Excretion Of Drugs

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Excretion Of Drugs:

Excretion Of Drugs Guided by : Presented by Dr V M Motghare Dr Rushikesh Deshpande Prof & Head JR II Dept of Pharmacology SWAMI RAMANAND TEERTH RURAL MEDICAL COLLEGE AMBAJOGAI 1

Drug Elimination :

Drug Elimination Termination of drug effect is by the process of drug elimination which involves mainly two processes: Metabolism : predominantly in the liver and kidney. Excretion of unchanged drug or its metabolite predominantly by kidney. Excretion also takes place in the gut, skin, lungs, sweat glands, breast and salivary glands. In addition there is a third process of termination of drug action i.e. process of redistribution of drug. 2

Drug Elimination :

Drug Elimination The onset of pharmacological response depends on: Drug absorption Drug distribution The duration and intensity of action depends upon: Tissue redistribution of drug and The rate of elimination 3

Excretion of drugs:

Excretion of drugs 4

Introduction :

Introduction “Excretion is defined as the process whereby the drugs and/or their metabolites are irreversibly transferred from internal to external environment.” 5

Types Of Excretion :

Types Of Excretion Renal excretion. Non-renal excretion. Lungs. Biliary system. Intestine. Salivary glands. Sweat glands. 6

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Renal excretion of drugs :

Renal excretion of drugs 8

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Agents that are excreted in urine are- Water soluble Non-volatile Small in molecular size (<500 daltons ) The ones that are metabolized slowly. The principle processes that determine the urinary excretion of a drug are- Glomerular filtration. Active tubular secretion. Active or passive tubular Reabsorption. 9

Renal Excretion :

Renal Excretion Rate of Excretion= (Rate of Filtration + Rate of Secretion) –(Rate of Reabsorption ) 10

Glomerular filtration::

Glomerular filtration: Non-selective, unidirectional. Most compounds, ionized or unionized are filtered except those that are bound to plasma proteins or blood cells , thus behaving as macromolecules. The driving force for filtration through the glomerulus is the hydrostatic pressure of the blood flowing in the capillaries. The glomerulus acts as a negatively charged selective barrier promoting retention of anionic compounds. 11

Glomerular filtration::

Glomerular filtration: Substances used for determination of GFR: Creatinine . Inulin . Mannitol . Sodium thiosulphate . 12

Active tubular secretion::

Active tubular secretion: Carrier mediated, capacity limited, saturable . Occurs in proximal tubule of nephron . Requires energy for transportation of compounds against concentration gradient. Unaffected by pH & protein binding. Dependent on renal blood flow. 13

Active tubular secretion::

Active tubular secretion: System for secretion of organic acids/anions: e.g. penicillin, salicylates , glucuronides , sulphates & endogenous substances like Uric acid. System for secretion of organic bases or cations ; e.g. Morphine, mecamylamine,hexamethonium , endogenous amines like catecholamines , choline , histamine. 14

Active tubular secretion:

Active tubular secretion Two structurally similar drugs having similar ionic charge and employing the same carrier- mediated process for excretion enter into competition. A drug with greater rate of clearance will retard the excretion of other drug with which it competes. The half life of both the drugs is increased since the total sites for active secretion are limited. 15

Active tubular secretion:

Active tubular secretion Competition Increased half-life Precipitation of toxicity 16

Active tubular secretion::

Active tubular secretion: Therapeutic advantages of competition: Probenicid inhibits active tubular secretion of organic acids e.g. Penicillin, PAS, PAH,17-ketosteroids: increases their plasma conc. 2 fold. Probenecid acts as a uricosuric agent in treatment of gout.  It suppresses the carrier mediated reabsorption of endogenous metabolite uric acid. 17

Active tubular secretion:

Active tubular secretion Therapeutic disadvantages of competition: Inhibition of nitrofurantoin secretion by probenecid decreased efficacy 18

Tubular Reabsorption::

Tubular Reabsorption: Takes place all along renal tubule. Results in increases in half-life of a drug. Active Tubular Reabsorption: Seen with high threshold endogenous substances or nutrients that the body needs to conserve. e.g. glucose, electrolytes, vitamins, amino acids, uric acid . Drugs – oxopurinol 19

Passive tubular Reabsorption::

Concentration gradient is the prime driving force. Primary determinant : Lipophilicity . Lipophilic substances are extensively reabsorbed as compared to polar substances. Passive tubular Reabsorption: 20

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Majority of drugs are weak electrolytes (weak acids or weak bases), so their re-absorption depends upon: pH of urine: (4.5-7.5) pKa of a drug pKa values govern the degree of ionisation at a particular pH. Urine flow rate . Those drugs whose reabsorption is pH-sensitive, e.g. weak acids and weak bases, show dependence on urine flow rate. 1 Reabsorption α ------------------------------- Urine Flow Rate 21

Factors Affecting Renal Excretion/Clearance:

Factors Affecting Renal Excretion/Clearance 22

Factors Affecting Renal Excretion:

Factors Affecting Renal Excretion Physicochemical properties of the drug Plasma concentration of the drug Distribution and binding charectiristics of the drug Urine pH Blood flows to the kidneys Biological factors Drug interactions Disease states. 23

a) Physicochemical Properties Of Drug:

a) Physicochemical Properties Of Drug Molecular size pKa 24 Mol. Wt. Excretion pattern < 300 Daltons Urine, < 5% in bile >500 Daltons Bile, <5% in urine 300-500 Both urine and bile

Physicochemical Properties Of Drug:

Physicochemical Properties Of Drug lipid solubility urinary excretion is inversely related to lipophilicity . Stereochemical nature: Chloroquine , disopyramide & terbutaline are stereoselectively secreted by kidneys. 25

b) Plasma Conc. Of Drug:

b) Plasma Conc. Of Drug Glomerular filtration and Reabsorption are directly affected by plasma concentration. 26

c) Distribution and binding characteristics of the drug :

c) Distribution and binding characteristics of the drug Clearance is inversely related to apparent volume of distribution of drugs. A drug with large V d is poorly excreted in urine. Drugs restricted to blood compartment have higher excretion rates. 27

d) Urine pH:

d) Urine pH The pH of urine varies between 4.5 – 7.5, thus creating large pH gradient between urine and plasma. The pH of urine is dependent upon diet, drug intake and patho -physiology of patient. The relative amount of ionised and unionised drug in the urine at a particular pH an the % of drug ionised at this pH can be computed from the Henderson- Hasselbach equations . pH = pKa + log ( Ionised drug/ Unionised drug)…Weak acids pH = pKa + log ( Unionised drug/ Ionised drug)…Weak bases The therapeutic activity of urinary antiseptic hexamine depends upon urine pH. (gets converted to active form formaldehyde at acidic pH) 28

e) Renal blood flow:

e) Renal blood flow Important for drugs excreted by Glomerular filtration only and those are actively secreted. In case of drugs which are actively secreted: increased perfusion  increased contact of drug with secretary site  increased excretion. i.e. perfusion rate limited. 29

f) Biological factors:

f) Biological factors Renal excretion is 10% lower in females . Newborns : 30-40% less (attains maturity between 2.5-5 months of age) Old age : GFR decreased, excretion decreased, increased t 1/2 . 30

g) Drug interactions:

g) Drug interactions Alteration of Protein-Drug binding: The renal clearance of drugs extensively bound to plasma proteins is increased after displacement with another drugs. E.g. Gentamicin induced nephrotoxicity by Furosemide .. ( Furosemide displaces gentamicin from protein) 31

Drug interactions:

Drug interactions Alteration of urine pH: Acidification of urine: by ammonium chloride, methionine and ascorbic acid  enhances excretion of basic drugs. E.g. morphine, Amphetamine. Alkanisation of urine : by citrates, tartarates , bicarbonates and carbonic anhydrase inhibitors  enhances excretion of acidic drugs e.g. barbiturates, salicylates . Prevention of crystalluria caused by precipitation of sulphonamides in the renal tubules. 32

Drug interactions:

Drug interactions Competition For Active Secretion: Probenicid : competitive inhibitor of organic anion transport system. Cimetidine : competitive inhibitor of organic cation transport system. 33

Drug interactions:

Drug interactions Forced diuresis : All diuretics increases elimination of drugs whose renal clearance gets affected by renal blood flow rate. 34

h) Disease states:

h) Disease states Renal dysfunction: Greatly impairs elimination of drugs primarily excreted by kidneys. 35

Disease states:

Disease states Uraemia : Impaired Glomerular Filtration Accumulation Of Drugs Toxicity. 36

Non-renal Routes Of Drug Administration:

Non-renal Routes Of Drug Administration 37

Introduction:

Introduction Drugs and their metabolites may also be excreted by routes other than renal route, called as extrarenal or nonrenal routes of drug excretion. Biliary excretion. Pulmonary excretion Salivary excretion Mammary excretion Skin/Dermal excretion Gastrointestinal excretion Genital excretion 38

Biliary Excretion Of Drugs -Enterohepatic Cycling :

Biliary Excretion Of Drugs - Enterohepatic Cycling 39

BILIARY EXCRETION:

BILIARY EXCRETION Bile juice is secreted by hepatic cells of the liver. The flow is steady-0.5 to 1 ml /min. 90% of bile acid is reabsorbed from intestine and transported back to the liver for resecretion . Greater the polarity better the excretion. The metabolites are more excreted in bile than parent drugs due to increased polarity. 40

Biliary Excretion:

Biliary Excretion Active process Capacity limited, saturable . E.g. Quinine Cholchicine Vinblastine D- tubocurarine Vecuronium Corticosteroids Erythromycin Chlorpromazine 41

Enterohepatic Cycling / Enterohepatic Circulation Of Drugs: :

Enterohepatic Cycling / Enterohepatic Circulation Of Drugs: 42

Enterohepatic Cycling:

Enterohepatic Cycling “The phenomenon of drug cycling between the intestine and the liver.” e.g. cardiac glycosides, rifampicin, chlorpromazine, indomethacin . Increased t 1/2 e.g oral contraceptives, DDT. Prolongation of drug action : e.g. Rifampicin – this drug is deacetylated by liver and both the free drug and deacetylated metabolite are excreted through bile into the gut from where rifampicin is reabsorbed while deacetylated metabolites is excreted through faeces . This drug acting as a small circulating reservoir  prolongation of drug action . 43

Enterohepatic Cycling:

Enterohepatic Cycling Certain drug metabolites (particularly Glucuronides ) are excreted through the bile and delivered to the intestine where these metabolites are deconjugated or hydrolysed releasing the parent active drug again. This free drug is then reabsorbed and the cycle is repeated. ( Enterohepatic circulation) E.g. Thyroxine Morphine Chloramphenicol Phenophthalin Ethynil Estradiol Indomethacin (partially secreted as glucuronide ) 44

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Factors Influencing Secretion Of Drugs In Bile: :

Factors Influencing Secretion Of Drugs In Bile: 1. Physicochemical properties of drug : Molecular Weight: Mol. Wt. Excretion pattern < 300 Daltons Urine, < 5% in bile >500 Daltons Bile, <5% in urine 300-500 Both urine and bile 47

Factors Influencing Secretion Of Drugs In Bile::

Factors Influencing Secretion Of Drugs In Bile: 1. Physicochemical properties of drug : b) Polarity Polarity α Excretion Thus metabolites are better excreted in bile rather than parent drug. 48

Factors Influencing Secretion Of Drugs In Bile::

Factors Influencing Secretion Of Drugs In Bile: 2.Nature of biotransformation process – 49

Factors Influencing Secretion Of Drugs In Bile::

Factors Influencing Secretion Of Drugs In Bile: 2. Nature of biotransformation process – e.g. phase II reactions 1. Glucuronidation : Morphine, Chloramphenicol , Indomethacin , Stilbesterol 2. Glutathione: 50

Factors Influencing Secretion Of Drugs In Bile::

Factors Influencing Secretion Of Drugs In Bile: 3.Other factors Sex and species differences Protein drug binding Disease states Drug interactions 51

Pulmonary Excretion:

Pulmonary Excretion 52

Pulmonary Excretion:

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 Excreion . Intact gaseous drugs are excreted but not metabolites. Alcohol which has high solubility in blood and tissues are excreted slowly by lungs. e.g. general anaesthetics - halothane, nitrous oxide etc. alcohol – excreted slowly through lungs. PARALDEHYDE 53

Salivary excretion :

Salivary excretion 54

Salivary Excretion:

Salivary Excretion 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. 55

Salivary Excretion:

Salivary Excretion Passive diffusion process Dependent on pH partition hypothesis Basic drugs secreted more than acidic drugs E.g. Lithium, Tetracycline Metronidazole Pyrizinamide Penicillin Ethosuximide Phenytoin Digoxin Sulphonamide Salicylates Clonidine Estimation of blood levels of drugs like caffeine, theophylline , Phenytoin, carbamazepine Since the S/P ratio is fairly constant . 56

Salivary Cycling Of Drugs:

Salivary Cycling Of Drugs Drugs excreted in saliva can undergo cycling in a fashion similar to enterohepatic cycling e.g. sulphonamides , antibiotics, clonidine etc. Oral Administration Salivary glands GIT distribution elimination Faecal Blood excretion 57

Mammary excretion:

Mammary excretion 58

Mammary excretion:

Mammary excretion Weakly basic drugs concentrate more in milk. E.g. Chloramphenicol , tetracyclines , ergotamine, morphine, metronidazole , carbimazole , bromocriptine , diazepam estrogens/progesterone, Oral contraceptives, antihistaminics senna alkaloids (purgatives) 59

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BREAST MILK PLASMA (pH 6.6) (pH 7.4) Weak Bases Weak Bases ( Ionised ) ( nonionised ) Weak Acids Weak Acids ( nonionised ) ( ionised ) 60

Mammary excretion:

Mammary excretion Drug Effect Chloramphenicol Bone marrow depression Diazepam Accumulation and sedation Heroin Prolonged neonatal dependence Methadone Possible withdrawal symptoms if breast feeding is stopped suddenly Propylthiouracil Suppression of thyroid function 61

Mammary excretion:

Mammary excretion Drug Effect Tetracycline Permanent staining on teeth Sulphonamides Kernicterus Penicillin Allergy Ampicillin Diarrhea Dapsone Hemolytic anemia Phenindione Bleeding Phenobarbitone Drowsiness Phenytoin Methhemoglobinemia Theophylline Restlessness 62

Skin excretion (Sweat) :

Skin excretion (Sweat) 63

Skin excretion(Sweat):

Skin excretion(Sweat) Depends on pH partition hypothesis. keratin precursor cells: Griseofulvin Hair follicles : Arsenic , Mercury, Iodides Sweat: urea derivatives, amines, heavy metals Benzoic acid , Salicylic acid , Alcohol. Sweat patch Amphetamine Ethanol Heroin cannabis Nicotine 64

Gastrointestinal excretion (faecal elimination) :

Gastrointestinal excretion ( faecal elimination) 65

Gastrointestinal Excretion:

Gastrointestinal Excretion Water soluble and ionised form of weakly acidic and basic drugs is excreted in GIT . E.g. Nicotine quinine MgSO4 Streptomycin Neomycin Bacitracin Cholestyramine Erythropoitein Chlorpromazine Corticosteroids 66

References :

References Study notes – Dr V M Motghare , Prof & Head, Dept of Pharmacology. Principles of Pharmacology- K K Sharma Biopharmaceutics & Pharmacokinetics – D M Brahmankar , Sunil Jaiswal . Pharmacology: basics and clinical aspects – Mrinal Kaushik Modern Pharmacology with clinical applications – Charles Craig. Internet . 67

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