Bupropion Benzodiazepines

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

Hypersensitivity to the drug seizure disorder current or prior diagnosis of bulimia or anorexia nervosa concurrent administration of a monoamine oxidase inhibitor (MAOl) (at least 14 days should elapse between discontinuation of an MAOl and initiation of treatment with bupropion) in patients being treated with other bupropion products (eg, for smoking cessation) in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines). 

Use caution during coadministration of bupropion and agents (eg, antipsychotics, other antidepressants, theophylline, systemic steroids) or treatment regimens (eg, abrupt discontinuation of benzodiazepines) that lower seizure threshold. Use low initial dosing and small gradual dose increases. 

Bupropion overdose (n = 58) and combined overdoses of bupropion and benzodiazepines (n = 9) have been associated with symptoms of neurological toxicity, including lethargy, tremors, and seizures, and an absence of cardiovascular toxicity (Spiller et ah, 1994). 

Much more is known about overdose with the immediate-release formulation of bupropion than with the newer, SR and XL formulations. Reported reactions to overdose with the immediate-release form include seizures, hallucinations, loss of consciousness, and sinus tachycardia. Treatment of overdose should include induction of vomiting, administration of activated charcoal, and electrocardiographic and electroencephalographic monitoring. For seizures, an intravenous benzodiazepine preparation is recommended. 

Antidepressants appear sometimes useful in aiding withdrawal attempts, rather as they can he in withdrawal from benzodiazepines or alcohol. There is some positive evidence for serotonin re-uptake inhibitors and nortriptyline, but the strongest is for bupropion, which in the UK at least is the only antidepressant licensed for use as a cessation aid. Success rates for this seem to be very similar to those with nicotine replacement, approximately doubling a smoker s chances (Hughes et al. 2007). The latest option is varenicline, which acts as a partial agonist on one of the nicotinic receptors. 

Specific factors to consider are both psychiatric and physical contraindications. For example, bupropion is contraindicated in a depressed patient with a history of seizures due to the increased risk of recurrence while on this agent. Conversely, it may be an appropriate choice for a bipolar disorder with intermittent depressive episodes that is otherwise under good control with standard mood stabilizers. This consideration is based on the limited data suggesting that bupropion is less likely to induce a manic switch in comparison with standard heterocyclic antidepressants. Another example is the avoidance of benzodiazepines for the treatment of panic disorder in a patient with a history of alcohol or sedative-hypnotic abuse due to the increased risk of misuse or dependency. In this situation, a selective serotonin reuptake inhibitor (SSRI) may be more appropriate. 

A 35-year-old woman with no history of a psychiatric disorder was given bupropion 300 mg/day for smoking cessation (24). After 5 days she developed an acute paranoid state with ideas of reference and fixed convictions concerning her partner s fidelity. She was also irritable and slightly grandiose. Bupropion was withdrawn and she was given benzodiazepines. She recovered over the next 2 days. 

Shuster J. Benzodiazepines and glucose control mycophe-nolate mofetil-induced dyshidrotic eczema concomitant use of bupropion and amantadine causes neurotoxicity intra-articular steroids and acute adrenal crisis. Hosp Pharm 2000 35 489-91. 

Bupropion (Wellbutrin) Abrupt benzodiazepine withdrawal increases seizure risk... 

Clinically important, potentially hazardous interactions with alfentanil, aminophylline, amisulpride, amoxicillin, ampicillin, anticonvulsants, astemizole, atorvastatin, benzodiazepines, bromocriptine, buprenorphine, bupropion, carbamazepine, cilostazol, ciprofloxacin, cisapride, clindamycin, colchicine, cyclosporine, dasatinib, digoxin, dihydroergotamine, diltiazem, disopyramide, enoxacin, eplerenone, ergotamine, eszopiclone, everolimus, fluconazole, fluoxetine, fluvastatin, gatifloxacin, HMG-CoA reductase inhibitors, imatinib, itraconazole, ketoconazole, lomefloxacin, lorazepam, lovastatin, methadone, methylprednisolone, methysergide, midazolam, mizolastine, moxifloxacin, nitrazepam, norfloxacin, ofloxacin, paroxetine, pimozide, pravastatin, quinolones, ranolazine, repaglinide, rupatadine, sertraline, sildenafil, simvastatin, sparfloxacin, sulpiride, tacrolimus, terfenadine, triazolam, troleandomycin, vardenafil, verapamil, vinblastine, warfarin, zaleplon, zolpidem, zuclopenthixol... 

I Drug-Drug Interactions. Carbamazepine induces the hepatic cytochrome P450 isoenzymes (1A2, 3A4, 2C9/10, and 2D6), which increases the metabolism of many medications, such as anticonvulsants (i.e., lamotrigine, topiramate, and valproate), antidepressants (i.e., tricyclics and bupropion), antipsychotics (i.e., clozapine, haloperi-dol, fluphenazine, olanzapine, and thiothixene), benzodiazepines, oral contraceptives, and protease inhibitors. " Women who receive carbamazepine require higher dosages of oral contraceptives or alternative contraceptive methods." ... 

Answer B. Buspirone has selective anxiolytic activity that is slow in onset The drug has no abuse liability and will not suppress withdrawal symptoms in patients who have become physically dependent on barbiturates, benzodiazepines, or ethanol. Bupropion is an antidepressant, also approved for management of dependence on nicotine. Baclofen is a spinal cord muscle relaxant that activates GABAfi receptors. Buprenorphine is a long-acting opioid analgesic with no effectiveness in GAD, and butabarbital is a barbiturate that may cause dependence. 

Occasional Confusion amnesia disinhibition paradoxical excitement depression dizziness witiidrawal symptoms, including convulsions, on abrupt discontinuance (witiidrawal may be especially difficult with alprazolam) rebound insomnia or excitement Rare Hypotension blood dyscrasias jaundice allergic reactions paradoxical rage reactions stuttering with alprazolam BUPROPION, Anxiety agitation insomnia tremor anorexia BUSPIRONE, Dizziness headache nausea paresthesias diarrhea CHLORDIAZEPOXIDE, see Benzodiazepines CHLORPROMAZINE, see Phenothiazines, aliphatic CHLORPROTHIXENE, similar to Phenothiazines CLOMIPRAMINE, see Tricyclic antidepressants CLORAZEPATE, see Benzodiazepines CLOZAPINE... 

For panic disorder, tricychc antidepressants and MAO inhibitors, as well as high-potency benzodiazepines (notably alprazolam, clonazepam, and lorazepam) (see Chapter 16), are effective in blocking the autonomic expression of panic itself, thereby facilitating a comprehensive rehabilitation program. Imipramine and phenelzine are well-studied antidepressants for panic disorder. SSRIs also may be effective, but /3 adrenergic receptor antagonists, buspirone, and low-potency benzodiazepines usually are not, and bupropion can worsen anxiety. 

Visual hallucinations have been seen in one patient given zolpi-dem with bupropion. Bupropion is contraindicated during the abrupt withdrawal from any drug known to be associated with seizures on withdrawal, particularly benzodiazepines and related drugs. 

Visual hallucinations lasting 3 to 4 hours occurred in a 17-year-oid boy who had been taking bupropion 450 mg daiiy for one month and zolpidem 5 to 10 mg daily for about 6 months, when he increased the zolpidem dose to 60 mg. Note that the recommended dose of zolpidem is 10 mg daily and that zolpidem itself can cause psychiatric adverse effects such as hallucinations. Therefore an interaction is not established. Bupropion is contraindicated during abrupt withdrawal from any drug known to be associated with seizures on withdrawal, particularly benzodiazepines and benzodiazepine-like drugs. ... 

Nervous system Seizures have been attributed to flumazenil [104, 105, 106, 107, 108, 109, 110, 111 ], including status epilepticus [112, 113 ], which can be fatal. However, it has been suggested that seizures are not a toxic effect of flumazenil, but are in many cases instead due to unmasking of the anticonvulsant effect of the benzodiazepine or to a severe benzodiazepine-withdrawal syndrome furthermore, in some cases they may be due to other drugs taken at the same time, such as tricyclic antidepressants [1143]. Thus, it has been recommended that flumazenil should not be given to patients who have used benzodiazepines for seizure disorders or to patients who have taken other drugs that increase the risk of seizures (e.g. bupropion, ciclosporin, cocaine, cyclic antidepressants, isoniazid, lithium, methylxanthines, monoamine oxidase inhibitors, and propoxyphene). 

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