Concept of clearance & factors affecting renal excretion

Concept of clearance & factors affecting renal excretion of drug

1. CONCEPT OF CLEARANCE & FACTORS AFFECTING RENAL EXCRETION PRESENTED BY CHIRANJIBI ADHIKARI M. Pharm. 1 st year   SUBMITTED TO MR. KEERTHY H.S. M. Pharm. Professor Department of Pharmaceutics, Mallige College of Pharmacy.  #71, SILVEPURA, BANGALORE: 560 090 EVALUATION SEMINAR ON

2. CONCEPT OF 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 concentration It is expressed in ml/min. A pplied to all organs involved in drug elimination and referred to as renal clearance, hepatic clearance, pulmonary clearance, biliary clearance and so on. Total body clearance is the sum of individual clearances by all eliminating organs.

3. Renal Clearance Renal clearance ( Cl R ) can be defined as “the volume of blood or plasma which is completely cleared of the unchanged drug by the kidney per unit time”. Cl R = Rate of urinary excretion Plasma drug concentration Cl R = Rate of (filtration + secretion – reabsorption ) Plasma drug concentration Renal clearance ratio = Cl R of drug Cl R of creatinine

4. Relationship between renal clearance values and mechanism of clearance Renal Clearance (ml/min) Renal Clearance Ratio Mechanism of Renal Clearance Examples 0 (least value) < 130 130 (GFR) >130 650 (highest value) Above 0 Below 1 1 > 1 5 Drug filtered and reabsorbed completely. Drug filtered and reabsorbed partially. Drug is filtered only. Drug is filtered and actively secreted. Clearance = renal plasma flow rate. Glucose. Lipophilic drugs. Creatinine , Insulin. Polar, ionic drugs. Iodopyracet , PAH.

5. FACTORS AFFECTING RENAL EXCRETION OR RENAL CLEARANCE 1. Physiochemical properties of drug 2. Plasma concentration of drug 3. Distribution and binding characteristics of drug 4. Urine pH 5. Blood flow to the kidney 6. Biological factors 7. Drug interactions 8. Disease state

6. PHYSIOCHEMICAL PROPERTIES OF DRUG Compounds of weights < 300 Daltons, if water soluble , easily excreted by the kidneys. Drugs or metabolites > 500 Daltons, mainly in bile . Drug pK a govern the degree of ionization at the particular pH. A polar & ionized drugs poorly reabsorbed passively excreted rapidly . Ionized but lipophilic drug passively reabsorbed. Unionized but polar excreted in urine.

7. Stereoselective protein binding drugs drug enantiomers exhibit differential filtration rate . Chloroquine , disopyramide and terbutaline stereoselectively secreted by kidneys . ( active tubular secretion) Stereoselective active tubular reabsorption glucose and amino acids . Passive reabsorption is unaffected.

8. PLASMA CONCENTRATION OF DRUG Affects glomerular filtration and reabsorption . (passive) Actively reabsorbed drugs excrete in urine only when their concentration in the glomerular filtrate > active reabsorption capacity, e.g. glucose.

9. DISTRIBUTION AND BINDING CHARACTERISTICS OF DRUG Drug with larger V d poorly excreted in urine. Drugs bound to plasma protein cannot be filtered through the glomerulus . Cl R = Urine drug concentration × Urine flow rate Plasma drug concentration F u = C u / C Cl R = F u × Urine flow rate

10. Drugs extensively bound to protein have longer half lives as renal clearance is small. Rena clearance oxytetracycline (66% unbound) = 99 ml/min. deoxycycline (7 % unbound) = 16 ml/min. Actively secreted drugs are much less affected by protein binding. E.g. penicillins .

11. BLOOD FLOW OF THE KIDNEY Important in case of: Drugs excreted by glomerular filtration only. Drugs that are actively secreted. In actively secreted drugs, renal clearance is perfusion rate- limited.

12. BIOLOGICAL FACTORS Renal excretion is approx. 10% lower in females. Renal function of newborns is 30-40% less. In old age, the GFR is reduced and tubular function is altered slow excretion of drugs prolonged half-life. Species and strain differences, genetic make-up and circardian rhythms also alter drug excretion.

13. DRUG INTERACTIONS Alteration in protein drug binding : gentamicin induced nephrotoxicity by furosemide . Alteration of urine pH : Acidification of urine with ammonium chloride or ascorbic acid excretion of basic drugs. Alkalinization of urine with citrates, tartarates and bicarbonates excretion of acidic drugs. Complexation for active secretion : phenylbutazone + hydroxyhexamide prolongs action. Probenicid & Cimetidine are competitive inhibitors of organic anion & cation transport system respectively. Forced diuretics

14. DISEASE STATES Renal dysfunction greately impairs elimination of drugs that are primarily excreted by kidneys. Uraemia also impairs renal clearance of drugs. Increase half-lives of drugs. Drug accumulation. Toxicity.

15. Reference: Biopharmaceutics & Pharmacokinetics- a treatise by DM Brahmankar and Sinil Jaiswal . 3 rd edition. P.206-211.