Download - Prescribing in Renal Disease
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).