Enhanced sedation or respiratory and cardiovascular depression may occur if diazepam or other benzodiazepines are given with other drugs that have CNS-depressant properties these include alcohol, antidepressants, sedative antihistamines, antipsychotics, general anaesthetics, other hypnotics or sedatives, and opioid analgesics. The sedative effect of benzodiazepines may also be enhanced by cisapride. Adverse effects may also be produced by use with drugs that interfere with the metabolism of benzodiazepines. Drugs that have been reported to alter the pharmacokinetics of benzodiazepines are discussed in detail below but few of these interactions are likely to be of clinical significance. Benzodiazepines such as diazepam that are metabolised primarily by hepatic microsomal oxidation may be more susceptible to pharmacokinetic changes than those eliminated primarily by glucuronide conjugation.
Analgesics. The peak plasma concentration of oxazepam was significantly decreased when diflunisal was given to 6 healthy subjects, while the renal clearance of the glucuronide metabolite was reduced and its mean elimination half-life increased from 10 to 13 hours. Diflunisal also displaced oxazepam from plasma protein binding sites in vitro. Aspirin shortened the time to induce anaesthesia with midazolam in 78 patients also possibly due to competition for plasma protein binding sites. Paracetamol produced no significant change in plasma concentrations of diazepam or its major metabolite and only marginal changes in urine concentrations in 4 healthy subjects. Benzodiazepines such as diazepam, lorazepam, and midazolam may be used with opioid analgesics in anaesthetic or analgesic regimens. An additive sedative effect is to be expected but there are also reports of severe respiratory depression with midazolam and fentanyl or sudden hypotension with midazolam and fentanyl or sufentanil The clearance of midazolam appears to be reduced by fentanyl, possibly as a result of competitive inhibition of metabolism by the cytochrome P450 isoenzyme CYP3A. Careful monitoring is therefore required during use of midazolam with these opioids and the dose of both drugs may need to be reduced. Synergistic potentiation of the induction of anaesthesia has been reported between midazolam and fentanyl, but one study has suggested that midazolam can reduce the analgesic effects of sufentanil. Pretreatment with morphine or pethidine has decreased the rate of oral absorption of diazepam. This has been attributed to the effect of opioid analgesics on gastrointestinal motility.
Dextropropoxyphene prolonged the half-life and reduced the clearance of alprazolam but not diazepam or lorazepam in healthy subjects.
Antiarrhythmics. An interaction between clonazepam and existing therapy with amiodarone was suspected in a 78-year-old man who experienced symptoms of benzodiazepine toxicity 2 months after starting with clonazepam 500 micrograms given at bedtime for restless leg syndrome symptoms resolved on withdrawal of clonazepam.
Antibacterials. Both erythromycin and troleandomycin have been reported to inhibit the hepatic metabolism of triazolam in healthy subjects. Peak plasma-triazolam concentrations were increased, half-life prolonged, and clearance reduced. Troleandomycin prolonged the psychomotor impairment and amnesia produced by triazolam. Loss of consciousness after erythromycin infusion in a child premedicated with midazolam was attributed to a similar interaction, and increases in peak plasma concentrations of midazolam with profound and prolonged sedation have been reported after use of erythromycin. Use of midazolam with erythromycin should be avoided or the dose of midazolam reduced by 50 to 75%. The clearance of midazolam is also reduced by clarithromycin, with an approximate doubling of the benzodiazepine’s oral bioavailability. The manufacturers of quinupristin/dalfopristin state that it too may increase plasma concentrations of midazolam. Roxithromycin has been reported to have some effects on the pharmacokinetics and pharmacodynamics of midazolam but these changes were not thought clinically relevant. However, it was recommended that as a precaution the lowest possible effective dose of midazolam should be used when given with roxithromycin. In another study azithromycin did not appear to have any effect on the metabolism or psychomotor effects of midazolam.
There is an isolated report of significant rises in steady-state blood-midazolam concentration coinciding with dosage of ciprofloxacin? Also ciprofloxacin has been reported to reduce diazepam clearance and prolong its terminal half-life, although psychometric tests did not show any changes in diazepam’s pharmacodynamics. However, ciprofloxacin appears to have no effect on the pharmacokinetics or pharmacodynamics of temazepam.
Isoniazid has been reported to increase the half-life of a single dose of diazepam and triazolam but not of oxazepam in healthy subjects. In contrast, rifampicin has decreased the half-life of alprazolam, diazepam, midazolam, and nitrazepam and more or less abolishes the effects of triazolam, while ethambutol has no effect on diazepam pharmacokinetics. In patients receiving therapy for tuberculosis with isoniazid, rifampicin, and ethambutol the half-life of a single diazepam dose was shortened and its clearance increased. Thus the enzyme-inducing effect of rifampicin appears to predominate over the enzyme-inhibiting effect of isoniazid.
Anticoagulants. Plasma binding of diazepam and desmethyldiazepam was reduced, and free concentrations increased, immediately following heparin intravenously. Benzodiazepmes do not usually interact with oral anticoagulants although there have been rare reports of altered anticoagulant activity.
Antidepressants. It has been recommended that the dosage of alprazolam should be reduced when given with fluvoxamine, as concomitant use has resulted in doubling of plasma-alprazolam concentrations. Since plasma concentrations of bromazepam and of diazepam also appear to be affected by fluvoxamine, it has been suggested that patients taking fluvoxamine who require a benzodiazepine should preferentially receive one such as lorazepam, which has a different metabolic pathway. Small studies suggest that fluoxetine can also increase plasma concentrations of alprazolam. Fluoxetine appears to have a similar effect on diazepam but plasma concentrations of diazepam’s active metabolite desmethyldiazepam are reduced and it is considered that the overall effect is likely to be minor. The potential for a clinically significant interaction with sertraline, paroxetine, or citalo-pram is considered to be less.
The US manufacturers have reported that alprazolam may increase the steady-state plasma concentrations of imipramine and desipramine, although the clinical significance of such changes
is unknown. For a suggestion that benzodiazepines may increase the oxidation of amineptine to a toxic metabolite, see Effects on the Liver under Adverse Effects of Amitriptyline. Nefazodone has been reported to raise concentrations of alprazolam and triazolam, resulting in increased sedation, and impairment of psychomotor performance. Nefazodone may inhibit the oxidative metabolism of alprazolam and triazolam. Raised concentrations of midazolam have similarly been seen when given by mouth with nefazodone. No interaction was reported with lorazepam, which is primarily eliminated by conjugation. For reference to an isolated report of hypothermia after administration of diazepam and lithium. There have been occasional reports of sexual disinhibition in patients taking tryptophan with benzodiazepines.
Antiepileptics. Carbamazepine, phenobarbital, andphenytoin are all inducers of hepatic drug-metabolising enzymes. Therefore, in patients receiving long-term therapy with these drugs the metabolism of benzodiazepines may be enhanced. For oral midazolam the effects of carbamazepine or phenytoin may be sufficient to virtually abolish the effects of a standard dose, with a more than 90% reduction in peak serum concentrations of the benzodiazepine. Interactions between benzodiazepines and these antiepileptics are further discussed — carbamazepine and phenytoin.
Results from a study involving 66 children and adults receiving clobazam as adjunctive therapy for epilepsy showed a significant increase in clobazam clearance, leading to accumulation of its principal active metabolite N-desmethylclobazam, in the 16 patients also takingfelbamate. The metabolism of clobazam and N-desmethylclobazam was reduced by stiripentol, a potent hepatic enzyme inhibitor, resulting in a threefold increase in the plasma concentrations of this metabolite.
Serum-clonazepam concentrations fell markedly in 4 of 8 children who had lamotrigine added to their therapy. Sodium valproate has been reported to displace diazepam from plasma-protein binding sites. Sporadic reports exist of adverse effects when valproate is given with clonazepam’ with the development of drowsiness and, more seriously, absence status epilepticus, but the existence of an interaction is considered to be unproven. Drowsiness has also been reported when valproate was given with nitrazepam. Use of valproate semisodium with lorazepam has resulted in raised concentrations of lorazepam due to inhibition of glucuronidation of lorazepam.
Antifungals. Both a single dose and multiple doses of ketoconazole decreased the clearance of a single intravenous injection of chlordiazepoxide. Studies” have shown that ketoconazole and itraconazole can produce marked pharmacokinetic interactions with midazolam or triazolam and greatly increase the intensity and duration of action of these benzodiazepines. The area under the plasma concentration-time curve for midazolam was increased by 15 times by ketoconazole and by 10 times by itraconazole while peak plasma concentrations of midazolam were increased fourfold and threefold, respectively. The area under the curve for triazolam was increased by 22 times by ketoconazole and by 27 times by itraconazole peak plasma concentrations of triazolam were increased about threefold by both antifungals. Ketoconazole has also been reported to have a similar effect on alprazolam. One study indicated that the risk of interaction persists for several days after cessation of itraconazole therapy. It is recommended that the use of these antifungals with benzodiazepines should be avoided or that the dose of the benzodiazepine should be greatly reduced. A similar but less pronounced interaction occurs between fluconazole and midazolam or triazolam nonetheless the dosage of the benzodiazepine should be reduced during use together.
Antihistamines. A suggestion that a reduction in temazepam metabolism caused by diphenhydramine may have contributed to perinatal death after ingestion of these drugs by the mother.
Antivirals. The NNRTIs delavirdine and efavirenz, and HIV-protease inhibitors such as indinavir, nelfinavir, ritonavi, and saquinavir may inhibit the hepatic microsomal systems involved in the metabolism of some benzodiazepines. Prolonged use of protease inhibitors may also induce these metabolic systems interactions may therefore be complex and difficult to predict. Monitoring and dosage adjustments for the benzodiazepine may be needed, or the combination should be avoided. Benzodiazepines which should not be used with HIV-protease inhibitors include alprazolam, clorazepate, diazepam, estazolam, flu-razepam, midazolam, and triazolam.
Beta blockers. A clear pattern of interactions between benzodiazepines and beta blockers has not emerged. Propranolol may inhibit the metabolism of diazepam and bromazepam, and metoprolol may inhibit the metabolism of diazepam or bromazepam to some extent, although in many cases the effect on pharmacokinetics and pharmacodynamics is unlikely to be of clinical significance. No significant pharmacokinetic interaction has been seen between propranolol and alprazolam, lorazepam, or oxazepam, although the rate of alprazolam absorption may be decreased. Similarly no pharmacokinetic interaction has been seen between atenolol and diazepam, labetalol and oxazepam, or metoprolol and lorazepam.
Calcium-channel blockers. Peak plasma concentrations of midazolam were doubled and the elimination half-life of midazolam prolonged when given to healthy subjects receiving diltiazem or verapamil.A similar interaction has been found between diltiazem and triazolam. Concomitant use should be avoided or the dose of these benzodiazepines reduced in such use.
Ciclosporin. In-vitro studies suggested that ciclosporin could inhibit the metabolism of midazolam. However, blood-ciclosporin concentrations in patients given ciclosporin to prevent graft rejection were considered too low to result in such an interaction.
Clonidine. Anxiety was reduced and sedation was enhanced when clonidine was given with flunitrazepam for premedication.
Clozapine. For reports of cardiorespiratory collapse and other adverse effects in patients taking benzodiazepines and clozapine.
Corticosteroids. The metabolism of midazolam was increased in chronic users of glucocorticoids} perhaps due to the induction of cytochrome P450 isoenzyme CYP3A4, or of enzymes responsible for glucuronidation. The changes were not considered clinically relevant if midazolam was given intravenously, but might be so if it was given orally.
Digoxin. For the effects of alprazolam and diazepam on digoxin pharmacokinetics.
Disulfiram. Evidence from healthy and alcoholic subjects suggests that chronic use of disulfiram can inhibit the metabolism of chlordiazepoxide and diazepam leading to a prolonged half-life and reduced clearance there was little effect on the disposition of oxazepam. No significant pharmacokinetic interaction was observed between disulfiram and alprazolam in alcoholic patients. Temazepam toxicity, attributed to use of disulfiram with temazepam, has been reported. See also under Disulfiram.
Gastrointestinal drugs. Antacids have variable effects on the absorption of benzodiazepines” but any resulting interaction is unlikely to be of major clinical significance. Several studies, usually involving single doses of diazepam given to healthy subj ects, have shown that cimetidine can inhibit the hepatic metabolism of diazepam. The clearance of diazepam has generally been decreased and the half-life prolonged. Some studies have also shown impaired metabolic clearance of the major metabolite, desmethyldiazepam (nordazepam). Cimetidine has also been reported to inhibit the metabolism of other benzodiazepines (generally those metabolised by oxidation) including alprazolam, bromazepam, chlordiazepoxide, clobazam, flurazepam, midazolam, nitrazepam, and triazolam. Cimetidine does not appear to inhibit the hepatic metabolism of lorazepam, oxazepam, or temazepam. The clinical significance of these interactions between cimetidine and benzodiazepines remains dubious, and little effect on cognitive function or degree of sedation has been shown.
Most studies have failed to find an effect of ranitidine on the hepatic metabolism of diazepam, although one study reported an increase in the bioavailability of a single oral dose of midazolam, and considered that an effect on hepatic clearance was more likely than an effect on absorption. These results were consistent with those of another study which showed an enhanced sedative effect of midazolam in patients pretreated with ranitidine. Ranitidine has been reported to have no effect on the pharmacokinetics of lorazepam or on the sedative effect of temazepam but has increased the bioavailability of triazolam. Famotidine® or nizatidine do not appear to inhibit the hepatic metabolism of diazepam.
Oral diazepam was absorbed more rapidly after intravenous metoclopramide Enhanced motility of the gastrointestinal tract was implicated. Cisapride may also accelerate the absorption of diazepam.
Studies of continuous omeprazole dosage on the pharmacokinetics of a single intravenous dose of diazepam in healthy subj ects indicate inhibition of diazepam metabolism in a similar manner to cimetidine. Omeprazole decreases the clearance and prolongs the elimination half-life of diazepam in addition both the formation and elimination of desmethyldiazepam appear to be decreased. The effects may be greater in rapid than in slow metabolisers of omeprazole and vary between ethnic groups.
The clinical significance of the interaction remains to be established. Lansoprazole and pantoprazole have been reported not to affect the pharmacokinetics of diazepam.
General anaesthetics. A synergistic interaction has been found for the hypnotic effects of midazolam and thiopental Although midazolam failed to produce anaesthesia at the doses used, the drug caused a twofold increase in the anaesthetic potency of thiopental. Similar synergistic interactions have been seen between midazolam and both methohexital and propofol. The interaction between midazolam and propofol could not be explained solely by alteration in free-plasma concentration of either drug, although a later study does suggest that propofol reduces the clearance of midazolam via its inhibitory effects on the metabolism of midazolam by the cytochrome P450 isoenzyme CYP3A4. It has been reported that midazolam can produce a marked reduction in the concentration of halothane required for anaesthesia.
Grapefruit juice. Grapefruit juice has been reported to be able to increase the bioavailability of oral midazolam or triazolam and to raise peak plasma concentrations. However, these results have been contradicted by another study, which found no evidence for an interaction.
Kava. A patient whose medication included alprazolam, cimetidine, and terazosin became lethargic and disoriented after starting to take kava. An interaction between kava and the benzodiazepine was suspected.
Levodopa. For reference to the effects of benzodiazepines on levodopa, see Anxiolytics.
Neuromuscular blockers. For reference to the effect of diazepam on neuromuscular blockade.
Oral contraceptives. Some studies with alprazolam, chlordiazepoxide, and diazepam have supported suggestions that oral contraceptives may inhibit the biotransformation of benzodiazepines metabolised by oxidation, although no significant pharmacokinetic alterations have been observed with clotiazepam, or triazolam. The biotransformation of benzodiazepines metabolised by conjugation, such as lorazepam, oxazepam, or temazepam, may be enhanced or unchanged. No consistent correlation has been observed between the above pharmacokinetic changes and clinical effects. It has been observed that psychomotor impairment due to oral diazepam was greater during the menstrual pause than during the 21-daily oral contraceptive cycle. This may have been due to an effect of oral contraceptives on diazepam absorption. Another study noted that women taking oral contraceptives appeared to be more sensitive to psychomotor impairment after single oral doses of alprazolam, lorazepam, or triazolam, than controls. The effects of temazepam were minimal in both groups. Alterations in sedative or amnesic effect could not be established with any certainty.
Penicillamine. Phlebitis associated with intravenous diazepam resolved with local heat but recurred on two separate occasions after oral penicillamine.
Probenecid. Probenecid increased the half-life of intravenous lorazepam in 9 healthy subjects. Probenecid was considered to impair glucuronide formation selectively and thus the clearance of drugs like lorazepam. Probenecid has also shortened the time to induce anaesthesia with midazolam in 46 patients. The effect was considered to be due to competition for plasma protein binding sites. Probenecid has also been reported to reduce the clearance of nitrazepam but not of temazepam.
Smooth muscle relaxants. Intracavernosal papaverine produced prolonged erection in 2 patients who had been given intravenous diazepam as an anxiolytic before the papaverine.
Tobacco smoking. The Boston Collaborative Drug Surveillance Program reported drowsiness as an adverse effect of diazepam or chlordiazepoxide less frequently in smokers than non smokers. Pharmacokinetic studies have, however, been divided between those indicating that smoking induces the hepatic metabolism of benzodiazepines and those showing no effect on benzodiazepine pharmacokinetics. Hence, diminished endorgan responsiveness may in part account for the observed clinical effects. Taking large amounts of xanthine-containing beverages as well may decrease any enzyme-inducing effects of smoking.
Xanthines. There are reports of aminophylline given intravenously reversing the sedation from intravenous diazepam, although not always completely nor as effectively as flumazenil. Blockade of adenosine receptors by aminophylline has been postulated as the mechanism of this interaction. Xanthine-containing beverages may be expected to decrease the incidence of benzodiazepine-induced drowsiness because of their CNS-stimulating effects and their ability to induce hepatic drug-metabolising enzymes. However, decreased drowsiness has only sometimes been seen and the actions of xanthines may themselves be decreased by heavy tobacco smoking.