Protect against drug-drug interactions with anxiolytics
Safe use of benzodiazepines, buspirone, and propranolol.
These studies indicate that alprazolam may be more toxic than other benzodiazepines in overdose and when used with other drugs. We recommend that you exercise great care when prescribing alprazolam, particularly for patients who may be at risk of deliberate self-poisoning and lethal DDIs.
Pharmacokinetic DDIs. Diazepam and chlordiazepoxide plasma concentrations increase in combination with drugs that inhibit CYP enzymes, including cimetidine, disulfiram, isoniazid, estrogen, and oral contraceptives.15
Nefazodone—a CYP 3A3/4 inhibitor—can increase plasma concentrations of triazolam and alprazolam to potentially toxic levels. Nefazodone’s manufacturer recommends lowering triazolam dosages by 75% and alprazolam dosages by 50% when used with nefazodone.3
Carbamazepine—a CYP 3A3/4 inducer—induces both its own and other drugs’ metabolism. It can lower plasma concentrations of alprazolam, clonazepam, midazolam, and triazolam, which are metabolized by 3A3/4. Smoking, food, and antacids also may decrease benzodiazepine plasma concentrations.
As perpetuator drugs, benzodiazepines might increase digoxin plasma concentration, probably because of reduced digoxin renal clearance.16 Diazepam may inhibit CYP 2C9 and/or 2C19 by being an alternate substrate for enzymebinding sites,15,17 increasing the concentration of other drugs such as phenytoin.
Buspirone: Complicated pharmacology
One of buspirone’s major clinical advantages is that it does not pharmacodynamically or pharmacokinetically affect benzodiazepines. Buspirone, the only azaspirodecanedione marketed in the United States, has complex central 5-HT effects.18,19 Because it is a partial 5-HT1A agonist, buspirone’s net effect depends on 5-HT concentration at the receptor:
- If 5-HT concentration is low, buspirone will act as an agonist.
- If 5-HT concentration is high, buspirone—being a partial agonist—will antagonize the effect of excessive 5-HT.
Buspirone’s pharmacology is further complicated by its conversion via oxidative metabolism into an active metabolite—1-pheyl-piperazine (1-PP). Buspirone is a CYP 3A3/4 enzyme substrate, so it is extensively metabolized as it crosses the duodenum and passes through the liver. As a result, the parent drug has low bioavailability and is principally converted into 1-PP before entering systemic circulation.6
1-PP works differently than the parent drug. As an alpha-2-adrenergic antagonist, 1-PP increases the firing rate of adrenergic neurons in the locus ceruleus by blocking a receptor in presynaptic feedback system.
Which traits of buspirone and its active metabolite produce the drug’s anxiolytic effect? It might be one of these, all of them, or some other unknown trait.
Pharmacodynamic DDIs. Presumably because of its effects on serotonin release at 5-HT1A receptors, buspirone may cause hypertensive episodes when used with monoamine oxidase inhibitors (MAOIs) (Table 3). This is why a 2-week washout is recommended between discontinuing an MAOIs and starting buspirone.21
Table 3
Clinical effects of drug-drug interactions with buspirone
| Pharmacodynamic |
| DO NOT use buspirone with monoamine oxidase inhibitors (MAOIs); allow 2-week washout after stopping an MAOI before starting buspirone |
| Pharmacokinetic |
| Food ↑ buspirone Cmax and AUC 2-fold |
| Renal impairment ↑ buspirone plasma concentration 2-fold |
| Hepatic impairment ↑ buspirone Cmax and AUC 15-fold and ↑ half-life 2-fold |
| Verapamil, diltiazem, erythromycin, itraconazole ↑ buspirone plasma concentration |
| Rifampicin ↓ buspirone plasma concentration 10-fold |
| Buspirone ↑ haloperidol plasma concentration |
| Erythromycin, itraconazole, nefazodone, grapefruit juice ↑ buspirone plasma concentration |
| Cmax: maximum drug concentration |
| AUC: area under the curve (mathematical calculation of the body’s total exposure to a drug over time) |
- buspirone affects 5-HT mechanisms
- drugs that affect serotonin reuptake inhibition, 5HT1A receptors, and 5HT2 receptors may have synergy.20
Some SSRIs—such as high-dose fluoxetine and usual doses of fluvoxamine—may increase buspirone serum concentration by inhibiting CYP 3A4.6 Consider this clinical effect before you combine an SSRI with buspirone. Using buspirone with fluoxetine, paroxetine, or bupropion also increases serum 1-PP. This increase, which occurs when CYP 2D6 slows 1-PP clearance, could cause euphoria, mania, or seizures.20
Coadministering rifampin can lower buspirone plasma concentrations almost 10-fold because rifampin induces CYP 3A3/4.22
As a perpetuator, buspirone can increase haloperidol plasma concentrations, but probably not to a clinically important extent. In an open trial, Goff23 added buspirone, mean dosage 23.8 mg/d, to a stable regimen of haloperidol in 7 patients with schizophrenia. Although haloperidol’s mean plasma concentration increased by 26% after 6 weeks, this modest change would be difficult to detect in clinical practice.
