EXCRETION OF DRUGS

SUBMITTED BY

V.SUHASINI M.PHARM

(PHARMACEUTICS)1

• Excretion is a process whereby drugs are transferred from the internal to the external environment

• Despite the reduction in activity that occurs as a drug leaves its site of action, it may remain in the body for a considerable period, especially if it is strongly bound to tissue components.

• Excretion, along with metabolism and tissue redistribution, is important in determining both the duration of drug action and the rate of drug elimination.

• Principal organs involved – Kidneys, – Lungs, – Biliary system– Intestines– Saliva– Milk.

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TYPES OF EXCRETIONTYPES OF EXCRETION1.1. RENAL EXCRETIONRENAL EXCRETION2.2. NON RENAL EXCRETIONNON RENAL EXCRETION

Biliary excretion. Pulmonary excretion. Salivary excretion. Mammary excretion. Skin / Dermal excretion. Gastrointestinal excretion. Genital excretion

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Renal excretion

• The major organ for the excretion of drugs is the KIDNEY.

• The functional unit of the kidney is the nephron.

• Rate of = rate of + rate of - rate of excretion filtration secretion reabsorption

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Urinary excretion of drug

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Kidney is the primary organ of removal for most drugs especially for those that are water soluble and not volatile.

The three principal processes that determine the urinary excretion of a drug

1.glomerular filtration,2. tubular secretion, and 3.tubular reabsorption

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Glomerular Filtration• The ultrastructure of the glomerular capillary

wall is such that it permits a high degree of fluid filtration while restricting the passage of compounds having relatively large molecular weights.

• This selective filtration is important in that it prevents the filtration of plasma proteins (e.g., albumin)

• Several factors, including molecular size, charge, and shape, influence the glomerular filtration.

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• Compounds with 20 Å to 42Å may undergo glomerular filtration.

• Charged substances (e.g., sulfated dextrans) are usually filtered at slower rates than neutral compounds (e.g., neutral dextrans), even when their molecular sizes are comparable.

Factors that affect the glomerular filtration rate (GFR) also can influence the rate of drug clearance.

• For instance, inflammation of the glomerular capillaries may increase GFR

• Anything that alters drug–protein binding, however, will change the drug filtration rate. 9

• 25% cardiac output or 1.2 liters of blood/min that goes to the kidneys via renal artery and 10% or 120 to 130 ml/min is filtered through the glomeruli the rate being called as the glomerular filtration rate

• The GFR can be determined by an agent that is excreted exclusively by filtration and is neither secreted nor reabsorbed in the tubules

• The excretion rate value is 120 to 130 ml/min • Creatinine , inulin , mannitol and sodium thio sulfate are used

to estimate GFR of which the former two are widely used to renal function

1. Active tubular secretion 2. Active tubular reabsorption

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Active Tubular Secretion• This mainly occurs in proximal tubule.• This is an active process. • It is a carrier mediated process which requires energy for

transportation of compounds against the conc gradient • This active tubular secretion mechanism have been

identified 1. System for secretion of organic acids/anion like penicillins ,

salicylates , glucuronides , sulfate . It is the same system by which endogenous acid such as uric acid are secreted

2. System for scretion of organic bases/ cation like morphine , mecamylamine , hexamethonium . It is the same system by which endogenous amines such as catecholamines , choline , histamine

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TUBULAR REABSORPTION • Tubular reabsorption occurs after the

glomerular filtration of drug. It takes place all along the renal tubule

• Tubular secretion and reabsorption results in an increase in the half life of a drug

• Tubular reabsorption can either be an 1.Active process 2.Passive process

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ACTIVE TUBULAR RE-ABSORPTION• Is commonly seen with high threshold

endogenous substances or nutrients that the body needs to conserve such as electrolytes, glucose, vitamins, amino acids etc.

• Uric acid is also actively re-absorbed. Reabsorption is inhibited by a uricosoric agent, through competitive inhibition.

• Very few drugs undergo reabsorption actively example : oxopurinol

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PASSIVE TUBULAR REABSORPTION• The membrane is readily permeable to lipids, so

filtered lipid-soluble substances are extensively reabsorbed.

• At this site, much of the water in the filtrate has been reabsorbed and therefore the concentration gradient is now in the direction of re-absorption.

• Thus, if a drug is non-ionized or in the unionized form it may be readily reabsorbed.

• Depend upon the degree of ionization on two important factor

1. pH of the urine2. pKa of the drug

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pH OF THE URINE• Urine pH 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.

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HENDERSON-HESSELBACH HENDERSON-HESSELBACH EQUATIONEQUATION

1)FOR WEAK ACIDS pH= pKa +log % of drug ionized =

[ ionized ]

[unionized]

10 pH – pKa X 100

1+10pH –pKa

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HENDERSON-HESSELBACH HENDERSON-HESSELBACH EQUATIONEQUATION

2)FOR WEAK BASE pH= pKa +log

% of drug ionized

[unionized]

[ionized]

10 pH – pKa X 100

1+10pH –pKa

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pKa OF THE DRUG

• compound is greatly dependent upon its pKa and lipid solubility

• A polar and ionized drug will be poorly reabsorbed passively and excreted rapidly

• Reabsorption is also affected by the lipid solubility of drug.

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• urine pH and drug pKa and lipid solubility on reabsorbed of drugs is summarized as follows

1. An acidic drug eg. penicillin or a basic drug eg. gentamicin are polar in their unionized form, is not reabsorbed passively, irrespective of the extent of ionization in urine

2. Only for an acidic drug in the pKa range 3– 8 example : NSAIDS and basics drug in pKa range 6-12 morphine

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CONCEPT OF CLEARANCE

• The clearance concept was 1st introduced to described renal excretion of endogenous compound in order measure the kidney function

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.

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• Renal clearance can be calculated as part of the total body clearance for a particular drug.

TOTAL BODY CLEARANCE:-

Is defined as the sum of individual clearances by all eliminating organs is called total body clearance/ total systemic clearance.

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• Renal clearance can be used to investigate the mechanism of drug excretion

RENAL CLEARANCE:- is defined as the volume of blood/ plasma which is completely cleared of the unchanged drug by the kidney/unit time ClR = rate of urinary excretion ÷ plasma drug concentration

Or

ClR = rate of filtration + rate of secretion – rate reabsorption C

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FACTORS AFFECTING FACTORS AFFECTING RENAL EXCRETIONRENAL EXCRETION

Physicochemical properties of drugPhysicochemical properties of drug

Urine pHUrine pH

Blood flow to the kidney Blood flow to the kidney

Biological factor Biological factor

Drug interactionDrug interaction

Disease stateDisease state

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PHYSICOCHEMICAL PHYSICOCHEMICAL PROPERTIES OF DRUGPROPERTIES 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.

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BIOLOGICAL FACTORSBIOLOGICAL FACTORS• Age, sex, species, 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..

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DRUG INTERACTIONDRUG INTERACTION1. Any drug interaction that result in alteration of

binding characteristics, renal blood flow, active secretion, urine pH, intrinsic clearance would alter renal clearance of drug.

2. 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.

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DISEASE STATEDISEASE STATE•RENAL DYSFUNCTIONRENAL 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. •UREMIAUREMIA 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.

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NON-RENAL ROUTE OF NON-RENAL ROUTE OF DRUG EXCRETIONDRUG EXCRETION

Biliary Excretion

Pulmonary Excretion

Salivary Excretion

Mammary Excretion

Skin/dermal Excretion

Gastrointestinal Excretion

Genital Excretion

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BILIARY EXCRETIONBILIARY EXCRETION

Bile juice is secreted by hepatic cells of the liver.

Its important in the digestion and absorption of fats

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

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PULMONARY EXCRETIONPULMONARY 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 PE

• gaseous drugs are excreted but not metabolites• Alcohol which has high solubility in blood and

tissues are excreted slowly by lungs

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SALIVARY EXCRETIONSALIVARY 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.• Compounds excreted in saliva are Caffeine,

Phenytoin, Theophylline

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MAMMARY EXCRETIONMAMMARY EXCRETION• Milk consists of lactic secretions which is rich in fats and

proteins• 0.5 to 1 litr of milk is secreted per day in lactating mothers• pH of milk varies from 6.4 to 7.6• Highly plasma bound drug like Diazepam is less secreted in

milk• 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.

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SKIN EXCRETIONSKIN EXCRETION• Drugs excreted through skin via sweat• Compounds like benzoic acid, salicylic acid,

alcohol and heavy metals like lead, mercury and arsenic are excreted in sweat.

• Excretion of drugs through skin may lead to urticaria and dermatitis

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GASTROINTESTINAL EXCRETIONGASTROINTESTINAL EXCRETION• 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 GIT • Drugs excreted in GIT are reabsorbed into

systemic circulation

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Hemodialysis

• Hemodialysis or ‘artificial kidney’ therapy is used in renal failure patient to remove toxic waste material from the body

• Only water soluble substance are dialyzed. Lipid soluble drug cannot be removed by dialysis method example: glutethimide

• molecular weight less then 500 daltons should be dialyzed . Drug having large molecular weight cannot dialyzed example : vancomycin

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• Biopharmaceutics and clinical pharmacokinetics by Milo Gibaldi, 4th ed.; 1991.

• Brahmankar MD,Jaiswal S., Biopharmaceutics & pharmacokinetics A treatise

• www.google.com

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