Anxiolytics and Sedative/ Hypnotics (Full Lect.)

Anxiolytics and Sedative/
Hypnotics
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

1. Classify anxiolytics and hypnotics drugs.
2. Discuss the molecular mechanisms of agents interacting with the GABA
receptor complex.
3. Recognize the pharmacological actions of barbiturates and
benzodiazepines.
4. Identify the Therapeutic uses of barbiturates and benzodiazepines.
5. Predict the most serious adverse effects of barbiturates and
benzodiazepines.
6. Apply the pharmacological basis for proper selection of the anxiolytics
and hypnotics drugs in the management of anxiety disorders and sleep
disorders.
7. realize the advantages of selective hypnotics (e.g. zolpidem) and
selective anxiolytics (e.g. buspirone) over benzodiazepines.
8. Explain the action and advantages of Ramelteon.

Anxiolytics and Sedative/Hypnotics
are drugs used mainly in treatment
of Anxiety and Insomnia.

Anxiety Disorders
• Anxiety is an unpleasant state of
tension, apprehension, ( as Generalized
Anxiety Disorder GAD) or uneasiness (a
fear that arises from either a known
“Phobia” or an unknown “Panic”
source). …DSM5……………
• The Physical Symptoms of severe anxiety are
similar to those of fear (e.g. tachycardia,
sweating, trembling, and palpitations) and
involve sympathetic activation.

GAD
10. Other specified & unspecified Anxiety Disorder
(Social Phobia)

I. Drugs Facilitating GABAAction
• Barbiturates
• Benzodiazepines (BZDs)
• Zolpidem - Zaleplon.
• Alcohol
II. 5-HT1A Partial Agonists: Buspirone
III. Melatonin (MT1 &2) Receptor Agonists: Ramelteon
Classification Sedative/ Hypnotics of According to
Mechanism of Action

1. Antidepressants (e.g. TCA, Mirtazapine) ……….
2. Antipsychotics e.g. Quetiapine, Clozapine
3. Antihistamines e.g. diphenhydramine and doxylamine
4.  Blockers e.g. Propranolol (Inderal)
Drugs with anxiolytic or hypnotic Effects

Types of GABA Receptors (A & B)
GABAB receptors: Metabotropic (G-prot.)
More in Spinal cord
❑ Presynaptic inhibit Ca2+ influx  ↓ release
of the excitatory transmitter glutamate.
• Postsynaptic  K+ outflux  hyperpolarization
GABAA receptors: Ionotropic (Cl- channel)
Neuronal inhibition in CNS (mech. of Sedative/Hypnotic drugs)
Baclofen is selective GABAB agonist, used as a muscle
relaxant – spasticity & skeletal muscle rigidity
Postsynaptic
GABAB

More powerful CNS depressant than BZDs since in addition to
enhancing GABA effect: It has
• direct GABA-mimetic effects as well as
• inhibitory effects on glutamate receptors “AMPA” (?!).
In high conc. Of barbiturates
Barbiturates
Direct Block Na channel (in Higher doses?!)

Katzung & Trevor’s Pharmacology Examination & Board Review 12th Edition, 2019

1. Depression of CNS:
Sedation→ Hypnosis → Anesthesia → Finally,
Coma & death.
2. Respiration and CVS depression (Medullary depression)
depression of Resp. center (↓response to CO2) and
VMC. In overdose → death.
Pharmacological actions of Barbiturates

1. Ultrashort acting, e.g. thiopental IV anesthetic.
2. Short/ intermediate acting, e.g. pentobarbital
secobarbital sedative-hypnotic (Abuse) Not used Now
3. Long acting, e.g. Phenobarbital antiepileptic
(BUT not 1st choice)
Members and uses of Barbiturates

1. Narrow Therapeutic Index
2. No Antidote
Adverse effects of Barbiturates

3. Drug tolerance & dependence
tolerance of barbiturates (kinetic & -dynamic) > BZDs
(dynamic only “GABA receptors”).
4. Enzyme induction  drug interactions
And Kinetic tolerance (not with BZDs).
5. Acute porphyria ?!
CYPs 1A2, 2C9,
2C19,,3A4
(ALA) synthetase induction

Barbiturates and Sulfonamides
Barbiturates are contraindicated in patients with acute intermittent porphyria or variegate porphyria because they may precipitate an
attack, manifested by severe abdominal pain, nausea, vomiting, psychiatric disorders, and neurologic abnormalities.

Therefore, In 1950. Benzodiazepines are used in placed of barbiturates for
treatment of anxiety and sleep disorders
(Lippincott 7th ed., 2018)

1. Correction of life-threatening symptoms:
-Artificial respiration with (O2 +CO2 )
-Fluids and vasopressors (e.g. dopamine)
2. Prevention of absorption:
Emesis &gastric lavage, Activated charcoal and Saline cathartics.
3. Facilitation of its removal :
-Forced diuresis
-Alkalinization of urine (Why?)
-Peritoneal dialysis, hemodialysis and hemoperfusion
Management of barbiturate intoxication :

- C/P: Excitement, insomnia, convulsions, sweating, delirium
hallucinations & toxic psychosis. In first 3 days of abstinence.
Treatment
A. Symptomatically by:
• Antipsychotics e.g. haloperidol (injection in agitated patients), olanzapine,
• Anti-epileptics e.g. Valproate, Carbamazepine (also to ↓ impulsivity).
B. Phenobarbitone stabilization then, gradual reduction over 3-4 weeks.
[Replace short-acting by a longer-acting  ↓withdrawal Symptoms]
Management of Barbiturate Abuse & Withdrawal:

Mechanism of actions of barbiturates and benzodiazepines via GABAA receptors

Mechanism of BZD Action
BZ1 and BZ2 receptors includes the α1 subunit or the α2 subunit,

Benzodiazepines enhance GABA by increasing the frequency
of Cl channel-opening.
Common BZ receptor subtypes in the CNS are designated as BZ1 or BZ2
depending on whether the binding site includes an α1 or α2 subunit, respectively.
• α1 subunit is associated with sedation/hypnosis. (Z-Hypnotics)
• α2 subunit has greater anxiolytic and muscle relaxation actions

1. Wide safety margin
2. Antidote (Flumazenil)
3. No enzyme induction (↓ drug interactions).
4. No porphyria
5. Less tolerance & dependence
6. Less Respiratory & CVS depression
Q: Advantages of BZD over Barbiturates
ED50 TD50

Clonazepam
Midazolam
Classification of BZDs

Pharmacokinetics of BZD
➢ Lipophilic absorbed orally &, distribute to body &CNS.
➢ IMI of BZDs are slower /erratic than oral absorption except Lorazepam
➢ Metabolized in liver (mainly by CYP3A4 Then/or Conjugation
“Lorazepam”)
➢ BZD & their metabolites are Excreted in the urine.
➢ The longer-action of some BZD due to …..
Also receptor dissociation rates in the
CNS and redistribution to fatty tissues
Flurazepam & Diazepam (Long t1/2)
→active metabolites (>Long t1/2)

Temazepam
LOT : Lorazepam, Oxazepam & Temazepam have no active Metabolites & metabolized By
Conjugation directly (phase II) No CYP metabolism
(Katzung Basic & Clinical Pharmacology, 14ed , 2018)

No active Metabolites
Cumulative and residual effects “excessive drowsiness” is less with Temazepam, oxazepam& lorazepam,
which have relatively short half-lives and are metabolized directly to inactive glucuronides.
The metabolism of several commonly used benzodiazepines including diazepam, midazolam,
and triazolam is affected by inhibitors and inducers of hepatic P450 isozymes
(Katzung Basic & Clinical Pharmacology, 14ed , 2018)

-Bromazepam is intermediate acting (t1/2 ~ 17 hrs) BZD
used anxiety & insomnia
-Main metabolic pathway involves hydroxylation with
subsequent glucuronidation (No CYP)
Bromazepam

BZD Pharmacological
Actions and uses
According to Brain Area & dose

Q: Pharmacological Actions of BZD
according to the dose ?
I. Anxiolytic /Euphoric
Potentiate GABA in limbic system
Uses
1- Anxiety disorders
e.g. Alprazolam, Lorazepam, Clonazepam, Diazepam
2- Panic Disorder
e.g. Alprazolam , Clonazepam (FDA)

II. Sedative (low dose)
Hypnotic (high dose)
Potentiate GABA in brainstem reticular formation
Uses
1. Insomnia :
▪ Promote sleep onset
▪  stage 2 of NREM
2. Night mares: (↓ REM sleep)
3. Night terrors:
↓ Stage 3,4 of NREM sleep
e.g. short and intermediate acting BZD
Night mares
Night terrors

In general,
hypnotics should be used < 4-6 weeks.
➢ Triazolam (Short) is effective in treating
difficulty in going to sleep.
➢ Temazepam (intermediate) is useful for
insomnia due to inability to stay asleep

Q: What is the effect of benzodiazepines on
sleep patterns and its clinical significance?
Effect on Sleep Patterns Clinical Significance
↓ Sleep latency (induce sleep) -Treat insomnia
↑ Stage 2 NREM sleep
↓ REM sleep (Dreams)
& So, ↓consolidation of memory
-Treat Night mares (& others..) BUT
- Induce Anterograde Amnesia
- On withdrawal →Vivid dreams
↓ Stage 3 & 4 NREM (slow-wave
sleep “SWS” deep sleep).
- Treat Night terrors (& other SWS
disorders e.g sleep walking….)
- Impaired Quality of sleep …..

III. Anesthetic
- Amnesia & sedation.
- Potentiate narcotics (as opioids).
Uses
1. Conscious sedation (Midazolam+Fentanyl).
2. Pre-anesthesia.
3. Balanced anesthesia , as adjuncts.
e.g. Midazolam

IV. Anticonvulsant
(Antiepileptic)
Uses
1. Epilepsy (Not 1st line)
e.g. Clonazepam
2. Status epilepticus
e.g. Lorazepam, Diazepam, Midazolam
(BZD are 1st line)
American Epilepsy Society Guideline

V. Skeletal Muscle Relaxant
(at spinal & supraspinal levels)
Uses
Muscle Spasticity in inflammation -trauma, cerebral palsy, MS.
e.g. Diazepam

VI. Alcohol Withdrawal in Addicts
(Both Alcohol and BZD Potentiate GABA)
Uses
Alcohol withdrawal
(alcohol is replaced by a longer acting BZD 
smoother withdrawal) e.g. Diazepam

BZD adverse effects
1. Drowsiness – confusion -  cognitive function - Hangover.
2. Amnesia (anterograde).
3. Ataxia &  motor skills  difficulty in driving &  risk of falls in elderly.
4. Abuse (tolerance & dependence; most serious, but less than barbiturates).
5. Additive CNS depression with alcohol and other CNS depressants.
6. Abnormal response: paradoxical excitement (genetic receptor alteration).
7.Withdrawal of hypnotics rebound insomnia & rebound  in REM sleep.

Rebound insomnia
(Withdrawal)
more common with potent
short acting and less with
low potent long acting

Dose of BZD should be reduced in elderly to avoid
accumulation (reduced liver metabolism) and also to
reduce risks of falling due to confusion and ataxia.

Toxicity of Benzodiazepines
1. Prolonged sleep.
2. Respiratory & CVS depression (esp. rapidly IV or with
other CNS depressants).
Management:
1. Support respiration and circulation (see barbiturates)
2. Antidote : Flumazenil

Flumazenil
Competitive antagonist at BZDs receptor ( BZDs & zolpidem).
Short t½; → re-administered after 1 hour
Therapeutic Uses
1. BZDs toxicity.
2. Termination of BZDs effects in anesthesia.
Adverse Effects
1. Agitation.
2. Withdrawal syndrome or convulsions in BZDs dependent

Benzodiazepines withdrawal
C/P :excitement, insomnia, convulsions, delirium, hallucinations and
toxic psychosis, depression, ………….
Treated by
A. Symptomatic (see Barbiturates)
B. Replacing short-acting agent by a longer-acting one
e.g. Diazepam for clonazepam, alprazolam.

Z-Hypnotics
▪ Non-BZDs acting on BZD1 receptor subtype involved in hypnosis
▪ Effects are antagonized by flumazenil
▪ Selective Hypnotic (Not Anxiolytic) so should not used in insomnia associated or 2ry
to Anxiety.
(Zolpidem, Zaleplon, Zopiclone, Eszopiclone)

Advantages of Z-Hypnotics over BZDs
1. Rapid onset & shorter duration (?!)
2. Less cognitive impairment.
3. Less hangover
4. Less tolerance ,dependence, rebound insomnia , withdrawal
5. Less suppression of REM sleep (less Amnesia).
N.B. This group still has the risk of abuse and cognitive dysfunction but less than BZDs
Z-Hypnotics

Zolpidem
Short-acting hypnotic (an extended release)
Zaleplon
Fewer residual effects on cognitive & psychomotor
function due to its rapid elimination.
Eszopiclone
Adverse events:
Anxiety, dry mouth, headache, peripheral edema,
somnolence, and unpleasant taste.
(It has risk of abuse and addiction).

• Selective Hypnotic; agonist at MT1 & MT2 melatonin receptors.
Ramelteon
- (↓ testosterone and ↑ prolactin)
FDA approved 2005
-Drug interaction:
should not be used with inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine) or CYP2C9 (eg, fluconazole)
Advantages:
- Latency to sleep→ useful in difficulty in falling asleep.
-Minimal abuse , No withdrawal or rebound insomnia.
Side effects:
Dizziness, somnolence & fatigue.

Selective Hypnotic

Dual Orexin Receptor Antagonists
(DORA)
Approved for treatment of insomnia characterized by difficulties with sleep onset
and/or sleep maintenance in adults (Safer than BZD)
Orexin neuropeptides (A & B) promote
wakefulness (neuronal excitability) via
Orexin receptors (OX1R & OX2R)
-↑Na/Ca exchange,
-↑NMDA receptor expression
DORA are
competitive
antagonists at
OX1R and OR2R
Suvorexant (Belsomra) FDA approved 2014
Lemborexant (DAYVIGO) FDA approved 2019

Mechanism of action:
- Mainly : 5-HT1A Agonist
- some affinity for D2 dopamine receptors and 5-HT2A
Uses:
Chronic Anxiety
Buspirone

Differs from BZD:
1. Selective anxiolytic in generalized anxiety disorders (GAD) only.
2. No amnesia or  cognitive function.
3. No ataxia or reduction of psychomotor skills.
4. No additive CNS depression with alcohol or sedatives.
5. No abuse (delayed onset & dysphoria), useful in pts liable to abuse.
Disadvantages
1. Delayed onset (requires 1-2 weeks to act).
2. Does not treat insomnia or panic attacks.
Side effects
1. Nausea.
2. Headache, dizziness
Buspirone

1. start with a small oral dose for a limited period (4-6 weeks) to avoid drug abuse &
dependence (major limitation to the use of BZDs).
2. Termination of therapy should be gradual to avoid a withdrawal syndrome.
3. The preferred agent for insomnia in patients with difficulty in falling asleep is an
agent with rapid onset and short duration to avoid hangover; excessive sedation the
following day, e.g. midazolam.
4. Insomnic patients who complain of early morning awakenings & who require
anxiolytic effect during the day → longer acting BZD, e.g., diazepam (??!!).
General Guidelines for Therapy with Sedative-Hypnotics

5. Chronic insomnia is usually associated with anxiety or depression thus should be
treated with an antidepressant (e.g., mirtazapine has also hypnotic effect).
6. Chronic anxiety “as GAD” is treated by antidepressants e.g. SSRIs, and BZDs are
added to calm the patient until the antidepressant becomes effective.

7. Panic Disorder requires highly potent drugs as alprazolam (its antidepressant
effect is also useful). Buspirone is not useful.
8. Most BZDs are metabolized in liver → dose adjustment is required in liver
cirrhosis to avoid accumulation to toxic levels specially of long acting agents and
those metabolized to active metabolites such as diazepam.
Lorazepam has no active metabolites thus preferred in liver dysfunction.
9. Dose of BZD should be reduced in elderly to avoid accumulation (reduced liver metabolism)
& to reduce risks of falling due to drug induced confusion & Ataxia

Anxiolytics and Sedative/ Hypnotics (Full Lect.)

Anxiolytics and Sedative/ Hypnotics (Full Lect.)

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