Drug use in Renal Disease

Dr Teo Sue MeiConsultant NephrologistHospital Ipoh

Drug use in Renal disease

Patients with renal failure receive multiple drugs

Higher tendency to develop adverse reaction from drug use.

Additional care required for drugs eliminated by renal route

Pharmacokinetics

Bioavailability(%) : fraction of dose absorbed from site of administration

Vd (L) : Relates to the amount of drug in the body with the serum concentration, may be determined by drug molecular size, plasma protein binding, hydrophilicity

Half-life (hrs) : time required to decrease the levels of the compound by half

Effects of renal failure on pharmacokinetics of drugs Altered bioavailability

Changes in gastric transit time due to: 1) uraemic gastroparesis 2) Changes in gastric pH 3) Gut wall oedema 4) Vomiting due to uraemia

Effects of renal failure on pharmacokinetics of drugs Altered Vd *Oedema

increases the Vd of water soluble or protein bound drugs resulting in low plasma levels *Acidic drugs are less protein bound in renal failure *basic drugs are unaffected by uraemia

Effect of renal failure on drug elimination Effect on Hepatic metabolism

* Renal failure reduces the non renal elimination of drugs by affecting their hepatic metabolism * Examples of drugs: Acyclovir, Cimetidine, Imipenam, Cefotaxime

Effect of renal failure on drug elimination Effect on renal metabolism

* All polypeptide hormones are metabolized by the kidneys * eg: Clearance of Insulin is reduced

Effect on renal excretion * Renal drug elimination depends on the fraction of the drug excreted by the kidney and the degree of renal failure.

Pharmacodynamics

Patients with renal failure may exhibit alterations in the degree of response to some drugs

Altered phamacodynamics due to: * Changes in receptor sensitivity * More severe form of disorder under treatment eg: HPT, Fluid overload

Diuretic resistance in renal failure Increased sensitivity of benzodiazepines Reduced effect of normal doses of commonly

used anti HPT because of fluid overload

Adjusting Dosage for renal failure Estimated renal function? Is it changing? What is the extent of the drug renal

elimination? Are the drug’s metabolites toxic and do

they accumulate in renal failure? Should the maintenance dose be

adjusted? Is the patient on dialysis? What is the mode of dialysis?

Adjusting Dosage for renal failure Estimated renal function? Is it changing? What is the extent of the drug renal

elimination? Are the drug’s metabolites toxic and do

they accumulate in renal failure? Should the maintenance dose be

adjusted? Is the patient on dialysis? What is the mode of dialysis?

Estimation of GFR

Creatinine clearance

Cockroft-Gault Formula

Ccr = (140-age) X BW (kg) ------------------------------ 72 X ( Cr)

Multiple by 0.85 for females

Adjusting Dosage for renal failure Estimated renal function? Is it changing? What is the extent of the drug renal

elimination? Are the drug’s metabolites toxic and do

they accumulate in renal failure? Should the maintenance dose be

adjusted? Is the patient on dialysis? What is the mode of dialysis?

Route of drug elimination

Drugs with extensive renal elimination will require dosage adjustment

Drugs that are metabolized extra renally need no dosage adjustment

Drugs which have dual routes of elimination will need some dosage adjustment but based on clinical pharmacokinetic studies.

Adjusting Dosage for renal failure Estimated renal function? Is it changing? What is the extent of the drug renal

elimination? Are the drug’s metabolites toxic and do

they accumulate in renal failure? Should the maintenance dose be

adjusted? Is the patient on dialysis? What is the mode of dialysis?

Parent drug Metabolite Metabolite Activity

Allopurinol Oxypurinol Inhibitor of Xanthine Oxidase

Azathioprine 6 MP Immunosuppressant

Diazepam Oxazepam Anxiolytic

Sulfadiazine Acetylsulfadiazine Nausea,Vomiting,rash

Metabolite Accumulation

Adjusting Dosage for renal failure Estimated renal function? Is it changing? What is the extent of the drug renal

elimination? Are the drug’s metabolites toxic and do

they accumulate in renal failure? Should the maintenance dose be

adjusted? Is the patient on dialysis? What is the mode of dialysis?

Dosage adjustment

Most product info provides dosage adjustments

Dosage adjustment made on a case to case basis

Drug dosing in renal disease

History * Drug allergies/toxicity * Use of concomitant drugs: interactions * Alcohol/recreational drug consumption

Physical examination * Fluid status-oedema,dehydration * BMI * Evidence of liver disease

Therapeutic Drug monitoring (TDM) Required for drugs with narrow

therapeutic index TDM requires drug dose, route and time

of administration Toxicity can still occur when serum drug

levels is within therapeutic range Eg: Digoxin toxicity is enhanced in the

presence of hypokalaemia

Drugs requiring Therapeutic Drug monitoringAmikacin LithiumCarbamazepine NetilmycinCyclosporin PhenobarbitalDigoxin Sodium ValproateGentamycin TheophyllineVancoumycin Phenytoin

Adjusting Dosage for renal failure Estimated renal function? Is it changing? What is the extent of the drug renal

elimination? Are the drug’s metabolites toxic and do

they accumulate in renal failure? Should the maintenance dose be

adjusted? Is the patient on dialysis? What is the mode of dialysis?

Drug removal via dialysis

The effects of HD, PD and CRRT on drug elimination is difficult to predict.

Factors which affects drug removal include: * Molecular weight * Lipid solubility * Protein binding * SA of the dialysis membrane * Blood and dialysate flow rates

Dosage adjustment in dialysis

The degree to which a drug is removed via dialysis determines if a supplemental dose is needed or not.

Drug clearance during peritoneal dialysis is generally lower than haemodialysis

Drugs which are removed by HD should be given after dialysis

Factors That increase Drug Dialyzability

Drug properties

Molecular Weight < 500 DHigh Water solubilitySmall VdLow non renal elimination

Dialysis properties

Large membrane surface areaLarge membrane pore sizeHigh dialysate flow rateHigh blood flow rateLong dialysis time

Drug dosing tables

Drugs % excreted unchanged Half life( normal/ESRF) Plasma protein binding Vd Dose for normal renal function Adjustment for renal failure (dosage or interval

adjustment) according to GFR Supplement for dialysis