All Benzodiazepines are Metabolized by the Liver

All Benzodiazepines are Metabolized by the Liver

LiverInOut copyWe sometimes hear information stated as fact that may not be entirely accurate. One such example is, “I’m going to use lorazepam because it isn’t metabolized by the liver.”

Let’s set the record straight.

ALL benzodiazepines are metabolized by the liver. 

Benzodiazepines and the Liver

Some are just metabolized by different pathways that are less dependent on global liver function.

The ‘LOT’ drugs are those metabolized mostly by conjugation.

  • L – Lorazepam
  • O – Oxazepam
  • T – Temazepam

These do not have active metabolites, and the half-life remains relatively the same even in the setting of liver disease.

The rest of the benzodiazepines are primarily metabolized via hepatic CYP-mediated oxidation. These may have prolonged duration of effect in patients with marked liver impairment, particularly the drugs with active metabolites such as diazepam, clonazepam, and midazolam. Some practitioners like to take advantage of the longer duration of action and active metabolites. Others prefer to have more predictable kinetics in patients with liver disease and stick with the ‘LOT’ options.

Bottom Line

‘LOT’ drugs do not have active metabolites after hepatic conjugation, and therefore have minimally affected half-lives in patients with liver disease.

Further Reading

  1. Mihic SJ, Harris RA. Chapter 17. Hypnotics and Sedatives. In: Chabner BA, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=16663643. Accessed November 7, 2013.
  2. Lee DC, Ferguson KL. Chapter 74. Sedative-Hypnotics. In: Lee DC, Ferguson KL, eds.Goldfrank’s Toxicologic Emergencies. 9th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=6520459. Accessed November 7, 2013.

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Expert Peer Review

>Prescribing in kidney disease

Prescribing medications in patients with renal disease can be a hassle, but it isn’t complicated. We estimate renal function with a readily available test and then reduce the dose, lengthen the dosing interval or both. What we do depends of course on the drug, the degree of renal dysfunction and our therapeutic objectives. But the point is that it’s not difficult because we can readily estimate GFR and because, for most drugs, ready guidance exists on how to make adjustments.

Liver disease is different

Although we have readily available measures of hepatic function such as INR, albumin and bilirubin, these tests are subject to a variety of other influences. Even if they weren’t, there is no “creatinine equivalent” to guide dose adjustment in patients with liver disease. The liver is a complicated thing. It metabolizes many drugs, it eliminates some through the biliary system, and even the delivery of drugs to the liver can be perturbed by alterations in hepatic blood flow that can occur in patients with liver disease. And as if that wasn’t enough, the hepatic fate of many drugs is governed by dozens of uptake and efflux transporters, a discussion of which would put even the most well-meaning clinician promptly to sleep.

But prescribing in the setting of liver disease is not a complete black box. @PharmERToxGuy reminds us that “hepatic metabolism” isn’t just about the cytochrome P450 (CYP450) system - the various enzymes that effect subtle changes in drug molecules, adding a hydroxyl group here, removing an amino group there, and so on. The liver is also responsible for more substantive modifications, including acetylation, sulfation and glucuronidation. Like CYP450 reactions, these reactions sometimes yield active metabolites, with the glucuronides of morphine and hydromorphone among the more relevant examples. Let’s not equate hepatic metabolism exclusively with the CYP450 system.

Liver Disease and Benzodiazepines

The more clinically relevant point of the post is that liver disease does influence the pharmacokinetics of drugs, sometimes in large and quantifiable ways. In the case of benzodiazepines, most of the key research was done in the 1970s in patients with cirrhosis and viral hepatitis. Consider diazepam, which is metabolized to both temazepam and desmethyldiazepam. The latter, in turn, is converted to oxazepam. All of these compounds are pharmacologically active, but the plasma clearance of diazepam and its desmethyl metabolite decline by about half in patients with cirrhosis. In fact, the mean elimination half-life of diazepam is about 27 hours in normal subjects but more than 100 hours in patient with alcoholic cirrhosis. In contrast, there is little change in the clearances of oxazepam and lorazepam, which are metabolized to inactive glucuronides and eliminated in the urine.

The takeaway point here is that the “LOT” drugs are simply more predictable in such patients.

Two final points merit emphasis. First, we’re talking about cirrhosis and severe acute liver disease. There is no reason to extend this discussion to, for example, mild hepatic steatosis. Second, let’s keep in mind the pharmacodynamic angle here. Benzodiazepines and other sedatives are common precipitants of encephalopathy in patients with cirrhosis. In this setting, we need a very good reason to prescribe any of these drugs, active metabolite or not.

David Juurlink, BPhm, MD, PhD, FRCPC
Associate Professor of Medicine, Pediatrics, and Health Policy, Management, and Evaluation; Head, Division of Clinical Pharmacology and Toxicology Sunnybrook Health Sciences Centre
Bryan D. Hayes, PharmD, FAACT, FASHP

Bryan D. Hayes, PharmD, FAACT, FASHP

Chief Science Officer, ALiEM
Creator and Lead Editor, CAPSULES series, ALiEMU
Clinical Pharmacist, EM and Toxicology, MGH
Assistant Professor of EM, Harvard Medical School
Bryan D. Hayes, PharmD, FAACT, FASHP

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  • Jason West

    So there is actually a bunch of data on CONTINUOUS sedation agents in hepatic failure, but there is essentially no real meaningful literature that I know on acute ED sedation of patients with liver failure. Gastroenterologists have a lot of data on which sedation agents to use for outpatient endoscopies, but this kind of literature has never been written from the ER setting.

    In medical school, I think most of us are taught that in hepatic failure, phase 1 metabolism will fail before phase 2 metabolism; so that is why most clinicians feel comfortable giving ativan to an “agitated” patient with liver failure / hepatic encephalopathy. I prefer to use haldol in the liver-failed patients that I believe are both too agitated and encephalopathic at the expense of annoying the admitting physicians (who aren’t responsible for getting ANY of the initial workup or even interviewing the patient in the ED).

    From your perspective, what would you recommend for the average liver failure patient that requires sedation?

    Jason

    • Bryan D. Hayes

      In severe liver disease, the duration of effect for both lorazepam and haloperidol will be less affected than midazolam or diazepam. For acute control of agitation in a liver failure patient, lorezapam and/or haloperidol still are probably first line. Olanzapine and ziprasidone are both extensively metabolized by CYP enzymes, too. For intubated patients requiring sedation, start with analgesics and add propofol or dexmedetomidine if more sedation is needed. Benzodiazepines should be avoided.

  • Martine Evans

    i would like to ask a question as no one seems to have an answer for me. I keep testing positive for medazolam yet i’ve never taken it apart from when i had an operation 10 yrs ago. However every time i have tested positive i had recently taken Diazapam 3 – 7 days before hand. I seem to take ages to metabolise anything as i tested positive for Diazipam 10wks after taking it. Could this be a possible sign of liver damage – or can anyone give me a possible answer on why this is happening. Thanks. Martine

    • Michelle Lin

      Hi Martine: Thanks for your question. We would recommend asking your physician and consultants for further advice. We are an educational website for practitioners and do not comment on case-specific questions. Apologies.