Prescribing
Drugs in Renal
Disease
Evolution of medicine
• I have a headache ...
• 2000 BC – eat this root
• 1000 AD - That root is infected. Say this prayer
• 1850 AD - That prayer is superstition. drink this potion.
• 1940 AD - That potion is snake oil. swallow this pill.
• 1985 AD - That pill is ineffective. take this antibiotic.
• 2000 AD - That antibiotic is artificial. eat this root.
Drugs in Renal Disease
• Adverse drug reactions are common in
patients with renal disease
• Most drugs are eliminated by the kidneys
• Any degree of renal impairment may
affect drug metabolism
• Extracorporeal dialysis therapies
necessitate drug dosage adjustments to
minimise adverse reactions or toxicity
Drugs in Renal Disease
• General principles:
– degree of renal dysfunction
– age
– gender
– nutrition
– volume status
– comorbid diseases
• MAY BE NEPHROTOXIC!!!!!!!!!!!!!
Pharmacokinetics
IV admin. PO admin Other routes bioavailability
Depot Circulation Volume of
(lipid-cell storage, ECF, (free, protein bound, cell bound) distribution
ICF)
Pharmacologically active and
biotransformation
inactive metabolites
Renal elimination
(filtration, Other routes: GI Dialysis
secretion) lung, skin (biliary)
Pharmacokinetics in renal patients?
• Little data in renal patients:
– ? edema of GIT
– gastric motility
– pH
– 1st pass etc.
• Changes in blood pH may affect drug
binding, distribution and
biotransformation
Changes in renal patients
protein binding with albumin/renal
failure e.g.:
– Barbiturates
– Benzyl penicillin
– Diazepam
– Morphine
– Phenytoin
– Warfarin
– sulphonamides
Drug elimination
• Filtration capacity affected by:
– protein binding
– glomerular membrane structure
– molecular weight (< 500 Da)
– functioning nephrons
• Only free drug is filtered
• Secretion is ACTIVE, carrier
mediated in PT e.g. probenecid,
cimetidine
– depends on RBF
Drug elimination
• Reabsorption mainly in PT
– urine flow
– urine pH (e.g. vit C, bicarb)
– % dissociation
– pKa of drug
– non-ionised diffuse easily
• Renal metabolism e.g. vit D, insulin
Cl renal = filtration + secretion -
reabsorption
plasma concentration
Effects of renal disease
Absorption in uraemia edema, nausea,
vomiting,
neuropathy, peritonitis
Distribution free drug acidic drugs
total drug conc “therapeutic” level
protein binding nephrotic, nutrition
Vd need lower dose, e.g.
digoxin
Metabolism metabolism
oxidation induce cyt P450
1st pass e.g. propranolol
renal metab. Vit D, insulin
Effects of renal disease
Excretion parent drug excretion
excretn of metabolites
tissue distributionCNS drugs
sensitivity metabolic effects CKD Acidemia, K
metabolic K ACEI, -bl
loads Mg antacids,
laxat
Na load antibiotocs
e.g.penicillins
Nitrogen steroids
water excretion
Active metabolites in renal
failure
parent metabolite action
Allopurinol oxypurinol same as
parent
Azathioprine 6-MP immunosupp
Lidocaine glycinexlidide CNS
rxns, seizures
Meperidine normeperidine seizures
Nitroprusside thiocyanate CNS toxicity
Procainamide N-acetylprocan. Antiarrhyth.
Propranolol 4-hydroxy prop. B-blocker
Sulfonamides acetylated mets N,V, rashes
Diazepam oxazepam anxiolytic
Dialysis of drugs
• Drugs with MW < 1000 Da diffuse
• MW > 1000 e.g. vanco, ampho B,
erythromycin not easily removed
• protein binding affects diffusability (
PD)
• small Vd (i.e. predominantly
intravascular) diffuse more:
– > 1l/Kg dialysable
– 1-2 l/Kg ?
– >2 l/Kg not removed
• supplement if > 30% cleared
Drug prescription-look it
up!!
• Assess renal function (adjust if GFR<50)
– calculate creatinine clearance!!!
– Assume GFR < 10 in patients with ARF
• Choose a loading dose
– usually similar to non-renal patients
– total may be given in divided doses
• Choose a maintenance dose
– either dose or dosing interval
• Monitor drug levels (NB free vs. total)
– peak 2h po, 15-30 mins iv
– trough just before next dose
Specific drugs:
• Antimicrobials:
– choose empirically
– adjust doses
– NB nephrotoxicity e.g. AG, vanco, ampho
– toxicity 5-25%: with renal/liver disease,
volume depletion, other drugs, contrast etc
– NB electrolytes!! e.g. ampho → ↓ Mg, K
– penicillins cause AIN
– secreted drugs e.g, cipro still get high
urinary levels with low GFR, good for UTI,
cysts
Specific drugs:
• Analgesics:
– e.g. meperidine (pethidine) metabolised to
normeperidine accumulates seizures
– effects not reversed by naloxone!
• Anaesthetic agents:
– prolonged neuromuscular blockade/weakness
– atracurium is n-m blocker of choice in RF
because cleared by ester hydrolysis
activity of cholinesterases in RF prolongs
t1/2 of others
Specific drugs
• AntiHT and CVS:
– NB use of K-sparing diuretics and ACEi
– caution with K supplements
– Thiazides ineffective with GFR < 30 but
metolazone is effective
– t1/2 of atenolol and nadolol with GFR
– ? Lasix drip better than boluses with ARF
– cardiac glycosides add to uraemic GIT
symptoms
Specific drugs
• Endocrine/metabolic agents:
– glipzide, tolbutamide safest oral
hypoglycaemics in RI
– t1/2 of insulin
– NB risk of rhabdomyolysis in transplant
patients with HMG-CoA reductase inhibitors
• GIT:
– modify doses of H2 blockers
– tagamet confusion
– sucralfate Al toxicity
– OTC antacids contain Mg, Al, Ca
– OTC laxatives contain Mg
– metoclopromide Exrapyramidal
syndrome
Specific drugs
• Neurologic agents
– free phenytoin levels best correlate with toxicity
– Lithium Diabetes Insipidus, nephrotoxicity (IS
nephritis), toxicity by volume depletion,
diuretics, NSAIDS
• Rheumatologic agents
– NSAIDS!!!!!!!!!!!!
nephrotoxicity with CHF, cirrhosis, vol
depletion, post-op, RI, age, also K, oedema,
papillary necrosis
– allopurinol, colchicine dose adjustment
– uricosurics ineffective with GFR <25
Conclusions - be aware:
• Adverse drug reactions
• Risk of nephrotoxicity
• Adjust doses for renal dysfunction
• Co-morbid conditions
• Monitor drug levels and adjust doses
promptly (not at next monthly visit!!!)
• Inform patients of potential side
effects
The patient shook his doctor's hand in
gratitude and said, "Since we are the best
of friends, I would not want to insult you by
offering payment. But I would like for you
to know that I had mentioned you in my
will.“
"That is very kind of you," said the doctor
emotionally, and then added, "Can I see
that prescription I just gave you? I'd like to
make a little change..."
