Chapter.3 Antianxiety Agents and Hypnotics
OVERVIEW
Management of Anxiety
1. Assess relationship of anxiety to life events,and severity and duration of symptoms.
2. Evaluate response to prior drug therapy.
3. Trial of supportive psychotherapy or relaxation techniques.
4. In short-term uncomplicated anxiety consider a trial of sedating antihistamines or intermittent use of short-acting benzodiazepines.
5. If there is an associated sleep disturbance or other evidence of depression, begin a trial of antidepressant medication.
6. Panic attacks, agoraphobia, and obsessive symptoms respond better to MAOls, cyclic antidepressants, clonazepam, or alprazolam than to buspirone.
7. If there is evidence of psychcosis or mania, use antipsychotic drugs or lithiun. Neuroleptic-induced akathesia may be mistaken for anxiety and should be treated with antiparkinsonian medications or propranolol
8. Persistent severe arixiety may predispose to sedative abuse: buspirone may be effective without the risk of dependency; sedating cyclic antidepressants may be useful even in the absence of depression.
9. If there are prominent physiologic symptoms such as tachycardia. a trial of propranolol or other B blocker may be beneficial if there are no contraindications.
10. When prescribing benzodiazepines, those with shorter half-lives are generally preferable. The use of excessive doses or prolonged administration should be avoided because of the possibility of drug dependency.
11. Sedating antihistamines or cyclic antidepressants may he useful in insomnia.
12. Intermittent use of chloral hydrate or short-acting benzodiazepiness may be necessary in insomia. Long-term, nightly use of hypnotic drugs will disturb sleep architecture and lead to drug dependency.
Pharmacokinetic Aspects of Benzodiazepines
When benzodiazepines are administered for the treatment of anxiety or insomnia, it must be remembered that these drugs have long half-lives, and the majority of them yield pharmacologically active metabolites, further extending the half-life of the parent compound1 (Table 3-1).
The half-life and duration of pharmacologic action of these drugs differ depending on whether a single dose is administered to an experimental subject or multiple doses are given throughout the day over a period of several days or weeks.1 Thus the ability to observe drug effects and measure the blood and urine levels will be of longer duration in a patient receiving diazepam, a long-acting benzodiazepine, several times daily for a period of 2 weeks than it would be if the same individual were to receive a single dose of the medication. Likewise, since these drugs tend to be very lipid-soluble, they may persist longer in an obese individual or in an individual whose fat-to-lean body mass is increased, as in the elderly.1 Furthermore, reduced renal or hepatic function, related to disease or to aging, will likewise extend the duration of drug effect.
For these reasons, it is obviously advantageous to administer these drugs in the smallest possible dose, given as infrequently as possible over the shortest period of time, whatever the patient’s clinical status or age. Furthermore, since even the “short-acting” benzodiazepines have lengthy half-lives, it is certainly preferable to use one of the shorter-acting drugs in this group. In evaluating the literature describing a new drug, the physician must recognize that the half-lives normally quoted are for single-dose administration, which may seem favorably short compared to actual data based on an extended period of drug administration. There are currently three benzodiazepines with relatively short durations of action. These drugs-alprazolam, lorazepam, and oxazepam – have half-lives of about ten to 12 hours following administration of a single dose.1,10 In one study of alprazolam, administered in a dose of 0.5 mg three times daily for seven days, the elimination half-time increased from 11.7 hours after the first dose to 18.9 hours after the last dose.16 With lorazepam and oxazepam, repeated administration over a period of a week produces a somewhat longer elimination half-time, and it would not be surprising to see elimination half-times for any of these drugs approaching 48 to 72 hours when used extensively over a prolonged period of time. The shortest-acting benzodiazepine currently available is triazolam, which is indicated only for sleep induction in the short-term treatment of insomnia. This drug has a half-life of 2.5 to 3.5 hours following singledose administration; however, with prolonged administration, the halflife may become significantly longer.1
Antianxiety Agents: Therapeutic Application
One of the dangers in the use of diazepam is its disinhibiting effect; an individual prone to violence may become violent under the influence of the drug.17 Even in persons who do not have a prior history of violence, loss of behavioral control or the occurrence of violent behavior may occur during benzodiazepine administration.17,18 There is evidence to suggest that oxazepam is less likely to have a disinhibiting effect than the other drugs in this class.19
Alprazolam and triazolam are structurally unique among the benzodiazepines since their molecular configuration, which includes a triazolo ring, bears some similarity to the configuration of tricyclic antidepressants.1 Alprazolam is also functionally unique among the benzodiazopines in that several studies have documented specific antidepressant and antipanic effects of this compound.20,21 Aprazolam has been reported to induce manic symptoms.22,23 In this respect, it differs from other benzodiazepines such as lorazepam and clonazepam, which may actually have an antimanic effect.23, 24 A number of reports have appeared regarding increased hostility, acute paroxysmal excitement, and behavioral dyscontrol among alprazolam-treated patients. 18,25,26 In some instances, this may be connected with the antidepressant action of alprazolam and represent a manic equivalent, while in other instances the effect may simply parallel the disinhibiting effect of other benzodiazopines.
It is well known that tricyclic antidepressants may produce stuttering. This has generally been attributed to their anticholinergic action because it is less prominent among those agents with weaker anticholinergic activity. Although stuttering has not been associated with benzodiazepines, an interesting case report documented the occurrence of stuttering following 0.5 to 1.0 mg of orally administered alprazolam.27 In that patient attempts to provoke stuttering by the oral administration of 10 mg of diazepam or 2 mg of lorazepam were unsuccessful. I have observed repeated instances of stuttering in one patient during treatment with alprazolam in a dosage range of 0.5 to 1.0 mg daily. This patient did not stutter at low doses of lorazepam or conventional doses of amitriptyline, though she did stutter on one occasion while taking 6 mg of lorazepam daily. Though most clinicians would suspect a tricyclic antidepressant when a patient develops a speech disturbance on a combined tricyclic-alprazolam regimen, the case cited above and my clinical experience suggest the necessity to consider alprazolam on an equal footing with the tricyclic drug as a potential cause of stuttering speech. Since alprazolam has only minimal anticholinergic effect, it is unlikely that this pharmacologic mechanism is responsible for the speech disturbance.
Benzodiazepines have well-known amnestic properties. This phenomenon may be observed during the clinical treatment of patients as well as in studies on normal volunteers. Diazepam has been shown to selectively impair anterograde episodic memory and attention, while sparing access to information in long-term memory in a study of normal volunteers.28 Similar anterograde memory impairment has been observed in the clinical use of a variety of benzodiazepines, including short-acting drugs such as lorazepam and alprazolam.29 Triazolam is the shortest-acting benzodiazepine currently marketed, with a half-life of 2.5 to 3.5 hours. This drug has an abrupt onset of action and its major pharmacologic effect is rapidly dissipated, making it a potentially useful hypnotic with the advantage of less daytime hangover due to its short half-life. Confusion, delirium, and amnesia were reported in a patient who took an overdose of triazolam.30 I have observed episodes of amnesia and a blackout phenomenon in five patients receiving short-term courses of triazolam in a dose of 0.25 to 0.5 mg nightly at bedtime. Four of these patients had been concurrently receiving MAOls, which may have prolonged the half-life of triazolam, and the fifth patient was concurrently receiving a tricyclic antidepressant. Several reports in the literature have found that concurrent administration of cimetidine decreases clearance of triazolam and increases its plasma concentration.3′
A similar interaction has been reported when oral contraceptives or the macrolide antibiotic, erythromycin, are administered concurrtntly with triazolam.32, 33 Concurrent administration of alcohol or the antituberculous drug isoniazid have also been shown to impair metabolic degradation of triazolam and other benzodiazepines as well. The ability of other medications to delay metabolism and increase plasma concentrations of triazolam are particularly important since this agent is the most potent and rapidly acting of currently available benzodiazepines. Nevertheless, when any drug is combined with a benzodiazepine regimen, the physician must seriously consider the potential of enhanced and prolonged benzodiazepine activity.
Although benzodiazepines with shorter half-lives and durations of pharmacologic action may be relatively more benign from the standpoint of cumulative pharmacologic effects, drugs with a shorter half-life may present a greater risk of dependency and addiction.1 There is some evidence to suggest that triazolam may have a higher risk of addiction than other benzodiazepines, whose half-lives range between 10 and 24 hours.34 Psychosis and delirium have been reported following withdrawal of triazolam, and the addiction potential of this drug needs to be kept firmly in mind, even when it is employed for relatively short courses of therapy.40 Withdrawal syndromes, including the ocurrence of seizures, are known to occur following abrupt discontinuation or too rapid dosage reduction of alprazolam.31, 37, 38 Since alprazolam is often used in high doses (3 – 6 mg/day or more in the treatment of panic disorder, agoraphobia, and depression), the potential of withdrawal reactions and the risk of seizures needs to be emphasized. Furthermore, since patients receiving alprazolam for these latter indications may not achieve an adequate therapeutic response and may, subsequently, be treated with tricyclic antidepressants, which may lower seizure threshold, there is the potential for a significantly enhanced risk of withdrawal symptoms and seizures occurring when a patient is switched from alprazolam to a tricyclic antidepressant.
Good therapeutic technique dictates against the use of benzodiazepines in a manner that would be conducive to the development of addiction; if, however, one encounters a patient who has utilized these drugs excessively, it is important that they not be discontinued suddenly, but rather that that dosage be gradually tapered.39 40 The same obviously applies for barbiturates, meprobamate, glutethimide, methaqualone, methyprylon, ethchlorvynol, and chloral hydrate.1, 2 ,41 When single bed time doses of benzodiazepines are used to induce sleep, their lengthy duration of action may provide some continuing antianxiety effect during the course of the next day (see Table 3-1
These drugs tend to be more effective and safer if patients are encouraged to use them on an intermittent basis, rather than every night. Because of the risk of addiction with barbiturates such as secobarbital and pentobarbital, these drugs probably have little place in the physician’s battle against insomnia.1 Methaqualone is an addictive drug without therapeutic advantages. It is no longer available on the United States prescription market, although it is occasionally encountered as an imported illicit drug.
Occasionally, barbiturates such as phenobarbital and amobarbital may be of value in alleviating anxiety, if the dose and duration of administration are limited. Agitated psychotic patients receiving optimal doses of antipsychotic medication occasionally experience a persistence of agitation during the day and at night, in which case the addition of amobarbital in a dose of 100 to 200 mg may help to produce some daytime calming and may also be used to encourage sleep at night.1 Meprobamate, when used cautiously, may provide mild sedation and thereby improve anxiety and insomnia in nonpsychotic individuals.1 Chloral hydrate is an effective nighttime sedative, and it is relatively safe if used intermittently. Chloral hydrate may produce Gl irritation and considerable gastric distress in some people, however. The ability of chloral hydrate to displace anticoagulants such as warfarin from plasma protein binding sites may produce excessive prolongation of prothrombin time and a risk of hemorrhage in anticoagulated patients; therefore, this drug should be avoided in patients receiving anticoagulants.1 Fortunately, the benzodiazepines have minimal interaction with anticoagulants.
The high lipid solubility and risk of addiction with drugs such as ethchlorvynol, glutethimide, methyprylon, and methaqualone are good reasons for avoiding the therapeutic use of these drugs.1 High lipid solubility makes it exceedingly difficult to remove these drugs by dialysis in the event of an overdose, and there is no clinical or scientific evidence to support the particular therapeutic advantage of any of these compounds.1 Prescriptions for any sedative medication should strictly limit the quantity prescribed, and refill authorization must be limited to reduce the risk of overdose and drug abuse.1,2