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