• Removal of the drug and its metabolite from the body • Main channels - lungs, bile, feces, sweat, saliva, tears, milk
Elimination of Excretion ofthe body drugs from drugs KIDNEY
M A J O R
M I N O R
mother's milk sweat, saliva etc.
Glomerular filtration, passive tubular reabsorption and active tubular secretion Glomerular filtration and active tubular secretion facilitate drug excretion whereas tubular reabsorption decreases drug excretion
Glomerular filtration: • Smaller molecular size - readily filtered • The extent of filtration is directly proportional to the GFR and to the fraction of the unbound drug in plasma
• Glomerular capillaries allow drug molecules of molecular weight below about 20 000 to diffuse into the glomerular filtrate. • Plasma albumin (68 000) is almost completely impermeable • If, like warfarin a drug is approximately 98% bound to albumin, the concentration in the filtrate is only 2% of that in plasma and clearance by filtration is correspondingly reduced.
Passive tubular reabsorption: • The main factor - pH of the renal tubular fluid and the degree of ionization
• filtration free drug only, not protein bound • reabsorption passive, lipid soluble form only (pH) • secretion active, acids and bases, saturable Plasma pH is constant; urine pH varies from 5.0-8.0
• What about weakly acidic drugs (e.g. salicylates, barbiturates)?
• What about weakly basic drugs (e.g. morphine, amphetamine etc.)?
How do you facilitate excretion of these drugs in case of poisoning?
Active tubular secretion: • Is a carrier mediated active transport (Energy?) • Unaffected by changes in the pH of urine and protein binding • Most of the acidic drugs (e.g. Penicillin, diuretics, probenecid, sulfonamides etc.) and basic drugs (e.g. quinine, procaine, morphine etc) are secreted by the renal tubules.
• Up to 20% of renal plasma flow is filtered through the glomerulus, leaving at least 80% of delivered drug to pass on to the peritubular capillaries of the proximal tubule. • Here drug molecules are transferred to the tubular lumen by two independent and relatively non-selective carrier systems.
• Since at least 80% of the drug delivered to the kidney is presented to the carrier, tubular secretion is potentially the most effective mechanism of renal drug elimination. • Unlike glomerular filtration, carriermediated transport can achieve maximal drug clearance even when most of the drug is bound to plasma protein.*
• Penicillin for example, though about 80% protein bound and therefore cleared only slowly by filtration, is almost completely removed by proximal tubular secretion, and its overall rate of elimination is very high.
• Carrier system is relatively nonselective drugs having similar physicochemical properties compete for the same carrier system E.g. probenecid competitively inhibits the tubular secretion of penicillins / cephalosporins – What happens? Treatment of diseases like gonococcal infections
Elimination of drugs by the kidney
• Most drugs, unless highly bound to plasma protein, cross the glomerular filter freely. • Many drugs, especially weak acids and weak bases, are actively secreted into the renal tubule, and thus more rapidly excreted. • Lipid-soluble drugs are passively reabsorbed by diffusion across the tubule so are not efficiently excreted in the urine.
• Because of pH partition, weak acids are more rapidly excreted in alkaline urine, and vice versa. • Several important drugs are removed predominantly by renal excretion and are liable to cause toxicity in elderly persons and patients with renal disease.
• Lungs: Volatile general anaesthetics like ether, halothane, alcohol, enflurane, isoflurane and alcohol are excreted via lungs. • Feces: Drugs which are not completely absorbed from the GI tract are excreted in feces eg. purgatives like senna, cascara.
• Bile: Some drugs are secreted via bile but after reaching the intestine they are reabsorbed and the cycle is repeated such recycling is called enterohepatic circulation and it increases the bioavailability as well as the duration of action of the drug. eg. erythromycin, phenolphthalein etc
Skin: Arsenic, mercury Saliva: • Potassium iodide, phenytoin and metronidazole are excreted in saliva • Some drugs are actively secreted in saliva. e.g.. lithium. This may be used for noninvasive monitoring of lithium therapy.
Milk: • Has acidic pH, hence basic drugs like tetracycline, chloramphenicol, morphine, diazepam, senna etc. are excreted through milk and may affect the suckling infant • Antithyroid drug like thiouracil may interfere with the thyroid function of the suckling infant.