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  • Pharmacology of Anxiety Disorders; Sedative-hypnoticJosJ G. Ortiz Ph. D.

    Depto. De FarmacologRa y ToxicologRaUniv. de Puerto Rico Esc. de Medicina,

    PO Box 365067San Juan, Puerto Rico 00936-5067

    jg_ortiz@yahoo.com

  • Objectives Physiology, pathophysiology and therapeutic actions

    Briefly describe the concepts of sedation, hypnosis, anesthesia,coma.

    List and describe the stages of sleep. Define anxiety, differentiate the major anxiety disorders. (from

    previous presentation?) Mechanism of action

    Discuss the GABAA receptor channel complex, the heterogeneity of its subunits and the physiological and therapeutic implications.

    Describe the effects of various sedative/hypnotic/anxiolytic drugs on GABAA function, their selectivity for different receptors with different subunit subtypes, and differences in their sites of action on the GABAA receptor channel complex.

    List sedatives, hypnotics and anxiolytics whose mechanism of action does not involve enhancement of GABAA function, and describe their molecular targets.

  • Objectives Adverse effects, drug interactions and contraindications

    List the signs and symptoms of barbiturate and benzodiazepine overdose and its treatment. Explain how flumazenil might be used, and the rationale for its use. Describe the interactions of the various classes of drugs used as hypnotics, sedatives and anxiolytics

    with other CNS depressants. Compare the dependence liability, and withdrawal syndromes of the various classes of drugs used as

    hypnotics, sedatives and anxiolytics. Discuss the interactions with alcohol.

    Therapeutic uses Compare and contrast the effects of barbiturates, benzodiazepines, and nonbenzodiazepine agonists

    at the benzodiazepine site on induction and maintenance of sleep (including effects on sleep stages), and the adverse effects of these classes of drugs.

    Explain why drugs acting at the benzodiazepine receptor have virtually totally replaced barbiturates as hypnotics.

    List the therapeutic uses of benzodiazepines, and prototypes for each use. Explain how pharmacokinetics of various benzodiazepines relates to their therapeutic utility.

    Compare and contrast the hypnotic action of ramelteon and the anxiolytic action of buspirone with those of drugs acting at the benzodiazepine site of the GABAA receptor channel complex, and describe how their adverse effects including abuse potential differ.

    Compare and contrast the sedative action of chloral hydrate, hydroxyzine and dexmedetomidinewith those of drugs acting at the benzodiazepine site of the GABAA receptor channel complex, and describe how their adverse effects including abuse potential differ.

  • JG Ortiz

    Anxiolytic, Sedative-Hypnoticsclinical uses

    relief of anxiety insomnia balanced anesthesia, IV treatment of ethanol (and other sed.-hyp)

    withdrawal muscle relaxation epilepsy and seizure states diagnostic tool in psychiatry

  • Sedative-Hypnotics Anxiolytic

    reduces anxiety and exerts calming effect with little effect on motor or mental function

    Sedative produces stupor from which the patient can be

    easily aroused. Complex motor functions may be impaired

    Hypnotic produces drowsiness, encourages onset and

    maintenance of sleep

  • Treatments for AnxietySSRIs(Zoloft, Prozac)

    Benzodiazepines(Xanax, Klonopin)

    Azaspirones(Buspar)

  • JG Ortiz

    Pharmacology of Anxiety 5-HT

    SSRI, buspirone, GABAa

    Diazepam, zolpidem, zaleplon ethanol barbiturates - pentobarbital Others (chloral hydrate, meprobamate)

    NE propanolol

  • Selective Serotonin reuptake InhibitorsSelective Serotonin reuptake Inhibitors(SSRI)

    fluoxetine (Prozac)

    sertraline (Zoloft)

    paroxetine (Paxil)

    fluvoxamine (Lovox)

    Citalopram (Celexa)

    Escitalopram (Lexapro)

  • Buspirone partial agonist at 5-HT1a

    receptors Takes at least 2 weeks to

    work headache, nausea,

    dizziness Lacks muscle relaxant,

    marked sedation, withdrawal, abuse

    MD2017

  • GABAafarmacologa

  • GABAa subunits

  • GABAA receptors

  • JG Ortiz

    Anxiolytic, Sedative-Hypnotics mechanism(s)

    Benzodiazepines- promote Cl- channel opening at GABAA receptors, promote GABA binding

    Barbiturates - prolong Cl- channel opening at GABAA

    receptors, inhibit NMDA receptors many others

    MD2017

    MD2017

  • GABAa

  • JG Ortiz

    Benzodiazepines (Bz) Old (long acting), usually produce active metabolites

    Diazepam (Valium), flurazepam (Dalmane), chlordiazepoxide (Librium), Clonazepam (Klonopin),

    flunitrazepam, illegal in USA, one of the date rape drugs

    New (short acting), little, if any active metabolites Midazolam, (Versed), Alprazolam (Xanax),

    Lorazepam (Ativan), Oxazepam (Serax), Triazolam(Halcion)

    Flumazenil ANTAGONIST at Bz sites

    MD2017

  • Pharmacokinetics of some BDZ

  • BDZ metabolism

  • Benzodiazepines

  • Non-anxolytic effects of Bdz Sedation muscle relaxation Development of tolerance Possible dependence Withdrawal seizures Amnesia

  • JG Ortiz

    Ethanol modifies Cl- channel opening at GABAA

    receptors,

    inhibition of AMPA and NMDA receptors?

    Strong potentiation with other CNS drugs

  • Alcohol Withdrawal Syndrome Alcohol craving,

    Tremor, irritability, Nausea, Sleep disturbance, Tachycardia, Hypertension, Sweating, Perceptual distortion, Seizures (6 to 48 hours after last drink),Visual(and occasionally auditory or tactile) hallucinations (12 to 48 hours after last drink)

    Delirium tremens (48 to 96 hours after last drink; rare in uncomplicated withdrawal) Severe agitation, Confusion, Fever, profuse sweating,

    Tachycardia, Nausea, diarrhea, Dilated pupil

  • Barbiturates prolong Cl- channel

    opening at GABAAreceptors,

    inhibit NMDA receptors and possibly others

    Induce P450 many interactions low therapeutic

    index

  • Barbiturates Thiobarbiturates

    thiopental extremely liposoluble,

    DISTRIBUTIONamong tissues determines duration of the effects

    Oxybarbiturates entirely metabolized by

    liver - pentobarbital phenobarbital partially

    (%30%) excreted by kidney w/o metabolism

  • Barbiturates

  • Others Zolpidem, Zaleplon - bind to Bdz1

    (omega-1 site?) in GABAA receptor, Alpha-1 subunit selective? sedation

    Chloral Hydrate gastric disturbances sedation

    Clonidine, propanolol Diphenylhydramine (Benadryl)

    antimuscarinic

  • Newer hypnotics Eszopiclone, Zaleplon, Zolpidem Bind to GABAA receptor sites (close to

    benzodiazepine site) facilitate chloride channel opening

    Sleep disorders, esp when sleep onset is delayed Oral activity, CYP substrates Additive CNS depression with ethanol and other

    depressants Short half-lives Extension of CNS depressant effects

    dependence liability

  • Melatonin receptor agonist Ramelteon Activates MT1 and MT2

    receptors in suprachiasmatic nucleus Sleep disorders, esp when sleep onset is

    delayed Not a controlled substance Oral activity; forms active metabolite via

    CYP1A2 fluvoxamine inhibits metabolism

    Dizziness, fatigue, endocrine changes

  • Pharmacokinetic parameters

  • Sleep stages

  • Long term treatment

  • Anxiolytic, Sedative-Hypnoticsclinical classification

    Short-acting (3-8 hrs) Triazolam, Oxazepam, Secobarbital,

    Amobarbital and Pentobarbital Intermediate-acting (10-20 hrs)

    Lorazepam, Temazepam Long-Acting (1-3 days)

    Diazepam, Clorazepate, Chlordiazepoxide, Flurazepam

  • JG Ortiz

    Anxiolytic, Sedative-Hypnoticssummary

    purpose of pharmacotherapy duration Metabolism and excretion of patient significant interaction(s) with other drugs

    increase in P450 by barbspotentiation of CNS depressiondisplacement of plasma binding sites

  • Anxiolytic, Sedative-Hypnotics multiple interactions with other protein-bound

    drugs barbs and ETOH induce P450, BZ do not potentiation of the effects of CNS depressants

    (ie. EtOH) paradoxical effects in children prolonged use results in REM rebound prolongued use leads to tolerance and cross

    tolerance