DRUGS FOR ANXIETY AND PANIC DISORDERS

Robert L. Balster, Ph.D.Director, Institute for Drug and Alcohol Studies

Butler Professor of Pharmacology and ToxicologyVirginia Commonwealth University

Anxiety/Panic Medications

1. Benzodiazepines2. Meprobamate (Miltown, Equanil)3.

Buspirone (BuSpar)

4.

Antihistamines5.

Beta Blockers

6.

Antidepressants and SSRIs

for panic

Benzodiazepines Used for Anxiety/Panic Disorders

1. chlordiazepoxide (Librium)2. diazepam (Valium)3. oxazepam (Serax)4.

alprazolam (Xanax)

5.

chlorazepate

(Tranxene)6.

lorazepam (Ativan)

7.

prazepam (Centrax)

Benzodiazepines Used as Sedative/Hypnotics

1.

flurazepam (Dalmane)2.

temazepam (Restoril)

3.

triazolam (Halcion)4.

estazolam (Prosom)

5.

quazepam (Doral)

Benzodiazepines Specifically Indicated for Convulsive

Disorders

1.

clonazepam (Klonopin)

2.

clorazepate (Tranxene)

3.

diazepam (Valium, generic)

Benzodiazepines Used as Anesthetics/Preanesthetics

1.

diazepam (Valium, generic)

2.

midazolam (Versed)

Biodispositional Differences Between Benzodiazepines1.

Absorption

2.

Metabolism•

Oxidation

•

Conjugation 3. Active metabolite formation

Biodispositional

Determinants of Drug Effects

Drug Accumulation

N

N

Cl

OCH3

DIAZEPAM

N

N

Cl

OCH3

OH

TEMAZEPAM

N

N

Cl

O

DESMETHYLDIAZEPAM

N

N

Cl

O

OH

OXAZEPAM

OXAZEPAM GLUCURONIDE

Benzodiazepine metabolism

Diazepam Conversion to Desmethyldiazepam

Diazepam and Desmethyldiazepam

accumulation

Half-lives of Benzodiazepines

Diazepam half-life and Age

Benzodiazepine Duration of Action Summary

Short Intermediate Long

oxazepam alprazolam chlordiazepoxide

triazolam temazepam diazepam

midazolam clonazepam

CNS Depressant Dose Effect Curves

Mechanism of Action of Benzodiazepines

1.

Bind to selective receptors

2.

Enhance inhibitory neurotransmission

GABA Channel

GABA Channel Subunit Anatomy

GABA Benzodiazepine Receptor Complex

Role of Alpha Subunits

•

Alpha subunit critical for actions of benzodiiazepines

•

Alpha2

and/or alpha3

containing receptors are targets for antianxiety

effects of

benzodiazepines•

Alpha1

containing receptors involved in sleep

Zolpidem (Ambien and Ambien CR), Zaleplon (Sonata) and

Eszopiclone (Lunesta)•

Not benzodiazepine structures (“Z-drugs”)

• Have GABA-agonist effects by acting at benzodiazepine receptor

• Selectivity for BZ1 (Ω1

) subtype (containing α1

subunits)•

Used for sleep disorders

Benzodiazepines Differ in Agonist Efficacy

Benzodiazepine Antagonists

•

flumazenil (Mazicon)

•

reverse acute effects of benzodiazepines, either when taken alone or with other depressants

•

precipitate withdrawal

Clinical Uses of Benzodiazepines

1.

Anxiety and Panic Disorders2.

Sleep Disorders

3.

Convulsive Disorders4.

Muscle Relaxation

5.

Anesthesia6.

Alcohol and Barbiturate Withdrawal

Side Effects of Benzodiazepines

1. CNS Depression

--

sedation--

motor incoordination

2.

Paradoxical Excitement3.

Confusion and Amnesia

4.

Drug Interactions

Benzodiazepine Drug Interactions

1.

Alcohol2.

Sedatives and Anticonvulsants

3.

Antihistamines4. Opioid Analgesics5. Antidepressants6. Metabolic Interactions

Side Effects of Benzodiazepines

5. Abuse and Misuse

6. Physical Dependence

Signs and Symptoms of Benzodiazepine Withdrawal

1.

Anxiety2.

Insomnia

3.

Tremors and Hyperreflexia4.

Nausea and Vomiting

5.

Delirium6.

Convulsions

graph

Pharmacology of Buspirone (BuSpar and generic)

1.

No CNS depressant effects

2.

Probably acts on serotonergic systems

3.

No abuse liability

4.

Poor transition from benzodiazepines to buspirone

Pharmacology of Hydroxyzine (Vistaril, Atarax, generic)

1.

Antihistamine

(H1 Blocker)

2.

Psychosomatic allergies, etc.3.

Side effects

•

CNS depression•

anticholinergic

•

drug interactions

Pharmacology of Propranolol

1.

Beta-adrenergic blocker

2.

Blocks sympathetic nervous system signs of fear and anxiety

3.

Used for situation-specific anxiety and acute panic symptoms