DRUG EXCRETION DRUG EXCRETION

DRUG EXCRETIONDRUG EXCRETION

The process by which drugs or

metabolites are irreversibly transferred from

internal to external environment through

renal or non renal route.

Most drugs are excreted in urine either as

unchanged drugs or drug metabolites.

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TYPES OF EXCRETIONTYPES OF EXCRETION

1.1. 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 EXCRETIONRENAL EXCRETION

ANATOMY OF NEPHRONANATOMY OF NEPHRON

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Major Excretory Processes in the Nephron

1. Glomerular filtration

2. Tubular secretion

3. Tubular re-absorption

GLOMERULAR GLOMERULAR FILTRATIONFILTRATION It Is non selective ,

unidirectional process

Ionized or unionized drugs are filtered, except those that are bound to plasma proteins.

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ACTIVE ACTIVE TUBULAR SECRETION SECRETION

This mainly occurs in proximal tubule. Active secretion is Unaffected by change in pH and

protein binding.

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PASSIVE TUBULAR PASSIVE TUBULAR REABSORPTIONREABSORPTION

most substances are reabsorbed across renal tubular cells if unionized and lipid soluble

It occurs after the glomerular filtration of drugs. It takes place all along the renal tubules. Reabsorption results in increase in the half life of

the drug.

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pH OF THE URINEpH OF THE URINE

• It varies between 4.5 to 7.5

• It depends upon diet, drug intake and pathophysiology .

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Acidic drugs usually contain weakly acidic functionalities, such as COOH.

Basic drugs usually contain weakly basic functionalities, such as amines.

Drugs which are acidic are ionized in basic media (pH > 7). Drugs which are basic are ionized in acidic media (pH < 7) The ionized form of the drug provides it with improved water

solubility But the unionized form generally passes nonpolar membranes

more readily. Acidification of urine increases reabsorption and decreases

excretion of weak acids and decreases reabsorption of weak bases. Alkalinization of urine has the opposite effect.

In some cases of overdose, these principles are used to enhance the excretion of weak bases or acids.

e.g. salicylate (Aspirin ) (a weak acid) overdose may be treated by making the urine more alkaline with sodium bicarbonate injection.

Effect of lipid solubility and pH

Glomerular

blood flow; filtrate

99% of GF is re-absorbed;concentration of drug rises in tubule

If lipid soluble drug moves down concentration gradient back into blood

Re-absorption

ionised drug is less lipid soluble

FACTORS AFFECTING FACTORS AFFECTING RENAL EXCRETIONRENAL EXCRETION1.1. Physicochemical properties of drugPhysicochemical 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 drug: 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.

2.2. Biological factor:Biological factor: Age, sex

3. 3. Drug interaction: Drug interaction: increase or decrease

4. 4. Disease state Urine pH: Disease state Urine pH: RF

5. 5. Blood flow to the kidney Blood flow to the kidney

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Handling of Drugs by the Nephron

Glome-rulus

Proximaltubule

Distaltubule

Collectingtubule

Flowml/min

pH control

100

1000Blood flow

Filtrate flow

Water

Drugs

Filter

Filter

80% reabsorb.

secretionReabsorption

10 - 20 % reabsorbed

Blood Flow in the Kidney Is Important

Renal blood flow is ~25% of cardiac output 1.3 L/min

Renal plasma flow is 50% of renal blood flow 650 ml/min

Glomerular filtration rate (GFR) is 20% of plasma flow 130 ml/min In 24 hr, 185-190 Liters are filtered by the glomerulus 24 hr urine output is 1.5-1.7 Liters More than 99% of glomerular filtrate volume must be reabsorbed

BUT water reabsorption does NOT equal solute reabsorption

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. Intact gaseous drugs are excreted but not

metabolites. Alcohol which has high solubility in blood and tissues

are excreted slowly by lungs.

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.

MAMMARY EXCRETIONMAMMARY EXCRETION

Milk consists of lactic secretions which is rich in

fats and proteins.

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..

SKIN EXCRETIONSKIN EXCRETION

Drugs excreted through skin via sweat

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.

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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 stomach.

Drugs excreted in GIT are reabsorbed into

systemic circulation & undergo recycling.

CLEARANCE A very important concept for drug use Clearance (Cl) is the VOLUME of fluid (plasma)

“cleared” (freed) of drug per unit time

Clearance of most drugs is a first order process A constant fraction of drug is cleared per unit time

A fraction is NOT a concentration Therefore, first order clearance is independent of drug

concentration

CLEARANCE

Clearance is independent of the method and route of clearance Hepatic clearance Renal clearance Lung (inhalational) clearance Saliva Mother’s milk

Therapeutic Implications of Clearance Highly ionized drugs tend to be rapidly cleared

Minimal tubular reabsorption since only non-ionized drug is reabsorbed

Alkalinizing urinary pH with Na bicarbonate can accelerate clearance of WOAs Salicylate and barbiturates

Acidifying urinary pH with arginine hydrochloride can accelerate clearance of WOBs Amphetamines

Therapeutic Implications of Clearance

Drug forms that are quite lipid soluble at the pH of the urine (5.5) are readily reabsorbed Maximal tubular reabsorption since non-ionized drug is

reabsorbed

Increasing osmolarity of urine (mannitol) may increase elimination of a lipophilic drug

Therapeutic Implications of Clearance

Tubular secretion of a drug may be inhibited by another drug by competition for the transporter Probenecid competes with penicillins

Thus prolongs action of antibiotic

Probenecid competes with some diuretics (furosemide) and thus may prevent diuretic access to the tubule which is where they act

Decreases effect of diuretic

Therapeutic Implications of Clearance

Drug clearance is decreased by renal disease Measured by creatinine clearance Caused by

Decreased renal blood flow Glomerular tubular damage Tubular nephropathy

Drug clearance is greater in an adult than in Children (immaturity of kidney function) Elderly (decreased renal function Alcoholics