Mohammed T. Abou-Saleh

PSYCHOPHARMACOLOGICAL TREATMENT OF ANXIETY 565Table 103.3Commonly used benzodiazepines in the elderlyGeneric name Trade name Onset of action IndicationHalf-life(h)MetabolismActivemetabolitesGeriatric dose(mg/day)Route ofadministrationShort to intermediate half-lifeTriazolam Halcion Fast Hypnotic 2–5 Conjugation None 0.125–0.5 OralOxazepam Serax Intermediate to slow Anxiolytic 5–15 Conjugation None 5–30 OralAlprazolam Xanax Intermediate Anxiolytic 6–15 Oxidation Yes 0.125–3.0 OralLorazepam Ativan Intermediate Anxiolytic 10–20 Conjugation None 0.5–3 Oral, IV, IMTemazepam Restoril Intermediate to slow Hypnotic 12–24 Conjugation None 15–30 OralLong half-lifeChlordiazepoxide Librium Intermediate Anxiolytic 8–30 Oxidation Yes 5–30 Oral, IV, IMDiazepam Valium Fastest Anxiolytic 26–53 Oxidation Yes 2–10 Oral, IV, IMClorazepate Tranxene Fast Anxiolytic 30–200 Oxidation Yes 7.5–15 OralFlurazepam Dalmane Fast Hypnotic 64–150 Oxidation Yes 15 OralKlonopin Clonazepam Intermediate Anxiolytic 30–40 Oxidation Yes 0.25–3.0 OralPharmacokineticsBenzodiazepines undergo two kinds of biotransformation: oxidationand glucuronide conjugation. Oxidative transformationoccurs slowly, giving the drugs a long half-life and producingmany active metabolites. Conjugative transformation differs fromoxidative transformation in that it occurs rapidly and themetabolic products are pharmacologically inactive. As a generalrule, benzodiazepines that are inactivated by conjugation reactionsappear to be less likely to interact with other medications.For example, cimetidine has been found to inhibit the metabolismof benzodiazepines that require oxidation, but not benzodiazepinesinactivated by conjugation (such as lorazepam oroxazepam). Table 103.4 lists several important drug interactionswith benzodiazepines.Elimination half-lives of benzodiazepines are variable in theelderly. Usually the effects of ultrashort, short and intermediatehalf-life benzodiazepines do not carry over to the next day whenthey are used as a sedative 20 . Ultrashort benzodiazepines aregenerally used to treat insomnia rather than daytime anxiety.They can cause rebound insomnia after abrupt discontinuation.Safety concerns about triazolam (i.e. after being noted to causeconfusion, agitation and hallucinations) have led to its ban inseveral European countries 18 . Benzodiazepines with long half-livescan significantly contribute to increased risk of falls and hipfracture in elderly patients 21 .The onset of action after a single dose is primarily dependentupon the drug’s absorption rate. Most benzodiazepines are highlyTable 103.4DrugDrug interactions with the benzodiazepinesEffectlipophilic. Benzodiazepines that are more lipid-soluble have afaster onset of action because they are absorbed and diffused intocentral synapses more rapidly 22,23 . This rapid onset of action canproduce euphoria and thereby enhance abuse potential.EfficacyBenzodiazepines are effective for generalized anxiety disorder(GAD). Clonazepam has been shown effective for social phobia.Clonazepam and alprazolam are effective in panic disorder.Efficacy and use in post-traumatic stress disorder (PTSD) islimited. A paradoxical reaction has been documented when somepatients with PTSD are treated with benzodiazepines. None of thebenzodiazepines appear effective for obsessive–compulsive disorder(OCD).Dependence and WithdrawalTrue physiologic dependence, resulting in a withdrawal andabstinence syndrome, develops to benzodiazepines usually after3–4 months of daily use 14 . Withdrawal symptoms are likely to bemore severe with abruptly discontinued therapy, and with patientsreceiving short half-life benzodiazepines, or higher daily doses.The symptoms of withdrawal include tachycardia, orthostasis,intention tremors, diaphoresis, hyper-reflexia, anxiety, insomnia,nightmares, malaise, anorexia, headache, muscle pain andtwitching, tinnitus, hyperacusis, photophobia, metallic taste,strange smells and, in more severe cases, hyperthermia, nausea,vomiting, delirium, seizures and psychosis.AlcoholNeurolepticsNarcoticsAntihistaminesMAO InhibitorsCimetidineIsoniazidRifampinAntacidsDigoxinLevodopaFluvoxamineIncreased CNS sedationIncreased CNS sedationIncreased CNS sedationIncreased CNS sedationIncreased CNS sedationIncreased elimination half-life and decreasedclearance of alprazolam, diazepam andchlordiazepoxideDecreased metabolism of diazepamIncreased metabolism of diazepamDecreased absorption of clorazepate andchlordiazepoxideIncreased digoxin levelsDecreased control of parkinsonism by levodopaIncreased levels of alprazolamSide EffectsAlthough benzodiazepines have been shown to be effective inyounger populations, systematic studies in the elderly are lacking.Judicious use is therefore important, since they may have severalsignificant side effects. Adverse drug reactions to the benzodiazepinesare almost twice as common in patients over the age of 70years compared with those aged 40 years or less 24 .Benzodiazepines do tend to produce greater effects on thecentral nervous system of the elderly than in younger patients 12,13 .This is due partly to increased target-organ sensitivity and partlyto altered pharmacokinetics in the elderly (i.e. duration of half-lifeand peak blood level) 7 . The most common benzodiazepine sideeffect is a dose-dependent CNS depression. Symptoms include