Impact of Hepatic and Renal Dysfunction on Pharmacology of Palliative Care Drugs

Thomas Strouse

OVERVIEW

Diminished liver and kidney function are common in palliative care patients. These alterations may be transient, as in the patient with cancer who suffers reversible renal injury from nephrotoxic chemotherapy, or permanent and worsening, such as in the patient with a progressing malignancy metastatic to the liver. Although this chapter is limited to reviewing how hepatic and renal dysfunction affect the pharmacology of common palliative care drugs, it is important to note that a host of other variables are also relevant to the pharmacokinetic (how drugs are absorbed, biotransformed, and excreted) and pharmacodynamic (how drugs work at their target site and the relationship between [drug] and clinical effects) balance in the patient. The reader can consult comprehensive pharmacology textbooks for a more complete picture (1,2).

OPIOIDS

Opioids remain the cornerstone for pain management in palliative care. In the hands of a competent prescriber and responsible patient, they are also quite safe: by contrast to many of the non-opioid analgesics described below, opioids lack organotoxicity, they are broadly effective for a variety of pain states, and there are sufficient data to guide prescribing them in an informed way in end-organ failure.

For the interested reader, many comprehensive reviews of opioid metabolism and pharmacokinetics well beyond the scope of this chapter are available (3,4,5,6,7,8,9). For the purposes of this overview, it is useful to divide opioids into two broad metabolic categories: those that undergo little or no hepatic oxidative metabolism, requiring instead the uridine diphosphate glucuronosyltransferases (UGTs), and those that undergo primary or exclusive metabolism via CYP450/hepatic oxidative biotransformation (see also Table 34.1).

The primary UGT group is comprised of morphine, hydromorphone, and oxymorphone, while the CYP450 group includes methadone, fentanyl, oxycodone, hydrocodone, codeine, and tramadol. Not surprisingly, normal metabolism of the UGT group is more susceptible to embarrassment as a result of changes in renal function, whereas the CYP450 group is subject to pharmacokinetic variability as a result of anomalies in hepatic function. Serum levels of drugs in this latter group are also more vulnerable to the inhibitory or inductive effects on liver isoenzyme activity conferred by starting, stopping, or dose changes of other agents.

In the most general sense, the addition of potent CYP inhibitor drugs to a regimen that already includes regular dosing of an opioid that is primarily a CYP substrate (codeine, hydrocodone, oxycodone, methadone, fentanyl, and tramadol) is likely to result in higher peak plasma concentrations of the opioid parent molecule and a longer duration of action of that molecule, compared with circumstances before the addition of the inhibitor. Decrements in hepatic oxidative function will likely have similar consequences. Conversely, the addition of drugs that are potent CYP inducers may lower peak plasma concentrations of relevant opioids and shorten their duration of action, just as recovery in hepatic function from an impaired baseline will do the same.

NON-OPIOID ANALGESICS

Anticonvulsants

Nearly every commercially available anticonvulsant has been demonstrated to have at least modest analgesic efficacy (10,11). Clinician choice from among them tends to be determined by perceived ease of use: side-effect profile, dosing convenience, monitoring requirements, and increasingly whether or not the manufacturer has obtained an FDA indication for pain. Two of the most commonly prescribed anticonvulsant analgesics, gabapentin and its congener pregabalin, are mediators of the alpha-2-delta subunit of the calcium channel and show broad efficacy in neuropathic pain states. Gabapentin is FDA approved for the treatment of post-herpetic neuralgia and pregabalin for diabetic neuropathic pain, fibromyalgia, and postherpetic neuralgia. Both drugs are biologically inert: they do not undergo oxidative metabolism and are excreted in urine unchanged, making them particularly well-suited for use in patients with complex medical illness, polypharmacy issues, and organ failure. Table 34.2 provides summary data on routes of metabolism and dosing considerations in renal and hepatic dysfunction for the commonly prescribed anticonvulsants.

TABLE 34.1 Metabolic Pathways of Commonly Prescribed Opioids

Drug Category/Name	Uses	Primary Route of Metabolism	Renal Notes	Hepatic Notes	Comments
Opioids
Morphine	Analgesic	UGT2B7	M3G metabolite neuroexcitatory, antianalgesic		Avoid, and consider switching in new-onset renal insufficiency
Hydromorphone		UGT2B7	H3G in rodents neuroexcitatory, antianalgesic; human data inconclusive		In renal insufficiency, monitor patient for toxicities, otherwise no change
Oxymorphone		UGT2B7	O3G measurable but has no known pharmacologic activity		No changes unless symptoms emerge
Codeine		CYP2D6	UGT2B7 secondary		Pro-drug; 2D6-mediated biotransformation to morphine required
Hydrocodone		CYP2D6, 3A4			Lower doses in new-onset hepatic failure
Oxycodone		CYP2D6, 3A4	UGT2B7 secondary		Lower doses in new-onset hepatic failure
Methadone		CYP2C8/9/19, 2D6, 1A2			P-gp inhibitors may ↑ potency
Fentanyl		CYP3A4, 2B6, UGT secondary	UGT secondary		Lower doses in new-onset hepatic and renal failure
Tramadol		CYP2D6	CrCl <30: max 200 mg/d immediate-release formulation only	Cirrhosis: max 100 mg/d immediate release only
Tapentadol		CYP2C9/19, UGT secondary	PI: avoid use in “severe renal insufficiency”	PI: 50 mg q8h in “moderate” impairment; “avoid use” in severe impairment
Adapted from Strouse TB. Pharmacokinetic drug interactions in palliative care: focus on opioids. J Palliat Med. 2009;12:1043-1050. Reprinted/amended with publisher’s permission.
CYP, cytochrome P450 isoenzyme systems, with trailing roman numeral/letter/numeral denoting family, subfamily, etc; UGT, uridine diphosphate glucuronosyltransferase family/subfamily/etc; p-gp, p-glycoprotein cellular membrane ion pumps; CrCl, creatinine clearance; PI, package insert.

TABLE 34.2 Metabolic Pathways of Commonly Prescribed Anticonvulsants

Drug Category/Name	Uses	Primary Route of Metabolism	Renal Notes	Hepatic Notes	Comments
Anticonvulsants	Seizure prophylaxis Analgesia Anxiolysis
Gabapentin		Exclusively renal; inert	CrCl 30-60: 200-700 mg BID CrCl 16-29: 200-700 mg qd CrCl 15: 100-300 mg qd CrCl < 15: dose proportionately to CrCl	None	Like lithium, may be given once orally after dialysis in patients getting renal replacement therapy at regular intervals: 125-350 mg/dose
Pregabalin		Exclusively renal; inert	CrCl 30-60: 75-300 mg/d BID or TID CrCl 15-30: 25-150 mg/d in one or two doses CrCl < 15: 25-75 mg/d	None	Like lithium, may be given once orally after dialysis in patients getting renal replacement therapy at regular intervals: 2× calculated mg/d for CrCl < 15
Topiramate		Not extensively metabolized by hepatic or renal processes	CrCl < 70: 50% of usual adult dose HD: Rapidly cleared (see comments)	Plasma levels may be increased in hepatic dysfunction; no recs in PI	May require both pre- and post-dialysis doses See PI for detail
Lamotrigine		Glucuronidation	Limited data; use with caution	No dose adjustment in mild hepatic impairment; 25% reduction in moderate/severe; 50% in severe with ascites	Maintenance dose after dialysis in patients getting it at regular intervals
Carbamazepine		Hepatic, via CYP3A4, which it also induces	No recs in PI	No recs in PI	In view of primary hepatic route and glucuronidated metabolites, dose modification downward in hepatic and renal dysfunction is reasonable
Oxcarbazepine		Glucuronidation and renal clearance	CrCl < 30: start at 1/2 usual dose and titrate	No dose adjustment required in mild-moderate impairment	No recs in PI for patients on HD or with severe liver impairment
Phenytoin		CYP2C9 and 2C19	Little direct impact	Dose adjustment (see notes and PI)	Hypoalbuminemia (inc. free fraction of DPH) in renal and hepatic failure more important than direct impact or organ dysfunction. Dose decreases needed
Primidone		Poorly understood	No recs in PI	No recs in PI	Post-marketing studies suggest dose decrements in renal/hepatic failure
Valproic acid		Hepatic	Valproic acid accumulates in hepatic dysfunction but PI lacks dosing recs	Per PI, no dose adjustment needed
Felbamate		Hepatic	No recs in PI	FB clearance decreased with renal failure; no recs in PI
Tiagabine		CYP3A3/4	No impact of mild/moderate/severe renal dysfunction per PI	Child-Pugh class B (moderate) impairment associated with 60% decrease in clearance
Levetiracetam		Nonenzymatic hydrolysis and renal excretion	Linear relationship to CrCl; dose decrement suggested	No impact	Dose after dialysis
Zonisamide		CYP3A4, 3A5, 3A7 acetylation to glucuronide	CrCl 50-80: caution advised; titrate slowly CrCl < 50: contraindicated	No specific recs in PI; “caution advised, titrate slowly” in hepatic impairment
All data referenced in this table are abstracted from the package insert for the indicated drug and is thus consistent with FDA’s most current analysis of these agents. Many of the older drugs (e.g., phenytoin and primidone) were approved long before the CYP450 system had been identified. For these, there is often a paucity of what by today’s standards would be considered “basic” metabolic information required for approval. HD, hemodialysis; recs, recommendations; PI, package insert; DPH, diphenylhydantoin (dilantin); FB, felbamate.