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  • 1. MAHARISHI ARVIND INSTITUTE OF PHARMACY MANSAROVAR, JAIPUR. Presented by : Mr. Pinkesh Patel Guided by : Mr. Mahesh Goyal
  • 2. EXCRETION OF DRUGS <ul><li>“ Excretion is defined as the process where by drugs or </li></ul><ul><li>metabolites are irreversibly transferred from internal to </li></ul><ul><li>external environment through renal or non renal route.” </li></ul><ul><li>Excretion of unchanged or intact drug is needed in </li></ul><ul><li>termination of its pharmacological action. </li></ul><ul><li>The principal organ of excretion are kidneys. </li></ul><ul><li>Agent that excreted in urine are : </li></ul><ul><li>1. water soluble 2.non volatile </li></ul><ul><li>3. small in molecular size(< 500 daltons.) </li></ul>
  • 3. TYPES OF EXCRETION <ul><li>RENAL EXCRETION </li></ul><ul><li>NON RENAL EXCRETION </li></ul><ul><ul><li>Biliary excretion. </li></ul></ul><ul><ul><li>Pulmonary excretion. </li></ul></ul><ul><ul><li>Salivary excretion. </li></ul></ul><ul><ul><li>Mammary excretion. </li></ul></ul><ul><ul><li>Skin / Dermal excretion. </li></ul></ul><ul><ul><li>Gastrointestinal excretion. </li></ul></ul><ul><ul><li>Genital excretion. </li></ul></ul>
  • 4. ANATOMY OF NEPHRON
  • 5. <ul><li>GLOMERULAR FILTRATION </li></ul><ul><li>It Is non selective , unidirectional process </li></ul><ul><li>Ionized or unionized drugs are filtered, except those that are bound to plasma proteins. </li></ul><ul><li>Driving force for GF is hydrostatic pressure of blood flowing in capillaries. </li></ul><ul><li>GLOMERULAR FILTRATION RATE: </li></ul><ul><li>Out of 25% of cardiac output 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 </li></ul><ul><li>GFR can be determined by an agent which are excreted by filtration and is neither reabsorbed nor secreted in tubules. Ex. Creatinine, inulin etc. </li></ul><ul><li>The normal GFR rate is 120-130 ml/min. </li></ul>
  • 6. <ul><li>ACTIVE TUBULAR SECRETION </li></ul><ul><li>This mainly occurs in proximal tubule. </li></ul><ul><li>It is carrier mediated process which requires energy for </li></ul><ul><li>transportation of compounds against conc. gradient </li></ul><ul><li>Two secretion mechanisms are identified. </li></ul><ul><li>System for secretion of organic acids/anions </li></ul><ul><li>E.g. Penicillin, salicylates etc uric acid secreted </li></ul><ul><li>System for organic base / cations </li></ul><ul><ul><li>E.g. morphine, mecamylamine hexamethonium </li></ul></ul><ul><ul><li>Active secretion is unaffected by change in pH and protein </li></ul></ul><ul><ul><li>binding. </li></ul></ul><ul><ul><li>Drug undergoes active secretion have excretion rate values </li></ul></ul><ul><ul><li>greater than normal GFR e.g. Penicillin. </li></ul></ul>
  • 7. <ul><li>TUBULAR REABSORPTION </li></ul><ul><li>It occurs after the glomerular filtration of drugs. It takes place all along the renal tubules. </li></ul><ul><li>Reabsorption of drugs indicated when the excretion rate value are less than the GFR 130ml/min.e.g. Glucose </li></ul><ul><li>TR can be active or passive processes. </li></ul><ul><ul><ul><ul><ul><li>Reabsorption results in increase in the half life of the drug. </li></ul></ul></ul></ul></ul><ul><li>Active Tubular Reabsorption: </li></ul><ul><li>Its commonly seen with endogenous substances or nutrients that the body needs to conserve e.g. electrolytes, glucose, vitamins, amino acids. </li></ul>
  • 8. <ul><li>Passive Tubular Reabsorption: </li></ul><ul><li>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. </li></ul><ul><li>If a drug is neither secreted nor re-absorbed its conc. In urine will be 100 times that of free drug in plasma. </li></ul><ul><li>Reabsorption is mainly depend on several factor that are pH, pKa, lipophilicity of drug, urine flow rate. </li></ul>
  • 9. FACTORS AFFECTING RENAL EXCRETION <ul><li>Urine pH and pKa. </li></ul><ul><li>Urine flow rate. </li></ul><ul><li>Physicochemical properties of drug. </li></ul><ul><li>Distribution and Binding characteristic of drug. </li></ul><ul><li>Blood flow to the kidneys. </li></ul><ul><li>Biological factors. </li></ul><ul><li>Drug interactions. </li></ul><ul><li>Disease states. </li></ul>
  • 10. <ul><li>pH and pKa OF THE URINE : </li></ul><ul><li>It varies between 4.5 to 7.5 </li></ul><ul><li>It depends upon diet, drug intake and pathophysiology of the patient . </li></ul><ul><li>Acetazolamide and antacids produce alkaline urine, while ascorbic acid makes it acidic. </li></ul><ul><li>IV infusion of sodium and ammonium chloride used in treatment of acid base imbalance shows alteration in urine pH. </li></ul><ul><li>Relative amount of ionized ,unionized drug in the urine at particular pH & % drug ionized at this pH can be given by “ HENDERSON-HESSELBACH” equation. </li></ul>
  • 11. HENDERSON-HESSELBACH EQUATION <ul><li>For weak acids : </li></ul><ul><li>pH= pKa +log [ ionized ] </li></ul><ul><li>[unionized] </li></ul><ul><li>% of drug ionized = 10 X 100 </li></ul><ul><li>1+10 </li></ul><ul><li>For weak base : </li></ul><ul><li>pH=pKa +log [unionized] </li></ul><ul><li> [ionized] </li></ul><ul><li>% of drug ionized = 10 X 100 </li></ul><ul><li>1+10 </li></ul>(pH – pKa) (pH – pKa) (pKa - pH) (pKa - pH)
  • 12. <ul><li>The significance of pH-dependant excretion for any particular compound is greatly depends upon its pKa & lipid solubility. </li></ul><ul><li>A characteristic of drugs, pKa value govern the degree of ionization at a particular pH. </li></ul><ul><li>A polar & ionized drug will be poorly reabsorbed passively & excreted rapidly. </li></ul><ul><li>Reabsorption is also affected by the lipid solubility of drug ; am ionized but lipophilic drug will be reabsorbed while an unionized but polar one will be excreted. </li></ul><ul><li>The toxicity due to overdose of the drug whose excretion is sensitive to pH change can be treated by acidification or alkalinisation of the urine. </li></ul>
  • 13. <ul><li>PHYSICOCHEMICAL PROPERTIES OF DRUG : </li></ul><ul><li>Like molecular size, pKa , lipid solubility </li></ul><ul><li>Molecular size </li></ul><ul><ul><li>Drugs with Mol.wt <300 are excreted in kidney. </li></ul></ul><ul><ul><li>Mol.wt 300 to 500 Dalton are excreted both through urine and bile. </li></ul></ul><ul><li>BINDING CHARACTERISTICS OF THE DRUGS : </li></ul><ul><ul><li>Drugs that are bound to plasma proteins behave as macromolecules and cannot be filtered through glomerulus. </li></ul></ul><ul><ul><li>Only unbound or free drug appear in glomerular filtrate. </li></ul></ul><ul><ul><li>Protein bound drug has long half lives. </li></ul></ul>
  • 14. <ul><li>BIOLOGICAL FACTORS : </li></ul><ul><li>Age, sex, species, strain difference etc alter the excretion of the drug. </li></ul><ul><li>Sex – Renal excretion is 10% lower in female than in males. </li></ul><ul><li>Age – The renal excretion in newborn is 30-40 % less in comparison to adults. </li></ul><ul><li>Old age – The GFR is reduced and tubular function is altered which results in slow excretion of drugs and prolonged half lives . </li></ul><ul><li>BLOOD FLOW TO THE KIDNEY : </li></ul><ul><li>Important in case of drug excreted by glomerular filteration and those are actively secreted only. </li></ul><ul><li>Increase the perfusion enhance the elimination. </li></ul>
  • 15. <ul><li>URINE FLOW RATE : </li></ul><ul><li>Polar drug are not affected by urine pH hence not get reabsorbed so unaffected by urine flow rate. </li></ul><ul><li>Only those drugs whose reabsorption is pH sensitive Ex. Weak acids and bases depend on urine flow rate. </li></ul><ul><li>Urine flow rate can be incresed by forced diuresis by large fluid intake or other diuretics. </li></ul><ul><li>DRUG INTERACTIONS : </li></ul><ul><li>Any drug interaction that result in alteration of binding characteristics, renal blood flow, active secretion, urine pH, and forced diuresis would alter renal clearance of drug. </li></ul><ul><li>Alkalinization of urine with citrates and bicarbonates promote excretion of acidic drugs. </li></ul>
  • 16. <ul><li>DISEASE STATE : </li></ul><ul><li>RENAL DYSFUNCTION </li></ul><ul><ul><li>Greatly cause the elimination of drugs those are primarily excreted by kidney. </li></ul></ul><ul><ul><li>Some of the causes of renal failure are hypertention, Diabetes, hypovolemiya(low blood supply to kidney), heavy metals. </li></ul></ul><ul><li>UREMIA </li></ul><ul><ul><li>Characterized by Impaired GF , accumulation of fluids & protein metabolites. </li></ul></ul><ul><ul><li>Half life increased resulting in drug accumulation and increased toxicity. </li></ul></ul>
  • 17. <ul><li>Drug Clearance : </li></ul><ul><li>‘ Clearance is defined as the hypothetical volume of body fluids containing drug from which the drug is removed or cleared completely in a specific period of time.’ </li></ul><ul><li>Clearance [CL]=Elimination rate/plasma drug conc . </li></ul><ul><li>The sum of individual clearance by all eliminating organ (kidney, liver, lungs, biliary systems) called as ‘Total body clearance’. </li></ul><ul><li>Renal Clearance ; </li></ul><ul><li>‘ The volume of plasma which is completely cleared of the unchanged drug by the kidney per unit time’ </li></ul>
  • 18. <ul><ul><li>RC = UV/P </li></ul></ul><ul><ul><li>RC = renal clearance rate </li></ul></ul><ul><ul><li>U = drug concentration in urine </li></ul></ul><ul><ul><li>V = flow rate of urine (ml/min) </li></ul></ul><ul><ul><li>P = plasma drug concentration </li></ul></ul><ul><li>Renal clearance tests are used to: </li></ul><ul><ul><li>Determine the GFR </li></ul></ul><ul><ul><li>Detect glomerular damage </li></ul></ul><ul><ul><li>Follow the progress of diagnosed renal disease </li></ul></ul><ul><ul><li>RC = rf+rs-rr/P </li></ul></ul><ul><ul><li>rf = rate of filtration </li></ul></ul><ul><ul><li>rs = rate of secretion </li></ul></ul><ul><ul><li>rr = rate of reabsorption </li></ul></ul>
  • 19. NON-RENAL ROUTE OF DRUG EXCRETION <ul><li>Various routes are ; </li></ul><ul><ul><ul><li>Biliary Excretion </li></ul></ul></ul><ul><ul><ul><li>Pulmonary Excretion </li></ul></ul></ul><ul><ul><ul><li>Salivary Excretion </li></ul></ul></ul><ul><ul><ul><li>Mammary Excretion </li></ul></ul></ul><ul><ul><ul><li>Skin/dermal Excretion </li></ul></ul></ul><ul><ul><ul><li>Gastrointestinal Excretion </li></ul></ul></ul><ul><ul><ul><li>Genital Excretion </li></ul></ul></ul>
  • 20. <ul><ul><ul><li>1 ) BILIARY EXCRETION : </li></ul></ul></ul><ul><ul><ul><li>Bile juice is secreted by hepatic cells of the liver. </li></ul></ul></ul><ul><ul><ul><li>Its important in the digestion and absorption of fats. </li></ul></ul></ul><ul><ul><ul><li>90% of bile acid is reabsorbed from intestine and transported back to the liver for resecretion. </li></ul></ul></ul><ul><ul><ul><li>The metabolites are more excreted in bile than parent drugs due to increased polarity. </li></ul></ul></ul><ul><li>Several factor influence secretion of drug in bile are; </li></ul><ul><ul><li>Molecular weight. </li></ul></ul><ul><ul><li>Polarity. </li></ul></ul><ul><ul><li>Nature of biotransformation. </li></ul></ul><ul><ul><li>Other factor like sex,spices, disease state, drug interation. </li></ul></ul>
  • 21. <ul><ul><ul><li>Nature of bio-transformation process: </li></ul></ul></ul><ul><ul><ul><li>Phase-II reactions mainly glucuronidation and conjugation with glutathione result in metabolites with increased polarity and molecular weight for biliary excretion. </li></ul></ul></ul><ul><ul><ul><li>Ex. of drugs excreted in the bile are chloromphenicol, morphine and indomethacin. </li></ul></ul></ul><ul><ul><ul><li>For a drug to be excreted in bile must have polar groups like –COOH, -SO 3 H. </li></ul></ul></ul><ul><ul><ul><li>Conjugation with amino acids ,acetylation ,methylation do not result in metabolites with high molecular weight and polarity hence little influence on biliary excretion. </li></ul></ul></ul>
  • 22. <ul><li>Efficacy of drug excretion by biliary system can be tested by an agent that is completely eliminated in bile, Ex. sulfobromophthalein. </li></ul><ul><li>This marker is excreted in half an hour in intestine when hepatic function is normal. Delay in its excretion indicates hepatic and biliary malfunction. </li></ul><ul><li>Some drugs which are excreted as glucuronides or as glutathione conjugates are hydrolyzed by intestinal or bacterial enzymes to the parent drugs which are reabsorbed. </li></ul><ul><li>The reabsorbed drugs are again carried to the liver for resecretion via bile into the intestine. </li></ul>
  • 23. <ul><ul><ul><li>This phenomenon of drug cycling between the intestine & the liver is called Enterohepatic circulation </li></ul></ul></ul><ul><ul><ul><li>Enterohepatic Circulation is important in conservation of vitamins, folic acid and hormones. </li></ul></ul></ul><ul><ul><ul><li>This process results in prolongation of half lives of drugs like DDT, oral contraceptives. </li></ul></ul></ul><ul><ul><ul><li>2 ) PULMONARY EXCRETION : </li></ul></ul></ul><ul><ul><ul><li>Gaseous and volatile substances such as general anesthetics (Halothane) are absorbed through lungs by simple diffusion. </li></ul></ul></ul><ul><ul><ul><li>Pulmonary blood flow, rate of respiration and solubility of substance effect pulmonary excretion. </li></ul></ul></ul><ul><ul><ul><li>Intact gaseous drugs are excreted but not metabolites. </li></ul></ul></ul><ul><ul><ul><li>Alcohol which has high solubility in blood and tissues are excreted slowly by lungs. </li></ul></ul></ul>
  • 24. <ul><ul><ul><li>3 ) SALIVARY EXCRETION : </li></ul></ul></ul><ul><ul><ul><li>The pH of saliva varies from 5.8 to 8.4. Unionized lipid soluble drugs are excreted passively. </li></ul></ul></ul><ul><ul><ul><li>The bitter taste in the mouth of a patient is indication of drug excreted. Some basic drugs inhibit saliva secretion and are responsible for mouth dryness. Compounds excreted in saliva are Caffeine, Phenytoin, Theophylline. </li></ul></ul></ul><ul><ul><ul><li>4 ) MAMMARY EXCRETION : </li></ul></ul></ul><ul><ul><ul><li>Milk consists of lactic secretions which is rich in fats and proteins. 0.5 to one litre of milk is secreted per day in lactating mothers. </li></ul></ul></ul><ul><ul><ul><li>Excretion of drug in milk is important as it gains entry in breast feeding infants. </li></ul></ul></ul>
  • 25. <ul><ul><ul><li>pH of milk varies from 6.4 to 7.6.Free un-ionized and lipid soluble drugs diffuse passively. </li></ul></ul></ul><ul><ul><ul><li>Highly plasma bound drug like Diazepam is less secreted in milk. </li></ul></ul></ul><ul><ul><ul><li>Since milk contains proteins. Drugs excreted can bind to it. </li></ul></ul></ul><ul><ul><ul><li>Amount of drug excreted in milk is less than 1% and fraction consumed by infant is too less to produce toxic effects. Some potent drugs like barbiturates and morphine may induce toxicity. </li></ul></ul></ul><ul><ul><ul><li>ADVERSE EFFECTS : </li></ul></ul></ul><ul><ul><ul><ul><li>Discoloration of teeth with tetracycline and jaundice due to interaction of bilirubin with sulfonamides. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Nicotine is secreted in the milk of mothers who smoke. </li></ul></ul></ul></ul>
  • 26. <ul><ul><ul><li>5 ) SKIN EXCRETION : </li></ul></ul></ul><ul><ul><ul><li>Drugs excreted through skin via sweat follows pH partition hypothesis. </li></ul></ul></ul><ul><ul><ul><li>Excretion of drugs through skin may lead to urticaria and dermatitis. </li></ul></ul></ul><ul><ul><ul><li>Compounds like benzoic acid, salicylic acid, alcohol and heavy metals are excreted in sweat. </li></ul></ul></ul><ul><ul><ul><li>6 ) GASTROINTESTINAL EXCRETION : </li></ul></ul></ul><ul><ul><ul><li>Excretion of drugs through GIT usually occurs after parenteral administration. </li></ul></ul></ul><ul><ul><ul><li>Water soluble and ionized form of weakly acidic and basic drugs are excreted in GIT. </li></ul></ul></ul><ul><ul><ul><li>Example are nicotine and quinine are excreted in stomach. </li></ul></ul></ul><ul><ul><ul><li>Drugs excreted in GIT are reabsorbed into systemic circulation & undergo recycling. </li></ul></ul></ul>
  • 27. EXCRETION PATHWAYS, TRANSPORT MECHANISMS & DRUG EXCRETED. Excretory route Mechanism Drug Excreted Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/ metabolites of MW< 300 Bile Active secretion Hydrophilic, unchanged drugs/ metabolites/ conjugates of MW >500 Lung Passive diffusion Gaseous &volatile, blood & tissue insoluble drugs saliva Passive diffusion Active transport Free, unionized, lipophilic drugs. Some polar drugs Milk Passive diffusion Free, unionized, lipophilic drugs (basic) Sweat / Passive diffusion Free, unionized lipophilic drugs Intestine Passive diffusion Water soluble. Ionized drugs
  • 28. REFERENCES <ul><li>Brahmankar M D., Jaiswal S B., Biopharmaceutics and Pharmacokinetics A Treatise vallabh prakasan I edition 2002, p.no;178-192. </li></ul><ul><li>Shrgel L., Wu-Pong S., Yu A B C., Applied Biopharmaceutics & Pharmacokinetics V edition 2005,Mc Graw Hill publication house p.no;131-159. </li></ul><ul><li>Venkateswarlu V., Biopharmaceutics and Pharmacokinetics II edition 2008, PharmaMed Press, p.no;103-145. </li></ul><ul><li>Gibaldi M., Biopharmaceutics and Clinical Pharmacokinetics IV edition 2006, PharmaMed Press,p.no; 203 </li></ul><ul><li>Ali J., Khar R K., Ahuja A., A Text Book of Biopharmaceutics and Pharmacokinetics , II edition 2005, Birla Publication Pvt.Ltd, p.no;121-131. </li></ul>
  • 29. <ul><li>THANK YOU … </li></ul>

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