Lorazepam metabolism

Volkow ND, Wang GJ, Begleiter H, et al Regional brain metabolic response to lorazepam in subjects at risk for alcoholism. Alcohol Clin Exp Res 19 510-316, 1995... 

Disulfiram inhibits CYP enzymes 1A2, 2C9, and 3A4 many benzodiazepines are metabolized via these pathways lorazepam, temazepam, and oxazepam are NOT metabolized via the CYP4S0 system and are reasonable alternatives. 

In contrast to chlordiazepoxide and diazepam, lorazepam and oxazepam are not metabolized into active compounds in the liver. Instead, they are excreted by the kidneys following glucuronidation. This is important because many alcohol-dependent patients have compromised liver function. Therefore, when treatment is initiated before the results of blood tests for liver function are known, as is often the case in outpatient clinics, lorazepam and oxazepam may be preferred. Patients with liver disease may still be treated with diazepam and chlordiazepoxide, but at lower doses. This can be accommodated with the loading technique, although hourly dosing with 5 mg of diazepam or 25 mg of chlordiazepoxide may be sufficient. 

Refractory GCSE has also been treated with large-dose continuous infusion lorazepam or diazepam. Lorazepam contains propylene glycol, which can accumulate and cause marked osmolar gap, metabolic acidosis, and renal toxicity. 

It does bear special mention that many mental health practitioners consider lorazepam (Ativan) to be the most versatile of the benzodiazepines. Lorazepam has an intermediate onset and duration of action. Because it is easily metabolized, lorazepam is preferred when a benzodiazepine must be used to treat medically compromised or elderly patients. Most importantly, lorazepam is the only benzodiazepine that can be administered via oral, intramuscular, and intravenous routes. As a result, the transition between inpatient and outpatient care is rendered much easier with lorazepam than other benzodiazepines. 

Benzodiazepines should be used with caution in dementia patients. Used improperly, they can disinhibit patients and worsen behavior, or they can accumulate and lead to a state of intoxication. To minimize the risk of accumulation, benzodiazepines that are easily metabolized are preferred for elderly patients. Specifically, lorazepam (Ativan) and oxazepam (Serax) are easier for elderly patients to tolerate than other benzodiazepines. 

Anxiety. Like psychosis, choosing a medication to treat anxiety in demented patients depends in large part on whether the anxiety is acute or longstanding. Acute severe anxiety requires rapid relief. For this, we recommend a benzodiazepine. Our first choice is lorazepam (Ativan) that is given as needed at 0.25-0.5 mg per dose. We prefer lorazepam because elderly patients tolerate it well (i.e., they metabolize it easily), and it is available in both oral and injectable forms. Oxazepam (Serax) is another benzodiazepine that older patients metabolize easily, but it is only available in oral form. When using benzodiazepines, be careful that your patients do not become overly sedated or delirious. 

Midazolam is a rapidly metabolized benzodiazepine (p. 228) that is used for induction of anesthesia. The longer-acting lorazepam is preferred as adjunct anesthetic in prolonged cardiac surgery with cardiopulmonary bypass its am-nesiogenic effect is pronounced. 

Does not include agents metabolized by glucuronidation (lorazepam, oxazepam, temazepam). 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Most benzodiazepines undergo oxidative metabolism in the liver that may be enhanced by enzyme inducers (e.g. carbamazepine, phenytoin) or slowed by inhibitors (sodium valproate, fluoxetine, fluvoxamine). Oxazepam, lorazepam and temazepam are directly conjugated and are not subject to these interactions. 

The BZs are all metabolized in the liver via the hepatic cytochrome P450 (CYP) enzymes through one or both of the following pathways phase I oxidation and dealkylation, and/or phase II conjugation to glucuron-ides, sulfates, and acetylated compounds. Diazepam, chlordiazepoxide, and flurazepam all undergo both phase 1 and phase 11 metabolism. Lorazepam, lorme-tazepam, oxazepam, and temazepam are all metabolized by phase 11 alone and are better tolerated by patients with liver impairment. 

Knowing the structure of a particular BZ drug can help predict the metabolic pathway for that drug. For example, oxazepam, lorazepam, and temazepam are all 3-OH BZs and are directly conjugated (Chouinard et ah, 1999). Temazepam is partly demethylated to oxazepam, but otherwise these drugs have no active metabolites (Bellantuono et ah, 1980). 

As mentioned above, oxidative reactions will be rate-limiting in most instances. However, some medications are simply metabolized through conjugation. For example, benzodiazepines such as lorazepam are conjugated and excreted. The rate of conjugative reactions may be increased by OCs accelerating the elimination of these compounds because this reaction is rate-limiting [Yonkers and Hamilton 1995 Stoehr et al. 1984). 

At equipotent doses, all benzodiazepines have similar effects. The choice of benzodiazepine is generally based on half-life, rapidity of onset, metabolism, and potency. In patients with moderate to severe hepatic dysfunction, it may be useful to avoid benzodiazepines. All benzodiazepines are metabolized at various levels by the liver, which leads to an increased risk of sedation and confusion in hepatic failure. If it is necessary to prescribe this class of medication, lorazepam and oxazepam are reasonable choices because they are predominantly eliminated by renal excretion. 

Most sedative drugs, including narcotics and alcohol, potentiate the sedative effects of benzodiazepines. In addition, medications that inhibit hepatic cytochrome P450 (CYP) 3A3/4 increase blood levels and hence side effects of clonazepam, alprazolam, midazolam, and triazolam. Lorazepam, oxazepam, and temazepam are not dependent on hepatic enzymes for metabolism. Therefore, they are not affected by hepatic disease or the inhibition of hepatic enzymes. 

Treatment of ethanol withdrawal is supportive and relies on benzodiazepines, taking care to use compounds such as oxazepam and lorazepam, which are not as dependent on hepatic metabolism as most other benzodiazepines. In patients in whom monitoring is not reliable and liver function is adequate, a longer-acting benzodiazepine such as chlordiazepoxide is preferred. 

Benzodiazepines [P] Decreased metabolism of alprazolam, chlordiazepoxide, diazepam, halazepam, prazepam, and clorazepate but not oxazepam, lorazepam, or temazepam. 

Metabolic acidosis and hyperlactatemia have been attributed to lorazepam (706). 

A 34-year-old woman with a history of renal insufficiency induced by long-term use of cocaine developed respiratory failure and was intubated and sedated with intravenous lorazepam (65 mg, 313 mg, and 305 mg on 3 consecutive days). After 2 days she had a metabolic acidosis, with hyperlactatemia and hyperosmolality. Propylene glycol, a component of the lorazepam intravenous formulation, was considered as a potential source of the acidosis, as she had received more than 40 times the recommended amount over 72 hours. Withdrawal of lorazepam produced major improvements in lactic acid and serum osmolality. 

Alprazolam (Xanax), lorazepam (Ativan), and oxazepam (Serax) are metabolized and cleared from the body more quickly than the other members of this family, and are therefore more likely to produce withdrawal symptoms when they are discontinued. These three drugs, however, are less likely to produce side effects such as impaired coordination, concentration, and memory and muscular weakness or sedation. 

The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relationship to the time course of pharmacologic effects. Those benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have shorter half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines are listed in Table 22-1. 

The pharmacokinetic properties of the benzodiazepines in part determine their clinical use. In general, the drugs are well absorbed, widely distributed, and extensively metabolized, with many active metabolites. The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg. The onset of action is very rapid. Total body clearances of the parent drug and its metabolites are low, corresponding to half-lives of 20-40 hours. 

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