What factors need to be considered when dosing patients ...



What factors need to be considered when dosing patients with renal impairment?Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionalsBefore using this Q&A, read the disclaimer at prepared: January 2018 Background Many commonly used drugs or their metabolites are excreted by the kidney, and this has particular significance for people with renal impairment (RI). Impaired renal function alters drug pharmacokinetics, potentially changing drug efficacy and increasing the likelihood of unwanted effects, including renal toxicity (). There may also be pharmacodynamic changes ().AnswerGeneral drug dosing guidance in renal impairment Drugs, or their metabolites, that are mainly excreted by the kidney may have a prolonged half-life in RI (,). Accumulation sufficient to be of clinical concern occurs in patients with RI if ≥30% of the drug is eliminated unchanged in the urine or if the drug has active or toxic metabolites which are renally excreted (). Dose reduction needs to be considered, in order to avoid potential toxicity ( NOTEREF _Ref513192872 \h 3, NOTEREF _Ref513195750 \h 4, NOTEREF _Ref513195753 \h 5). Single doses are not thought to be dangerous as accumulation is unlikely ( NOTEREF _Ref513192872 \h 3). If a drug has potential renal adverse effects, serious dose-related adverse effects, or a narrow therapeutic index with no potential for monitoring, an alternative should be found, if possible ( NOTEREF _Ref504661392 \h 2).There are three approaches to altering drug maintenance doses in patients with RI, depending on the desired goal of therapy ( NOTEREF _Ref513195753 \h 5,):either the standard dose can be given but at extended intervals ora reduced dose is given at the usual intervals ora combination of reduced dose and extended intervalDrugs that require maintenance of a serum concentration over the dosing interval should be administered at the usual intervals, but with reduced doses. Drugs for which specific peak serum concentrations must be achieved will be dosed with the standard dose at extended intervals (). In general, the latter approach will achieve similar peak and trough concentrations and AUC to those in patients with normal renal function (). Drugs with a narrow therapeutic index (e.g. vancomycin, lithium) require the greatest care in use ( NOTEREF _Ref513192872 \h \* MERGEFORMAT 3). Some drugs known to be mainly excreted hepatically, with no toxic metabolites, e.g. carbamazepine, theophylline may be safe to use in full doses in all degrees of RI ( NOTEREF _Ref513192872 \h \* MERGEFORMAT 3). However, as there is emerging data on the effect of CKD on drug metabolism (see metabolism section below) careful monitoring of plasma levels and clinical response may be prudent, followed by dose adjustments, if appropriate.When a rapid therapeutic response is needed, a loading dose may even be needed if one was not routinely recommended for patients with normal renal function ( NOTEREF _Ref355359141 \h \* MERGEFORMAT 8). The loading dose may be calculated by the following formula: patient’s loading dose = usual loading dose x [(patient’s VD)/(normal VD)] ( NOTEREF _Ref355359141 \h \* MERGEFORMAT 8). The plasma half-life of drugs excreted by the kidney is prolonged in RI and it takes about five times the half-life of a drug to reach steady state concentrations, therefore it can take many doses for the reduced dosage to achieve a therapeutic plasma concentration (). Consequently, it may be problematic to reduce initial dose/s of a course of a critical medicine (e.g. an antibiotic) because it may take a long time to reach therapeutic levels ( NOTEREF _Ref513192872 \h 3). Pharmacokinetics The absorption, distribution, metabolism and excretion of drugs can be affected by RI to varying degrees ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2, NOTEREF _Ref513192872 \h 3). These will be discussed individually.Absorption and bioavailability Absorption (proportion of drug absorbed from the gastrointestinal tract) and bioavailability (the proportion of the administered dose which reaches the systemic circulation of the patient) can both be affected in renally impaired patients. Absorption may be reduced due to a number of factors such as nausea, vomiting or diarrhoea associated with uraemia and gut oedema. An increase in the gut pH from increased gastric ammonia production in uraemia, or from co-administered drugs, reduces the bioavailability of drugs requiring an acidic environment for absorption. The increase in pH may increase the bioavailability of weakly acidic drugs ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2). The effect of CKD on intestinal cytochrome P 450 metabolic enzymes and transporters may lead to decreased first-pass metabolism and an increase in bioavailability of orally administered drugs e.g. tacrolimus, in these patients (,). This may be incorrectly interpreted as being caused by decreased elimination rather than increased bioavailability ( NOTEREF _Ref504658475 \h 10). A change in dose or route of administration may need to be considered if the desired therapeutic effect is not being achieved ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2).DistributionThe state of hydration of a patient will affect the volume of distribution (Vd) of water soluble drugs with a small Vd ( NOTEREF _Ref504661392 \h 2) e.g. aminoglycosides with a Vd of approximately 0.25L/kg ( NOTEREF _Ref217460169 \h \* MERGEFORMAT 7). In patients with conditions such as sepsis, major burn injury etc., oedema formation and administration of IV fluids leads to an increase in total body water thus increasing the Vd of hydrophilic drugs. Adequate loading doses are therefore essential (). In critically ill patients with associated acute kidney injury (AKI) the loading dose of hydrophilic antimicrobials e.g. beta-lactams, cephalosporins and penems may need to be increased by up to 25-50% ( NOTEREF _Ref442881501 \h \* MERGEFORMAT 8). Conversely dehydration or muscle wasting may result in unexpectedly high concentrations of drugs (). Another factor affecting Vd in patients with CKD is reduction in protein binding (Pb) to albumin of many acidic drugs including penicillins, cephalosporins, aminoglycosides, furosemide and phenytoin ( NOTEREF _Ref504659778 \h 10). This is clinically important for highly protein bound drugs (>80%) whose Vd and clearance will increase ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2). In patients with CKD, care must be taken in interpreting plasma level results. Apparently low total plasma concentrations of these drugs will still be therapeutic since there is less bound (pharmacologically inactive) drug available for measurement but the concentration of free (pharmacologically active) drug in the plasma often remains more or less unchanged, due to distribution, metabolism, and excretion. An important example of this is phenytoin ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2, NOTEREF _Ref509931965 \h 7,,). Basic drugs bind mainly to 1-acid glycoprotein (AAG) and this process generally seems to be unaffected by CKD ( NOTEREF _Ref504659778 \h 10). Alterations in tissue binding may also affect the Vd of a drug ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2). For example, the Vd of digoxin is decreased by up to 50% in patients with severe RI (stage 5 CKD) leading to elevated serum concentrations if the loading dose is not adjusted accordingly ( NOTEREF _Ref504661392 \h 2, NOTEREF _Ref504659778 \h 10). However changes to distribution (Pb and Vd) are most likely to be a significant issue in renal replacement therapies (refer to Q&A Dosing in Renal Replacement Therapies and to (subscription required). Metabolism Renal impairment affects the metabolism of drugs ( NOTEREF _Ref509932467 \h 14) e.g. reduction, hydrolysis and conjugation are slowed ( NOTEREF _Ref504661392 \h 2, NOTEREF _Ref355190843 \h 11). This may increase serum concentrations of the parent drug and consequent toxicity if the drug is metabolised to inactive metabolites ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2). Many drugs and/or their phase I metabolites are eliminated by glucuronidation and the glucuronides are excreted by renal mechanisms. Therefore in patients with RI, glucuronide conjugates will accumulate in the plasma and may be hydrolysed leading to increased levels of the parent compound; an example of this is ketoprofen ( NOTEREF _Ref513195750 \h 4, NOTEREF _Ref513195753 \h 5). Many active or toxic metabolites depend on renal function for elimination; therefore they may accumulate in RI, for example norpethidine following the administration of pethidine ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2, NOTEREF _Ref292285731 \h \* MERGEFORMAT 16). Norpethidine is a central nervous system stimulant but not an analgesic. Even in patients with mild RI, such as elderly patients, this metabolite can reach sufficient concentrations to cause seizures. The use of lower doses of pethidine may limit its efficacy, therefore alternative analgesics should be considered ( NOTEREF _Ref513195753 \h 5). Most drugs are cleared by a combination of renal and non-renal clearance; few drugs are eliminated entirely unchanged by the kidney ( NOTEREF _Ref509932642 \h 10). There is clinical evidence that alterations in hepatic and extra-hepatic drug metabolism and transport occur during renal failure ( NOTEREF _Ref504659778 \h 10,,). In patients with severe chronic RI the accumulation of uraemic toxins and inflammatory cytokines may affect the activity of cytochrome P 450 metabolic enzymes and of P-glycoprotein, organic anion-transporting peptides (OATPs) and multidrug resistance-associated protein transporters (MRPs) in the hepatobiliary and gastro-intestinal tracts ( NOTEREF _Ref504659778 \h 10, NOTEREF _Ref355190843 \h \* MERGEFORMAT 11, NOTEREF _Ref292885629 \h \* MERGEFORMAT 17). Drugs whose bioavailability is increased in CKD include imipenem, meropenem, vancomycin ( NOTEREF _Ref292795182 \h \* MERGEFORMAT 16), and erythromycin ( NOTEREF _Ref504659778 \h 10, NOTEREF _Ref355190843 \h \* MERGEFORMAT 11). Even drugs such as lidocaine which is mostly metabolised by hepatic CYP1A2 and CYP3A4 have been reported to have reduced clearance and prolonged half-life in patients with CKD, compared with control subjects ( NOTEREF _Ref355190843 \h \* MERGEFORMAT 11). The activity of other metabolic pathways e.g. uridine diphosphate-glucuronosyltransferase (UGT) and N-acetyl-transferase (NAT) may also be reduced in patients with CKD which affects drugs such as zidovudine and isoniazid ( NOTEREF _Ref504659778 \h 10). The determination of specific drug-metabolising enzymes and transporters that are affected by RI is complicated because of:the interactions between them, apparent differential effects in the intestine and liver, as yet incomplete understanding of the effect of uraemia on metabolism mediators. This makes it difficult to translate pharmacokinetic data into clinically useful drug dosing recommendations. Pharmacokinetic studies in patients with RI should be performed for all drugs, even those primarily cleared by the liver (). Careful monitoring of patients is therefore essential.Excretion Renal drug clearance is a dynamic process involving glomerular filtration, tubular secretion, and reabsorption (). The extent to which a reduction in kidney function is important for the elimination of a drug depends on the proportion of the administered drug or any active or toxic metabolites which are eliminated by the kidney ( NOTEREF _Ref215305555 \h \* MERGEFORMAT 2). For some drugs, e.g. methotrexate, reduction of renal excretion in patients with CKD is thought to occur also through inhibition of renal transporter proteins ( NOTEREF _Ref355190843 \h \* MERGEFORMAT 11). The excretion of several other drugs eliminated in the urine by active tubular secretion, is also reduced in RI e.g. sitagliptin () and varenicline (). For some drugs the decline in tubular secretion does not occur in parallel with a decline in GFR, and dosing on the basis of GFR alone may lead to over- or under- dosage. Future developments in drug dosing algorithms that include measures of proximal tubular function, would lead to safer and more efficacious use of drugs in patients with CKD (). It is also worth noting that for some drugs e.g. ciprofloxacin, compensatory increases in alternative elimination pathways occur in patients with AKI, therefore dosage reduction on the basis of serum creatinine alone, may lead to underdosing ( NOTEREF _Ref509993537 \h 19). The therapeutic effects of a number of drugs are measured by direct physiological response. These drugs can be used, with caution (i.e. lower starting doses), in renally impaired patients. Indeed many of the drugs used to manage renal failure (e.g. calcitriol, phosphate binders) are titrated according to response ( NOTEREF _Ref513192872 \h 3).PharmacodynamicsUraemia in RI can alter the clinical response to certain drugs for example;Increased sensitivity to drugs acting on the central nervous system, due to increased permeability of the blood-brain barrier ( NOTEREF _Ref504661392 \h 2, NOTEREF _Ref436833736 \h \* MERGEFORMAT 13) Increased risk of hyperkalaemia with drugs such as potassium-sparing diuretics ( NOTEREF _Ref504661392 \h 2,).Increased risk of gastrointestinal bleeding or oedema with non-steroidal anti-inflammatory drugs (NSAID) ( NOTEREF _Ref504661392 \h 2, NOTEREF _Ref509993991 \h 23).Reduced efficacy or increased toxicity of drugs such as warfarin or statins, independent of changes in the pharmacokinetics of these drugs. Kidney disease is thought to alter the physiological or pathological processes involved in the condition being treated ().Acute Kidney InjuryCritically ill patients will often develop acute kidney injury (AKI), multiorgan dysfunction syndrome or multisystem organ failure. When dosing patients with AKI, these and other factors - rapidly fluctuating levels of renal function, changes in volume status and the effects of renal replacement therapy (RRT) - need to be considered in addition to those discussed above ( NOTEREF _Ref355359141 \h \* MERGEFORMAT 8). Dosage adjustment should be guided by clinical judgement and monitoring, in addition to published guidance which may be based on older studies in CKD patients or patients on RRT( NOTEREF _Ref442881501 \h 8). For information relating to RRT please refer to Q&A What factors need to be considered when dosing in renal replacement therapies? Volume status will affect the size of the loading dose of water-soluble antimicrobials (see above under 'Distribution'). For subsequent doses, the dose or dose interval is adjusted according to whether the antimicrobial effect is concentration- or time-dependent or both concentration- and time-dependent ( NOTEREF _Ref509994381 \h 12,) (please refer to references NOTEREF _Ref509994381 \h 12, NOTEREF _Ref509993537 \h 19 and NOTEREF _Ref509994423 \h 25 for a discussion of the pharmacodynamics and pharmacokinetics of antimicrobials in RI and AKI).Nephrotoxic DrugsNephrotoxic drugs should, if possible, be avoided in patients with renal disease because the consequences of nephrotoxicity are likely to be more serious when renal reserve is already reduced. During intercurrent illness the risk of acute kidney injury is increased in patients with an eGFR of less than 60?mL/min/1.73?m2; potentially nephrotoxic or renally excreted drugs may require dose reduction or temporary discontinuation ( NOTEREF _Ref355709369 \h 9).Summary The absorption, distribution, metabolism and excretion of drugs can be affected by renal impairment (RI) to varying degrees. The effect of CKD on intestinal cytochrome P450 metabolic enzymes and transporters may lead to an increase in bioavailability of some orally administered drugs in patients with RI. Changes to drug distribution (protein binding and Vd) may be clinically important for a few drugs, but are more likely to be an issue in renal replacement therapies (RRT). Drugs that are most affected by RI are those that are normally substantially renally excreted or have active or toxic metabolites which are renally excreted. Renal excretion of a drug is dependent on GFR and when renal function is impaired, clearance of the drug is decreased and the plasma half-life prolonged. The excretion of some drugs that are mainly eliminated in the urine by active tubular secretion can also be reduced in RI. Therefore patients with RI who are given drugs that are mainly renally cleared will require the dose or dose frequency to be adjusted. This is usually either by the standard dose being given at extended intervals or a reduced dose given at the usual intervals. Single doses are not thought to need adjustment as accumulation is unlikely. Loading doses of some drugs may need adjustment. Use plasma concentration measurements to adjust drug dosage wherever possible and monitor the patient carefully for evidence of clinical effectiveness and toxicity of drugs.When dosing patients with AKI - multisystem organ failure, rapidly fluctuating levels of renal function, changes in volume status and the effects of RRT need to be considered in addition to those factors discussed above.Nephrotoxic drugs should, if possible, be avoided in patients with renal disease because the consequences of nephrotoxicity are likely to be more serious when renal reserve is already reduced. LimitationsThis Q&A discusses general principles of drug dosage adjustment in adults with renal impairment (RI). For information on estimating renal function for dosing in RI – see Q&A Which estimate of renal function should be used when dosing patients with renal impairment?. For information on dose adjustment of specific drugs or information on drug dosage adjustment in children or in pregnant patients with RI, please consult the latest BNF, BNF for children, SPC and/or specialist sources of information (). References ................
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