• Structure - benzene ring attached to a seven-membered diazepene ring. Halogens increase lipid solubility and potency.
• Uses - anxiolytics, hypnotics, muscle relaxants, and anticonvulsants. They can be used as pre-anesthetic medication.
• Pharmacokinetics
• Most benzodiazepines are well absorbed. Peak plasma concentration is reached at 0.5-8 hours.
• Minimal pharmacokinetic interaction with other drugs.
• Excessive metabolism in the liver. Long-acting metabolites are produced.
• Highly protein bound (75-95%), lipophilic, concentrates all over the brain.
• Examples of commonly used benzodiazepenes, therapeutic uses of a given agent are usually dependent on the half-life.
• Long-acting compounds:
• Diazepam (Valium), T_½ is 43 ± 13 hours; parent compound has short T_½ but produces a longer-acting metabolite
• Flurazepam (Dalmane), half-life of major metabolite is at least 50 hours, parent compound 2-3 hours.
• Chlorodiazepoxide (Librium)
• Intermediate-acting compounds:
• Alproxalam (Xanax) - T_½ is 12 ± 2 hours; parent metabolite lasts longer than long-acting but no metabolite
• rapid oral absorption
• Qxazepam (Serax) - T_½ is 8 ± 2 hours.
• Short-acting compounds:
• Triazolam (Halcion) - T_½ is 3 hours. High publicity about bad side effects.
• Midazolam (Versed) - T_½ is 2 hours. Used as pre-anesthetic medication.
• Advantages - high margin of safety; produce little respiratory and cardiovascular depression
• interactions with other drugs are insignificant
• Disadvantages - excess CNS depression; interactions with alcohol
• physiological dependence can occur after prolonged treatment with benzodiazepines
• prolonged use of therapeutic doses can lead to physiological dependence
• physiological dependence does not occur in everybody; dependence usually in people who take other drugs
• short-acting drugs - cause more problems with withdrawal
• no craving
• withdrawal symptoms can include temporary intensification of anxiety, sleep disturbances, irritability, increased tension and anxiety, panic attacks, hand tremor, sweating, nausea, weight loss, palpitations
• Adverse behavioral effects
• recall is affected, especially delayed recall is impaired
• occurrence of untoward behavioral effects (inappropriate) remain controversial, especially with triazolam
• Site of action
• Benzodiazepines work at the GABA_A receptor complex - mostly located at interneurons in the CNS, ligand gated Cl^- channel, pentameric structure and subunits; inhibitory neurotransmitter,so it hyperpolarizes cells Þ reduces excitability
• Benzodiazepenes (GABA agonist) enhance the actions of GABA, by acting at a distant site other than the GABA site, GABA has to be around to have an effect.
• Barbituates act in a similar manner as benzodiazepines but act at a different site.
• Ethanol potentiates GABA actions, neuroactive steroids can increase/decrease effect of GABA.
• Agonists - work to increase the action of GABA, midazolam.
• Partial agonist - can be used to isolate and treat a certain symptom and minimize side effects, Proteazonil.
• Antagonist - action of 0, blocks agonist effects at receptor.
• Flumazenil used in management of OD, elim. by hepatic metabolism after IV admin.; clinical effect in 30-60 min.
• Inverse agonist - decrease actions of receptor, exact opposite of agonists.
• Endogenous benzodiazepines is suggested by a site of action for benzodiazepines, candidates include: inosine, hypoxanthine, nicotinamide, diazepam binding inhibitor (DBI)

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