Evidence-Based Reviews

Protect against drug-drug interactions with anxiolytics

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Safe use of benzodiazepines, buspirone, and propranolol.


 

References

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.

Box

3 variables explain a drug’s clinical effect

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

BenzodiazepineMetabolismHalf-life (includes metabolites)
AlprazolamOxidation 3A3/48 to 12 hrs
ChlordiazepoxideOxidation 3A3/410 to 20 hrs
ClonazepamOxidation 3A3/418 to 50 hrs
ClorazepateOxidation 3A3/440 to 100 hrs
DiazepamOxidation 1A2, 2C8/9, 2C19, 3A3/420 to 70 hrs
LorazepamConjugation10 to 20 hrs
OxazepamConjugation5 to 15 hrs
Source: References 5-7.
Diazepam is a classic example of the first group; its oxidative metabolism is mediated by cytochrome P-450 (CYP) enzymes 1A2, 2C8/9, 2D19, and 3A3/4. Others in this group—alprazolam, clonazepam, midazolam, and triazolam—depend on CYP 3A3/4 for oxidative metabolism.

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
Patients with anxiety disorders may use alcohol to self-medicate their anxiety, especially in social situations. Acute and chronic alcohol use with psychotropics may trigger toxic interactions, including fatal poisoning. Combining benzodiazepines with alcohol, opioids, or mirtazapine potentiates sedation through central H-1 antagonism and GABA promotion.2 Acute alcohol ingestion also delays the oxidative metabolism of many drugs.9

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

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