Anxiolytic and Hypnotic Drugs 2
Dr. Entisar Al-Mukhtar
Other Anxiolytic Agents
A. Antidepressants
• SSRIs (eg. escitalopram or paroxetine), SNRIs (eg. venlafaxine or duloxetine)
are the first-line treatment in patients with concerns for addiction or dependence,
used for GAD alone or in combination with BZD (low dose) & when anxiolytic
effect begins the BZD dose can be tapered.
B.
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Buspirone
Used for chronic treatment of GAD, it's efficacy is comparable to that of BZDs.
Ineffective for acute anxiety states because its onset is slow.
Its actions are mediated by 5-HT1A receptors, the dopamine DA2 & 5-HT2A
receptors could be involved.
buspirone lacks anticonvulsant & muscle-relaxant effects, also sedation,
psychomotor & cognitive dysfunction are minimal & dependence is unlikely.
It does not potentiate the CNS depression of alcohol.
C. Hydroxyzine
• Useful for anxiety in patients who have a history of drug abuse.
• Used for sedation prior to dental procedures or surgery.
Barbiturates
• They were the mainstay for sedation or hypnosis. But today they have been
largely replaced by BZDs because they induce (1) tolerance (2) drug-metabolizing
enzymes (3) physical dependence & are associated with very severe withdrawal
symptoms.
Mechanism of action
1. Bind to GABAA receptors (note: binding site is distinct from that of BZDs),
enhancing GABAergic transmission by prolonging chloride-channel openings.
2. Block excitatory glutamate receptors.
3. Pentobarbital anesthetic dose also block sodium channels.
Actions
Barbiturates are classified into:
• Ultra short-acting e.g. thiopental acts within seconds & has a duration of action of
about 30 minutes.
• Long-acting e.g. phenobarbital duration of action is greater than a day.
• Short-acting e.g. pentobarbital, secobarbital, amobarbital & butalbital, are
effective as sedative & hypnotic (but not anxiolytic) agents.
1. CNS depression:
• barbiturates low doses cause sedation. Whereas, higher doses cause hypnosis,
anesthesia, coma & death.
• Barbiturates have no analgesic properties, they may even exacerbate pain.
• Chronic use leads to tolerance.
2. Respiratory depression: overdose cause respiratory depression & death.
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Therapeutic uses
1. Anesthesia:
Thiopental is still used (IV) to induce anesthesia.
2. Anticonvulsant:
• Phenobarbital is used for long-term management of tonic-clonic seizures &
refractory status epilepticus. It can depress cognitive development in children &
decrease cognitive performance in adults thus, it should be used only if other
therapies have failed.
3. Sedative/hypnotic:
• Barbiturates were used to treat anxiety, nervous tension & insomnia.
• Butalbital is used (in combination with acetaminophen & caffeine or aspirin &
caffeine) as a sedative for tension or migraine headaches.
Pharmacokinetics
• Redistribution from the brain to other areas (e.g. adipose tissue) shorten the
duration of action e.g., of thiopental & similar short-acting agents.
• They can depress the fetus.
Adverse effects
1. CNS:
• Drowsiness, impaired concentration & mental & physical sluggishness.
• Ethanol synergizes the barbiturates CNS depressant effects.
2. Drug hangover:
The drug hangover may impair the ability to function normally for many hours after
waking.
3. Precauions & contraindication: Barbiturates
• induce hepatic microsomal enzymes thus, their chronic use diminishes the action
of many drugs..
• increase porphyrin synthesis & are contraindicated in patients with acute
intermittent porphyria.
4. Physical dependence:
• Barbiturates abrupt withdrawal may cause tremors, anxiety, weakness,
restlessness, nausea & vomiting, seizures, delirium & cardiac arrest.
• Withdrawal is much more severe than that associated with opiates & can result in
death.
5. Poisoning:
• Barbiturate overdose is a leading cause of death.
• Severe respiratory depression coupled with central CV depression result in a
shock-like condition with shallow, infrequent breathing.
• Treatment includes supportive care and gastric decontamination for recent
ingestions (note: no specific barbiturate antagonist is available).
Other hypnotic agents: Zolpidem, Zaleplon & Eszopiclone
A. Zolpidem
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A non BZD, but it acts on BZD1 receptor.
Has no anticonvulsant or muscle-relaxing properties.
Shows few withdrawal effects & exhibits minimal rebound insomnia & little or no
tolerance occurs with prolonged use.
• Has rapid onset & short elimination half-life (2-3 hours), it provides about 5 hours
of hypnosis. A lingual spray & an extended- release formulation are available.
• Some drugs eg. Rifampin shortened zolpidem half-life, while others that inhibit
CYP 3A4 isoenzyme increased it.
• Adverse effects: nightmares, agitation, headache, GI upset, dizziness & daytime
drowsiness.
• The non-BZD drugs( zolpidem, zaleplon, and eszopiclone), do not significantly
alter the various sleep stages and, hence, are often the preferred hypnotics.. All
three agents are controlled substances.
B. Zaleplon
Compared to Zolpidem or BZDs it causes fewer residual effects on psychomotor &
cognitive functions. This may be due to its rapid elimination.
C. Eszopiclone
• An oral non BZD hypnotic (like Zolpidem & Zaleplon it also utilizes the BZD1).
• Elimination half-life is 6 hours.
• Adverse effects: anxiety, dry mouth, headache, peripheral edema, somnolence &
unpleasant taste.
D. Ramelteon
• Selective agonist at melatonin receptors (MT1 & MT2).
Note: normally melatonin maintain circadian rhythm of sleep-wake cycle (it induce &
promote sleep).
• indicated for falling asleep insomnia (increased sleep latency).
• Potential for abuse is minimal with no evidence of dependence or withdrawal
effects. Thus, ramelteon can be administered for long term.
• Adverse effects: dizziness, fatigue& somnolence. Also prolactin levels may
increased.
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Antihistamines: Diphenhydramine, Hydroxyzine & Doxylamine
Have sedating properties.
Effective for mild insomnia.
Their anticholinergic side effects make them less useful than BZDs & non BZDs.
F. Antidepressants: e.g. Doxepin, Trazodone & Mirtazapine
• Have sedative with strong antihistaminic effects.
• Doxepin, an older TCA with SNRI mechanisms of antidepressant & anxiolytic
action, it is approved for the management of insomnia.
• Other antidepressants, such as trazodone, mirtazapine & other older TCAs
antidepressants with strong antihistamine properties are used off-label for the
treatment of insomnia.
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