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high lipid solubility, may explain the popularity of diazepam In the average case of anxiety, diazepam, 5 10 mg orally twice daily as needed, is a reasonable starting regimen The duration of action of the benzodiazepines varies as a function of the active metabolites they produce Benzodiazepines such as lorazepam do not produce active metabolites and have intermediate half-lives of 10 20 hours, characteristics useful in treating elderly patients Ultra-short-acting agents such as triazolam have half-lives of 1 3 hours and may lead to rebound withdrawal anxiety Longer-acting benzodiazepines such as flurazepam and diazepam produce active metabolites, have half-lives of 20 120 hours, and should be avoided in the elderly Since people vary widely in their response and since the drugs are long-lasting, the dosage must be individualized Once this is established, an adequate dose early in the course of symptom development will obviate the need for pill popping, which contributes to dependency problems Panic disorder does not usually respond to benzodiazepines other than clonazepam and alprazolam Those high-potency benzodiazepines and the antidepressants are most commonly used for panic disorder Notably, alprazolam has a relatively short half-life and over time can lead to interdose rebound anxiety, although the extended release form is available and obviates some of this difficulty Whether the indications for benzodiazepines are anxiety or insomnia, the drugs should be used judiciously The longer-acting benzodiazepines are used for the treatment of alcohol withdrawal and anxiety symptoms; the intermediate drugs are useful as sedatives for insomnia (eg, lorazepam), while short-acting agents (eg, midazolam) are used for medical procedures such as endoscopy The side effects of all the benzodiazepine antianxiety agents are patient and dose dependent As the dosage exceeds the levels necessary for sedation, the side effects include disinhibition, ataxia, dysarthria, nystagmus, and delirium (The patient should be told not to operate machinery until he or she is well stabilized without side effects) Paradoxical agitation, anxiety, psychosis, confusion, mood lability, and anterograde amnesia have been reported, particularly with the shorter-acting benzodiazepines These agents produce cumulative clinical effects with repeated dosage (especially if the patient has not had time to metabolize the previous dose), additive effects when given with other classes of sedatives or alcohol (many apparently accidental deaths are the result of concomitant use of sedatives and alcohol), and residual effects after termination of treatment (particularly in the case of drugs that undergo slow biotransformation) Overdosage results in respiratory depression, hypotension, shock syndrome, coma, and death Flumazenil, a benzodiazepine antagonist, is effective in overdosage Overdosage (see 38) and withdrawal states are medical emergencies Serious side effects of chronic excessive dosage are development of tolerance, resulting in increasing dose requirements, and physiologic dependence, resulting in withdrawal symptoms similar in appearance to alcohol and barbiturate withdrawal (withdrawal effects must be distinguished from reemergent anxiety) Abrupt withdrawal of sedative drugs may cause serious and even fatal convulsive seizures Psychosis, delirium, and autonomic dysfunction have also been
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described Both duration of action and duration of exposure are major factors related to likelihood of withdrawal Common withdrawal symptoms after low to moderate daily use of benzodiazepines are classified as somatic (disturbed sleep, tremor, nausea, muscle aches), psychological (anxiety, poor concentration, irritability, mild depression), or perceptual (poor coordination, mild paranoia, mild confusion) The presentation of symptoms will vary depending on the half-life of the drug There are no significant side effects on organ systems other than the brain, and the drugs are safe in most medical conditions Benzodiazepine interactions with other drugs are listed in Table 25 2 Antidepressants are the first-line medications for sustained treatment of generalized anxiety disorder, having the advantage of not causing serious physiologic dependency problems At initiation of treatment, antidepressants can themselves be anxiogenic thus, an initial dose, in conjunction with short-term treatment with a benzodiazepine, is often indicated Venlafaxine (a sustained-release serotonin and norepinephrine reuptake inhibitor) is FDA-approved for the treatment of generalized anxiety disorder in usual antidepressant doses (75 225 mg) Initial daily dosing should start low (375 75 mg) and be titrated upward as needed SSRIs, such as paroxetine, are also used Similarly, buspirone, sometimes used as an augmenting agent in the treatment of depression and compulsive behaviors, is also effective for generalized anxiety Buspirone is usually given in a total dosage of 15 60 mg/d in three divided doses Higher doses tend to be counterproductive and produce gastrointestinal symptoms and dizziness There is a 2- to 4week delay before antidepressants and buspirone take effect, and patients require education regarding this lag Sleep is sometimes negatively affected -Blockers such as propranolol may help reduce peripheral somatic symptoms Alcohol is the most frequently self-administered drug and should be interdicted The highly addicting drugs with a narrow margin of safety such as glutethimide, ethchlorvynol, methprylon, meprobamate, and the barbiturates (with the exception of phenobarbital) should be avoided Phenobarbital, in addition to its anticonvulsant properties, is a reasonably safe and very inexpensive sedative but has the disadvantage of
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