ANXIOLYTICS

By

Rashida Manzoor

Roll # 18 2nd

semester
 SEDATIVE/HYPNOTICS
ANXIOLYTICS
• Major therapeutic use is to relief anxiety
(anxiolytics) or induce sleep (hypnotics).
• Hypnotic effects can be achieved with most
anxiolytic drugs just by increasing the dose.
• The distinction between a "pathological" and
"normal" state of anxiety is hard to draw, but
in spite of, or despite of, this diagnostic
vagueness, anxiolytics are among the most
prescribed substances worldwide.
 Manifestations of anxiety:

• Verbal complaints. The patient says he/she

is anxious, nervous, edgy.
• Somatic and autonomic effects. The
patient is restless and agitated, has
tachycardia, increased sweating, weeping
and often gastrointestinal disorders.
• Social effects. Interference with normal
productive activities.
 Pathological Anxiety
Generalized anxiety disorder (GAD): People suffering
from GAD have general symptoms of motor
tension, autonomic hyperactivity, etc. for at least
one month.
Phobic anxiety:
Simple phobias. Agoraphobia, fear of animals, etc.
Social phobias.
Panic disorders: Characterized by acute attacks of
fear as compared to the chronic presentation of
GAD.
Obsessive-compulsive behaviors: These patients
show repetitive ideas (obsessions) and behaviors
(compulsions).
 Anxiolytics

Strategy for treatment

Reduce anxiety without causing sedation.
 Anxiolytics
– Benzodiazepines (BZDs).
– Barbiturates (BARBs).
– 5-HT1A receptor agonists.
4) 5-HT3 receptor
antagonists.
 Anxiolytics
• Other Drugs with anxiolytic activity.
– TCAs (Fluvoxamine). Used for Obsessive
compulsive Disorder.
– MAOIs. Used in panic attacks.
– Antihistaminic agents. Present in over the
counter medications.
– Antipsychotics (Ziprasidone).
 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
ANXYOLITICS

B E N Z O D IA Z E P IN E S B A R B IT U R A T E S

GABAergic SYSTEM
 Benzodiazepines
• Diazepam
• Chlordiazepoxide
• Triazolam
• Lorazepam
• Alprazolam
• Clorazepate => nordiazepam
• Halazepam
• Clonazepam
• Oxazepam
• Prazepam
 Barbiturates

• 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 (αβδγεπρ)
glycoprotein.
BDZs
• Major player in
BARBs Inhibitory Synapses.
GABA AGONISTS
• It is a Cl- Channel.
• Binding of GABA
γ causes the channel
α to open and Cl- to
δ
flow into the cell with
β ε 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-HT3 receptors.
 Benzodiazepines
PHARMACOLOGY
• BDZs potentiate GABAergic inhibition at all
levels of the neuraxis.
• BDZs cause more frequent openings of the
GABA-Cl- channel via membrane
hyperpolarization, and increased receptor
affinity for GABA.
• BDZs act on BZ1 (α1 and α2 subunit-containing)
and BZ2 (α5 subunit-containing) receptors.
• May cause euphoria, impaired judgement, loss
of cell control and anterograde amnesic effects.
Pharmacokinetics of Benzodiazepines

• Although BDZs are highly protein bound

(60-95%), few clinically significant
interactions.*
• High lipid solubility  high rate of entry
into CNS  rapid onset.

*The only exception is chloral hydrate and warfarin

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

• Many have active metabolites with half-

lives greater than the parent drug.
• Prototype drug is diazepam (Valium),
which has active metabolites (desmethyl-
diazepam and oxazepam) and is long
acting (t½ = 20-80 hr).
• Differing times of onset and elimination
half-lives (long half-life => daytime
sedation).
 Properties of Benzodiazepines

• BDZs have a wide margin of safety if used

for short periods. Prolonged use may cause
dependence.
• BDZs have little effect on respiratory or
cardiovascular function compared to BARBS
and other sedative-hypnotics.
• BDZs depress the turnover rates of
norepinephrine (NE), dopamine (DA) and
serotonin (5-HT) in various brain nuclei.
 Side Effects of Benzodiazepines

• Related primarily to the CNS depression

and include: drowsiness, excess sedation,
impaired coordination, nausea, vomiting,
confusion and memory loss. Tolerance
develops to most of these effects.
• Dependence with these drugs may
develop.
• Serious withdrawal syndrome can
include convulsions and death.
 Toxicity/Overdose with
Benzodiazepines
• Drug overdose is treated with flumazenil (a BDZ
receptor antagonist, short half-life), but respiratory
function should be adequately supported and
carefully monitored.

• Seizures and cardiac arrhythmias may occur

following flumazenil administration when BDZ are
taken with TCAs.

• Flumazenil is not effective against BARBs

overdose.
 Drug-Drug Interactions with BDZs
• BDZ's have additive effects with other CNS
depressants (narcotics), alcohol => have a
greatly reduced margin of safety.
• BDZs reduce the effect of antiepileptic
drugs.
• Combination of anxiolytic drugs should be
avoided.
• Concurrent use with ODC antihistaminic and
anticholinergic drugs as well as the
consumption of alcohol should be avoided.
• SSRI’s and oral contraceptives decrease
metabolism of BDZs.
 Pharmacokinetics of Barbiturates
• Rapid absorption following oral
administration.
• Rapid onset of central effects.
• Extensively metabolized in liver (except
phenobarbital), however, there are no
active metabolites.
• Phenobarbital is excreted unchanged.
Its excretion can be increased by
alkalinization of the urine.
 Pharmacokinetics of Barbiturates
• In the elderly and in those with limited
hepatic function, dosages should be
reduced.
• Phenobarbital and meprobamate cause
autometabolism by induction of liver
enzymes.
 Properties of Barbiturates
Mechanism of Action.
• They increase the duration of GABA-gated
channel openings.
• At high concentrations may be GABA-
mimetic.

Less selective than BDZs, they also:

• Depress actions of excitatory
neurotransmitters.
• Exert nonsynaptic membrane effects.
 Toxicity/Overdose
• Strong physiological dependence may
develop upon long-term use.
• Depression of the medullary respiratory
centers is the usual cause of death of
sedative/hypnotic overdose. Also loss of
brainstem vasomotor control and
myocardial depression.
 Toxicity/Overdose
• Withdrawal is characterized by increase
anxiety, insomnia, CNS excitability and
convulsions.
• Drugs with long-half lives have mildest
withdrawal (.
• Drugs with quick onset of action are most
abused.
• No medication against overdose with
BARBs..
 Miscellaneous Drugs

• 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 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 α2 -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.

• Actions are antagonized by flumazenil

 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.