Prescribing in Renal DiseaseDr S.A Jayaratne

Dept of Pharmacology

Objectives

• Should know• The pharmacokinetic changes that occur in

renal impairment• the effect of theses changes on drugs• nephrotoxic effects of drugs• The precautions taken in prescribing drugs in

renal impairment

Introduction

• Kidney comprises of 5% of body weight-• Kidney receives 25% of cardiac out put

• Therefore drugs can have damaging effects on kidneys

• Diseases of the kidney can effect the response to drugs

• Renal excretion is a major route of elimination

of drugs and their metabolites

How can renal disease effect drugs?• Drugs & metabolites eliminated predominantly

by the kidneys can accumulate

• Renal disease also effect other pharmacokinetic processes ( ADME)

Common causes of renal impairment

• Diabetes mellitus• Hypertension• Nephrotoxic drugs (aminoglycosides)• Heavy metals (mercury, lead)• Hypovolemia• Allergic reactions to certain diseases• Normal ageing (due to loss of nephrons)• Acute disease or trauma (causes accumulation

of fluid & nitrogenous products in the body)

• Most drugs are lipid soluble able to cross membranes

• Kidneys can excrete only water soluble substances

• Metabolism convert fat soluble drugs to water soluble substances

Effect of renal disease on pharmacokinetics

Absorption

of oral drug may be decreased indirectly in renal

failure ?

delayed gastric emptying

changes in gastric pH

GI symptoms (vomiting & nausea)

oedema of GIT in the presence of generalized

oedema

Distribution

Altered by :-

1) Changes in ECF ( water soluble drugs are

distributed in ECF including oedema fluid

which is increased in renal failure

• Metabolic acidosis and respiratory alkalosis in

renal failure alter distribution

Distribution contd--

2) Protein binding• Albumin is the main drug-binding plasma

protein for acidic drugs.

• Drug binding with albumin is decreased with renal impairment.?

• This is due to decreased albumin or reduced binding capacity.

Distribution contd--

• Decreased albumin ?

–Nephrotic states - albumin is lost in the urine.

–Hypermetabolic states (stress, trauma, sepsis) in

which protein breakdown exceeds protein

synthesis.

–Liver disease that decreases hepatic synthesis of

albumin.

Distribution

• reduced binding capacity ?

–Uremic toxins that compete with drugs for

binding sites.

–Accumulation of acidic substances may

compete with drugs for protein binding

–Structural changes in the albumin molecules

Metabolism• Metabolism can increase, decrease, or does not

change by renal impairment. 1) metabolism in the liver:

In uremia,– reduction and hydrolysis is slower, – oxidation by CYP enzymes and conjugation

reactions proceed at normal rates.

Metabolism contd--

2) inability of impaired kidneys to eliminate drugs and active metabolites:

–Metabolites may have pharmacologic

activity similar to or different from that of

the parent drug.

Metabolism contd--

• 3) impaired renal metabolism of drugs.

• The kidney contains many of the same

metabolizing enzymes found in the liver.

egCYP enzymes,

Elimination

• Excretion of many drugs is reduced in renal failure.

• The kidneys normally excrete both the parent drug and metabolites produced by the liver.

• Renal excretion includes: glomerular filtration tubular secretion and tubular reabsorption all of which is affected by renal impairment

Effect of renal disease on pharmacokinetics

EliminationSome drugs are excreted unchanged by the kidneysMost drugs are partly metabolised & partly

excreted unchanged by the kidneysSome drugs produce intermediate metabolites that

are activeRenal disease retards the excretion of both

unchanged drugs as well as active intermediate metabolites

This prolongs the t1/2

Elimination contd--

• some drugs are inactivated by metabolism & excreted

The t1/2 is unaffected in such drugs

Elimination contd--

• An adequate fluid intake is required to excrete drugs by the kidneys.

• Any factor that depletes ECF increases the risk of worsening renal impairment which include:

– Inadequate fluid intake–Diuretic drugs–Loss of body fluids (bleeding, vomiting,

diarrhoea

Renal Functions

• The best guide to the renal impairment is the

creatinine clearance & not serum creatinine levels

• Creatinine clearance

• Is the volume of blood or plasma which is

completely cleared of creatinine by the kidney per

unit time

Limitations of serum creatinine levels

• Creatinine is determined by muscle mass and the GFR

• Inverse relationship between serum creatinine & renal functions

• Renal functions has an approximately linear relationship with lean body mass

Limitations of serum creatinine levels

1) Serum creatinine is a relatively unreliable

indicator of renal function in elderly .

have diminished muscle mass, ( may have a

normal creatinine even if their GFR is

markedly reduced.

2) Some drugs (cimetidine and trimethoprim)

increase creatinine and create a false

impression of renal failure.

(They interfere with secretion of creatinine into

kidney tubules.)

Drug selection

• Follow safety guidelines reducing dosage, renal function tests, avoiding dehydration.

• Drugs known to be nephrotoxic should be avoided when possible.

commonly used nephrotoxic drugs – aminoglycoside antibiotics,– amphotericin B, – cisplatin.

Dose adjustment in patients with renal disease

• Dose adjustment is neededWhen renal clearance is low

Those who have been taking a drug for years as they age

Adjustments achieved • Reduction in dose while retaining the dosage

interval or

• Retain the usual dose and increase the dosage interval

or

• Decrease the dose & prolong the dosage interval

Special caution:-

When patient is hypoprotinaemic & the drug is highly protein bound

or

in advanced renal disease when the accumulated organic products compete for the binding sites

• For drugs with minor or no dose related side effects precise dose modification are unnecessary

• For those drugs with a narrow therapeutic index precise dose reductions are necessary

General Rules

1

Consider the possibility of renal disease before

prescribing drugs & use available data to

estimate renal functions

2) Check how drugs are eliminated,

• If drugs are completely or largely excreted by the

kidneys or

• drugs that produce active metabolites that are excreted

by the kidneys

give a normal initial dose ( unless there are special

cautions)

Reduce the maintenance dose or lengthen the dose

interval

• If drugs are largely or mainly metabolised

to inactive products give normal dose

• Drugs that are partly metabolised & partly

eliminated by the kidneys

give normal initial dose &modify the

maintenance dose or dose interval

depending on renal functions

• Monitor therapeutic & adverse effects

• If possible avoid nephrotoxic drugs

• If such drugs are necessary use them with care

NSAIDs

inhibit synthesis of prostoglandins that dilate renal blood vessels. Decrease blood flow in the kidneys

• When renal blood flow is decreased, PG synthesis is increased to protect the kidneys from ischemia.

• In those who depend on PGs to maintain renal blood flow, NSAIDs result in decreased GFR, and retention of salt and water.

NSAIDS contd--

• NSAIDs can also cause kidney damage by a hypersensitivity reaction that leads to ARF.

• NSAIDs may adversely affect a fetus’s kidneys when:– Given during late pregnancy to prevent premature

labour.– Given shortly after birth for patent ductus

arteriosus (PDA).