SEDATIVE/HYPNOTICS
ANXIOLYTICS
Martha I. Dávila-García, Ph.D.
Howard University
Department of Pharmacology
Optimal
Performance
Nervous
Breakdown
Sedated
Anxiety
GOAL
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).
Causes 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.
3). Drug Withdrawal:
• BDZs, narcotics, BARBs, other
sedatives, alcohol.
Anxiolytics
Strategy for treatment
Reduce anxiety without causing sedation.
Anxiolytics
1) Benzodiazepines (BZDs).
2) Barbiturates (BARBs).
3) 5-HT1A receptor agonists.
4) 5-HT2A, 5-HT2C & 5-HT3 receptor
antagonists.
If ANS symptoms are prominent:
• ß-Adrenoreceptor antagonists.
• 2-AR agonists (clonidine).
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).
• Novel drugs. (Most of these are still on clinical trials).
– CCKB (e.g. CCK4).
– EAA's/NMDA (e.g. HA966).
Sedative/Hypnotics
• A hypnotic should produce, as much as
possible, a state of sleep that resembles
normal sleep.
Properties of Sedative/Hypnotics in
Sleep
1) The latency of sleep onset is decreased
(time to fall asleep).
2) The duration of stage 2 NREM sleep is
increased.
3) The duration of REM sleep is decreased.
4) The duration of slow-wave sleep (when
somnambulism and nightmares occur) is
decreased.
Tolerance occurs after 1-2 weeks.
Sedative/Hypnotics
1) Benzodiazepines (BZDs):
Alprazolam, diazepam, oxazepam, triazolam
2) Barbiturates:
Pentobarbital, phenobarbital
3) Alcohols:
Ethanol, chloral hydrate, paraldehyde,
trichloroethanol,
4) Imidazopyridine Derivatives:
Zolpidem
5) Pyrazolopyrimidine
Zaleplon
Sedative/Hypnotics
6) Propanediol carbamates:
Meprobamate
7) Piperidinediones
Glutethimide
8) Azaspirodecanedione
Buspirone
9) -Blockers**
Propranolol
10) 2-AR partial agonist**
Clonidine
Sedative/Hypnotics
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
Glutethimide
Meprobamate
Benzodiazepines
Zolpidem
Zaleplon
**All others differ in their effects and therapeutic
uses. They do not produce general anesthesia
and do not have abuse liability.
SEDATIVE/HYPNOTICS
ANXYOLITICS
BENZODIAZEPINES
BARBITURATES
GABAergic SYSTEM
Sedative/Hypnotics
The benzodiazepines are the most
important sedative hypnotics.
Developed to avoid undesirable
effects of barbiturates (abuse
liability).
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
Ataxia
ETOH
Sedation
Anticonvulsant
Anxiolytic
DOSE
Respiratory
Depression
BARBS
Coma/
Anesthesia
BDZs
Ataxia
Sedation
Anticonvulsant
Anxiolytic
DOSE
GABAergic SYNAPSE
glucose
glutamate
GAD
GABA
Cl
-
GABA-A Receptor
BDZs
BARBs
GABA AGONISTS
g

d

e
• Oligomeric (dgepr)
glycoprotein.
• Major player in
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
From Katzung et al., 1996
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 (1 and 2 subunit-containing)
and BZ2 (5 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
Lipid solubility
Pharmacokinetics of Benzodiazepines
 Hepatic metabolism. Almost all BDZs
undergo
microsomal
oxidation
(Ndealkylation 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 halflives greater than the parent drug.
 Prototype drug is diazepam (Valium), which
has
active
metabolites
(desmethyldiazepam and oxazepam) and is long
acting (t½ = 20-80 hr).
 Differing times of onset and elimination
half-lives (long half-life => daytime
sedation).
Biotransformation of Benzodiazepines
From Katzung, 1998
Biotransformation of
Benzodiazepines
• Keep in mind that with formation of active
metabolites, the kinetics of the parent drug
may not reflect the time course of the
pharmacological effect.
• Estazolam, oxazepam, and lorazepam,
which are directly metabolized to
glucoronides have the least residual
(drowsiness) effects.
• All of these drugs and their metabolites are
excreted in urine.
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.
Sedative/Hypnotics
• They produce a pronounce, graded,
dose-dependent depression of the
central nervous system.
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 GABAmimetic.
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.
• Contraindicated in patients with porphyria.
Sedative/Hypnotics
SLEEP PER NIGHT
(%)
Tolerance and excessive rebound occur in
response to barbiturate hypnotics.
CONTROL
WITHDRAWAL
REM
NREM III and IV
1
2
3
NIGTHS OF DRUG DOSING
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 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-(2pyrimidyl-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
GABA
(-)
(-)
(-)
(-)
(-)
?
NE
ANTICONVULSANT/
MUSCLE RELAXANT ?
DA
ACh
5-HT
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
Chlordiazepoxide
Buspirone
Diazepam
Lorazepam
Oxazepam
Triazolam
Phenobarbital
Halazepam
Prazepam
Chloral hydrate
Estazolam
Flurazepam
Pentobarbital
Lorazepam
Quazepam
Triazolam
Secobarbital
Temazepam
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.