renal clearance

PRESENTED BY: SHEEMA MUSTAFA 15S66S0103M.PHARM 1 YR 1 SEM

GUIDED BY : MR. SAFFWAN ALI KHAN M.PHARM . PHD DEPT. OF PHARMACOLOGY

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Drug Excretion

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Excretion:• Excretion is the process by which waste products of metabolism and other

non-useful materials are eliminated from an organism• or• Excretion is defines as the process where by drugs and / or their

metabolites irreversibly transferred from internal to external environment.• the principal organs of excretion are kidneys. • The excretion of drugs by kidneys is called as Renal excretion.• Excretion by organs other than kidneys such as lungs , biliary system ,

intestine , salivary gland and sweat glands is known as Non-renal excretion.

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RENAL EXCRETION

NON RENAL EXCRETION

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CL = Rate of drug eliminatoin (dX/dt) Drug concentration in plasma(C)

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It is the ability of the liver to clear off the drug from the blood is called hepatic clearance.It is related to two variables namely hepatic blood flow rate (QH) and intrinsic hepatic clearance (clint) by the following equation,

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The rate of the drug from a particular organ is known as organ clearance.

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Renal clearance(CLr) is defines as the volume of blood or plasma that is completely cleared off the drug by the kidneys per unit time.

CLr = rate of elimination through kidneys C

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kidneys are the most important organs for the excreting unchanged drugs and their metabolites. Polar drugs are usually excreted in unchanged from but lipid soluble drugs are eliminated as metabolites. Drugs are eliminated unchanged from are digoxin , furosemide , gentamycin and t-tubocurarine where as drugs eliminated as metabolites are sulfonamides , penicillin , nalidixic acid , barbiturates , aspirin etc… the three important process that take place in nephrons , which determine the excretions of drugs in urine are:

1.Glomerular filtration 2. Tubular secretion 3. Tubular reabsorption

Net renal excretion= (Glomerular filtration + tubular secretion) – (tubular reabsorption)

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1.GLOMERULAR FILTRATION:

About 1.2 liters/min of blood flow through the kidneys and about 120 ml/min is filtered through glomerular filtration. It is a passive process, where the excretion of drugs is influenced by the following factors.

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a) Molecular size

b) Plasma protein-drug binding

c) Renal blood flow

d) Ionized drug

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2.TUBULAR SECRETION:

It is a carrier-mediated active transport process ( i.e energy dependent process). The transporters involved in tubular secretion of weak acids (anionic substances)And weak bases (cation substances ) are organic anion transporter (OAT) , organic cation transporter OCT), p-glycoprotein andmulti drug resistance associated protein type-2 (MRP-2) in the proximal tubule. this transport process is further catogorized into,

a) Organic acid / anion transport

b) Organic base / cation transport

EXAMPLES:a)Both probenecid (an organic acid ) and penicillin are usually secretd by tubular OATP ( organic acid transport protein). Probenecid competitively inhibits the tubular secretion of penicillin and increases the its concentration in plasma .b)Tubular secretion of methotrexate is decreased by salicylates.c)Excretion of tolbutamide is inhibited by sulfinpyrazone.

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3. TUBULAR REABSORPTION: Tubular reabsorption is a bidirectional process which takes place along the entire length of the convoluted tubule. Tubular reabsorption of a drug is said to occur when the glomerular filterationrate is less than 120 ml/min. it may be active or passive.

ACTIVE PROCESS

PASSIVE PROCESS

A) pka of the Drug and PH of Urine B) Rate of the urine Flow

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a) PKA OF THE DRUG AND PH OF URINE:

Ionization of the drugs is effected by the changes in urinary PH which may be brought about by diet ,drugs , or any diseased condition . In acidic urine , the weak bases get ionized and their reabsorption decreases. Similarly , in alkaline urine , ionization of weak acids occur resulting in their decreased reabsorption.

THE HANDERSON –HASSEL BATCH EQUATION help to determine the relative amounts of ionized and unionized (weakly acidic and basic) drugs in urine at a given PH as well as percentge of ionized drug at that particular PH.

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FACTORS AFFECTING RENAL CLEARANCE :

1.Physiochemical properties of drug molecules.2.Plasma drug concentration3.Urine pH4.Apparent volume of distribution (vd)5.Blood flow to kidneys 6.Disease states7.Biological factors8.Drug interactions

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1) PHYSICOCHEMICAL PROPERTIES OF DRUG MOLECULES:

The important physicochemical factors affecting renal exretion of a drug are

Molecular size Pka Lipid solubility

2). PLASMA CONCENTRATION OF THE DRUG:

Glomerular filtration and reabsorption are directly affected by plasma drug concentration since both are passive process.

A drug that is not bound to plasma and excreted by filtration only shows alinear relationship between rate of excretion and plasma drug concentration.

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3 Urine PH: In acidic urine , weak bases get ionized and thus their reabsorption decreases. In alkaline urine , weak acids occur resulting in their decreased reabsorption.4.Apparent volume of distribution: Higher the( VD ), poor is the rate of urinary excretion of drugs and vice versa.

5. Blood flow to kidneys: Higher the renal blood flow is desirable for faster urinary excretion og drugs.

6. Disease states:

uraemia: impaired glomerular filtration

accumulation of drugs

toxicity

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7)BIOLOGICAL FACTORS:

AGE :

Age can affect the renal clearance .

Renal clearance is reduced in NEONATES and ELDERLY.

Renal clearance of drugs is about 10% lower in females than in males.

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Renal excretion of drugs gets severely affected when drug interactions have altered the protein drug binding , urinary PH renal blood flow , active secretion etc.. Examples:Gentamycin is highly protein bound drug . However , when it is displaced from its binding sites by furosemide , its plasma levels increase which accelerate its renal clearance.

8)DRUG INTERACTIONS:

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Mechanism of renal clearance

Renal clearance ratio

Renal clearance (ml/min)

example

1.Glomerular filtration+ tubular reabsorption (completely)

0 0 glucose

2.Glomerular filtration+ tubular reabsorption

0-1 <130 lipophilic drugs

3.Only glomerular filtration

1 130 creatinine , inulin

4.Glomerular filtraion + tubular secretion

5. When clearannce = renal plasma flow rate

>1 >130

650

polar drugs

iodopyracet

Renal clearance ratio:

Renal clearance ratio or excretion ratio may be defined as the ratio of renal clearance of a drug to the renal clearance of creatinine . It has no units.

Renal clearance ratio = renal clearance of drug / renal clearance of creatinine

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CONCLUSIONS:

It helps to determine the contribution of glomerular filtration , secretion and tubular reabsorption in clearing a particular drug by comparing the clearance of the drug with that of the creatinine ( excreted only by glomerular filtration).

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• www.authorstream.com/.../kesarwaniarti-1755814-excretion-drugs-renal.

• Kaplan Step1 Pharmacology.• www.ncbi.nlm.nih.gov/pubmed/20727508.• www.austincc.edu/emeyerth/clearancehtm.htm• www.authorstream.com/.../swathinaveen-

919516-excretion-seminar.

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