Pharmacology of Anxiolytic Sedative Hypnotics

8/3/2019 Pharmacology of Anxiolytic Sedative Hypnotics

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Pharmacology of Anxiolytic/

Sedative-Hypnotics

Philip G. Janicak, MD

Professor of Psychiatry and PharmacologyUniversity of Illinois at Chicago



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Abstract

Recent anxiolytic and sedative-hypnotic agents offercomparable efficacy, fewer serious adverse effects, and less risk ofa fatal consequence due to accidental or intentional overdose in

comparison to alcohol, barbiturates and other non-barbiturateagents (e.g., meprobamate). Unfortunately, they have not entirelyeliminated the hazards of tolerance, dependency, and withdrawalsyndromes, although they have a lower abuse potential than theirpredecessors.

For these reasons, it is important to becomeknowledgeable about the basic pharmacology of these drugs, inaddition to their appropriate clinical indications, dosages, andduration of usage. Most importantly, their limitations must receiveas much attention as their assets.

pharmacology of anxiolytic/sedative-hypnotics



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pharmacology of anxiolytic/sedative-hypnotics Objectives

Review diagnostic indications for anxiolytic/ sedative-hypnotics

Review different classes of antianxiety andsedative-hypnotic agents in terms of theirpharmacodynamics; pharmacokinetics;adverse effects; and potential for drug

interactions.

Review treatment strategies for anxiety andsleep disorders.



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pharmacology of anxiolytic/sedative-hypnotics Anxiety

Natural human experience

Subjective qualities of fear or related emotions

Ensures survival and adaptation

In excess, can cripple and destroy



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pharmacology of anxiolytic/sedative-hypnotics Anxiety Symptoms

Anxiety symptoms are associatedwith numerous medical conditions:

Cardiovascular disease

Endocrine disease

Gastrointestinal disease

Neurologic disease

Drug-induced



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pharmacology of anxiolytic/sedative-hypnotics Indications for Antianxiety/Sedative-Hypnotics

Generalized anxiety disorder (GAD)

Phobic disorders

Psychological factors affecting medical condition

Panic disorder

Obsessive-compulsive disorderPosttraumatic stress disorder

Sleep disorders (dyssomnias; parasomnias)



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pharmacology of anxiolytic/sedative-hypnotics GAD

Represents up to 50% of anxiouspatients seen by physicians

Increased annual medical expenses

Often unnecessary medical consultations

55 million prescriptions for BZDs in 1989

Anxiolytic agents fourth most prescribedclass of medication



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Phobic Disorders

Disabling anxiety (at times associatedwith panic attacks) and avoidance

Agoraphobia

Social phobia (Social Anxiety Disorder)

Specific phobia




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Psychological Factors

Affecting Medical Condition

Psychologically meaningful environmental stimuli

Temporally related to the initiation or exacerbationof a physical condition

Demonstrable organic pathology (e.g., rheumatoidarthritis)

Known physiological process (e.g., migraine)




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Panic Disorder

Sudden, spontaneous, unexpected feelings ofterror and anxiety

The autonomic equivalence of anxiety

The desire to flee the situation and return toa safe place

A phobic avoidance of the places wheresuch attacks occur



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Symptomatology of Panic Attacks

Shortness of breath /smothering sensations

Dizziness, unsteady

feelings, or faintness Palpitations/tachycardia

Trembling/shaking

Sweating

Choking

Nausea/abdominal distress

Depresonalization/ derealization

Paresthesias

Flushes/chills

Chest pain or discomfort

Fear of dying

Fear of going crazy or doingsomething uncontrolled




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Course of Illness

Panic

GAD

Normal

anxiety level

time




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pharmacology of anxiolytic/sedative-hypnotics Obsessive-Compulsive Disorder (OCD)

Recurrent obsessions and/or compulsions:

Cause marked distress, are time-consuming, orinterfere with functioning

Are recognized as excessive or unreasonable

Are not due to the effect of a substance or general

medical condition



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pharmacology of anxiolytic/sedative-hypnotics Obsessions in OCD

Contamination

Pathological doubt

Aggressive impulses

Somatic concerns

Need for symmetry

Sexual impulses



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pharmacology of anxiolytic/sedative-hypnotics Compulsive Behaviors in OCD

Cleaning

Washing

Checking

Excessive ordering/arranging

Counting

RepeatingCollecting



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Posttraumatic Stress Disorder (PTSD)

Due to an unusual experience that would be very stressful foralmost anyone (e.g., combat, rape, sudden unexpecteddeath of a loved one)

Symptoms include: Intrusive recollections; frightening dreams; sense of event recurring

Intensive physiological stress; hyperarousal

Emotional numbing

Persistent avoidance of stimuli associated with the trauma

High comorbidity with other psychiatric disorders

Increase suicide attempt risk

Female-to-male lifetime prevalence ratio of 2:1




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Sleep Disorders

Dyssomnias (difficulty initiating or maintaining sleepor not feeling rested)

Primary Insomnia

Primary Hypersomnia

Circadian Rhythm Disorder

Parasomnias (abnormal event)

Nightmare Disorder

Sleep Terror DisorderSleepwalking Disorder




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pharmacology of anxiolytic/sedative-hypnotics Pharmacodynamics

Benzodiazepines Specific binding site associated with GABAA receptor-

chloride ion channel Potentiate GABA

Serotonergic effects (e.g., clonazepam)Azapirone (e.g., buspirone)

5-HT1A agonist: acutely, firing, in dorsal raphe nuclei;chronically, receptor desensitization activity

Beta-blockers receptors central and peripheral, post synaptic

Clonidine Agonist at 2 receptors, central, pre-synaptic

Antidepressants



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pharmacology of anxiolytic/sedative-hypnotics GABA Function and Distribution

Inhibitory neurotransmitter

Widely distributed throughout CNS

Local inhibitory action, thereforerapidly alters neuronal output

Desensitization to inhibitory effectswith chronic stimulation of GABA



GABAA-BZD Supramolecular Complex



4/22/2012 21S.M. Paul, 1995

GABAA Receptor Structure

BenzodiazepinesAgonists

Antagonists-

Inverse Agonists

DBI Peptides

Convulsants

PicrotoxinTBPS

Cl-

GABA AgonistsMuscimol

GABA Antagonists

Bicuculline

Barbiturates

Neuroactive Steroids

Alcohols

Anesthetics



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GABAA receptorCytoplasm

Benzodiazepine-binding domain




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BZD Receptors

Type IPredominates in cerebellum

Anxiolytic properties

Less sedative properties

Type II Located in cortex, hippocampus, spinal cord

No anxiolytic properties

Sedative properties

Type III Located in peripheral tissue

No anxiolytic properties

? other properties




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BZD Receptor Activity

Full AgonistPartialAgonist Anta onist

Partial InverseAgonist

Full InverseAgonist

AnxiolyticSed-HypnoticMyorelaxantAnticonvulsantAmnesticDependency

Anxiolytic No clinicaleffect

PromnesticAnxiogenicPro-convulsant

PromnesticAnxiolyticConvulsant




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Non-Benzodiazepine Agents

Imidazopyridines (e.g., zolpidem, alpidem)

Pyrazolopyrimidine (e.g., zaleplon)

Cyclopyrralone (e.g., zopiclone)

Sedating antidepressants (e.g., trazodone)




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Non-Benzodiazepine Agents (con’t)

Antihistamines (e.g., diphenhydramine)

Natural Remedies (e.g., melatonin, valerian)

B-carbolines (e.g., abecarnil)

BZD structural derivatives (e.g., biretazanil)




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pharmacology of anxiolytic/sedative-hypnotics Serotonin Model

Majority of 5-HT pathways originatein the dorsal raphe (DR)

DR innervates cortex, hypothalamus,thalamus, and limbic system

5-HT mediates behavioral effects in

animal models and humans



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Serotonin Receptors5-HT1A -Anxiety, alcoholism, sexual function

5-HT1C -Anxiety, migraine pain

5-HT1D -Migraine pain

5-HT2 -Anxiety, depression, schizophrenianegative symptoms, sexual function

5-HT3 -Migraine pain, emesis, schizophrenia(e.g., ondansetron)

5-HT4 -Anxiety, schizophrenia?




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Serotonin Agents: Indications for

Anxiety-Related Disorders

SSRI

Sertraline - OCD; PD; PTSDParoxetine - OCD; PD; SAD; GAD

Fluoxetine - OCD; BN; PMDD

Fluvoxamine - OCD

Venlafaxine - GAD

Buspirone - GAD




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Noradrenergic Model

Hypersensitivity to autonomic nervous system

Locus coeruleus (LC)

Stimuli norepinephrine release stimulationof the sympathetic nervous system




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Norepinephrine Receptors

Locus coeruleus

Alpha -2 adrenergic receptors

somatodendritic autoreceptors

terminal autoreceptors

negative feedback system

antagonists are anxiogenic

agonists may be anxiolytic and decrease withdrawal

symptoms (e.g., clonidine)Beta adrenergic receptors

Beta-blockers (e.g., propranolol)

Social phobia

Performance anxiety




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Pharmacokinetics: Benzodiazepines

Absorption: rapid absorption, except clorazepate

Onset of action: increase lipid solubility faster onset

Duration of action: single dose with increased lipid solubility faster redistribution to fat tissues shorter duration of action. Chronic use:in equilibrium with fat tissues

Half life: In part, determines duration of action

Metabolism: lorazepam, oxazepam, temazepam notmetabolized by liver




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Drug Interactions: Benzodiazepines

Additive pharmacodynamic effects (e.g., alcohol)

BZD withdrawal when other drugs that increase

seizure risk are also taken

Inhibit BZD metabolism (e.g., nefazodone viaP450 3A 3/4 inhibits metabolism of triazolam)

Diazepam may increase levels of digoxin andphenytoin


f



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Adverse Effects: Benzodiazepines

Sedation and impairment of performance Psychomotor skills: driving; engaging in dangerous physicalactivities; using hazardous machinery, especially duringinitial phase of treatment

Memory impairment Anterograde amnesia (desired before surgery, otherprocedures).

Dose-related, and tolerance may not develop.

Most likely with triazolam

Disinhibition Possible risk factors: history of aggression, impulsivity,borderline or antisocial personality


h l f i l i / d i h i



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Abuse, Dependence, Withdrawal, and

Rebound Anxiety: Benzodiazepines

Abuse potential decreased when properly prescribed and supervised.

Dependence may occur at usual doses taken beyond several weeks.

Withdrawal may occur even when discontinuation is not abrupt (e.g.,by 10% every 3 days). Symptoms include: tachycardia, increased bloodpressure, muscle cramps, anxiety, insomnia, panic attacks, impairmentof memory and concentration, perceptual disturbances, derealization,

hallucinations, hyperpyrexia, seizures. May continue for months.

Rebound anxiety: return of target symptoms, with increase intensity.


h l f i l i / d i h i



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Pharmacokinetics/Pharmacodynamics:

Buspirone

Onset of action (i.e., weeks versus days)

No sedation or impairment of performance

No cross-tolerance with BZDs

No tolerance or withdrawal

No abuse potential


h l f i l ti / d ti h ti



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Adverse Effects: Buspirone

Nausea

Headache

Insomnia, nervousness

Restlessness

Dizziness,lightheadedness




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CLINICAL PRESENTATION TREATMENT STRATEGY

PSYCHOTHERAPY:Supportive, Cognitive-Behavioral or Insight-Oriented

Acute anxiety (mild)

Acute anxiety (more severe) (start) Benzodiazepine (BZD)plus Psychotherapy

(may start)

(insufficient response)

Treatment Strategy for GAD

(may add)


(may try)



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Buspirone (up to 90 mg/day forup to 6 weeks) plus CBT

Chronic anxiety(no prior BZD therapy)

Venlafaxine

(may start)






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Buspirone or Venlafaxine plusBZD initially, then taper BZD

plus CBT

Chronic anxiety,prior BZD therapy

Chronic anxiety with panicor depressive symptoms

(may start)

Buspirone or Venlafaxine plus BZD for longer period

plus CBT

(may start)



Other Antidepressants (TCA,SSRI, MAOI) w/wo a BZD orBuspirone




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Cognitive Behavioral TherapySocial Phobia, Generalized(Social Anxiety Disorder)

(may start)


Treatment Strategyfor PHOBIC Disorders

(or)

Selective Serotonin ReuptakeInhibitor (e.g., Paroxetine)




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BEHAVIORAL THERAPYPLUS SSRI

MAOI (must wait at least 2 weeksafter discontinuation of SSRI [longerfor fluoxetine] before starting MAOI)



orAlprazolam

orClonidine



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Cognitive Behavioral Therapy

Systematic desensitization

Specific Phobia

B-blocker (e.g., performance anxiety)

(start)



MAOI (e.g., phenelzine)




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Behavioral Therapy only

(may require several months)

Cognitive

In-vivo exposure

Relaxation

Systematic desensitization

Panic attacks (mild)w/wo agoraphobia

(start)


Treatment Strategy for PANIC Disorder withor without Agoraphobia

(may add)From Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr. Principles and Practice of Psychopharmacotherapy . 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.



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SSRI plus Behavioral TherapyPanic attacks (moderate)w/wo agoraphobia

(may start)


(or)

Other Antidepressant (e.g.,Venlafaxine, TCA) plus

Behavioral Therapy



From Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr. Principles and Practice of Psychopharmacotherapy . 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.



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ALPRAZOLAM/CLONAZEPAM

plus Behavioral Therapy






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TCA/SSRI and Behavioral TherapyPanic attacks (severe)w/wo agoraphobia

Alprazolam/Clonazepam

for first month

(start)

(plus)






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Alprazolam/Clonazepam

indefinitely


TCA/SSRI and Behavioral Therapy


(plus)





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MONOAMINE OXIDASE INHIBITOR (N.B. SSRI) must be stopped prior tobeginning MAOI:

Fluoxetine, at least 5 weeks

Other SSRIs, at least 2 weeks

Valproate w/wo BZD


(may try)





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Behavioral Therapy

(e.g., exposure and responseprevention)

Mild symptoms (may start)


Treatment Strategy for OBSESSIVE-COMPULSIVE and Related Disorders

(may add)




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SSRIFluvoxamineSertraline

ParoxetineCitalopram

Fluoxetine

Moderate to severesymptoms

(start)


Clomipramine


Behavioral Therapy

(plus)

(or)




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Alternate SRI





Clonazepam/Buspironeplus SRI



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Pimozide/Haloperidol/Risperidoneor Lithium w/wo SRI

TrichotillomaniaTics (e.g., Tourette’s) Delusional symptoms

MAOI (SRI must be completelycleared first)

(may start)





(may consider)



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Somatic Therapy

ECTNeurosurgery

TMS (?)

Severe, unremitting

course (e.g., 5 years;failed trials with SSRI,CMI, MAOI; severedysfunction)

(consider)





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Clarify diagnosis

treat any medical or psychiatricdisorder

check for non-prescribed drugs

Transient or short-term insomnia

(first)

(insufficient response or noother disorder discovered)

Treatment Strategy for SLEEP Disorders

Adapted from Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr. Principles and Practice of Psychopharmacotherapy . 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.



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Nonpharmacological therapies

Stimulus control

Sleep restriction

Relaxation techniques

Paradoxical intention

Sleep hygiene techniques






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Short- to intermediate-actingBZD Sedative-Hypnotic (e.g.,estazolam 0.5-1 mg QHS)


Zolpidem or Zaleplon (5-20 mg QHS)

(or)





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Non-pharmacological therapiesw/wo sedating antidepressant

Chronic insomnia(7-12 weeks)

(start)

e.g., trazodone (25-50 mg QHS)


COMBINED TREATMENTnon-pharmacological andintermittent, sedative-hypnotic when necessary



ANTIANXIETY AGENTS



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Generic Names Trade Names Daily Dosage(mg/day)

BENZODIAZEPINES Chlordiazepoxide Librium, others 10-100Diazepam Valium, others 2-40Oxazepam Serax, others 30-120Chlorazepate Tranxene, others 15-60Lorazepam Ativan 1-10Prazepam Centrax 20-60Halazepam Paxipam 60-160Alprazolam Xanax 0.75-4

AZAPIRONES

Buspirone Buspar 15-60ANTIDEPRESSANTS

SSRI Sertraline, others 25-250Venlafaxine Effexor 75-375

ANTIANXIETY AGENTS

SEDATIVE-HYPNOTICS



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Generic Names Trade Names Daily Dosage (mg /day)BENZODIAZEPINESLong-actingFlurazepam Dalmane 15-45 Quazepam Doral 7.5-15Intermediate-actingEstazolam Prosom 0.5-2 Temazepam Restoril 15-45 Short-acting

Triazolam Halcion 0.125-0.25NONBENZODIAZEPINEZolpidem Ambien 5-20 Zaleplon Sonata 5-20

SEDATING ANTIDEPRESSANTS

Trazodone Dyserel 25-100

BARBITURATE-LIKEChloral Hydrate Notec 500-1500

OTHERMelatonin 0.3-2




References

Ayd FJ Jr, Janicak PG, Davis JM, Preskorn SH. Advances in thepharmacotherapy of anxiety-related disorders. In: Janicak PG, ed.Principles and Practice of Psychopharmacotherapy Update. Baltimore,MD: Williams & Wilkins; 1996. Vol 1.

Janicak PG, Ayd FJ Jr. Sedatives and hypnotics in the elderly patient.In: Nelson JC, ed. Geriatric Psychopharmacology . New York, NY:Marcel-Dekker; 1998:347-366.

Janicak PG, Davis JM, Preskorn SH, Ayd FJ Jr. Principles and Practice of Psychopharmacotherapy . 3rd Ed. Philadelphia, PA: Lippincott

Williams & Wilkins; 2001:463-558.

Israni TH, Janicak PG, Davis JM. Obsessive compulsive disorder. In:Flaherty JA, Davis JM, Janicak PG, eds. Psychiatry: diagnosis and therapy . 2nd ed. Norwalk, CN: Appleton & Lange; 1993:145-155.

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Pharmacology of Anxiolytic Sedative Hypnotics