Pharmacology of anxiolytic -sedative-hypnotics (2)

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Pharmacology of Anxiolytic/ Sedative-Hypnotics

Philip G. Janicak, MDProfessor of Psychiatry and Pharmacology

University of Illinois at Chicago

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Abstract

Recent anxiolytic and sedative-hypnotic agents offer comparable efficacy, fewer serious adverse effects, and less risk of a fatal consequence due to accidental or intentional overdose in comparison to alcohol, barbiturates and other non-barbiturate agents (e.g., meprobamate). Unfortunately, they have not entirely eliminated the hazards of tolerance, dependency, and withdrawal syndromes, although they have a lower abuse potential than their predecessors.

For these reasons, it is important to become knowledgeable about the basic pharmacology of these drugs, in addition to their appropriate clinical indications, dosages, and duration of usage. Most importantly, their limitations must receive as much attention as their assets.

pharmacology of anxiolytic/sedative-hypnotics

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Objectives

Review diagnostic indications for anxiolytic/ sedative-hypnotics

Review different classes of antianxiety and sedative-hypnotic agents in terms of their pharmacodynamics; pharmacokinetics; adverse effects; and potential for drug interactions.

Review treatment strategies for anxiety and sleep disorders.

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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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Anxiety Symptoms

Anxiety symptoms are associated with numerous medical conditions: Cardiovascular disease Endocrine disease Gastrointestinal disease Neurologic disease Drug-induced

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Indications for Antianxiety/Sedative-Hypnotics

Generalized anxiety disorder (GAD) Phobic disorders Psychological factors affecting medical condition

Panic disorder Obsessive-compulsive disorder Posttraumatic stress disorder

Sleep disorders (dyssomnias; parasomnias)

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Represents up to 50% of anxious patients seen by physicians

Increased annual medical expenses

Often unnecessary medical consultations

55 million prescriptions for BZDs in 1989

Anxiolytic agents fourth most prescribed class of medication

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Phobic Disorders

Disabling anxiety (at times associated with panic attacks) and avoidance

Agoraphobia

Social phobia (Social Anxiety Disorder)

Specific phobia

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Psychological FactorsAffecting Medical Condition

Psychologically meaningful environmental stimuli

Temporally related to the initiation or exacerbation of a physical condition

Demonstrable organic pathology (e.g., rheumatoid arthritis)

Known physiological process (e.g., migraine)

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Panic Disorder

Sudden, spontaneous, unexpected feelings of terror and anxiety

The autonomic equivalence of anxiety The desire to flee the situation and return to

a safe place A phobic avoidance of the places where

such 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 doing

something uncontrolled

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Course of Illness

Normal

anxiety level

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Obsessive-Compulsive Disorder (OCD)

Recurrent obsessions and/or compulsions:Cause marked distress, are time-consuming, or

interfere with functioningAre recognized as excessive or unreasonableAre not due to the effect of a substance or general

medical condition

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Obsessions in OCD

Contamination Pathological doubt Aggressive impulses Somatic concerns Need for symmetry Sexual impulses

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Compulsive Behaviors in OCD

Cleaning Washing Checking Excessive ordering/arranging Counting Repeating Collecting

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Posttraumatic Stress Disorder (PTSD)

Due to an unusual experience that would be very stressful for almost anyone (e.g., combat, rape, sudden unexpected death 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 sleep or not feeling rested) Primary Insomnia Primary Hypersomnia Circadian Rhythm Disorder

Parasomnias (abnormal event) Nightmare Disorder Sleep Terror Disorder Sleepwalking Disorder

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Pharmacodynamics

BenzodiazepinesSpecific binding site associated with GABAA receptor-

chloride ion channelPotentiate 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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GABA Function and Distribution

Inhibitory neurotransmitter

Widely distributed throughout CNS

Local inhibitory action, therefore rapidly alters neuronal output

Desensitization to inhibitory effects with chronic stimulation of GABA

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GABAA-BZD Supramolecular Complex

04/11/23 21S.M. Paul, 1995

GABAA Receptor Structure

BenzodiazepinesAgonists

Antagonists-Inverse Agonists

DBI Peptides

ConvulsantsPicrotoxinTBPS

GABA AgonistsMuscimol

GABA AntagonistsBicuculline

Barbiturates

Neuroactive Steroids

Alcohols

Anesthetics

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GABAA receptorCytoplasm

Benzodiazepine-binding domain

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BZD Receptors Type I

Predominates 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 Antagonist

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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Serotonin Model

Majority of 5-HT pathways originate in 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 Receptors

5-HT1A -Anxiety, alcoholism, sexual function

5-HT1C -Anxiety, migraine pain

5-HT1D -Migraine pain

5-HT2 -Anxiety, depression, schizophrenia negative symptoms, sexual function

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

5-HT4 -Anxiety, schizophrenia?

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Serotonin Agents: Indications forAnxiety-Related Disorders

Sertraline - OCD; PD; PTSD

Paroxetine - 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 stimulation of 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 phobiaPerformance 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

not metabolized 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 via P450 3A 3/4 inhibits metabolism of triazolam)

Diazepam may increase levels of digoxin and phenytoin

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Adverse Effects: Benzodiazepines

Sedation and impairment of performancePsychomotor skills: driving; engaging in dangerous physical activities; using hazardous machinery, especially during initial phase of treatment

Memory impairmentAnterograde amnesia (desired before surgery, other procedures).

Dose-related, and tolerance may not develop.

Most likely with triazolam

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

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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 blood pressure, muscle cramps, anxiety, insomnia, panic attacks, impairment of memory and concentration, perceptual disturbances, derealization, hallucinations, hyperpyrexia, seizures. May continue for months.

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

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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

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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 for up to 6 weeks) plus CBT

Chronic anxiety(no prior BZD therapy)

Venlafaxine

(may start)

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Buspirone or Venlafaxine plus BZD initially, then taper BZD

plus CBT

Chronic anxiety,prior BZD therapy

Chronic anxiety with panic or 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 or Buspirone

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Cognitive Behavioral TherapySocial Phobia, Generalized (Social Anxiety Disorder)

(may start)

Treatment Strategyfor PHOBIC Disorders

Selective Serotonin Reuptake Inhibitor (e.g., Paroxetine)

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BEHAVIORAL THERAPY PLUS SSRI

MAOI (must wait at least 2 weeks after discontinuation of SSRI [longer for fluoxetine] before starting MAOI)

orAlprazolam

orClonidine

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Cognitive Behavioral TherapySystematic 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)CognitiveIn-vivo exposureRelaxationSystematic desensitization

Panic attacks (mild) w/wo agoraphobia

(start)

Treatment Strategy for PANIC Disorder with or 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)

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/Clonazepamfor first month

(start)

(plus)

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Alprazolam/Clonazepamindefinitely

TCA/SSRI and Behavioral Therapy

(plus)

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MONOAMINE OXIDASE INHIBITOR (N.B. SSRI) must be stopped prior to beginning MAOI:Fluoxetine, at least 5 weeksOther SSRIs, at least 2 weeks

Valproate w/wo BZD

(may try)

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Behavioral Therapy

(e.g., exposure and response prevention)

Mild symptoms (may start)

Treatment Strategy for OBSESSIVE-COMPULSIVE and Related Disorders

(may add)

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SSRIFluvoxamineSertralineParoxetineCitalopramFluoxetine

Moderate to severe symptoms

(start)

Clomipramine

Behavioral Therapy(plus)

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Alternate SRI

Clonazepam/Buspirone plus SRI

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Pimozide/Haloperidol/Risperidone or Lithium w/wo SRI

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

MAOI (SRI must be completely cleared first)

(may start)

(may consider)

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Somatic TherapyECTNeurosurgeryTMS (?)

Severe, unremitting course (e.g., 5 years; failed trials with SSRI, CMI, MAOI; severe dysfunction)

(consider)

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Clarify diagnosistreat any medical or psychiatric disordercheck for non-prescribed drugs

Transient or short-term insomnia

(first)

(insufficient response or no other 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 therapiesStimulus controlSleep restrictionRelaxation techniquesParadoxical intentionSleep hygiene techniques

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

Zolpidem or Zaleplon (5-20 mg QHS)

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Non-pharmacological therapies w/wo sedating antidepressant

Chronic insomnia (7-12 weeks)

(start)

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

COMBINED TREATMENT non-pharmacological and intermittent, sedative-hypnotic when necessary

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Generic Names Trade Names Daily Dosage (mg/day)

BENZODIAZEPINESChlordiazepoxide 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

AZAPIRONESBuspirone Buspar 15-60

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

ANTIANXIETY AGENTS

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Generic Names Trade Names Daily Dosage (mg /day)BENZODIAZEPINESLong-actingFlurazepam Dalmane 15-45Quazepam Doral 7.5-15Intermediate-actingEstazolam Prosom 0.5-2Temazepam Restoril 15-45Short-actingTriazolam Halcion 0.125-0.25

NONBENZODIAZEPINE Zolpidem Ambien 5-20Zaleplon Sonata 5-20

SEDATING ANTIDEPRESSANTSTrazodone Dyserel 25-100

BARBITURATE-LIKEChloral Hydrate Notec 500-1500

OTHERMelatonin 0.3-2

SEDATIVE-HYPNOTICS

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References

Ayd FJ Jr, Janicak PG, Davis JM, Preskorn SH. Advances in the pharmacotherapy 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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