Butabarbital Interactions
- Acetaminophen
- Acetazolamide
- Anagrelide
Anti-retroviral protease inhibitors
Anxiolytics, Sedatives, and Hypnotics
- Betaxolol
- Buprenorphine
- Butorphanol
- Caffeine
Calcium-Channel Blockers
- Carbamazepine
- Chloramphenicol
- Clonazepam
Corticosteroids
- Cyclophosphamide
- Cyclosporine
- Delavirdine
- Digitoxin
- Disopyramide
- Doxorubicin
- Doxycycline
- Dronabinol, THC
- Efavirenz
- Entacapone
- Escitalopram
Estrogens
- Ethanol
- Ethotoin
- Fosphenytoin
- Galantamine
- Green Tea
- Guarana
- Imatinib, STI-571
- Kava Kava, Piper methysticum
- Ketamine
- Labetalol
- Lidocaine
- Melatonin
- Methazolamide
- Methoxyflurane
- Metoprolol
- Metronidazole
- Mexiletine
Monoamine oxidase inhibitors (MAOIs)
- Nalbuphine
- Nevirapine
- Nifedipine
Opiate agonists
Oral contraceptives
- Paroxetine
- Pentazocine
Phenothiazines
- Phenytoin
- Pindolol
- Pregabalin
- Primidone
- Propranolol
- Quinidine
- Quinine
- Ramelteon
- Ranolazine
Sedating H1-blockers
- Theophylline, Aminophylline
Thyroid hormones
- Timolol
- Tolcapone
- Tramadol
Tricyclic antidepressants
- Trimethobenzamide
- Valerian, Valeriana officinalis
- Valproic Acid, Divalproex Sodium
- Verapamil
Vitamin D analogs
- Voriconazole
- Warfarin
Butabarbital Interactions
NOTE: Most data describing drug interactions with barbiturates involves phenobarbital. It is generally assumed that other barbiturates interact similarly to phenobarbital.
Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
Barbiturates can interact with many anticonvulsants. Barbiturates can accelerate carbamazepine hepatic metabolism due to induction of hepatic microsomal enzyme activity. Carbamazepine serum concentrations and half-life are decreased during concomitant therapy with phenobarbital. Carbamazepine serum concentrations should be monitored closely if a barbiturate is added or discontinued during therapy. The anticonvulsant action of the barbiturate, however, may help to offset the decreased carbamazepine concentrations. Phenobarbital slightly enhances the hepatic clearance of clonazepam but the clinical effect is likely to be insignificant. Because primidone is metabolized to phenobarbital, the combination of primidone with phenobarbital may lead to excessive phenobarbital concentrations. Barbiturates can stimulate the hydroxylating enzyme that metabolizes phenytoin or, conversely, may inhibit phenytoin metabolism. In general, therapeutic doses of phenobarbital stimulate phenytoin hepatic metabolism, producing lower phenytoin serum concentrations. Large doses of phenobarbital, however, tend to increase phenytoin serum concentrations due to competition for hepatic pathways. Thus, phenytoin serum concentrations can increase, decrease, or not change during concomitant therapy with barbiturates. Conversely, phenytoin can increase serum concentrations of the barbiturate, however this has not been as well studied as the effect of barbiturates on phenytoin. Similar interactions may occur with fosphenytoin or ethotoin. Valproic acid has been shown to inhibit the hepatic metabolism of phenobarbital. It is likely that other barbiturates would be affected similarly by valproic acid. Patients should be monitored for an exaggerated barbiturate effect if valproic acid is used concomitantly. No pharmacokinetic interaction occurs between phenobarbital and gabapentin.
Barbiturates can enhance the hepatic metabolism of beta-blockers that are significantly metabolized by the liver. Beta-blockers that may be affected include betaxolol, labetalol, metoprolol, pindolol, propranolol, and timolol. Clinicians should monitor patients for loss of beta-blockade if a barbiturate is added.
Hepatic enzyme-inducing drugs, including barbiturates, can increase the catabolism of thyroid hormones. Clinicians should be alert for a decreased response to thyroid replacement agents with dosage adjustments, discontinuation or addition of barbiturates during thyroid hormone therapy.
Phenobarbital and chloramphenicol have been shown to affect the pharmacokinetics of each other. Phenobarbital, a known hepatic enzyme inducer, can enhance chloramphenicol metabolism, lowering chloramphenicol serum concentrations. Conversely, chloramphenicol caused phenobarbital concentrations to increase. Although these data were obtained in a very small number of patients and there are no data regarding butabarbital and chloramphenicol, it is likely that a similar interaction is possible. Clinicians should be alert for a potential interaction if barbiturates and chloramphenicol are administered together.
The therapeutic action of some phenothiazines (i.e., chlorpromazine, thioridazine) and the plasma concentrations of barbiturates may be reduced when these drugs are coadministered. The mechanism may relate to induction of CYP450 hepatic metabolism by the barbiturate. The clinical significance is unknown. Patients should be monitored for reduced effects of either agent; dosage adjustments may be needed. Phenothiazines can also potentiate the CNS-depressant action of the barbiturates.
The effects of corticosteroids can be decreased during concomitant treatment with secobarbital. Barbiturates have been shown to affect the clinical response to prednisone in asthmatics and to affect the pharmacokinetics of dexamethasone, methylprednisolone, and prednisolone. It is likely that barbiturates affect all corticosteroids similarly. Dose adjustments may be necessary. The effects of barbiturate therapy on the pharmacokinetics or clinical response to corticotropin, ACTH are unknown.
Barbiturates may accelerate the conversion of cyclophosphamide to its active alkylating metabolite, however, the clearance of this metabolite may also be enhanced. Although the clinical significance of this pharmacokinetic interaction is uncertain, any patient receiving cyclophosphamide should be observed for leukopenia or hemorrhagic cystitis.
Although data are limited, barbiturates should be avoided in patients receiving cyclosporine. In a single case report, phenobarbital was shown to decrease cyclosporine concentrations. Also, there is strong evidence that other hepatic enzyme inducers such as rifampin exert the same effect on cyclosporine. A similar interaction with cyclosporine would be expected for all the barbiturates.
Barbiturates may accelerate the hepatic conversion of digitoxin to digoxin, potentially lowering digitoxin serum concentrations, however; the clinical significance of this pharmacokinetic interaction is uncertain. Close monitoring for clinical and laboratory evidence of altered digitoxin effect is indicated if a barbiturate and digitoxin must be coadministered. Digoxin is not expected to interact with the barbiturates to the same extent.
Barbiturates have been shown to accelerate the clearance of doxorubicin in humans and shorten the elimination half-life of doxorubicin in mice. The clinical significance of this pharmacokinetic interaction is uncertain.
Phenobarbital has been shown to affect the pharmacokinetics of doxycycline. Doxycycline half-life was decreased from 15.3 hours to 11.1 hours. It is likely that other barbiturates may exert the same effect. Clinicians should keep in mind that larger doses of doxycycline may be necessary in patients receiving barbiturates. This interaction may not apply to other tetracyclines since they are less dependent on hepatic metabolism for elimination.
Barbiturates can accelerate the hepatic clearance of estrogens. As a result, the effectiveness of oral contraceptives can be lost, particularly if the dose of ethinyl estradiol is < 50 mcg/day. Higher dosages of oral contraceptives (e.g, ethinyl estradiol >= 50 mcg/day) or a second contraceptive method are typically suggested if women use an enzyme-inducing anti-epileptic drug or a barbiturate. For patients taking estrogens for other indications, a higher dose of estrogen may be required during barbiturate therapy.
Additive CNS depression may occur if barbiturates are used concomitantly with buprenorphine, butorphanol, dronabinol, THC, ethanol, entacapone, sedating H1-blockers, nalbuphine, opiate agonists, pentazocine, pregabalin, tolcapone, tramadol, tricyclic antidepressants, or other anxiolytics, sedatives, and hypnotics. Although barbiturates can induce hepatic metabolism and may eventually accelerate the clearance of ethanol, ramelteon, tricyclic antidepressants, or some opiate agonists such as meperidine or methadone, this action would likely require several days of barbiturate administration while additive drowsiness would appear immediately. Caution should be exercised during concomitant use of any of these CNS-depressant drugs and any barbiturate. Dosage reduction of one or both agents may be necessary. Additionally, barbiturates may induce CYP1A2 hepatic enzymes and may reduce efficacy of ramelteon over a longer period of time.
There is some concern that barbiturates may also affect the clearance of paroxetine, however, data are conflicting. It is suggested by that paroxetine serum concentration and half-life will decrease if coadministered with barbiturates, probably via hepatic enzyme induction from the barbiturate. The patient should be monitored for loss of clinical effect from the SSRI and doses adjusted, if needed.
Barbiturates can decrease the oral absorption of griseofulvin, however the clinical significance of this interaction is uncertain.
Chronic administration of secobarbital has been shown to enhance the nephrotoxicity of methoxyflurane. Serum fluoride concentrations were higher in a patient receiving secobarbital than in patients not receiving this barbiturate who were given methoxyflurane. It is thought that barbiturates enhance the hepatic conversion of methoxyflurane to its nephrotoxic metabolite. If butabarbital is used for preoperative anesthesia, it can promote hypotension. Concurrent use of barbiturates with ketamine may lead to excessive hypotension.
Concurrent use of barbiturates with some antihypertensive agents may lead to excessive hypotension. Barbiturates have been shown to enhance the hepatic clearance of calcium-channel blockers (e.g., nifedipine, verapamil). The effect on oral verapamil is greater than for IV verapamil, but a significant increase in clearance has been noted for both verapamil dosage forms during concomitant administration of a barbiturate.
Phenobarbital has been shown to reduce the serum concentrations of disopyramide and of quinidine. It is likely that secobarbital would produce the same effect as phenobarbital. Serum disopyramide or quinidine concentrations should be monitored during concomitant therapy with secobarbital. Dose adjustments for disopyramide or quinidine may be necessary if secobarbital is either added to discontinued during therapy. Barbiturates also enhance the hepatic clearance of lidocaine although the effects on IV lidocaine are modest. While other hepatic enzyme inducers (e.g., rifampin) have been shown to accelerate the metabolism of mexiletine, no data are available regarding the effects of barbiturates on mexiletine. An interaction between barbiturates and mexiletine, however, may be possible.
Quinine may interfere with the hepatic metabolism of phenobarbital (the major metabolite of mephobarbital) or other barbiturates, resulting in higher plasma concentrations of the barbiturate; clinical data are lacking. Until more data are known, patients should be observed for increased barbiturate effects if quinine is administered concurrently.
Phenobarbital has been shown to affect the pharmacokinetics and the clinical response to metronidazole in a single case report. It is likely that other barbiturates may exert the same effect. Until more data are available, clinicians should keep in mind that larger doses of metronidazole may be necessary in patients receiving barbiturates.
Monoamine oxidase inhibitors (MAOIs) may prolong the effect of some barbiturates, although data are very limited. Until more data are available, barbiturates should be used cautiously in patients receiving MAOIs.
The metabolism of xanthines, such as caffeine or theophylline, can be increased by concurrent use with barbiturates. While it is clear that barbiturates can accelerate the clearance of theophylline, the magnitude of this interaction is uncertain. Patients should be monitored for loss of therapeutic effect if a barbiturate is added is added to theophylline therapy. Conversely, the hypnotic effects of barbiturates can be reduced by caffeine or theophylline. Patients that ingest theophylline or high amounts of caffeine from foods, beverages (e.g., coffee, green tea, other teas, cola, and chocolate), or from dietary supplements such as guarana should be monitored for therapeutic effect while taking barbiturates.
A serious drug interaction can occur between barbiturates and warfarin. All barbiturates are hepatic enzyme inducers and the clinical effects of warfarin can be compromised if a barbiturate is added. More importantly, discontinuation of a barbiturate during warfarin therapy has lead to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy.
Any substance that acts on the CNS may interact with valerian, Valeriana officinalis; kava kava, Piper methysticum; or melatonin. These interactions are probably pharmacodynamic in nature. Patients should avoid concomitant administration of dietary supplements promoted for sleep and relaxation with prescription sedatives and/or seizure medications (i.e. barbiturates).
Barbiturates are inducers of the hepatic CYP3A4 isoenzyme, and use may lower the plasma levels of other medications metabolized through these pathways. The effectiveness of medications such as galantamine could theoretically be decreased.
When both an inhibitor and/or inducer of the cytochrome P450 enzyme system, such as anti-retroviral protease inhibitors, delavirdine, efavirenz, or nevirapine, is used with butabarbital a complex interaction occurs. Decreased efficacy of the anti-retroviral agent due to decreased plasma concentrations may be observed in patients taking barbiturates concomitantly. Additionally, increased doses of butabarbital may be required due to metabolism induction by ritonavir, efavirenz or nevirapine. The appropriate drug-dose adjustments necessary to ensure optimum levels of both anti-retroviral agent and phenobarbital are unknown. Anticonvulsant serum concentrations should be monitored closely if these agents are added; the patient should be observed for changes in the clinical efficacy of the antiretroviral or anticonvulsant regimen.
Agents that induce cytochrome P450 3A4, such as butabarbital, may increase the metabolism and decrease the concentrations and clinical effects of imatinib, STI-571.
Acetazolamide or methazolamide can induce osteomalacia in patients treated chronically with phenobarbital; the potential for this interaction with other barbiturates seems probable. Potential mechanisms for this interaction include a carbonic-anhydrase inhibitor-induced increase in the urinary excretion of calcium and an increase in phenobarbital effects resulting from metabolic acidosis. Acetazolamide and methazolamide can also increase the rate of excretion of weakly acidic drugs such as barbiturates.
Barbiturates may induce various hepatic CYP450 isoenzymes, including those responsible for the metabolism of some SSRIs. For example, phenobarbital can reduce paroxetine AUC by 25% and half-life by 38%, respectively. Although clinical data may not be available to support significant interactions, citalopram, escitalopram, or sertraline may also be affected by such interactions. Clinicians should be aware of the potential for reduced SSRI efficacy with concurrent administration of a barbiturate, especially in chronic use. This interaction would be unlikely with the short-term use of butabarbital.
The concurrent use of trimethobenzamide with barbiturates may potentiate the CNS effects of either trimethobenzamide or the barbiturate.
The manufacturer of voriconazole considers the concomitant use of long-acting barbiturates and voriconazole a contraindication; caution is advised in using voriconazole with short-acting barbiturates. Long-acting barbiturates, such as phenobarbital, are CYP3A4, CYP2C19 and CYP2C9 inducers and may increase the metabolism and reduce the effective serum concentrations of voriconazole. Barbiturates are also substrates for the CYP2C9 isoenzyme, and voriconazole (known to inhibit CYP2C9) may also theoretically increase the serum concentrations of the barbiturates.
Barbiturates, such as butabarbital, can decrease the activity of vitamin D and vitamin D analogs by increasing metabolism of the vitamins. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. In addition, barbiturates are CYP3A4 inducers and thus may further lower serum concentrations of paricalcitol (a vitamin D analog) through increased CYP3A4-mediated metabolism. Vitamin D supplementation may be required in patients with inadequate dietary intake of vitamin D who are receiving chronic treatment with anticonvulsants. Similarly, dosage adjustments in Vitamin D analogs may be necessary with concomitant use.
Ranolazine is primarily metabolized by CYP3A isoenzymes. Although not studied, barbiturates may induce the metabolism of ranolazine and potentially result in reduced antianginal effects. Monitor the antianginal response to ranolazine therapy closely during coadministration with barbiturates.
Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that induce CYP1A2, such as barbiturates, could theoretically increase the elimination of anagrelide and decrease its efficacy. Patients should be monitored for changes in efficacy if these drugs are coadministered.
[ Last revised: 4/28/2006 10:04:00 AM ]
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