Dose Adjustment in Special cases

Functions of Kidney in Drug excretion Cause of kidney failure and its impact in drug excretion
Inflammation and deterioration of pyelonephrons due to antigens, infection or other cause Hypertension Chronic overloading of kidney with fluid and electrolytes may lead to kidney insufficiency Diabetes mellitus Disturbance of sugar metabolsim and acid-base balance may lead to degenerative renal disease Nephrotoxic drugs/ Certain drugs taken chronically may cause Metals irreversible kidney damage e.g aminoglycosides, phenacetin, heavy metals such as Hg, Pb etc. Hypovolemia Any condition that causes a reduction in renal blood flow will eventually lead to renal ischemia and damage Nephroallergens Certain compounds may produce an immune type sensitivity reaction with nephritic syndroms e.g quartan malaria nephrotoxic serum Pyelonephritis

Impact - The condition in which glomerular filtration is impaired or reduced, leading to accumulation of excessive fluid and blood nitrogenous products, is commonly described as uremia - Oral bioavailability of a drug in severe uremia may be decreased due to disease related changes in GI motility and pH caused by nausea, vomiting and diarrhea (except propanolol) - Renal impairment may change the distribution of a drug due to change in drug-protein binding or changes in Vd. PPB of acidic drug is decreased whereas in basic drug less affected. - Total body clearance of drugs in uremic patients is also reduced by either a decrease in GFR or reduced hepatic clearance due to decrease in intrinsic hepatic clearance

General approach for dose adjustment in renal disease - No change in the desired and target drug concentration i.e the therapeutic plasma drug concentration in uremic patients is similar to that required in normal person with normal renal function - Diminished renal clearance but unchanged non-renal clearance - Unaltered drug-protein binding and volume of distribution in the renal impaired patients - Unchanged drug absorption from the GIT - The design of dosage regimen is based on the pharmacokinetic changes that have occurred due to the uremic condition - Two general pharmacokinetic approach for dose adjustment include method based on drug clearance and method based on elimination half-life

Dose adjustment based on drug clearance Assumption: The plasma drug concentration in uremic patient is Similar to that of normal person CEav= FD0/ClTM (for multiple oral dose) Css = R/ClT to measure GFR (for IV infusion) Measurement of GFR Criteria for using drugs - The drug must be freely filtered at the glomerulus - The drug must not be reabsorbed nor actively secreted by renal tubules -The drug should not be metabolised - The drug should not significantly bind with the plasma proteins - The drug should not have an effect on the filtration rate nor alter renal functions - The drug should be non toxic - The drug may be infused in a a sufficient dose which permits -Simple and accurate quantification in plasma and in urine

Chemicals used for measuring GFR - Inulin (fructose polysaccharide) - Creatinine (endogenous substance formed during muscle metabolism from creatine phosphate Calculation of Creatinine clearance: 1. Jellife method (1973) For male, Clr = [98 - 0.8(age - 20)] / Ccr For female, it would be 90% of male 2. Cockcroft and Gault method (1976) For male, Clr =[(140 - age in year)XBody weight in kg] /72Ccr For female, it would be 85% of male Problem: What is the creatinine clearance for a 25-year-old male patients with a Ccr of 1 mg% and a body weight of 80 kg.

Nomogram for evaluation of endogenous creatinine clearance

TI

(U c r

QuickTi r ss ) c r ss r t s t is ictur .

Dose adjustment of Uremic patients by Giusti -Hayton method

This method assumes that the effect of reduced kidney function on the renal portion of the elimination constant can be estimated from the ratio of the uremic creatinine clearance (Clucr) to the normal creatinine clearance (ClNcr) Kur/Knr = Clucr / ClNcr ----------------(i) Where Kur is the uremic renal excretion rate constant and Knr is the normal renal excretion rate constant Because the overall uremic elimination rate constant is the sum of renal and nonrenal factors, Ku = Kunr + Kur = Kunr + Knr(Clucr / ClNcr) [from equation (I)] Dividing the above equation by Kn Ku/Kn = Kunr / Kn + (Knr/ Kn)(Clucr/ClNcr)------------(ii) Knr/ Kn = fraction of drug excreted renal route = f Kunr / Kn= fraction of drug excreted non-renal route = 1-f

From equation (ii) we getKu/Kn =(1-f) + f (Clucr/ClNcr)) Ku/Kn = 1-f(1 - Clucr/ClNcr) = G ------------(iii) Where G factor is a ratio that can be obtained from the fraction of drug excreted by the kidney and the creatinine clearance of the uremic patients. Problem: The maintenance dose of gentamicin is 80 mg every 6 h for a patient with normal renal function.What would be the maintenance dose of for a uremic patient with creatinine clearance of 20 ml/min? Gentamicin is found to be 100% Excreted through urine. Equation (iii) G G = Du/Dn = Ku/Kn = Mn/Mu

Problem
QuickTime and a TIFF ( ncompressed) decompressor are needed to see this picture.

fe=0.93 Clcr G Du

Extracorporeal removal of disease Hemodialysis: - The blood is channeled to a machine where the drug material is removed from blood before returning to body - It is preferred in situation where rapid removal removal of drug from the body is important - Often applied to patients with terminal renal failure - It may be required from once every 2 days to 3 times a week, each treatment period lasting from 5 to 6 h -During dialysis the rate at which the drug is removed depends upon the rate of blood flow and the efficiency of the machine Hemoperfusion: - It is the process of removing of drug by passing the blood from the patients through an adsorbent materials and back to the patients - It is an useful method for rapid removal of drug from accidental

poisoning - Adsorbent: activated charcoal and ambelite resin - Effiency depends upon affinity of the drug to the adsorbent adsorption capacity of the adsorbent blood flow rate surface area of the adsorbent Hemofiltration: It is a process by which fluids, electrolytes and small molecular substances are removed from the blood by means of low-pressreFlow through hollow artificial fiber or flat plate membrane

Qui U

i i i ure.