A seminar on ALTERED KINETICS IN RENAL DISEASES BY A.SRILATHA (M.Pharm I sem ) Department of Pharmaceutics BLUE BIRDS COLLEGE OF PHARMACY (Affiliated to Kakatiya University) Bheemaram, Warangal.

CONTENTS Introduction Glomerular Filtration Rate Creatinine Clearance Pharmacokinetic Parameters Dosage Regimen Drugs effect on Binding Conclusion References

Introduction Pharmacokinetics involves the kinetics of drug absorption, distribution & elimination(excretion & metabolism). Statistical methods are used for pharmacokinetic parameter estimation and data interpretation. Disease affects the way drugs are absorbed,distributed,excreted and metabolized. Renal disease directly affects drug excretion but also affects drug binding. Hepatic disease affects drug metabolism.

Renal dysfunction greatly impairs the elimination of drugs especially those that are primarily excreted by the kidneys. Some of the causes of renal failure are hypertension, diabetes mellitus, hypovolemia, pyelonephritis, nephrotoxic agents such as amino glycosides, phenacetin and heavy metals such as lead and mercury. Uraemia characterized by impaired GFR and accumulation of fluids and protein metabolites also impairs renal clearance of drugs. In both these conditions the half lives of the drugs are incresed, as a result drug accumulation and toxicity may result.

Glomerular filtration rate Several drugs and endogenous substances have been used as markers to measure GFR.These markers are carried to the kidney by the blood via the renal artery and are filtered at the glomerulus. Criteria necessary for using a drug to measure GFR  The drug must be freely filtered at the glomerulus.  The drug must not be reabsorbed nor actively secreted by the renal tubules.  The drug should not be metabolized.  Drug should not bind to plasma proteins.

Inulin, a fructose poly saccharide fulfills most of the criteria listed above and is therefore used as a standard reference for the measurement of GFR. Clearance Creatinine is used most extensively as a measurement of GFR. In humans, creatinine is mainly filtered at the glomerulus with no reabsorption. Blood urea nitrogen (BUN) is a commonly used clinical diagnostic laboratory test for renal disease, urea is the end product of protein catabolism and is excreted through the kidney, normal BUN ranges from 10-20mg/dl. Higher BUN levels indicate the presence of renal disease.

Creatinine Clearance It is an endogenous amine produced as a result of muscle catabolism. Excreted unchanged in the urine by GFR.An advantage of this test is that it can be correlated to steady state concentration of creatinine in plasma and no needs no collection of urine. Normal values adjusted to 1.73m 2 body surface area range from ml/min. Creatinine clearance values of ml/min, indicates moderate renal failure, values less than 10ml/min indicates severe renal failure.

Estimation of creatinine clearance PopulationCreatinine clearance/ Serum creatinine Adults(20-100yrs) Males Females Children(1-20yrs) (140-age)*wt/ 72*sc (140-age)*wt/ 85*sc 0.48*ht/ sc *(wt/70) *(140-age)*wt/sc 1.04*(140age)*wt/sc 42.5*ht /sc*(wt/70) 0.7 5

C B A CREATININE CLEARANCE, BIOLOGIC HALF-LIFE TOTAL CLEARANCE, 60 Eg: Relationship between total clearance and renal function (creatinine clearance) for three drugs that are excreted in the urine to different degrees in patients with normal renal function. Vertical line shows clearances and half- lives when renal function is reduced to one-sixth of normal. Renal disease has the largest effect on drug A and the smallest effect on drug C.

Nomograms A nomogram is a chart that displays values of three related variables in vertical columns in such a way that when a ruler is placed across values in any two columns the corresponding values of the variables in the third column can be read directly from chart. Nomograms are used for the calculation of drug dosage regimens in patient with renal disease.

Pharmacokinetic parameters Drug clearance: the volume of plasma cleared of drug per unit time. It determines the maintenance dose rate, required to maintain a plasma concentration. Clearance=rate of elimination/plasma concentration. Volume of distribution: it determines the loading dose(the dose required to achieve a target plasma concentration). Half-life: The time for the concentration of drug in plasma(or the amount of drug in the body) to halve.

Relationship between t 1/2’ Vd and Cl t ½ =0.693 Vd/Cl. It indicates that the half life is dependent on Vd and Cl. vd and Cl are the independent variables. larger Vd largerCl Time Cp

Modification of Pharmacokinetic parameters Patients with renal insufficiency often show modifications of pharmacokinetic parameters which do not bear a direct relationship with the decreasing of GFR. Some drugs often show alteration of the volume of distribution. Eg: Oedema disturbs the behaviour of drugs, the volume of distribution of wish approximately equals the extracellular space, such as sulphonamides. 9

Drugs elliminated almost entirely by the kidneys Drugs elimination entirely unchanged by the kidney (fu=1) (e.g.gentamicin) for these drugs, doses should be reduced in direct proportion to the degree of impairment in creatinine clearance. Drug cl Creatinine clearance

Drugs eliminated almost entirely by extra renal mechanism Drugs eliminated entirely by metabolism (fu=0) (e.g.phenytoin) Drugs cl Creatinine clearance

Drug eliminated by both metabolism and by renal elimination (fu=0.5) (e.g.captopril ). Drug cl Creatinine clearance Drugs that are eliminated partly by the kidney and partly by the metabolism

Dosage regimens The stategy for treating patients with drugs is to give sufficient amounts that the required therepeutic effect. Increase of dosage intervals without changing the dose: it is useful for the drug which are having long serum half life. Reduction of the dose without changing the frequency of administration : the amount of drug in the body during a given dosage interval will be the same for both types of patient, this is reached by reducing the maintenance dose. Loading dose: if the initial dose is the same as the maintenance dose,the height of peak plasma concentrations will increase progressively to reach the steady state blood level after 6 half lives.

Disease effects on drug binding The half life of most drugs depends strongly on tissue binding and protein binding. Albumin is considered to be the most important binding protein in plasma for acid and neutral drugs,AAG is of prime importance in the plasma binding of basic drugs. Protein binding decreases the renal excretion of drugs and enhances the biological half life. Tetracycline's are excreted mainly by glomerular filtration, these drugs bind to protein and results in decreased renal excretion. In hypoalbuminaemia an acidic drug such as phenytoin will have a lower total drug concentration because of lower protein binding. 10

Contraindicated drugs Kidneys already suffering from a nephropathy have an increased sensitivity to nephrotoxic drugs such as some antibiotics, phenyl butazone, gold salts, mercurial diuretics and anaesthetics.

Conclusion Drugs that are extensively excreted unchanged in urine, alteration of the renal function will alter the drugs elimination rate. Many drugs or their metabolites are eliminated partly or completely by the kidneys, thus the usual dosage regimens may need to be adjusted to provide safe and effective treatment for patients with impaired renal function. So i conclude that determination of renal function is important to monitor the dosage regimen. 19

REFERENCES Gibaldi,M, “Biopharmaceutics and Clinical Pharmacokinetics”, fourth edition, ,(2005). Notari, E, Robert, “Biopharmaceutics and Clinical pharmacokinetics”, fourth edition, ,(1987). Rowland M,Tozer N,Thomas, “Clinical Pharmacokinetics and Applications” third edition, ,(2007). Shargel, L, Andrew, Y, “Applied Biopharmaceutics and Pharmacokinetics", fourth edition, ,(1999). Tipnis, H.P,Amrita Bajaj “Principles and Applications of Biopharmaceutics and Pharmacokinets”, ,(2002). Venkateshwarlu V, “Biopharmaceutics and Pharmacokinetics”, ,(2004).

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