Dr kifayat khan

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pharmacokinetics

• Deals with absorbtion,distribution, biotransfermation(metabolism) and excreation of drug

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.)

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TYPES OF EXCRETION

1. RENAL EXCRETION2. NON RENAL EXCRETION

Biliary excretion.

Pulmonary excretion.

Salivary excretion.

Mammary excretion.

Skin / Dermal excretion.

Gastrointestinal excretion.

Genital excretion.

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ANATOMY OF NEPHRON

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Major Excretory Processes in the Nephron

• Glomerular filtration – Increase drug conc. in lumen

• Tubular secretion – Increases drug conc. in lumen

• Tubular re-absorption – Decreases drug conc. in lumen

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1) 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. Molecules of low molecular weight are filtered out of the blood • Most drugs are readily filtered from the blood unless they are tightly bound to

plasma protein or have been incorporated into red blood cells. • Normal GFR in healthy individuals is 110 to 130 ml/min. • About 10% of the blood which enters the glomerulus is filtered

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. This filtration rate is often measured by determining the renal clearance of inulin.,creatinine

• Inulin is readily filtered in the glomerulus, and is not subject to tubular secretion or re-absorption. Thus inulin clearance is equal to the GFR.

• The normal GFR rate is 120-130 ml/min.

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2) ACTIVE 2) ACTIVE TUBULAR SECRETION SECRETION It is carrier mediated active process(requires a carrier and a

supply of energy) This mainly occurs in proximal tubule.• The process; also subject to competitive inhibition (e.g. Penicillin

& Probenecid), and is saturable.• Not affected by pH and protein binding.

• Drugs or compounds which are extensively secreted, such as p-aminohippuric acid (PAH), may have clearance values approaching the renal plasma flow rate of 425 to 650 ml/min,

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

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3) 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. Active Tubular Reabsorption:

Its commonly seen with endogenous substances or nutrients that the body needs to conserve e.g. electrolytes, glucose, vitamins, amino acids.

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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.

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FACTORS AFFECTING RENAL EXCRETION

1) Urine pH and pKa.

2) Urine flow rate.

3) Physicochemical properties of drug.

4) Distribution and Binding characteristic of drug.

5) Blood flow to the kidneys.

6) Biological factors.

7) Drug interactions.

8) Disease states.

i) pH and pKa OF THE URINE :It varies between 4.5 to 7.5 depending on the diet (e.g. meat can cause a more

acidic urine) or food rich in carbohydrate ↑ pH

Many drugs are either weak bases or acids and therefore the pH of the filtrate can greatly influence the extent of tubular re-absorption for many drugs.

When urine is acidic, weak acid drugs tend to be reabsorbed. Alternatively when urine is more alkaline, weak bases are more extensively reabsorbed

Excretion of some drugs can be increased by suitable adjustment of urine pH e.g. pentobarbital (a weak acid) overdose may be treated by making the urine more alkaline with sodium bicarbonate injection.

• Acetazolamide(carbonic anhydrase inhibitor) and antacids produce alkaline urine, while ascorbic acid makes it acidic

• 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 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)

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

Reabsorption is also affected by the lipid solubility of drug ; an 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.

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ii) 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.iii)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.

iv) 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.

v) 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.

vi) 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.

vii)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.

viii) 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(azotemia)

– Characterized by Impaired GF , accumulation of fluids & protein metabolites(NH3),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’

• If the renal clearance is less than 120 ml/min then we can assume that at least two processes are in operation, glomerular filtration and tubular re-absorption.

• If the renal clearance is greater than 120 ml/min then tubular secretion must be contributing to the elimination process.

• It is also possible that all three processes are occurring simultaneously..

Renal clearance values can range from 0 ml/min ( glucose) to a value equal to the renal plasma flow of about 650 ml/min (for compounds like p-aminohippuric acid). We can calculate renal clearance using the pharmacokinetic parameters kel and Vd. CLrenal = kel * Vd.

RC = UV/P

RC = renal clearance rateU = drug concentration in urineV = 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

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NON-RENAL ROUTE OF DRUG EXCRETION

Various routes are ;

1) Biliary Excretion

2) Pulmonary Excretion

3) Salivary Excretion

4) Mammary Excretion

5) Skin/dermal Excretion

6) Gastrointestinal Excretion

7) Genital Excretion

1 ) 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(illium) and transported back to the liver for resecretion. The metabolites are more excreted in bile than parent drugs due to increased polarity. Ex. of drugs excreted in the bile are chloromphenicol, morphine and indomethacin.The reabsorbed drugs are again carried to the liver for resecretion via bile into the intestine.

Several factor influence secretion of drug in bile are;

1) Molecular weight.2)Polarity.3)Other factor like sex,spices, disease state, drug interation.

Enterohapatic circulation

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.mettalic taste in mouth after taking flagyl(metronidazole) is other example

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.

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 :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

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