Section 3.3.1

Benzodiazepines

General Description

Benzodiazepines are variously referred to as antianxiety agents, anxiolytics and minor tranquilizers. Benzodiazepines are also classified as sedative-hypnotics. A sedative drug reduces daytime activity, tempers excitement and generally quiets the patient. An anxiolytic drug reduces pathological anxiety. A hypnotic drug produces drowsiness and facilitates sleep. In general, benzodiazepines act as a soporific/hypnotic in high doses, as anxiolytics in moderate doses, and as mild sedatives in low doses.

Indications for Medication

The major clinical application for benzodiazepines in psychiatry is the treatment of anxiety - generalized anxiety, panic disorder with agoraphobia, panic disorder without agoraphobia and anxiety associated with specific life events. Most patients should be treated for a specific and relatively brief period. A minority of patients may require long-term maintenance with these medications.

For insomnia, flurazepam (dalmane), temazepam (Restoril), quazepam, estazolam and triazolam are approved for use as hypnotics. They differ principally in their half-lives; flurazepam has the longest half-life and triazolam has the shortest half-life.

For depression, alprazolam (Xanax) has been shown to have antidepressant effects equal to some of the tricyclic antidepressants. The dose levels for alprazolam range from 1-4mg daily. The use of high dose levels is controversial because of the high risk of withdrawal symptoms.

For acute mania and other psychoses, benzodiazepines may be useful adjuncts in their medication management. In the maintenance treatment of bipolar disorder this class of medication, and perhaps clonazepam (Klonopin) in particular, may also serve as a useful adjunct.

For panic disorder and social phobia, both alprazolam and clonazepam have been useful for reducing anxiety and panic periods. The effective clonazepam dose range varies from 1.5-4mg daily. Clonazepam is less controversial than alprazolam because of clonazepam?s longer half-life and reduced risk of rebound anxiety and withdrawal symptoms.

For akathisia, the benzodiazepines have been shown to be effective. The standard anticholinergic drugs are often ineffective. Propranolol (Inderal) is usually the first-line drug for akathisia. But the benzodiazepines may also be effective in some of these patients.

Clinical Guidelines

The clinical decision to treat a patient for anxiety with a benzodiazepine should be carefully considered. Medical causes for anxiety such as thyroid dysfunction, caffeine intoxication and medications, should be ruled out. The benzodiazepine should be started at a very low dose level, should be stabilized at the lowest possible dosages, and an estimated length of therapy should be established.

The long-term efficacy of benzodiazepines should be evaluated and reviewed on a regular basis because of potential problems with long-term use. When the drug is to be discontinued the medications should be tapered slowly, perhaps 25% per week. Faster tapering results in rebound symptoms and/or recurrence of the illness.

Alprazolam is the benzodiazepine with the highest risk of rebound anxiety, panic periods and withdrawal symptoms. Many clinicians favor switching the patient from alprazolam to clonazepam to facilitate this tapering process. Clonazepam with its half-life of 18-54 hours, lowers the risks for these patients.

The literature has reports which document the use of benzodiazepines over a long period of time for the chronically anxious patients. Many of these studies show the significant value of long-term benzodiazepines. However, these long-term patients must be carefully selected and regularly reviewed.

The literature also has reports that document the use of benzodiazepines as adjunctive medications in a combined medication regimen. Many of these studies show a reduction of mixed or atypical symptoms, the improvement in compliance and improved long-term functioning. These long-term combined medication patients must be carefully selected and regularly reviewed.

Benzodiazepine withdrawal syndrome occurs when benzodiazepines are abruptly discontinued. The withdrawal syndrome consists of anxiety, nervousness, diaphoresis, restlessness, irritability, fatigue, light-headedness, tremor, insomnia and weakness. The higher the dose and the shorter the half-life, the worse will be the withdrawal symptoms.

Adverse Effects

The most common adverse effect of benzodiazepines is drowsiness, occurring in approximately 10% of patients. Some patients also experience ataxia (less than 2%) and dizziness (less than 1%). The most serious adverse effects of benzodiazepines occur when other sedative drugs such as alcohol, are taken concurrently. These combinations can result in marked drowsiness, disinhibition and even respiratory depression.

Other relatively rare adverse effects include weakness, nausea, vomiting, blurred vision and epigastric distress. Mild cognitive deficits, which could impair job performance, have been reported. Anterograde amnesia has also been reported with the high-potency benzodiazepines, and a rare paradoxical increase in aggression has also been reported.

Some data suggests that benzodiazepines are teratogenic. Therefore, the use of benzodiazepines in pregnancy is not advised. The use of benzodiazepines in the third trimester may precipitate withdrawal in the newborn. Benzodiazepines are secreted in the breast milk in sufficient concentrations to affect the newborn. The benzodiazepines should be avoided in nursing mothers.

Drug-Drug Interactions

Because benzodiazepines are widely used, clinicians must be aware of the possible drug interaction of benzodiazepines and other drugs. Drugs that inhibit certain liver isoenzymes will increase plasma levels of certain benzodiazepines. For example, erythromycin increases benzodiazepine levels.

Antacids and food may decrease the absorption of benzodiazepines, and smoking may increase the metabolism of benzodiazepines. Antacids, food and smoking may all possibly decrease the efficacy of benzodiazepines.

All benzodiazepines have additive central nervous system (CNS) depressant effects with other sedative drugs. Ataxia and dysarthria may occur when relatively high doses of lithium, antipsychotics and clonazepam are combined.

The consent form for these medications is "Anti-anxiety Medication (benzodiazepines)".

Benzodiazepine Pharmacokinetics

Drug

Dosage Rane

(mg/day)

Peak Plasma

level(hrs)

Elimination

t1/2(hrs)

Metabolites Speed of onset Protein Binding
Alprazolam 0.75-4 1-2 6.3-26.9

Alpha-hydroxalprazolam;

Benzophenone

Intermediate 80%
Chlordiazepoxide 15-100 0.5-4 5-30

Desmethylchlordiaze

poxide (2);

Demoxepam;

desmethyldiazepam

intermediate 96%
Clonazepam 1.5-20 1-2 18-50

Inactive 7-amino or 7- acetyl amino

derivatives (2)

Intermediate 97%
Chlorazepate 15-60 1-2 40-50 Desmethyldiazepam Fast 97-98%(3)
Diazepam 4-40 0.5-2 20-80

Desmthyldiazepam;

Nordiazepam

Very Fast 98%
Halazepam 60-160 1-3 14

Desmethyldiazepam

(2);3-

hydroxyhalazepam

Slow 97%
Lorazepam 2-4 2-4 10-20

Inactive Glucuronide

conjugate

Intermediate 85%
Oxazepam 30-120 2-4 5-20 Inactive Glucuronide conjugate Slow 87%

Benzodiazepine Drug Interactions

Precipitant drug Object drug Increase or Decrease Description
Benzodiazepines Inc. Increased CNS effects (e.g. imparied psychomotor function, sedation) may occur
Benzodiazepines Alcohol/CNS depressants (e.g. barbiturates, narcotics)
Antacids Benzodiazepines Dec. Antacids may after the rate but generally not the extend of GI absorption. Staggering administration times may help avoid possible interaction.
Cimetidine Alprazolam Inc. The elimination of benzodiazepines that undergo oxidative metabolism (alprazolam, chlordiazepoxide, clorazepate, diazepam, halazepam) may be decreased by the following drugs due to inhibition of hepatic metabolism. Pharmacologic effects of these benzodiazepines may be increased and excessive sedation/impaired psychomotor function may occur.
Contraceptives, oral Chlordiazepoxide
Disulfram Clorazepate
Fluoxetine Diazepam
Isoniazid Halazepam
Ketoconazole
Metoprolol
Propoxyphene
Propranolol
Valproic acid
Contraceptives, oral lorazepam, Oxazepam Dec. The clearance rate of benzodiazepines that unedergo glucuronidation(lorazepma, oxazepam)may be increased.
Probenecid Benzodiazepines Inc. Probenecid may interfere with benzodiazepine congugation in the liver, possibly resulting in a more rapid onset or prolonged effect.
Ranitidine Diazepam Dec. ranitidine may decrease the GI absorption of diazepam
Rifampin Benzodiazepines Dec. the oxidative metabolism of benzodiazepines may be increased due to microsomal enzyme induction. Pharmacologic effects of some benzodiazepines may be decreased.
Scopolamine Lorazepam Inc. Scopolamine, used concomittantly with parenteral lorazepam, may incrase the incidence of sedation, hallucinations, and irrational behavior.
Theophyllines Benzodiazepines Dec. Theophyllines may antagonize the sedative effects of the benzodiazepines.
Benzodiazepines Digoxin Inc. Digoxin's serum concentration may be inceased. Toxicity characterized by GI and neuropsychiatric symptoms and cardiac arrhythmias may occur. Monitor digoxin serum levels.
Benzodiazepines Levodopa dec. Levodopa's antiparkinson efficacy may be decreased by coadministration of benzodiazepines.
Benzodiazepines Neuromuscular blocking agents Inc/Dec. Benzodiazepines may potentiate, counteract, or have no effect on the actions of these agents
Benzodiazepines Phenytoin Inc. Phenytoin serum concentrations may be increased, resulting in toxicity, but data are conflicting. Phenytoin may increase oxazepam clearance.
1. Oral administration
2. Major Metabolite
3. Nordiazepam (active metabolite)