Drug Excretion PDF

Drug excretion B Y R I D A J A M I L Biliary excretion and enterohepatic circulation Liver cells utilize transport systems like those in the renal tubule, including OCTs, OATs, P-gps to transfer substances, including drugs from the plasma to the bile Hydrophilic drug conjugates partic...

Drug excretion B Y R I D A J A M I L Biliary excretion and enterohepatic circulation Liver cells utilize transport systems like those in the renal tubule, including OCTs, OATs, P-gps to transfer substances, including drugs from the plasma to the bile Hydrophilic drug conjugates particularly glucuronides, are concentrated in the bile and delivered to the intestine In the intestine, glucuronides can be hydrolysed, regenerating active drug, which can then be reabsorbed, leading to enterohepatic circulation Enterohepatic circulation creates a reservoir of recirculation drug, prolonging drug action and accounting for about 20% of total drug in the body Examples: morphine and ethinylestradiol Some drugs are excreted to a significant extent in the bile, such as, vecuronium, which is mainly excreted unchanged in the bile Rifampicin, absorbed from the gut, is slowly deacetylated and secreted in the bile. The deacetylated form is not reabsorbed, leading to most of the drug leaving the body in the form of faeces Renal clearance It quantifies the elimination of drugs by the kidneys Defined as the volume of plasma containing the amount of drug removed from the body by the kidneys in a unit of time CLren is calculated from the plasma concentration (Cp), urinary concentration (Cu), and the rate if urine flow (Vu) using the equation: CLren = (Cu x Vu)/ Cp Glomerular filtration, active tubular secretion and passive reabsorption are the three fundamental processes accounting for renal drug excretion Drugs differ in the rate at which they are excreted by the kidney, from penicillin & PAH, which is cleared almost completely on a single transit through the kidney, drugs like amiodarone & risedronate, which is cleared extremely slowly Glomerular filtration Glomerular capillaries allow drug molecules with a MW of about 20 kDa to pass into the glomerular filtrate Plasma albumin, MW of 68 kDa, almost completely impermeable to the glomerular barrier Most drugs, except for macromolecules like heparin or biopharmaceuticals, freely cross the glomerular barrier If drug binds to plasma albumin, only the free drug is filtered into the glomerular filtrate Drugs like warfarin, approx. 98% bound to albumin, reduced concentration in the filtrate (2% of plasma concentration), leading to reduced clearance by filtration  Tubular secretion Approx. 20% of renal plasma flow is filtered through the glomerulus in a healthy human, leaving at least 80% of delivered drug to pass to the peritubular capillaries of the PCT In the PCT, drug molecules are transferred to the tubular lumen by 2 independent and non-selective carrier systems: OATs and OCTs OAT transports acidic drugs in their negatively charged anionic form, while OCT handles organic bases in their protonated cationic form Tubular secretion by these carrier systems is the most effective mechanism of renal drug elimination, as it can achieve maximal drug clearance even when most of the drug is bound to plasma protein Carrier-mediated transport reduces plasma concentration of drugs, with OAT transporting the drug molecules against an electrochemical gradient Drugs like penicillin, are 80% protein-bound and cleared slowly by filtration, almost completely removed by the proximal tubular secretion, leading to rapid elimination Many drugs compete for the same transport systems, leading to drug interactions. Example: probenecid developed to prolong penicillin by retarding its tubular secretion  Diffusion across the renal tubular epithelium Water is reabsorbed as fluid transverses the tubule, resulting in only about 1% of the glomerular filtrate volume emerging as urine per unit of time If tubule is permeable to drug molecules, approx. 99% of filtered drug will be reabsorbed passively down the resulting concentration gradient Lipid soluble drugs are excreted poorly, while polar drugs of low tubular permeability remain in the lumen and become progressively concentrated as water is reabsorbed Drugs like digoxin and aminoglycoside antibiotics, are not activated by metabolism, rely on renal elimination as the main factor determining their duration of action Renally eliminated drugs should be used cautiously in individuals with impaired renal function, including elderly and patients with renal disease or severe acute illness Degree of ionisation of many drugs, particularly weak acids or bases, is pH dependent significantly affecting their renal excretion Ion trapping effect in basic drugs are more rapidly excreted by acidic urine, favouring charged form and inhibiting reabsorption, while acidic drugs are most rapidly excreted in alkaline urine What mechanisms can drug-drug interactions affect drug excretion Altering protein binding, which affects filtration rates Inhibiting tubular secretion Altering urine flow and/or urine pH Inhibition of tubular secretion Probenecid was initially developed to inhibit the secretion of penicillin, extending its action Probenecid also inhibits the excretion of other drugs, like zidovudine Some drugs have unintended effects like probenecid, enhancing the actions of substances relying on tubular secretion for elimination Examples include diuretics like furosemide, whose effects are reduced by drugs inhibiting their secretion into the tubular fluid, such as NSAIDs Alteration of urine flow and pH Diuretics typically increase the urinary excretion of other drugs and their metabolites, which is usually not immediately clinically significant Loop and thiazide like diuretics indirectly decrease the excretion of lithium by reducing body sodium content, prompting increased proximal tubular reabsorption of sodium and lithium leading to potential lithium toxicity Lithium carbonate is used for mood disorders, and its toxicity can be exacerbated by loop and thiazide like diuretics Urinary pH affects the excretion of weak acids or bases, a factor utilized in treating salicylate poisoning, but not a common cause of accidental drug interactions