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excretion excretion Presentation Transcript

  • MAHARISHI ARVIND INSTITUTE OF PHARMACY MANSAROVAR, JAIPUR. Presented by : Mr. Pinkesh Patel Guided by : Mr. Mahesh Goyal
  • 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.
    • Agent that excreted in urine are :
    • 1. water soluble 2.non volatile
    • 3. small in molecular size(< 500 daltons.)
  • TYPES OF EXCRETION
    • RENAL EXCRETION
    • NON RENAL EXCRETION
      • Biliary excretion.
      • Pulmonary excretion.
      • Salivary excretion.
      • Mammary excretion.
      • Skin / Dermal excretion.
      • Gastrointestinal excretion.
      • Genital excretion.
  • ANATOMY OF NEPHRON
    • 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 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
    • GFR can be determined by an agent which are excreted by filtration and is neither reabsorbed nor secreted in tubules. Ex. Creatinine, inulin etc.
    • The normal GFR rate is 120-130 ml/min.
    • 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.
    • 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.
    • Active Tubular Reabsorption:
    • Its commonly seen with endogenous substances or nutrients that the body needs to conserve e.g. electrolytes, glucose, vitamins, amino acids.
    • 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 secreted nor re-absorbed its conc. In urine will be 100 times that of free drug in plasma.
    • Reabsorption is mainly depend on several factor that are pH, pKa, lipophilicity of drug, urine flow rate.
  • FACTORS AFFECTING RENAL EXCRETION
    • Urine pH and pKa.
    • Urine flow rate.
    • Physicochemical properties of drug.
    • Distribution and Binding characteristic of drug.
    • Blood flow to the kidneys.
    • Biological factors.
    • Drug interactions.
    • Disease states.
    • pH and pKa 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.
  • HENDERSON-HESSELBACH EQUATION
    • For weak acids :
    • pH= pKa +log [ ionized ]
    • [unionized]
    • % of drug ionized = 10 X 100
    • 1+10
    • For weak base :
    • pH=pKa +log [unionized]
    • [ionized]
    • % of drug ionized = 10 X 100
    • 1+10
    (pH – pKa) (pH – pKa) (pKa - pH) (pKa - pH)
    • The significance of pH-dependant excretion for any particular compound is greatly depends upon its pKa & lipid solubility.
    • A characteristic of drugs, pKa value govern the degree of ionization at a particular pH.
    • A polar & ionized drug will be poorly reabsorbed passively & excreted rapidly.
    • 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.
    • 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.
    • PHYSICOCHEMICAL PROPERTIES OF DRUG :
    • Like molecular size, pKa , lipid solubility
    • Molecular size
      • Drugs with Mol.wt <300 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.
    • BIOLOGICAL FACTORS :
    • 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 .
    • BLOOD FLOW TO THE KIDNEY :
    • Important in case of drug excreted by glomerular filteration and those are actively secreted only.
    • Increase the perfusion enhance the elimination.
    • URINE FLOW RATE :
    • Polar drug are not affected by urine pH hence not get reabsorbed so unaffected by urine flow rate.
    • Only those drugs whose reabsorption is pH sensitive Ex. Weak acids and bases depend on urine flow rate.
    • Urine flow rate can be incresed by forced diuresis by large fluid intake or other diuretics.
    • DRUG INTERACTIONS :
    • 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.
    • Alkalinization of urine with citrates and bicarbonates promote excretion of acidic drugs.
    • DISEASE STATE :
    • RENAL DYSFUNCTION
      • Greatly cause the elimination of drugs those are primarily excreted by kidney.
      • Some of the causes of renal failure are hypertention, Diabetes, hypovolemiya(low blood supply to kidney), heavy metals.
    • UREMIA
      • Characterized by Impaired GF , accumulation of fluids & protein metabolites.
      • Half life increased resulting in drug accumulation and increased toxicity.
    • Drug Clearance :
    • ‘ 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.’
    • Clearance [CL]=Elimination rate/plasma drug conc .
    • The sum of individual clearance by all eliminating organ (kidney, liver, lungs, biliary systems) called as ‘Total body clearance’.
    • Renal Clearance ;
    • ‘ The volume of plasma which is completely cleared of the unchanged drug by the kidney per unit time’
      • RC = UV/P
      • RC = renal clearance rate
      • U = drug concentration in urine
      • V = flow rate of urine (ml/min)
      • P = plasma drug concentration
    • Renal clearance tests are used to:
      • Determine the GFR
      • Detect glomerular damage
      • Follow the progress of diagnosed renal disease
      • RC = rf+rs-rr/P
      • rf = rate of filtration
      • rs = rate of secretion
      • rr = rate of reabsorption
  • NON-RENAL ROUTE OF DRUG EXCRETION
    • Various routes are ;
        • Biliary Excretion
        • Pulmonary Excretion
        • Salivary Excretion
        • Mammary Excretion
        • Skin/dermal Excretion
        • Gastrointestinal Excretion
        • Genital Excretion
        • 1 ) BILIARY EXCRETION :
        • Bile juice is secreted by hepatic cells of the liver.
        • 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.
        • The metabolites are more excreted in bile than parent drugs due to increased polarity.
    • Several factor influence secretion of drug in bile are;
      • Molecular weight.
      • Polarity.
      • Nature of biotransformation.
      • Other factor like sex,spices, disease state, drug interation.
        • Nature of bio-transformation process:
        • Phase-II reactions mainly glucuronidation and conjugation with glutathione result in metabolites with increased polarity and molecular weight for biliary excretion.
        • Ex. of drugs excreted in the bile are chloromphenicol, morphine and indomethacin.
        • For a drug to be excreted in bile must have polar groups like –COOH, -SO 3 H.
        • Conjugation with amino acids ,acetylation ,methylation do not result in metabolites with high molecular weight and polarity hence little influence on biliary excretion.
    • Efficacy of drug excretion by biliary system can be tested by an agent that is completely eliminated in bile, Ex. sulfobromophthalein.
    • This marker is excreted in half an hour in intestine when hepatic function is normal. Delay in its excretion indicates hepatic and biliary malfunction.
    • 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.
    • 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
        • Enterohepatic Circulation is important in conservation of vitamins, folic acid and hormones.
        • This process results in prolongation of half lives of drugs like DDT, oral contraceptives.
        • 2 ) PULMONARY EXCRETION :
        • Gaseous and volatile substances such as general anesthetics (Halothane) are absorbed through lungs by simple diffusion.
        • Pulmonary blood flow, rate of respiration and solubility of substance effect pulmonary excretion.
        • Intact gaseous drugs are excreted but not metabolites.
        • Alcohol which has high solubility in blood and tissues are excreted slowly by lungs.
        • 3 ) SALIVARY EXCRETION :
        • The pH of saliva varies from 5.8 to 8.4. Unionized lipid soluble drugs are excreted passively.
        • 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.
        • 4 ) MAMMARY EXCRETION :
        • 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.
        • 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.
        • 5 ) SKIN EXCRETION :
        • 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 are excreted in sweat.
        • 6 ) GASTROINTESTINAL EXCRETION :
        • Excretion of drugs through GIT usually occurs after parenteral administration.
        • Water soluble and ionized form 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.
  • 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
  • REFERENCES
    • Brahmankar M D., Jaiswal S B., Biopharmaceutics and Pharmacokinetics A Treatise vallabh prakasan I edition 2002, p.no;178-192.
    • Shrgel L., Wu-Pong S., Yu A B C., Applied Biopharmaceutics & Pharmacokinetics V edition 2005,Mc Graw Hill publication house p.no;131-159.
    • Venkateswarlu V., Biopharmaceutics and Pharmacokinetics II edition 2008, PharmaMed Press, p.no;103-145.
    • Gibaldi M., Biopharmaceutics and Clinical Pharmacokinetics IV edition 2006, PharmaMed Press,p.no; 203
    • 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.
    • THANK YOU …