Excretion

Elimination of drugs : 

Elimination of drugs Suryakant patel I st Year M.pharm Dept. of pharmacology

Excretion: 

Excretion It is Irreversible removal of drugs from body. Process whereby drugs and/or metabolites are irreversibly transferred from internal to external environment. Types : 1- renal excretion Kidneys 2- non renal excretion Lungs, biliary system, intestine, salivary gland, sweat gland. 2

Nephron is a basic functional unit of kidney: 

Nephron is a basic functional unit of kidney 3

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Principal steps of Renal Excretion : 1.Glomerular filtration 2.Active tubular secretion 3.Tubular reabsorption Glomerular Filtration It Is non selective , unidirectional process Ionized or unionized drugs are filtered, except those that are bound to plasma proteins. Driving force for GF is hydrostatic pressure of blood flowing in capillaries 5

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Glomerular filtration rate Out of 25% of cardiac out put or 1.2 liters of blood/min that goes to the kidney via renal artery only 10% or 120 to 130ml/min is filtered through glomeruli. The rate being called as glomerular filtration rate(GFR). The GFR can be determined by an agent that is excreted exclusively by filtration and is neither secreted nor reabsorbed in tubules. Eg . Creatinine , I nulin, mannitol (GFR≈120 ml/min) etc. 6

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Active tubular secretion This mainly occurs in proximal tubule . It is carrier mediated process which requires energy for transportation against conc. gradient . Two secretion mechanisms are identified . System for secretion of organic acids/anions E.g . Penicillin, salicylates , uric acid System for organic base / cations E.g . morphine, mecamylamine , hexamethonium Drug undergoes active secretion have excretion rate values greater than normal GFR e.g. Penicillin(500 ml/min) Such high value is indicative of both glomerular filtration as well as tubular secretion. Measurement: agents used are the ones that are filtered as well as secreted to such extent that they are removed from blood in single pass i.e. their GFR ≈600 to 700 ml/min. Eg . Para amino hippuric acid(PAH). 7

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Tubular reabsorption It occurs after the glomerular filtration of drugs. It takes place all along the renal tubules . Reabsorption of drugs indicated when the excretion rate value are less than the normal GFR . e.g. Glucose TR can be active or passive processes. Reabsorption results in increase in the half life of the drug. Active Tubular Reabsorption: Its commonly seen with endogenous substances or nutrients that the body needs to conserve e.g. electrolytes, glucose, vitamins. 8

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Passive Tubular Reabsorption: It is common for many exogenous substances including drugs. The driving force is Conc. Gradient which is due to re-absorption of water, sodium and inorganic ions. 9

Clearance : 

Clearance Is defined as the hypothetical volume of body fluids containing drug from which the drug is removed/ cleared completely in a specific period of time. Expressed in ml/min . Clearance = Rate of elimination ÷plasma conc . TOTAL BODY CLEARANCE:- Is defined as the sum of individual clearances by all eliminating organs is called total body clearance/ total systemic clearance. Total Body Clearance = CLliver + CLkidney + CLlungs + CLx 10

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RENAL CLEARANCE :- is defined as the volume of blood/ plasma which is completely cleared of the unchanged drug by the kidney per unit time Cl R = rate of urinary excretion ÷ plasma drug concentration Or Cl R = rate of filtration + rate of secretion – rate reabsorption C 11

FACTORS AFFECTING RENAL EXCRETION: 

FACTORS AFFECTING RENAL EXCRETION Physicochemical properties of drug Urine pH Blood flow to the kidney Biological factor Drug interaction Disease state 12

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Physicochemical properties of drug Molecular size Drugs with Mol.wt <300, water soluble are excreted in kidney. Mol.wt 300 to 500 Dalton are excreted both through urine and bile. Binding characteristics of the drugs Drugs that are bound to plasma proteins behave as macromolecules and cannot be filtered through glomerulus. Only unbound or free drug appear in glomerular filtrate. Protein bound drug has long half lives. 13

Biological factor : 

Biological factor Age, sex, species, strain difference etc alter the excretion of the drug. Sex – Renal excretion is 10% lower in female than in males. Age – The renal excretion in newborn is 30-40 % less in comparison to adults. Old age – The GFR is reduced and tubular function is altered which results in slow excretion of drugs and prolonged half lives 14

Disease state : 

Disease state RENAL DYSFUNCTION Greatly impairs the elimination of drugs especially those that are primarily excreted by kidney. Some of the causes of renal failure are B.P, Diabetes, Pyelonephritis. URAEMIA Characterized by Impaired GFR , accumulation of fluids & protein metabolites, also impairs the excretion of the drugs. Half life is increased resulting in drug accumulation and increased toxicity. 15

DRUG INTERACTION: 

DRUG INTERACTION Any drug interaction that result in alteration of binding characteristics, renal blood flow, active secretion, urine pH, intrinsic clearance and forced diuresis would alter renal clearance of drug. Renal clearance of a drug, highly bound to plasma proteins is increased after it is displaced with other drug e.g. Gentamicin induced nephrotoxicity by furosemide. 16

BILIARY EXCRETION : 

BILIARY EXCRETION Bile juice is secreted by hepatic cells of the liver. The flow is steady-0.5 to 1ml /min. Its important in the digestion and absorption of fats . 90 % of bile acid is reabsorbed from intestine and transported back to the liver for resecretion . Compounds excreted by this route are sodium, potassium, glucose, bilirubin, Glucuronide , sucrose, Inulin, muco -proteins etc . 17

references 1. Brahmankar MD, Jaiswal S., Biopharmaceutics & Pharmacokinetics. 2. Shargel L.,Susanna W., Applied Biopharmaceutics and Pharmacokinetics. 3.www.google.com : 

references 1. Brahmankar MD , Jaiswal S ., Biopharmaceutics & Pharmacokinetics. 2. Shargel L.,Susanna W., Applied Biopharmaceutics and Pharmacokinetics . 3.www.google.com 18

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