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ANXIOLYTICS
Optimal
Performance
Nervous
Performance
Sedated Breakdown
Anxiety
GOAL
Manifestations of anxiety:
1). Medical:
a) Respiratory
b) Endocrine
c) Cardiovascular
d) Metabolic
e) Neurologic.
Causes of Anxiety
2). Drug-Induced:
– Stimulants
• Amphetamines, cocaine, TCAs, caffeine.
– Sympathomimetics
• Ephedrine, epinephrine, pseudoephedrine
phenylpropanolamine.
– Anticholinergics\Antihistaminergics
• Trihexyphenidyl, benztropine, meperidine
diphenhydramine, oxybutinin.
– Dopaminergics
• Amantadine, bromocriptine, L-Dopa,
carbid/levodopa.
Causes of Anxiety
– Miscellaneous:
• Baclofen, cycloserine, hallucinogens,
indomethacin.
Others:
11) Antyipsychotics **
Ziprasidone
12) Antidepressants **
TCAs, SSRIs
13) Antihistaminic drugs **
Dephenhydramine
Sedative/Hypnotics
All of the anxiolytics/sedative/hypnotics
should be used only for symptomatic relief.
*************
All the drugs used alter the normal sleep
cycle and should be administered only for
days or weeks, never for months.
************
USE FOR
SHORT-TERM TREATMENT
ONLY!!
Sedative/Hypnotics
Relationship between
Older vs Newer Drugs
Barbiturates Benzodiazepines
Glutethimide Zolpidem
Meprobamate Zaleplon
GABAergic SYSTEM
Sedative/Hypnotics
• Phenobarbital
• Pentobarbital
• Amobarbital
• Mephobarbital
• Secobarbital
• Aprobarbital
NORMAL
ANXIETY
_________ _________________
SEDATION
HYPNOSIS
Confusion, Delirium, Ataxia
Surgical Anesthesia
COMA
DEATH
Respiratory
Depression
BARBS
BDZs
Coma/
Anesthesia
RESPONSE
Ataxia
ETOH
Sedation
Anticonvulsant
Anxiolytic
DOSE
Respiratory
Depression BARBS
Coma/ BDZs
Anesthesia
RESPONSE
Ataxia
Sedation
Anticonvulsant
Anxiolytic
DOSE
GABAergic SYNAPSE
glucose
glutamate
GAD
GABA
-
Cl
GABA-A Receptor
• Oligomeric
(glycoprotei
BDZs
n.
BARBs
• Major player in
GABA AGONISTS
Inhibitory Synapses.
• It is a Cl- Channel.
• Binding of GABA
causes the channel to
open and Cl- to flow
into the cell with the
resultant membrane
hyperpolarization.
Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic
channels. Benzodiazepines
opening time of GABAergic channels.
Barbiturates
receptor affinity for GABA. BDZs and BARBS
2) Stimulation of 5-HT1A receptors.
3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors.
Patch-Clamp Recording of Single
Channel GABA Evoked Currents
Lipid solubility
Pharmacokinetics of Benzodiazepines
Hepatic metabolism. Almost all BDZs
undergo microsomal oxidation (N-
dealkylation and aliphatic hydroxylation)
and conjugation (to glucoronides).
Rapid tissue redistribution long acting
long half lives and elimination half lives
(from 10 to > 100 hrs).
All BDZs cross the placenta detectable
in breast milk may exert depressant
effects on the CNS of the lactating infant.
Pharmacokinetics of Benzodiazepines
CONTROL WITHDRAWAL
(%)
REM
1 2 3
• Buspirone
• Chloral hydrate
• Hydroxyzine
• Meprobamate (Similar to BARBS)
• Zolpidem (BZ1 selective)
• Zaleplon (BZ1 selective)
BUSPIRONE
• Most selective anxiolytic currently available.
• The anxiolytic effect of this drug takes several
weeks to develop => used for GAD.
• Buspirone does not have sedative effects and
does not potentiate CNS depressants.
• Has a relatively high margin of safety, few side
effects and does not appear to be associated
with drug dependence.
• No rebound anxiety or signs of withdrawal
when discontinued.
BUSPIRONE
Side effects:
• Tachycardia, palpitations,
nervousness, GI distress and
paresthesias may occur.
• Causes a dose-dependent pupillary
constriction.
BUSPIRONE
Mechanism of Action:
• Acts as a partial agonist at the 5-HT1A
receptor presynaptically inhibiting
serotonin release.
• The metabolite 1-PP has 2 -AR
blocking action.
Pharmacokinetics of BUSPIRONE
• Not effective in panic disorders.
• Rapidly absorbed orally.
• Undergoes extensive hepatic metabolism
(hydroxylation and dealkylation) to form
several active metabolites (e.g. 1-(2-
pyrimidyl-piperazine, 1-PP)
• Well tolerated by elderly, but may have slow
clearance.
• Analogs: Ipsapirone, gepirone, tandospirone.
Zolpidem
• Structurally unrelated but as effective as
BDZs.
• Minimal muscle relaxing and anticonvulsant
effect.
• Rapidly metabolized by liver enzymes into
inactive metabolites.
• Dosage should be reduced in patients with
hepatic dysfunction, the elderly and patients
taking cimetidine.
Properties of Zolpidem
Mechanism of Action:
• Binds selectively to BZ1 receptors.
• Facilitates GABA-mediated neuronal
inhibition.
(-)
(-)
(-)
(-)
(-) ACh
?
NE
DA 5-HT
ANTICONVULSANT/ ANXIOLYTIC ?
SEDATION ?
Properties of Other drugs.
• Chloral hydrate
• Is used in institutionalized patients. It
displaces warfarin (anti-coagulant) from
plasma proteins.
• Extensive biotransformation.
Properties of Other Drugs
2-Adrenoreceptor Agonists (eg. Clonidine)
• Antihypertensive.
• Has been used for the treatment of panic
attacks.
• Has been useful in suppressing anxiety
during the management of withdrawal from
nicotine and opioid analgesics.
• Withdrawal from clonidine, after protracted
use, may lead to a life-threatening
hypertensive crisis.
Properties of Other Drugs
-Adrenoreceptor Antagonists
(eg. Propranolol)
• Use to treat some forms of anxiety,
particularly when physical (autonomic)
symptoms (sweating, tremor, tachycardia)
are severe.
• Adverse effects of propranolol may
include: lethargy, vivid dreams,
hallucinations.
OTHER USES
1. Generalized Anxiety Disorder
Diazepam, lorazepam, alprazolam, buspirone
2. Phobic Anxiety
a. Simple phobia. BDZs
b. Social phobia. BDZs
3. Panic Disorders
TCAs and MAOIs, alprazolam
4. Obsessive-Compulsive Behavior
Clomipramine (TCA), SSRI’s
5. Posttraumatic Stress Disorder (?)
Antidepressants, buspirone
ANXYOLITICS HYPNOTICS
Alprazolam Chloral hydrate
Chlordiazepoxide Estazolam
Buspirone Flurazepam
Diazepam Pentobarbital
Lorazepam Lorazepam
Oxazepam Quazepam
Triazolam Triazolam
Phenobarbital Secobarbital
Halazepam Temazepam
Prazepam Zolpidem
References:
• Katzung, B.G. (2001) Basic and Clinical
Pharmacology. 7th ed. Appleton and Lange.
Stamford, CT.
• Brody, T.M., Larner,J., and Minneman, K.P. (1998)
Human Pharmacology: Molecular to Clinical. 2nd ed.
Mosby-Year Book Inc. St. Louis, Missouri.
• Rang, H.P. et al. (1995) Pharmacology . Churchill
Livingston. NY., N.Y.
• Harman, J.G. et al. (1996) Goodman and Gilman's
The Pharmacological Basis of Therapeutics. 9th ed.
McGraw Hill.