drug-excretion.ppt
DESCRIPTION
Drug excretion. pharmacology, pharmacokinetics, Drug eliminationTRANSCRIPT
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