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Benzodiazepines. Ghyasvand , M.D. Roozbeh Hospital, TUMS 2013. BNZ receptors. BNZ-1 r.: sedation, hypnotic, antianxiety BNZ-2 r.: anxiolysis , muscle relaxation, sedation, anticonvulsant, psychomotor impairment BNZ-3 r.: tolerance, withdrawal. BNZs. Diazepam (tab 2&5&10& inj10mg/2ml)

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    1. Benzodiazepines Ghyasvand, M.D. Roozbeh Hospital, TUMS 2013

    2. BNZ receptors • BNZ-1 r.: sedation, hypnotic, antianxiety • BNZ-2 r.: anxiolysis, muscle relaxation, sedation, anticonvulsant, psychomotor impairment • BNZ-3 r.: tolerance, withdrawal

    3. BNZs • Diazepam (tab 2&5&10& inj10mg/2ml) • Lorazepam (1&2) • Clonazepam (1&2) • Alprazolam (0.5&1) • Oxazepam (10) • Chlordiazepoxide (5&10) • Flurazepam (tab30& cap15)

    4. Pharmacologic Actions • The absorption, the attainment of peak concentrations, and the onset of action are quickest for diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax). • Several benzodiazepines are effective following intravenous (IV) injection, whereas only lorazepam and midazolam (Versed) have rapid and reliable absorption following intramuscular (IM) administration.

    5. Pharmacologic Actions … • Diazepam, chlordiazepoxide, clonazepam, flurazepam have plasma half-lives of 30 to more than 100 hours and, therefore, are the longest-acting benzodiazepines. • The half-lives of lorazepam, oxazepamare between 8 and 30 hours. Alprazolam has a half-life of 10 to 15 hours.

    6. Pharmacologic Actions … • The advantages of long half-life drugs over short half-life drugs include less-frequent dosing, less variation in plasma concentration, and less-severe withdrawal phenomena. • The disadvantages include drug accumulation, increased risk of daytime psychomotor impairment, and increased daytime sedation.

    7. Pharmacologic Actions … • The advantages of the short half-life drugs over the long half-life drugs include no drug accumulation and less daytime sedation. • The disadvantages include more-frequent dosing and earlier and more-severe withdrawal syndromes. Rebound insomnia and antrograde amnesia are thought to be more of a problem with the short half-life drugs than with the long half-life drugs.

    8. Pharmacologic Actions …

    9. Therapeutic Indications • Insomnia • Anxiety Disorders: GAD, panic dis., social phobia • BMD1 • Other Indications: akathisia, alcohol withdrawal, agitation, catatonia.

    10. Insomnia • Because insomnia can be a symptom of a physical or psychiatric disorder, hypnotics should not be used for more than 7 to 10 consecutive days without a thorough investigation of the cause of the insomnia.

    11. GAD • Benzodiazepines are highly effective for the relief of anxiety associated with generalized anxiety disorder. • Most persons should be treated for a predetermined, specific, and relatively brief period.

    12. Panic Disorder • Alprazolam and clonazepam, both high-potency benzodiazepines, are commonly used medications for panic disorder, with or without agoraphobia. • SSRIs are still often preferred,because they target common comorbid conditions, such as depression or obsessive-compulsive disorder (OCD). • Benzodiazepines and SSRIs can be initiated together to treat acute panic symptoms; use of the benzodiazepine can be tapered after 3 to 4 weeks once the therapeutic benefits of the SSRI have emerged.

    13. Social Phobia • Clonazepam is an effective treatment for social phobia. • In addition, several other benzodiazepines (e.g., diazepam) have been used as adjunctive medications for treatment of social phobia.

    14. Other Anxiety Disorders • Benzodiazepines are used adjunctively for treatment of adjustment disorder with anxiety, OCD, and posttraumatic stress disorder.

    15. Adverse Reactions • The most common adverse effect of benzodiazepines is drowsiness. • The most serious adverse effects of benzodiazepines occur when other sedative substances, such as alcohol, are taken concurrently. These combinations can result in marked drowsiness, disinhibition, or even respiratory depression. • Ataxia, dizziness, mild cognitive deficits, antrograde amnesia, rashes, paradoxical increase in aggression .

    16. Adverse Reactions … • The symptoms of benzodiazepine intoxication include confusion, slurred speech, ataxia, drowsiness, dyspnea, and hyporeflexia.

    17. Adverse Reactions … • Persons with hepatic disease and elderly persons are particularly likely to have adverse effects and toxicity from the benzodiazepines, especially when the drugs are administered repeatedly or in high dosages. • Benzodiazepines can produce clinically significant impairment of respiration in persons with COPD and sleep apnea. • Alprazolam can exert a direct appetite stimulant effect and may cause weight gain.

    18. Adverse Reactions … • Benzodiazepines should be used with caution by persons with a history of substance abuse, cognitive disorders, renal disease, hepatic disease, porphyria, CNS depression, or myasthenia gravis.

    19. Pregnancy & breast feeding • Some data indicate that benzodiazepines are teratogenic; therefore, their use during pregnancy is not advised(group D/X). • The drugs are secreted in breast milk in sufficient concentrations to affect the newborn. Benzodiazepines can cause dyspnea, bradycardia, and drowsiness in nursing babies (group L3-moderately safe).

    20. Tolerance, Dependence, and Withdrawal • The appearance of a withdrawal syndrome, depends on the length of time the person has been taking a benzodiazepine, the dosage the person has been taking, the rate at which the drug is tapered, and the half-life of the compound. • Benzodiazepine withdrawal syndrome consists of anxiety, nervousness, diaphoresis, restlessness, irritability, fatigue, light-headedness, tremor, insomnia, and nausea. Delirium and seizures may occur.

    21. Drug Interactions • The most common and potentially serious benzodiazepine receptor agonist interaction results in excessive sedation and respiratory depression occurring when benzodiazepines, & zolpidem, are administered concomitantly with other CNS depressants, such as alcohol, barbiturates, tricyclic and tetracyclic drugs, dopamine receptor antagonists (DRAs), opioids, and antihistamines.

    22. Drug Interactions • Cimetidine , disulfiram , isoniazid, and oral contraceptives increase the plasma concentrations of diazepam, chlordiazepoxide and flurazepam. • The plasma concentrations of alprazolam are increased to potentially toxic concentrations by fluvoxamine . • The benzodiazepines can increase the plasma concentrations of phenytoin and digoxin .

    23. Dosage • Benzodiazepine use should be started at a low dosage, and the person should be instructed regarding the drug's sedative properties and abuse potential. • An estimated length of therapy should be decided at the beginning of treatment, and the need for continued therapy should be reevaluated at least monthly because of the problems associated with long-term use.

    24. Dosage

    25. Zolpidem • Zolpidem (tab 5&10) • Specific for BNZ-1 receptor • Zolpidem reaches peak plasma concentrations in 1.6 hours and has a half-life of 2.6 hours. • For insomnia • Lower rate of tolerance, abuse and dependence • Safe in pregnancy(group B) • In rare cases, zolpidem can cause hallucinations and behavioral changes.

    26. THANK YOU Any Question?