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Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”4
To help you “hit” the anxiety instead of the patient,1 we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.
Clinical effect=Affinity for site of action (pharmacodynamics)×Concentration at site of action (pharmacokinetics)×Patient’s biology (genetics, age, disease, internal environment)
Pharmacodynamics
What a drug does to the body (actions that mediate its efficacy and adverse effects)
Pharmacokinetics
What the body does to a drug (absorption, distribution, metabolism, elimination) that determines its concentration at the site of action
Patient’s biology
Why patients respond differently to the same dose of the same medication (internal environment includes what patients consume, such as foods and co-prescribed drugs)
Benzodiazepines
Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.5 As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.
Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).6-8
Table 1
Benzodiazepines: How metabolized and half-lives
| Benzodiazepine | Metabolism | Half-life (includes metabolites) |
|---|---|---|
| Alprazolam | Oxidation 3A3/4 | 8 to 12 hrs |
| Chlordiazepoxide | Oxidation 3A3/4 | 10 to 20 hrs |
| Clonazepam | Oxidation 3A3/4 | 18 to 50 hrs |
| Clorazepate | Oxidation 3A3/4 | 40 to 100 hrs |
| Diazepam | Oxidation 1A2, 2C8/9, 2C19, 3A3/4 | 20 to 70 hrs |
| Lorazepam | Conjugation | 10 to 20 hrs |
| Oxazepam | Conjugation | 5 to 15 hrs |
| Source: References 5-7. | ||
Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.
Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).
Table 2
Clinical effects of drug-drug interactions with benzodiazepines
| Pharmacodynamic |
| Respiratory depression with alcohol, barbiturates, tricyclic and tetracyclic drugs, dopamine receptor antagonists, opioids, antihistamines |
| With mirtazapine ↑ sedation |
| With lithium, antipsychotics, and clonazepam → ataxia and dysarthria |
| With clozapine → delirium |
| Pharmacokinetic |
| Cimetidine, disulfiram, isoniazid, estrogen, oral contraceptives ↑ diazepam, chlordiazepoxide plasma concentrations |
| Nefazodone and fluvoxamine ↑ plasma concentration of triazolam, alprazolam |
| Carbamazepine ↓ alprazolam plasma concentration |
| Food, antacids ↓ benzodiazepine plasma concentrations |
| Cigarette smoking ↑ benzodiazepine metabolism |
| Benzodiazepines ↑ plasma concentrations of digoxin, phenytoin |
Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.
At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.10 The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.
Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:
- A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.11
- Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.12
- Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.13
- In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.14
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.
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. http://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.
Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.
1. Preskorn S, Flockhart D. Psychiatric drug interactions guide. New York: MBL Communications.; 2004.
2. Bruce SE, Yonkers KA, Otto MW, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder 12-year prospective study. Am J Psychiatry 2005;162:1179-87.
3. Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin Psychiatry 2005;66(Suppl 8):13-21.
4. Bean RB, Bean WB. Sir William Osler: Aphorisms from his bedside teaching and writing. Springfield, IL: Charles C. Thomas; 1961:53.
5. Tasman A, Kay J, Lieberman JA. Psychiatry Therapeutics. 2nd ed. West Sussex, UK: John Wiley & Sons; 2003:347.
6. Fuller M, Sajatovic M. Drug information for mental health. 3rd ed. Hudson, OH: Lexi-Comp; 2001.
7. Stahl SM. Essential psychopharmacology: Neuroscientific basis and practical applications. 2nd ed. New York: Cambridge University Press; 2000.
8. Janicak PG, Davis JM, Preskorn SH, Ayad FJ. Principles and practice of psychopharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001.
9. Tanaka E. Toxicological interactions involving psychiatric drugs and alcohol: an update. J Clin Pharm Ther 2003;28(2):81-95.
10. Frels C, Williams P, Narayanan S, Gariballa SE. Iatrogenic causes of falls in hospitalised elderly patients: a case-control study. Postgrad Med 2002;78(922):487-9.
11. Wolf BC, Lavezzi WA, Sullivan LM, Flannagan LM. One hundred seventy two deaths involving the use of oxycodone in Palm Beach County. J Forensic Sci 2005;50(1):192-5.
12. Rogers WO, Hall MA, Brissie RM, Robinson CA. Detection of alprazolam in three cases of methadone/benzodiazepine overdose. J Forensic Sci 1997;42(1):155-6.
13. Wolf BC, Lavezzi WA, Sullivan LM, et al. Alprazolam-related deaths in Palm Beach County. Am J Forensic Med Pathol 2005;26(1):24-7.
14. Isbister GK, O’Regan L, Sibbritt D, et al. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol 2004;58(1):88-95.
15. Sadock BJ, Sadock VA. Kaplan and Sadock’s pocket handbook of psychiatric drug treatment. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
16. Tollefson G, Lesar T, Grothe D, et al. Alprazolam-related digoxin toxicity. Am J Psychiatry 1984;141(12):1612-3.
17. Murphy A, Wilbur K. Phenytoin-diazepam interaction. Ann Pharmacother 2003;37(5):659-3.
18. Sharp T, McQuade R, Bramwell S, et al. Effect of acute and repeated administration of 5-HT1A receptor agonists on 5-HT release in rat brain in vivo. Naunhyn Schmiedebergs Arch Pharmacol 1993;348(4):339-46.
19. Van den Hooff P, Galvan M. Actions of 5-hydroxytryptamine and 5-HT1A receptor ligands on rat dorso-lateral septal neurons in vitro. Br J Pharmacol 1992;106(4):893-9.
20. Preskorn SH Do you believe in magic? Journal of Practical Psychiatry and Behavioral Health March 1997;99-103
21. Physicians’ Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005.
22. Mahmood I, Sahajwalla C. Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet 1999;36(4):277-87.
23. Goff DC, Midha KK, Brotman AW, et al. An open trial of buspirone added to neuroleptics in schizophrenic patients. J Clin Psychopharmacol 1991;11(3):193-7.
24. Huang HF, Jann MW, Wei FC, et al. Lack of pharmacokinetic interaction between buspirone and haloperidol in patients with schizophrenia. J Clin Pharmacol 1996;36(10):963-9.
25. Avram MJ, Krejcie TC, Henthorn TK, et al. Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution. J Pharmacol Exp Ther 2004;311(2):617-24.
26. Hawksworth G, Betts T, Crowe A, et al. Diazepam/beta-adrenoceptor antagonist interactions. Br J Clin Pharmacol 1984;17(Suppl 1):69S-76S.
27. Hallengren B, Nilsson OR, Karlberg BE, et al. Influence of hyperthyroidism on the kinetics of methimazole, propranolol, metoprolol and atenolol. Eur J Clin Pharmacol 1982;21(5):379-84.
Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”4
To help you “hit” the anxiety instead of the patient,1 we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.
Clinical effect=Affinity for site of action (pharmacodynamics)×Concentration at site of action (pharmacokinetics)×Patient’s biology (genetics, age, disease, internal environment)
Pharmacodynamics
What a drug does to the body (actions that mediate its efficacy and adverse effects)
Pharmacokinetics
What the body does to a drug (absorption, distribution, metabolism, elimination) that determines its concentration at the site of action
Patient’s biology
Why patients respond differently to the same dose of the same medication (internal environment includes what patients consume, such as foods and co-prescribed drugs)
Benzodiazepines
Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.5 As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.
Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).6-8
Table 1
Benzodiazepines: How metabolized and half-lives
| Benzodiazepine | Metabolism | Half-life (includes metabolites) |
|---|---|---|
| Alprazolam | Oxidation 3A3/4 | 8 to 12 hrs |
| Chlordiazepoxide | Oxidation 3A3/4 | 10 to 20 hrs |
| Clonazepam | Oxidation 3A3/4 | 18 to 50 hrs |
| Clorazepate | Oxidation 3A3/4 | 40 to 100 hrs |
| Diazepam | Oxidation 1A2, 2C8/9, 2C19, 3A3/4 | 20 to 70 hrs |
| Lorazepam | Conjugation | 10 to 20 hrs |
| Oxazepam | Conjugation | 5 to 15 hrs |
| Source: References 5-7. | ||
Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.
Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).
Table 2
Clinical effects of drug-drug interactions with benzodiazepines
| Pharmacodynamic |
| Respiratory depression with alcohol, barbiturates, tricyclic and tetracyclic drugs, dopamine receptor antagonists, opioids, antihistamines |
| With mirtazapine ↑ sedation |
| With lithium, antipsychotics, and clonazepam → ataxia and dysarthria |
| With clozapine → delirium |
| Pharmacokinetic |
| Cimetidine, disulfiram, isoniazid, estrogen, oral contraceptives ↑ diazepam, chlordiazepoxide plasma concentrations |
| Nefazodone and fluvoxamine ↑ plasma concentration of triazolam, alprazolam |
| Carbamazepine ↓ alprazolam plasma concentration |
| Food, antacids ↓ benzodiazepine plasma concentrations |
| Cigarette smoking ↑ benzodiazepine metabolism |
| Benzodiazepines ↑ plasma concentrations of digoxin, phenytoin |
Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.
At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.10 The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.
Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:
- A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.11
- Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.12
- Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.13
- In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.14
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.
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. http://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.
Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.
Patients with anxiety disorders are at risk for drug-drug interactions (DDIs) with anxiolytics because they often take medications for comorbid medical or psychiatric illnesses.1-3 Prescribing anxiolytics for them without contemplating both physiology and chemistry leads to what Osler called “popgun pharmacy, hitting now the malady and again the patient,” while “not knowing which.”4
To help you “hit” the anxiety instead of the patient,1 we explain the pharmacokinetics and pharmacodynamics of benzodiazepines, buspirone, and propranolol. Practical tables provide information at a glance about which combinations to avoid and which have potential clinical effects (Box 1) you could use to your patients’ advantage.
Clinical effect=Affinity for site of action (pharmacodynamics)×Concentration at site of action (pharmacokinetics)×Patient’s biology (genetics, age, disease, internal environment)
Pharmacodynamics
What a drug does to the body (actions that mediate its efficacy and adverse effects)
Pharmacokinetics
What the body does to a drug (absorption, distribution, metabolism, elimination) that determines its concentration at the site of action
Patient’s biology
Why patients respond differently to the same dose of the same medication (internal environment includes what patients consume, such as foods and co-prescribed drugs)
Benzodiazepines
Benzodiazepines provide an anxiolytic effect by increasing the relative efficiency of the gamma-aminobutyric acid (GABA) receptor when it is stimulated by GABA.5 As a class, benzodiazepines are efficacious for treating panic disorder, social anxiety disorder, generalized anxiety disorder, alcohol withdrawal, and situational anxiety.
Oxidative metabolism. Some benzodiazepines require bio-transformation in the liver by oxidative metabolism; others—such as lorazepam, oxazepam, and emazepam—undergo only glucuronidation reactions and do not have active metabolites (Table 1).6-8
Table 1
Benzodiazepines: How metabolized and half-lives
| Benzodiazepine | Metabolism | Half-life (includes metabolites) |
|---|---|---|
| Alprazolam | Oxidation 3A3/4 | 8 to 12 hrs |
| Chlordiazepoxide | Oxidation 3A3/4 | 10 to 20 hrs |
| Clonazepam | Oxidation 3A3/4 | 18 to 50 hrs |
| Clorazepate | Oxidation 3A3/4 | 40 to 100 hrs |
| Diazepam | Oxidation 1A2, 2C8/9, 2C19, 3A3/4 | 20 to 70 hrs |
| Lorazepam | Conjugation | 10 to 20 hrs |
| Oxazepam | Conjugation | 5 to 15 hrs |
| Source: References 5-7. | ||
Benzodiazepines that undergo oxidative metabolism are more likely than those that do not to be influenced by old age, liver disease, or co-administration of other drugs that increase or decrease hepatic CYP enzyme function. Some (midazolam and triazolam) have high first-pass metabolism before reaching systemic circulation.
Pharmacodynamic DDIs. Giving benzodiazepines with other CNS depressants—such as barbiturates, tricyclics and tetracyclics, dopamine receptor antagonists, opioids, or antihistamines, or alcohol—can cause potentially serious oversedation and respiratory depression (Table 2).
Table 2
Clinical effects of drug-drug interactions with benzodiazepines
| Pharmacodynamic |
| Respiratory depression with alcohol, barbiturates, tricyclic and tetracyclic drugs, dopamine receptor antagonists, opioids, antihistamines |
| With mirtazapine ↑ sedation |
| With lithium, antipsychotics, and clonazepam → ataxia and dysarthria |
| With clozapine → delirium |
| Pharmacokinetic |
| Cimetidine, disulfiram, isoniazid, estrogen, oral contraceptives ↑ diazepam, chlordiazepoxide plasma concentrations |
| Nefazodone and fluvoxamine ↑ plasma concentration of triazolam, alprazolam |
| Carbamazepine ↓ alprazolam plasma concentration |
| Food, antacids ↓ benzodiazepine plasma concentrations |
| Cigarette smoking ↑ benzodiazepine metabolism |
| Benzodiazepines ↑ plasma concentrations of digoxin, phenytoin |
Using benzodiazepines with lithium or antipsychotics may cause ataxia and dysarthria, and benzodiazepines with clozapine can cause delirium.
At-risk patients. Benzodiazepine use is a significant predictor of falling, especially in elderly persons taking more than one sedative. In a controlled study of hospitalized older patients, 84 (46%) of 181 who fell were taking one or more benzodiazepine, compared with 48 (27%) of 181 age-matched controls who did not fall.10 The message: seek an alternative to benzodiazepines to sedate older patients, especially those taking another CNS depressant.
Alprazolam and DDIs. Alprazolam is commonly prescribed, despite its high potential for abuse and association with dangerous DDIs:
- A study of 172 deaths involving oxycodone showed that 117 patients died from combined drug toxicity. Benzodiazepines (detected in 96 cases) were the most common co-intoxicants and were led by alprazolam.11
- Benzodiazepine abuse is common among clients at methadone maintenance clinics and was reported in 3 fatal drug overdoses caused by co-ingestion of methadone and alprazolam.12
- Cocaine and methadone were the most common co-intoxicants with alprazolam in a study of 87 deaths attributed to combined drug toxicity.13
- In a study of patients who overdosed with benzodiazepines, 22% of those who took alprazolam required ICU admission. This was twice the rate of ICU admission after overdose with other benzodiazepines.14
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.
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. http://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.
Dr. Preskorn has received grants or has been a consultant or speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Boehringer-Ingelheim, Bristol-Myers Squibb Co., Merck & Co., Eisai, Eli Lilly and Co., GlaxoSmithKline, Janssen Pharmaceutica, Johnson & Johnson, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceutical, Pfizer, Solvay Pharmaceuticals, Sanofi-Aventis, and Wyeth.
1. Preskorn S, Flockhart D. Psychiatric drug interactions guide. New York: MBL Communications.; 2004.
2. Bruce SE, Yonkers KA, Otto MW, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder 12-year prospective study. Am J Psychiatry 2005;162:1179-87.
3. Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin Psychiatry 2005;66(Suppl 8):13-21.
4. Bean RB, Bean WB. Sir William Osler: Aphorisms from his bedside teaching and writing. Springfield, IL: Charles C. Thomas; 1961:53.
5. Tasman A, Kay J, Lieberman JA. Psychiatry Therapeutics. 2nd ed. West Sussex, UK: John Wiley & Sons; 2003:347.
6. Fuller M, Sajatovic M. Drug information for mental health. 3rd ed. Hudson, OH: Lexi-Comp; 2001.
7. Stahl SM. Essential psychopharmacology: Neuroscientific basis and practical applications. 2nd ed. New York: Cambridge University Press; 2000.
8. Janicak PG, Davis JM, Preskorn SH, Ayad FJ. Principles and practice of psychopharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001.
9. Tanaka E. Toxicological interactions involving psychiatric drugs and alcohol: an update. J Clin Pharm Ther 2003;28(2):81-95.
10. Frels C, Williams P, Narayanan S, Gariballa SE. Iatrogenic causes of falls in hospitalised elderly patients: a case-control study. Postgrad Med 2002;78(922):487-9.
11. Wolf BC, Lavezzi WA, Sullivan LM, Flannagan LM. One hundred seventy two deaths involving the use of oxycodone in Palm Beach County. J Forensic Sci 2005;50(1):192-5.
12. Rogers WO, Hall MA, Brissie RM, Robinson CA. Detection of alprazolam in three cases of methadone/benzodiazepine overdose. J Forensic Sci 1997;42(1):155-6.
13. Wolf BC, Lavezzi WA, Sullivan LM, et al. Alprazolam-related deaths in Palm Beach County. Am J Forensic Med Pathol 2005;26(1):24-7.
14. Isbister GK, O’Regan L, Sibbritt D, et al. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol 2004;58(1):88-95.
15. Sadock BJ, Sadock VA. Kaplan and Sadock’s pocket handbook of psychiatric drug treatment. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
16. Tollefson G, Lesar T, Grothe D, et al. Alprazolam-related digoxin toxicity. Am J Psychiatry 1984;141(12):1612-3.
17. Murphy A, Wilbur K. Phenytoin-diazepam interaction. Ann Pharmacother 2003;37(5):659-3.
18. Sharp T, McQuade R, Bramwell S, et al. Effect of acute and repeated administration of 5-HT1A receptor agonists on 5-HT release in rat brain in vivo. Naunhyn Schmiedebergs Arch Pharmacol 1993;348(4):339-46.
19. Van den Hooff P, Galvan M. Actions of 5-hydroxytryptamine and 5-HT1A receptor ligands on rat dorso-lateral septal neurons in vitro. Br J Pharmacol 1992;106(4):893-9.
20. Preskorn SH Do you believe in magic? Journal of Practical Psychiatry and Behavioral Health March 1997;99-103
21. Physicians’ Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005.
22. Mahmood I, Sahajwalla C. Clinical pharmacokinetics and pharmacodynamics of buspirone, an anxiolytic drug. Clin Pharmacokinet 1999;36(4):277-87.
23. Goff DC, Midha KK, Brotman AW, et al. An open trial of buspirone added to neuroleptics in schizophrenic patients. J Clin Psychopharmacol 1991;11(3):193-7.
24. Huang HF, Jann MW, Wei FC, et al. Lack of pharmacokinetic interaction between buspirone and haloperidol in patients with schizophrenia. J Clin Pharmacol 1996;36(10):963-9.
25. Avram MJ, Krejcie TC, Henthorn TK, et al. Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution. J Pharmacol Exp Ther 2004;311(2):617-24.
26. Hawksworth G, Betts T, Crowe A, et al. Diazepam/beta-adrenoceptor antagonist interactions. Br J Clin Pharmacol 1984;17(Suppl 1):69S-76S.
27. Hallengren B, Nilsson OR, Karlberg BE, et al. Influence of hyperthyroidism on the kinetics of methimazole, propranolol, metoprolol and atenolol. Eur J Clin Pharmacol 1982;21(5):379-84.
1. Preskorn S, Flockhart D. Psychiatric drug interactions guide. New York: MBL Communications.; 2004.
2. Bruce SE, Yonkers KA, Otto MW, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder 12-year prospective study. Am J Psychiatry 2005;162:1179-87.
3. Nemeroff CB. Use of atypical antipsychotics in refractory depression and anxiety. J Clin Psychiatry 2005;66(Suppl 8):13-21.
4. Bean RB, Bean WB. Sir William Osler: Aphorisms from his bedside teaching and writing. Springfield, IL: Charles C. Thomas; 1961:53.
5. Tasman A, Kay J, Lieberman JA. Psychiatry Therapeutics. 2nd ed. West Sussex, UK: John Wiley & Sons; 2003:347.
6. Fuller M, Sajatovic M. Drug information for mental health. 3rd ed. Hudson, OH: Lexi-Comp; 2001.
7. Stahl SM. Essential psychopharmacology: Neuroscientific basis and practical applications. 2nd ed. New York: Cambridge University Press; 2000.
8. Janicak PG, Davis JM, Preskorn SH, Ayad FJ. Principles and practice of psychopharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2001.
9. Tanaka E. Toxicological interactions involving psychiatric drugs and alcohol: an update. J Clin Pharm Ther 2003;28(2):81-95.
10. Frels C, Williams P, Narayanan S, Gariballa SE. Iatrogenic causes of falls in hospitalised elderly patients: a case-control study. Postgrad Med 2002;78(922):487-9.
11. Wolf BC, Lavezzi WA, Sullivan LM, Flannagan LM. One hundred seventy two deaths involving the use of oxycodone in Palm Beach County. J Forensic Sci 2005;50(1):192-5.
12. Rogers WO, Hall MA, Brissie RM, Robinson CA. Detection of alprazolam in three cases of methadone/benzodiazepine overdose. J Forensic Sci 1997;42(1):155-6.
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