l13 anxiety pharm
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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
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.
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
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)
Pharmacology of Anxiety 5-HT
SSRI, buspirone, GABAa
Diazepam, zolpidem, zaleplon ethanol barbiturates - pentobarbital Others (chloral hydrate, meprobamate)
Selective Serotonin reuptake InhibitorsSelective Serotonin reuptake Inhibitors(SSRI)
Buspirone partial agonist at 5-HT1a
receptors Takes at least 2 weeks to
work headache, nausea,
dizziness Lacks muscle relaxant,
marked sedation, withdrawal, abuse
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
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
Pharmacokinetics of some BDZ
Non-anxolytic effects of Bdz Sedation muscle relaxation Development of tolerance Possible dependence Withdrawal seizures Amnesia
Ethanol modifies Cl- channel opening at GABAA
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
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
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)
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
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
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
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