Slide 1: routes of drug excretion Slide 2: By VENKATA NAVEEN KASAGANA & SWATHI SREE KARUMURI, 1ST M-PHARM (pharmaceutics), SBCP COLLEGE, SIVAKASI,TAMIL NADU. Email: firstname.lastname@example.org Slide 3: renal route of drug excretion Slide 4: EXCRETION OF DRUGS Excretion is defined as the process where by drugs or metabolites are irreversibly transferred from internal to external environment through renal or non renal route. Excretion of unchanged or intact drug is needed in termination of its pharmacological action. The principal organ of excretion are kidneys. Slide 5: Drug Excretion and Clearance Drug Excretion: is the movement of drug from tissues and blood to the external environment. Drug Clearance (CL): is the apparent volume (ml, L) of blood that is cleared of the drug per time period (min, h). Slide 6: TYPES OF EXCRETION RENAL EXCRETION NON RENAL EXCRETION Slide 7: RENAL EXCRETION The kidneys regulate the amount of water, salts and other substances in the blood. The kidneys are fist-sized, bean shaped structures that remove nitrogenous wastes (urine) and excess salts from the blood. The ureters are tubes that carry urine from the pelvis of the kidneys to the urinary bladder. The urinary bladder temporarily stores urine until it is released from the body. The urethra is the tube that carries urine from the urinary bladder to the outside of the body. The outer end of the urethra is controlled by a circular muscle called a sphincter. Slide 8: The Kidney Each kidney is composed of three sections: The outer (renal) cortex, the (renal) medulla (middle part) and the hollow inner (renal) pelvis. The cortex is where the blood is filtered. The medulla contains the collecting ducts which carry filtrate (filtered substances) to the pelvis. The pelvis is a hollow cavity where urine accumulates and drains into the ureter. Slide 9: LONGITUDNAL SECTION OF KIDNEY Slide 10: ANATOMY OF NEPHRON Slide 12: The Glomerulus The glomerulus is a mass of thin-walled capillaries. The Bowman’s capsule is a double-walled, cup-shaped structure. The proximal tubule leads from the Bowman’s capsule to the Loop of Henle. The loop of Henle is a long loop which extends into the medulla. The distal tubule connects the loop of Henle to the collecting duct. Slide 13: 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. 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).e.g. creatinine, insulin. Slide 14: • Low molecular weight compounds (< 60,000 dalton ) filtered from blood • Tight protein binding will reduce filtration as would incorporation into red blood cells will reduce filtration • Glomerular Filtration Rate (GFR) 110 to 130 ml/min » 180 L/day • Inulin is filtered and not secreted or reabsorbed in tubule • 90% of water reabsorbed: Urine output » 1 - 2 L/day Slide 16: ACTIVE TUBULAR SECRETION This mainly occurs in proximal tubule. It is carrier mediated process which requires energy for transportation of compounds against conc. gradient Two secretion mechanisms are identified. System for secretion of organic acids/anions E.g. Penicillin, salicylates etc uric acid secreted System for organic base / cations E.g. morphine, mecamylamine hexamethonium Active secretion is Unaffected by change in pH and protein binding. Drug undergoes active secretion have excretion rate values greater than normal GFR e.g. Penicillin. Slide 18: 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 GFR 130ml/min.e.g. Glucose TR can be active or passive processes. Reabsorption results in increase in the half life of the drug. Slide 21: Active Tubular Reabsorption : Its commonly seen with endogenous substances or nutrients that the body needs to conserve e.g. electrolytes, glucose, vitamins. Active process, can be inhibited • e.g. penicillins and probenecid (also increased distribution) • e.g. cephalosporins 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. If a drug is neither excreted or re-absorbed its conc. In urine will be 100 times that of free drug in plasma. Slide 22: pH OF THE URINE It varies between 4.5 to 7.5 It depends upon diet, drug intake and pathophysiology of the patient . Acetazolamide and antacids produce alkaline urine, while ascorbic acid makes it acidic. IV infusion of sodium and ammonium chloride used in treatment of acid base imbalance shows alteration in urine pH. Relative amount of ionized ,unionized drug in the urine at particular pH & % drug ionized at this pH can be given by “ HENDERSON-HESSELBACH” equation. Slide 23: • Weak acids or bases - ionization depends on pH of filtrate and pKa of drug – e.g. urine acidic - weak acids reabsorbed (more in the unionized form) – e.g. urine acidic - weak bases not reabsorbed, excretion enhanced • Urine pH can vary from 4.5 to 8 depending on diet or drugs – e.g. meat will reduce pH – e.g. Bicarbonates will increase pH • Possible to increase excretion by adjusting urinary pH – e.g. pentobarbital (and other barbiturates) are weak acids and excretion can be increased with alkalinized urine (sodium bicarbonates) Slide 24: 1) FOR WEAK ACIDS pH= pKa +log [ ionized ] [unionized] % of drug ionized = 10 pH – pKa X 100 1+10pH –pKa Henderson- hesselbach equation Slide 25: 2) FOR WEAK BASE pH=pKa +log [unionized] [ionized] % of drug ionized = 10 pH – pKa X 100 1+10pH –pKa Henderson- hesselbach equation Slide 26: CONCEPT OF CLEARANCE Slide 27: Renal Clearance • Can be used to quantitate renal excretion • Used to study mechanism for renal excretion – GFR » 120 ml/min – Renal Blood Flow » 650 ml/min • Components of renal clearance include: – Filtration, secretion, reabsorption rate Cl R = rate of urinary excretion ÷ plasma drug concentration Or Cl R = rate of filtration + rate of secretion – rate reabsorption C Slide 28: FACTORS AFFECTING RENAL EXCRETION Physicochemical properties of drug Urine pH Blood flow to the kidney Biological factor Drug interaction Disease state Slide 29: 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. Slide 30: 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 . Biological factors Slide 31: 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 . Alkalinization of urine with citrates and bicarbonates promote excretion of acidic drugs. Drug interaction Slide 32: 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 . UREMIA 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. Disease state Slide 35: Non-renal route of drug excretion Slide 37: Factors effecting non –renal route of excretion Slide 38: What conditions can affect drug excretion? Hypertension Severe dehydration Diabetes (all types) Cardiac problems ( ie . CHF) Renal disease It is necessary to understand that if one system of the body is not working properly it affects other systems also. Slide 40: Metabolized drugs are mainly cleared from the body through chemical modification (biotransformation) in the liver. The goal of metabolism is to de- toxify drugs, and make them either more water soluble (for excretion in the urine) or more fat soluble (for excretion in the bile, and then into the feces).The liver does this in two ways: Slide 41: Cytochrome P450 enzymes chemically oxidize or reduce drugs (for example through hydroxylation). These are also known as Phase I reactions . Conjugation enzymes link one chemical to another. For example, glucuronyl transferases link a glucuronide group to zidovudine (AZT, Retrovir ® ), which makes it more water soluble and allows elimination in the urine. Acetylases link an acetyl group to isoniazid (INH), which is its major route of clearance. These are also known as Phase II reactions .Drugs administered orally have to pass from the intestinal tract into the liver via the portal circulation before reaching the systemic circulation. Some drugs, for example saquinavir ( Fortovase ®) , are metabolized so efficiently in the liver that little or no drug reaches the systemic circulation. Such drugs are said to be susceptible to first-pass metabolism . Some first-pass metabolism also takes place in the intestinal tract, since cytochrome P450 enzymes are also present there. Slide 42: 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 e.t.c . Greater the polarity better the excretion. The metabolites are more excreted in bile than parent drugs due to increased polarity. BILIARY EXCRETION Slide 43: Classification of substances undergoing biliary excretion Slide 44: Phase-II reactions mainly glucuronidation and conjugation with glutathione result in metabolites with increased tendency for biliary excretion. Drugs excreted in the bile are chloromphenicol , morphine and indomethacin . Glutathione conjugates have larger molecular weight and so not observed in the urine. For a drug to be excreted in bile must have polar groups like –COOH, -SO 3 H. Clomiphene citrate, ovulation inducer is completely removed from the body by BE. Bio transformation process: Slide 45: THE ENTEROHEPATIC CIRCULATION Some drugs which are excreted as glucuronides/ as glutathione conjugates are hydrolyzed by intestinal/ bacterial enzymes to the parent drugs which are reabsorbed. The reabsorbed drugs are again carried to the liver for resecretion via bile into the intestine. This phenomenon of drug cycling between the intestine & the liver is called Enterohepatic circulation Slide 47: Enterohepatic Recycling Slide 48: EC is important in conservation of Vitamins, Folic acid and hormones. This process results in prolongation of half lives of drugs like DDT, Carbenoxolone. Some drugs undergoing EC are cardiac glycosides, rifampicin and chlorpromazine. The principle of adsorption onto the resins in GIT is used to treat pesticide poisoning by promoting fecal excretion. THE ENTEROHEPATIC CIRCULATION Slide 49: The efficacy of drug excretion by biliary system can be tested by an agent i.e. completely eliminated in bile. Example sulfobromophthalein . This marker is excreted in half an hour in intestine at normal hepatic functioning. Delay in its excretion indicates hepatic and biliary mal function. The ability of liver to excrete the drug in the bile is expressed as Biliary clearance . OTHER FACTORS Slide 50: Gaseous and volatile substances such as general anesthetics are absorbed through lungs by simple diffusion. Pulmonary blood flow, rate of respiration and solubility of substance effect PE. Intact gaseous drugs are excreted but not metabolites. Alcohol which has high solubility in blood and tissues are excreted slowly by lungs. PULMONARY EXCRETION Slide 51: The pH of saliva varies from 5.8 to 8.4. Unionized lipid soluble drugs are excreted passively. The bitter after 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. SALIVARY EXCRETION Slide 52: For weak acids For weak bases Henderson- hesselbach equation Slide 53: 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. Excretion of drug in milk is important as it gains entry in breast feeding infants. pH of milk varies from 6.4 to 7.6.Free un-ionized and lipid soluble drugs diffuse passively. Highly plasma bound drug like Diazepam is less secreted in milk. Since milk contains proteins. Drugs excreted can bind to it. MAMMARY EXCRETION Slide 54: For weak acids For weak bases Henderson- hesselbach equation Slide 55: 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. ADVERSE EFFECTS Discoloration of teeth with tetracycline and jaundice due to interaction of bilirubin with sulfonamides. Nicotine is secreted in the milk of mothers who smoke. MAMMARY EXCRETION Slide 56: Drugs excreted through skin via sweat follows pH partition hypothesis. Excretion of drugs through skin may lead to urticaria and dermatitis. Compounds like benzoic acid, salicylic acid, alcohol and heavy metals like lead, mercury and arsenic are excreted in sweat. SKIN EXCRETION Slide 57: Excretion of drugs through GIT usually occurs after parenteral administration. Water soluble and ionized from of weakly acidic and basic drugs are excreted in GIT. Example are nicotine and quinine are excreted in stomach. Drugs excreted in GIT are reabsorbed into systemic circulation & undergo recycling. GASTROINTESTINAL EXCRETION Slide 59: EXCRETION PATHWAYS, TRANSPORT MECHANISMS & DRUG EXCRETED. Excretory route Mechanism Drug Excreted Urine GF/ ATS/ ATR, PTR Free, hydrophilic, unchanged drugs/ metabolites of MW< 500 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/ skin Passive diffusion Free, unionized lipophilic drugs Intestine Passive diffusion Water soluble. Ionized drugs Slide 60: Ex: Rifampicin Slide 61: 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 = CL liver + CL kidney + CL lungs +CL x Slide 62: HEPATIC CLEARANCE & ORGAN CLEARANCE Slide 63: OUT C A C V BLOOD ELIMINATED Rate of Elimination = QC A – QC V = Q(C A -C V ) Liver Clearance = Q(C A -C V )/C A = Q x ER SIMILARLY FOR OTHER ORGANS Total Body Clearance = CL liver + CL kidney + CL lungs + CL x BLOOD IN Slide 64: FOR CERTAIN DRUGS , THE NON-RENAL CLEARANCE CAN BE ASSUMED AS EQUAL TO HEPATIC CLEARANCE Cl H IT IS GIVEN AS : Cl H = Cl T – Cl R Slide 65: THE HEPATIC CLEARANCE OF DRUG CAN BE DIVIDED INTO 2 GROUPS DRUG WITH HEPATIC FLOW RATE-LIMITED CLEARANCE DRUGS WITH INTRINSIC CAPACITY-LIMITED CLEARANCE Slide 66: WHEN ER H IS ONE, Cl H APPROACHES ITS MAXIMUM VALUE i.e. HEPATIC BLOOD FLOW. IN SUCH A SITUATION, HEPATIC CLEARANCE IS SAID TO BE perfusion rate-limited OR flow dependent. ALTERATION IN HEPATIC BLOOD FLOW SIGNIFICANTLY AFFECTS THE ELIMINATION OF DRUGS WITH HIGH ER H . Eg. Propranolol , lidocaine etc…. SUCH DRUGS ARE REMOVED FROM THE BLOOD AS RAPIDLY AS THEY ARE PRESENTED TO THE LIVER 1. HEPATIC BLOOD FLOW : Slide 67: INDOCYANINE GREEN IS SO RAPIDLY ELIMINATED BY THE HUMAN LIVER THAT ITS CLEARANCE IS OFTEN USED AS AN INDICATOR. FIRST-PASS HEPATIC EXTRATION IS SUSPECTED WHEN THERE IS LACK OF UNCHANGED DRUG IN SYSTEMIC CIRCULATION AFTER ORAL ADMINISTRATION MAXIMUM ORAL AVAILABILITY F = 1 – ER H = AUC ORAL AUC i.v Slide 68: Q H = HEPATIC BLOOD FLOW (about 1.5 liters/min) ER H = HEPATIC EXTRACTION RATION Where , Slide 69: Hepatic blood flow has very little or no effect on drugs with low ER H eg . Theophylline. For such drugs, what ever concentration of drug present in the blood perfuses liver, is more than what the liver can eliminate. Hepatic clearance of a drug with high ER is independent of protein binding Slide 70: 2. INTRINSIC CAPACITY CLEARANCE ( Cl INT ) IT IS DEFINED AS THE ABILITY OF AN ORGAN TO IRREVERSIBLY REMOVE A DRUG IN THE ABSENCE OF ANY FLOW LIMITATION DRUG WITH LOW ER H AND WITH ELIMINATION PRIMARILY BY METABOLISM ARE GREATLY AFFECTED BY CHANGE IN ENZYME ACTIVITY HEPATIC CLEARANCE OF SUCH DRUGS IS SAID TO BE capacity-limited Eg . THEOPHYLINE THE t 1/2 OF SUCH DRUGS SHOW GREAT INTERSUBJECT VARIABILITY. HEPATIC CLEARANCE OF DRUGS WITH LOW ER IS INDEPENDENT OF BLOOD FLOW RATE BUT SENSITIVE TO CHANGE IN PROTEIN BINDING Slide 71: ORGAN CLEARANCE Slide 72: IT IS THE BEST WAY OF UNDERSTANDING CLEARANCE IS AT INDIVIDUAL ORGAN LEVEL. SUCH A PHYSIOLOGIC APPROCH IS ADVANTAGEOUS IN PREDICTING AND EVALUATING THE INFLUENCE OF PATHOLOGY , BLOOD FLOW , P-D BINDING , ENZYME ACTIVITY , ETC ON DRUG ELIMINATION Slide 73: AT ORGAN LEVEL , THE RATE OF ELIMINATION CAN BE WRITTEN AS : RATE OF ELIMINATION= _ BY ORGAN RATE OF PRESENTATION TO THE ORGAN RATE OF EXIT FROM THE ORGAN RATE OF PRESENTATION= TO THE ORGAN(INPUT) ORGAN BLOOD X FLOW (Q.C IN ) ENTERING CONC. RATE OF = EXIT ORGAN BLOOD X FLOW (Q.C OUT ) EXITING CONC. Slide 74: references Lehne, Richard A.. Pharmacology for Nursing Care, 6th Edition. 062006: Saunders Book Company, 062006. 69. Lewis, Sharon Mantik. Medical-Surgical Nursing (Single Volume): Assessment and Management of Clinical Problems, 7th Edition . 032007: Mosby, 032007. Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993). Human Biology and Health . Englewood Cliffs, New Jersey, USA: Prentice Hall. 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