Prescribing for sufferers on dialysis
Aust Prescr. 2016 Feb; 39(1): 21–24.
The pharmacokinetics of a drug could also be altered in sufferers with renal impairment who require dialysis. Some medicine are contraindicated.
The drug’s clearance and therapeutic index decide if a dose adjustment is required. A decrease dose or much less frequent dosing could also be required.
Seek the advice of a reference supply or the affected person’s nephrologist earlier than prescribing. Begin at a low dose and enhance steadily. If potential give once-daily medicine after dialysis.
Key phrases: haemodialysis, kidney, pharmacokinetics, renal illness
The prevalence of kidney illness is rising and there are actually over 11 400 Australians receiving dialysis.1 These sufferers could depend on their GPs for a lot of their medical care. Prescribing for sufferers who’re on dialysis could be difficult, nevertheless a couple of fundamental rules and the usage of simply obtainable reference supplies (Field) can be certain that these sufferers are managed safely. A examine within the USA discovered as much as one-third of haemodialysis sufferers are prescribed a drug at a dose that differs from the beneficial dose and antagonistic reactions happen in one-fifth.2 Polypharmacy, a number of comorbid diseases and drug clearance by dialysis all complicate prescribing.3
Prompt sources for drug dosing in dialysis
Australian Medicines Handbook (https://amhonline.amh.web.au)
Therapeutic Pointers: Antibiotic. Model 15 (www.tg.org.au)
MIMS Australia (http://mims.com.au)
Bailie and Mason’s 2014 Dialysis of Medicine (http://renalpharmacyconsultants.com/publications)
Oxford Handbook of Dialysis. third ed. Oxford: Oxford College Press; 2009.
The Renal Drug Handbook. 4th ed. London: Radcliffe Publishing; 2014.
Dialysis is the switch of uraemic solutes from blood to an extracorporeal fluid (dialysate) by diffusion throughout a semi-permeable membrane. This can be performed by pumping blood via a dialyser containing a membrane and dialysate (haemodialysis), or by instilling dialysate into the peritoneal cavity and utilizing the peritoneum itself as a membrane (peritoneal dialysis). Solute removing through haemodialysis is comparatively environment friendly and so could be performed intermittently – usually thrice per week – whereas peritoneal dialysis is much less environment friendly and so is normally required for 12–24 hours on daily basis.
Rules of prescribing
Renal impairment reduces the clearance of some medicine.4 When prescribing for sufferers on dialysis, it’s important to seek the advice of a reference information (Field) to find out if the drug is topic to renal clearance and requires a dose adjustment. Given the paucity of huge pharmacokinetic research, dosing suggestions usually differ and it might be tough to favour one supply over one other. If no ‘dialysis’ dose is obtainable, one ought to assume that the affected person’s glomerular filtration charge is lower than 10 mL/min/1.73m2. Though many sufferers have some residual renal operate, their serum creatinine could fluctuate markedly and it shouldn’t be used to estimate glomerular filtration charge.
Dose changes could be made by lowering the dose, rising the interval between doses or a mix of the 2. The strategy to take is decided by the relative significance of secure serum drug concentrations (as an example to keep up the antimicrobial impact of penicillins), the antagonistic results of peak concentrations after intermittent doses, and affected person comfort.
A number of practitioners usually share the care of sufferers on dialysis (e.g. GPs, specialist physicians, vascular surgeons and dialysis nurses). Details about the adjusted dosing routine ought to be included in correspondence and, the place acceptable, clarify why the dose has been adjusted, to keep away from confusion.
The 2 major concerns that decide if a selected drug requires dose discount in dialysis sufferers are renal clearance and therapeutic index. Different elements which will have an effect on dosing embody clearance by dialysis, elevated availability of extremely protein-bound medicine resulting from hypoalbuminaemia,5 altered quantity of distribution and the presence of comorbid hepatic dysfunction.
Contemplate the magnitude of the renal part of whole clearance of the drug and any lively metabolites. For medicine topic to vital renal clearance, the marked lower in glomerular filtration charge seen in sufferers on dialysis leads to a rise in half-life6 and drug accumulation with repeated dosing within the absence of dose adjustment. These adjustments additionally apply to renally cleared drug metabolites which can be lively or poisonous.
The elevated half-life additionally prolongs the time to attain a steady-state which, in scientific follow, means an extended interval is required earlier than judging that the utmost impact of a selected dose has been achieved.7 The beginning dose ought to be low and warning is required earlier than rising drug doses. Given the longer time to regular state, a loading dose could be thought of if giving a renally adjusted dose might result in a delay in reaching a therapeutic serum focus (as an example, if treating a extreme an infection). In follow, loading doses are hardly ever used.
A drug with a large therapeutic index could also be safely given with no dose discount realizing that, though the drug focus shall be larger, that is unlikely to lead to hurt. Nonetheless, medicine with slender therapeutic indices could require substantial dose reductions.7
Dialysis and drug clearance
Sufferers on dialysis are topic to extracorporeal clearance of small molecules, together with many medicine. The extent to which dialysis removes a selected drug from plasma depends on its water solubility, molecular weight, protein binding and quantity of distribution.3 Many reference sources include lists of medication cleared by dialysis (Field).
Haemodialysis can pose a problem as it’s intermittent and has the potential for comparatively fast drug clearance. In follow that is most essential when prescribing once-daily medicine, particularly antibiotics. It might be finest to present them after dialysis. Dose timing is usually left unchanged for medicine dosed extra steadily, as advanced dosing regimens could cut back adherence to remedy. In peritoneal dialysis, timing is just not essential because the clearance of small molecules is slower and extra even than in haemodialysis.7
Many medicine usually are not renally cleared. Particular examples of generally used medicine embody proton pump inhibitors, statins, corticosteroids and calcium channel blockers. They’re unlikely to wish a dose adjustment in sufferers on dialysis.
Sufferers on dialysis could have comorbid ache, however its therapy is commonly suboptimal.8,9 Paracetamol is the popular easy analgesic. It’s secure and can be utilized with out dose modification.10
Though nephrotoxicity may be thought of of little significance, non-steroidal anti-inflammatory medicine (NSAIDs) ought to be prevented as they could trigger sodium retention, hypertension and gastrointestinal toxicity. As a result of elevated threat of myocardial infarction seen within the basic inhabitants, we don’t advocate cyclo-oxygenase-2 inhibitors in dialysis sufferers as they’re already at markedly larger baseline cardiovascular threat.11,12 Topical NSAIDs look like secure as systemic absorption is minimal.7
Many opioids, or their lively metabolites, are renally cleared (Desk).7,10,13,14 Codeine and morphine have lively, renally excreted metabolites so they don’t seem to be beneficial due to the elevated threat of toxicity. Hydromorphone is our most popular oral opioid for treating extreme ache. It’s 5 to seven instances stronger than morphine so beginning doses are correspondingly low (0.5–1 mg orally 6-hourly).10 Its lively metabolite hydromorphone-3-glucuronide can accumulate, however is considerably cleared by haemodialysis and is much less prone to trigger antagonistic results than morphine metabolites.15 Oxycodone could also be used, though the sustained-release formulations ought to be used solely with warning as a result of threat of accumulation and toxicity. Fentanyl and buprenorphine each endure hepatic clearance and can be utilized when the oral route is just not appropriate.13 Whichever opioid is chosen, you will need to use small beginning doses and carefully monitor up-titration to keep away from toxicity.
|Drug||Clearance||Prompt beginning dose||Feedback|
|Hydromorphone||Its main renally excreted metabolite hydromorphone-3-glucuronide is inactive||0.5–1 mg orally
4 instances a day
|Most popular oral opioid in dialysis sufferers|
|Oxycodone||Each oxycodone and its lively metabolite oxymorphone are renally excreted||2.5–5 mg orally
3 instances a day
|Use controlled-release preparations with warning|
|Tramadol||Lively renally excreted metabolite O-desmethyltramadol||50 mg orally
twice a day
|Most 100 mg twice a day
Keep away from controlled-release preparations
|Buprenorphine||Hepatic metabolism with no accumulation of metabolites||5 microgram/hour transdermally||Not dialysed|
|Fentanyl||Hepatic metabolism with no lively metabolites||12 microgram/hour transdermally||Not dialysed
Use with warning in opioid-naïve sufferers
|Gabapentin||Renal excretion||100 mg orally at night time
on dialysis days
|Massive dose reductions required
Can deal with uraemic pruritis and stressed legs syndrome
|Pregabalin||Renal excretion||25 mg orally at night time
on dialysis days
|Massive dose reductions required
Can deal with uraemic pruritis and stressed legs syndrome
|Morphine||Metabolised to renally excreted glucuronide metabolites (M-6-G and M-3-G)
M-6-G is lively and accumulates inside the central nervous system, M-3-G lacks analgesic exercise however could trigger hyperalgesia and allodynia
|2.5 mg orally
3 instances a day
|Keep away from if potential
May very well be used for emergency analgesia if hydromorphone or fentanyl not instantly obtainable
|Codeine||Renally excreted lively metabolites||–||Keep away from|
|Dextro-propoxyphene||Cardiotoxic metabolite norpropoxyphene accumulates||–||Keep away from|
|Paracetamol||Hepatic clearance||1 g orally 3–4 instances a day||Most popular easy analgesic|
Neuropathic ache is widespread in sufferers on dialysis.16 Amitriptyline is hepatically metabolised and doesn’t accumulate. Nonetheless, it has quite a few antagonistic results together with anticholinergic results and postural hypotension which can restrict its use in sufferers with a number of comorbidities.10 Gabapentin and pregabalin are efficient and might also deal with uraemic pruritis. Nonetheless, they’re extensively renally cleared and marked dose reductions are essential to keep away from sedation, ataxia and dizziness. Doses ought to be taken after dialysis.10,17
In surveys, over half of the sufferers on dialysis report constipation.9 Prevention of opioid-induced constipation is especially essential in sufferers on peritoneal dialysis as constipation could markedly cut back its effectiveness. Lactulose, docusate, senna and bisacodyl are all appropriate remedies. Preparations containing polyethylene glycol (macrogol) are additionally usually secure as laxatives or bowel preparation. Sufferers ought to be suggested that the co-administered fluid is just not considerably absorbed and so doesn’t rely in the direction of a fluid restriction. Saline laxatives (containing magnesium or phosphate salts) are contraindicated in sufferers on dialysis resulting from the potential for extreme electrolyte disturbances.18 Specifically, sodium phosphate-containing bowel preparations (Fleet) may cause extreme hyperphosphataemia and calcium phosphate deposition.19
Many antibiotics require dose adjustment in sufferers receiving dialysis. Therapeutic Pointers: Antibiotic offers a complete and user-friendly reference.20 Quinolones, sulfamethoxazole with trimethoprim, glycopeptides and aminoglycosides all require vital dose reductions. Trimethoprim ought to be prevented in sufferers as a result of threat of hyperkalaemia and bone marrow suppression.20,21 Nitrofurantoin is primarily renally excreted, and depends on urinary focus to attain its impact. It’s hardly ever related to neurotoxicity and life-threatening pulmonary toxicity.22 Regardless of current help for extending its use in continual kidney illness, it ought to be prevented in sufferers on dialysis.23 Cephalosporins and penicillins have wider therapeutic indices and range within the want for dose adjustment.7 As soon as-daily doses ought to be prescribed after haemodialysis.
The antiviral drug aciclovir and its prodrugs, famciclovir and valaciclovir, are extensively renally excreted. These medicine accumulate quickly in sufferers on dialysis and will trigger extreme neurological toxicity.24 They need to solely be prescribed after dialogue with the treating nephrologist and with acceptable dose discount and shut scientific follow-up.
Regardless of controversy surrounding its use for stroke prevention in dialysis sufferers with atrial fibrillation, warfarin stays the anticoagulant of alternative for these with venous thromboembolism or different indications for anticoagulation. The dose is adjusted in accordance with the INR within the traditional method. Shut monitoring and avoidance of supratherapeutic INRs is especially essential as sufferers on dialysis have elevated charges of bleeding with warfarin.25 Low-molecular-weight heparins are renally excreted and they’re hardly ever used for anticoagulation as their impact is tough to foretell.7 Unfractionated heparin is most popular for acute therapy of venous thromboembolism in sufferers on dialysis.
The newer oral anticoagulants (similar to dabigatran and rivaroxaban) are contraindicated. All of them endure a level of renal clearance which makes them unsuitable for sufferers on dialysis.26
Medicine for diabetes
Sufferers with diabetes who want dialysis have diminished insulin clearance, so they could be extra liable to hypoglycaemia with each insulin and insulin secretagogues (sulfonylureas). These sufferers might also be at elevated threat of hypoglycaemia unawareness resulting from comorbid diseases and co-prescribed medicine.7
Gliclazide and glipizide are the popular sulfonylureas as they’ve quick half-lives and no lively metabolites. All sulfonylureas ought to be began at low doses and up-titrated rigorously. The dipeptidyl peptidase-4 inhibitors range of their suitability to be used in dialysis so the product data ought to be reviewed earlier than prescribing.27 Metformin is contraindicated as a result of threat of lactic acidosis. Though not renally excreted, thiazolidinediones are related to fluid retention and usually are not beneficial.7 The sodium-glucose co-transporter inhibitors are contraindicated in dialysis sufferers as they rely on the glomerular filtration of glucose for his or her impact.28
Recognising that sufferers on dialysis are extra liable to drug toxicity is step one in avoiding hurt. There are a lot of simply accessible reference sources to information dose changes in renal failure. Medical judgement is at all times required to steadiness the required therapy depth in opposition to the danger of toxicity in a person affected person. If doubtful, contact the treating nephrologist or renal unit pharmacist for recommendation. Generally, start with a low dose, observe carefully for antagonistic results and enhance the dose solely after a well timed interval. Put merely: ‘begin low and go gradual’.
Battle of curiosity: none declared
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