Protect against drug-drug interactions with anxiolytics
Safe use of benzodiazepines, buspirone, and propranolol.
Huang et al24 found no clinically significant pharmacokinetic interaction between buspirone, 10 mg tid, and haloperidol, 10 to 40 mg/d, during 6 weeks of coadministration in 27 patients with schizophrenia.
Propranolol: Beta-blocking anxiolytic
Propranolol is prescribed off-label for anxiety disorders more often than other beta blockers. It may help patients with situational or performance anxiety.
Beta-adrenergic blockers competitively antagonize norepinephrine and epinephrine at the beta-adrenergic receptor. These cardiovascular agents can reduce many of anxiety’s peripheral manifestations, such as tachycardia, diaphoresis, trembling, and blushing. All beta blockers share this pharmacologic effect, but their pharmacokinetics differ greatly. Some depend on a single CYP enzyme for clearance (metoprolol, by CYP 2D6), whereas others, such as propranolol, are metabolized by multiple CYP enzymes.
Pharmacodynamic DDIs. Drugs that block alpha-1 adrenergic receptors potentiate beta blockers’ blood pressure-lowering effects and increase the risk of orthostatic hypotension. This is probably why haloperidol can potentiate propranolol’s hypotensive effects.6 Other alpha-1 adrenergic antagonists—though not normally classified as such—include some tertiary amine tricyclic antidepressants (amitriptyline and imipramine) and some antipsychotics (quetiapine).
Reports have associated hypertensive crises and bradycardia with coadministration of beta blockers and MAOIs.21 Depressed myocardial contractility and A-V nodal conduction may occur when beta blockers are combined with calcium channel inhibitors.21 Beta blockers also can decrease IV anesthetic dose requirements because they decrease cardiac output.25
In patients using insulin for diabetes mellitus, propranolol inhibits recovery from insulin-induced hypoglycemia and may cause hypertension and bradycardia. Beta blockers also can mask the tachycardia that usually accompanies insulin-induced hypoglycemia.
Pharmacokinetic DDIs. Propranolol has an extensive first-pass effect, being etabolized in the liver to active and inactive compounds that interact with CYP enzymes 1A2, 2C18, 2C19 and 2D6.6
Coadministering strong CYP 2D6 inhibitors such as bupropion, fluoxetine, or paroxetine can reduce propanolol clearance, increasing its effect and risking cardiac toxicity6 (Table 4). CYP 1A2 inhibitors such as amiodarone and fluoroquinolones or CYP 2C19 inhibitors such as fluvoxamine also increase serum concentrations of propranolol.
Table 4
How to avoid drug interactions with three common anxiolytics*
| When prescribing benzodiazepines… | |
| DO | DO NOT |
| Advise patients not to combine benzodiazepines with alcohol | Use with other CNS depressants or nefazodone |
| Talk to patients about potential for abuse/dependency, and monitor benzodiazepine use | Use in elderly patients or in patients with high potential for substance abuse |
| When prescribing buspirone… | |
| DO | DO NOT |
| Allow a 2-week washout between discontinuing an MAOI and starting buspirone | Use with MAOIs, verapamil, diltiazem, erythromycin, or itraconazole |
| Consider adding buspirone when SSRI monotherapy has not adequately helped patients with anxiety | Co-administer with rifampin |
| Combine with benzodiazepines, if needed | |
| When prescribing propranolol… | |
| DO | DO NOT |
| Educate patients using insulin for diabetes mellitus that propranolol may inhibit recovery from insulin-induced hypoglycemia, cause bradycardia, or mask tachycardia | Combine with medications with strong hypotensive effects |
| Coadminister with strong CYP 2D6 or 1A2 inhibitors | |
| Recheck anticonvulsant plasma concentrations after starting propranolol | Add to calcium inhibitors for patients with ↓ myocardial contractility and A-V nodal conduction |
| * Before prescribing any anxiolytic, review all co-prescribed medications for potential DDIs | |
| DDI: drug-drug interaction | |
| MAOI: monoamine oxidase inhibitor | |
| SSRI: selective serotonin reuptake inhibitor | |
As a perpetuator, propranolol produces small increases in diazepam concentration, suggesting that the beta-blocker inhibits diazepam metabolism. This interaction can impair kinetic visual acuity, which is correlated with the ability to discriminate moving objects in space.26
Propranolol increases plasma concentrations of antipsychotics, anticonvulsants, theophylline, and levothyroxine (Table 5)—possibly because of the beta blocker’s negative inotropic effects (decreased cardiac output reduces hepatic and renal blood flow).
Table 5
Clinical effects of drug-drug interactions with propranolol
| Pharmacodynamic |
| With MAO inhibitors → hypertensive crisis and bradycardia |
| With calcium channel inhibitors → ↓ myocardial contractility and A-V nodal conduction |
| ↓ intravenous anesthetic dose requirements |
| ↓ diazepam metabolism |
| ↓ median effective dosage of valproate and diazepam; might improve antiepileptic potential of valproate |
| Pharmacokinetic |
| ↑ plasma concentration of antipsychotics, anticonvulsants, theophylline, levothyroxine |
| Barbiturates, phenytoin, and cigarette smoking ↑ propranolol elimination |
- Cytochrome P450 interactions. www.drug-interaction.com.
- FDA. Food and drug interactions. https://vm.cfsan.fda.gov/~lrd/fdinter.html.
- Psychiatric drug interactions. www.preskorn.com.
- Alprazolam • Xanax
- Bupropion • Wellbutrin
- Buspirone • BuSpar
- Carbamazepine • Carbatrol, others
- Chlordiazepoxide • Librium
- Cimetidine • Tagamet
- Clonazepam • Klonopin
- Clorazepate • Tranxene
- Clozapine • Clozaril
- Diazepam • Valium
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Haloperidol • Haldol
- Itraconazole • Sporanox
- Lorazepam • Ativan
- Midazolam • Versed
- Mirtazapine • Remeron
- Oxazepam • Serax
- Paroxetine • Paxil
- Phenytoin • Dilantin
- Propranolol • Inderal
- Quetiapine • Seroquel
- Rifampin • Rifadin, Rimactane
- Triazolam • Halcion
- Valproate • various
- Verapamil • Calan, Isoptin
Drs. Ramadan and Werder report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
