)

Distal tubules
* Passive diffusion down the concentration gradient
* Urinary pH affects excretion: acidic drugs are preferentially excreted in alkaline urine (as increases fraction present in the ionised form, which cannot be reabsorbed). Basic drugs preferentially excreted in acidic urine (trapped as cations)

Question 4

Biliary excretion

Answer 4

Secretion from hepatocyte -> biliary caniculus takes place against a concentration gradient: active and energy-requiring.

High-molecular weight compounds e.g. steroid-based muscle relaxants are excreted in bile

Componds may be excreted
* Unchanged in bile e.g. rifampicin
* After conjugation: e.g. morphine metabolites are excreted as glucuronides

Question 5

Enterohepatic circulation and interaction between broad-spectrum antibiotics and oral contraceptive pill

Answer 5

• Glucuronide conjugates excreted in the bile may be hydrolysed in the small bowel by glucuronidase secreted by bacteria
• -> lipid-soluble, active drugs, which may be reabsorbed into portal circulation -> liver
• Extracted fraction is reconjugated and re-excreted in bile, but rest passes into systemic circulation

Failure of OCP while taking broad-spectrum abx has been blamed on reduced bacterial intestinal flora -> reduced enterohepatic circuilation of oestrogen and progesterone

Question 6

Excretion in renal disease

Effect on drug effect duration

Answer 6

Drugs normally excreted via the renal tract may accumulate

Effect varies according to degree to which drugs is dependent on renal excretion: if clearance entirely renal, single dose may have prolonged effect
* e.g. gallamine (non-depolarising muscle relaxant): if given in context of renal failure, requires dialysis or haemofiltration to reverse the effect

Question 7

Dose adjustment in renal disease

Loading doses, formula

Answer 7

Reduce doses of drugs highly dependent on renal excretion

Loading doses
* If apparent volume of distribution remains the same, loading dose also remains the same, but repeated doses may need to be reduced and dosing interval increased
* Note due to fluid retention, volume of distribution often increased -> loading doses may be higher than in health

Can use creatinine clearance to approximate dose required in renal failure (D):
D = usual dose * (impaired clearance / normal clearance)