Drug use in Renal

Disease
Dr Teo Sue Mei
Consultant Nephrologist
Hospital 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 drugs 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 drugs 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 drugs 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 drugs 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?

Metabolite Accumulation
Parent drug

Metabolite

Metabolite Activity

Allopurinol

Oxypurinol

Inhibitor of Xanthine Oxidase

Azathioprine

6 MP

Immunosuppressant

Diazepam

Oxazepam

Anxiolytic

Sulfadiazine

Acetylsulfadiazine

Nausea,Vomiting,rash

Adjusting Dosage for renal

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

elimination?
Are the drugs 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 monitoring

Amikacin
Lithium
Carbamazepine
Netilmycin
Cyclosporin
Phenobarbital
Digoxin
Sodium Valproate
Gentamycin
Theophylline
Vancoumycin
Phenytoin

Adjusting Dosage for renal

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

elimination?
Are the drugs 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 D
High Water solubility
Small Vd
Low non renal elimination

Dialysis properties
Large membrane surface area
Large membrane pore size
High dialysate flow rate
High blood flow rate
Long 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