SIVANAGESWARARAO MEKALA EXCRETION OF DRUGS SIVANAGESWARARAO MEKALA ASSISTANT PROFESSOR DEPT OF CLINICAL PHARMACOLOGY

Drugs are eliminated from the body either unchanged by the process of excretion or converted to metabolites Drugs are excreted in Urine Feces and bile Lungs Breast milk Sweat ,saliva and tears . 4/3/2019

Renal excretion Excretion of drugs and metabolites in the urine involves : glomerular filtration active tubular secretion passive tubular reabsorption glomerular filtration and active tubular secretion facilitates drug excretion Where as tubular reabsorption decreases drug excretion In neonates renal function is low compared with body mass During adulthood, there is a slow decline in renal function, about 1% per year

GLOMERULAR FILTRATION: Glomerular capillaries allow drug molecules of molecular weight below 20 000 to diffuse into the glomerular filtrate. Unbound fraction is filtered at glomerulus but they are reabsorbed back in the tubular lumen The extent of filtration is directly proportional to the glomerular filtration rate and to the fraction of the unbound drug in plasma. If a drug binds appreciably to plasma albumin, its concentration in the filtrate will be less than the total plasma concentration Plasma albumin (68 000) is almost completely impermeable, but most drugs-with the exception of macromolecules such as heparin cross the barrier freely.

TUBULAR SECRETION: Drug molecules are transferred to the tubular lumen by two independent and relatively non-selective carrier systems. Unlike glomerular filtration, carrier-mediated transport can achieve maximal drug clearance even when most of the drug is bound to plasma protein. 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. The carriers can transport drug molecules against an electrochemical gradient

Active tubular secretion: proximal tubules Efflux - transporters P-glycoprotein MRP2 ( multidrug-resistance-associated protein) located in luminal membrane of PT cells. Active transport -  free drug in tubular vessels - dissociation of Protein bound drugs Organic base Transporter Organic acid

Organic acid transport :- Penicillin, Salicylates, Probenecid Organic base transport:- Thiazides, quinine, amiloride Both transport processes are bidirectional Drugs & metabolites – secretion into lumen Endogenous substrates- e.g.- uric acid reabsorbed into plasma

The carrier system is relatively non-selective and therefore drugs having similar physicochemical properties compete for the same carrier system Eg: Probenecid & Penicillin -  Penicillin excretion- useful in gonococal infection Probenecid & Uric acid - Uric acid excretion. Tubular transport mechanisms not well developed at birth- duration of action of many drugs in neonates e.g.-penicillin, aspirin

PASSIVE TUBULAR REABSORPTION : Passive diffusion is bidirectional process Drugs diffuse across tubules depending on: Drug concentration Lipid solubility pH – alkalanization of urine in barbiturate poisoning. If the drug is highly polar and thus low tubular permeability remains in the tubule, and its concentration rises until it is about 100 times as high in the urine as in the plasma. e.g., digoxin and aminoglycoside pH of urine influences excretion of certain weak acids bases

urinary pH affects tubular reabsorption Weakly Basic drugs better excreted in acidic urine- e.g. - morphine, amphetamine (PH of the urine is made acidic by ascorbic acid ) Acidic drugs better excreted in alkaline urine- e.g.- barbiturates, salicylates (PH of the urine is made alkaline by sodium bicarbonate) This principle is utilized for facilitating elimination of drugs in poisoning The effect of changes in urinary pH is greatest for those drugs having pKa values between 5-8.

Biliary and faecal excretion Faeces contain unabsorbed fraction and the drug in bile Drugs attaining high concentration in bile doxycycline cefoperazone ; only unbound drug is filtered

Enterohepatic circulation Most drugs secreted from liver into bile and then into small intestines are passively reabsorbed so that the compound reenters the blood that perfuses intestines and again be carried to liver Such recycling continues and is known as enterohepatic cycle or circulation Examples: Morphine, Metronidazole, Estradiol It continues till drug is metabolised in liver or excreted in kidneys or both

Excretion by other routes Saliva: Lithium, metronidazole, phenytoin Gases and volatile liquids (general anaesthetics) are excreted by lungs Excretion in hair and skin is of forensic importance As, Hg

Basic drugs like chloramphenicol, morphine, phenytoin Milk Milk has an acidic pH. Basic drugs like chloramphenicol, morphine, phenytoin are secreted through milk and may affect the suckling infant Basic drugs are unionized in plasma, diffuse through mammary epithelium and gets accumulated in milk which has acidic medium