This document summarizes different classes of sedative-hypnotic drugs, including benzodiazepines, barbiturates, non-benzodiazepine hypnotics (Z-drugs), melatonin agonists, and orexin antagonists. It describes their mechanisms of action, indications, pharmacokinetics, adverse effects, and contraindications. Sedative-hypnotics work by enhancing the effects of the inhibitory neurotransmitter GABA or by antagonizing orexin receptors to reduce arousal. Common side effects include drowsiness, respiratory depression, and withdrawal symptoms upon discontinuation. Long-term use carries risks of tolerance and dependence that limit the use of certain agents like

1. ANXIOLYTICS
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2. Sedative-hypnotics are a class of drugs that depress CNS function,
inducing sedation, sleep, and unconsciousness with increasing dose.
Agents in this drug class include
benzodiazepines,
nonbenzodiazepine hypnotics (Z-drugs),
barbiturates,
melatonin agonists.

5. Most sedative-
hypnotic drugs affect GABAergic transmission,
increasing the inhibition of neuronal excitability, except
for melatonin agonists, which act
on hypothalamic melatonin receptors.
Sedative-hypnotic drugs are used as anxiolytics,
sedatives, muscle relaxants, anesthetics,
and anticonvulsants. Common side effects result from
excessive CNS depression and include
confusion, somnolence, and respiratory
depression. Long-term use of sedative-hypnotics is
associated with a risk of tolerance and withdrawal.

9. •Short-acting (half-life 1–12 hours): midazolam, triazolam
•Intermediate-acting (half-life 12–40
hours): lorazepam, temazepam, oxazepam, lormetazepam, a
alprazolam
•Long-acting (half-life > 40
hours): diazepam, chlordiazepoxide, clonazepam, tetrazepa
m, flurazepam
Benzodiazepines

10. Mechanism of action
•Benzodiazepines are indirect GABAA receptor agonists that
bind to GABA-A receptors → ↑ affinity of GABA to bind
to GABAA receptors → ↑ GABA action → ↑ opening
frequency of chloride channels → hyperpolarization of the
postsynaptic neuronal membrane → ↓ neuronal excitability
•Benzodiazepines decrease the duration of N3 phase in NREM
sleep, thereby reducing the occurrence
of sleepwalking and night terrors

11. Benzodiazepines are widely used anxiolytic
drugs, largely replaced barbiturates and
meprobamate in treatment of anxiety and
insomnia, because benzodiazepines are
considered to be safer and more effective.
Though benzodiazepines are commonly
used, they are not necessarily the best
choice for anxiety or insomnia.
Certain antidepressants with anxiolytic
action, such as the selective serotonin
reuptake inhibitors, are preferred in many
cases, and nonbenzodiazepine hypnotics
and antihistamines may be preferable for
insomnia.

12. The targets for
benzodiazepine actions are
the γ-aminobutyric acid
(GABAA) receptors.
The GABAA receptors are
composed of a combination
of five α, β, and γ subunits
that span the postsynaptic
membrane .
Benzodiazepines modulate
GABA effects by binding to a
specific, high-affinity site
(distinct from the GABA-
binding site) located at the
interface of the α subunit and
the γ subunit

13. Effects
•Anxiolysis
•Sedation
•Hypnotic action
•Muscle relaxation
•Anticonvulsant action
•Amnesia

14. Indications
•Anxiety
disorders: chlordiazepoxide, diazepam, clonazepam, lorazepam, oxazepam,

15. Pharmacokinetics
1.Absorption and distribution:
The benzodiazepines are lipophilic.
Highly lipid-soluble compounds (midazolam, traiazolam, diazepam)
have a rapid onset of action than relatively less lipid-soluble
benzodiazepines.
2. Duration of action: The benzodiazepines can be roughly divided
into short-, intermediate-, and long-acting groups.
Short-acting benzodiazepines are more useful as they prevent
preanesthetic anxiety and insomnia, without causing hangover on
awakening. Long-acting benzodiazepines are generally more useful in
managing anxiety, withdrawal states, seizures, and insomnia.

16. Fate:
• Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by
phase I hepatic microsomal oxidation to compounds that are also active.
• The benzodiazepines are excreted in the urine as glucuronides or oxidized
metabolites.
• Short- and intermediate-acting benzodiazepines are biotransformed by hydroxylation
(estazolam) and/or direct glucuronidation (lorazepam, oxazepam, temazepam) to
inactive metabolites followed by renal clearance.
• Clearance of benzodiazepines is reduced in the elderly and in patients with impaired
hepatic function; therefore, the dose should be reduced in these patients.
• All benzodiazepines cross the placenta and may depress the CNS of the newborn if
given before birth.
• The benzodiazepines are not recommended for use during pregnancy. Nursing infants
may also be exposed to the drugs in breast milk.

17. Lorazepam, Oxazepam, and Temazepam are preferred
for individuals who drink a LOT (have alcoholic liver
disease), because hepatic dysfunction does not have a
a strong effect on their metabolism.
All benzodiazepines are metabolized by the liver, but
these three
undergo biotransformation through glucuronidation,
not CYP450activation, and are less affected
by liver disease.

18. In older
adults, benzodiazepines sh
ould be used with extreme
caution because they can
worsen cognitive
impairment, increase the
risk of falls, and lead
to paradoxical reactions.
Adverse effects
Anterograde amnesia
•Confusion
•Blunted affect
•Residual sedation: sedative effects (e.g., drowsiness) persist beyond the intended
time span
Reduced coordination
•Increased risk of injury (especially with benzodiazepine use in older adults)
•Paradoxical reactions to benzodiazepines
• Includes restlessness, irritability, impulsivity, and disinhibition.
• Risk groups: older adults and children, individuals with a history of
a substance use disorder or another psychiatric condition.
• Treatment: discontinuation of the drug
•Rebound phenomenon
• Reemergence of symptoms (e.g., depression, insomnia, and anxiety) upon
discontinuation of benzodiazepine therapy, often with increased intensity
• Especially common in the treatment of sleep disorders
•Risk of overdose
•Tolerance and withdrawal; short-acting agents are associated with a higher risk of
dependence
•Risk of developing substance use disorder

19. Benzodiazepine overdose
•Clinical features
• Symptoms
• Lethargy, somnolence
• Respiratory depression
• Due to a decrease in central respiratory drive and upper airway muscle tone
• Intensifies drastically when combined with other respiratory depressants such
such as alcohol or barbiturates
• Benzodiazepines have a wider margin of safety than barbiturates and,
consequently, a lower risk of coma and respiratory depression.
• Ataxia
• Hypotonia and hyporeflexia
• Slurred speech
• Mild hypotension
• Focused toxicological history and physical examination

20. •Treatment
• Supportive therapy according to overdose severity
• Airway obstruction, respiratory depression, and
decreased oxygen saturation: consider endotracheal
intubation
• Hypotension: fluid resuscitation
• Consider a trial of naloxone when opioid overdose is
suspected.
• Activated charcoal, hemodialysis, and whole bowel
irrigation are not effective treatment options.

21. Antidote: flumazenil
• Mechanism of action:
competitive antagonism at GABA receptor
• Indications
• Severe respiratory depression
• Overdose in benzodiazepine-
naive patients (e.g., accidental ingestion in
in children,
periprocedural oversedation with benzodi
iazepines)
• Due to the risk of seizures, the use
of flumazenil is contraindicated under the
following circumstances:
• Chronic benzodiazepine use
• Underlying seizure disorder
• Suspected coingestion of proconvulsive
substances (e.g., amphetamines, bupropi
on, methotrexate, clozapine)

22. Benzodiazepine dependence
•Definition: The physical adaptation to sustained use of a
substance with the development of tolerance and
withdrawal.
•Withdrawal symptoms
• Autonomic nervous system
• Diaphoresis
• Nausea, vomiting, and anorexia
• Tachycardia
• Hypertension
• Neurological
• Seizures
• Tremors
• Memory impairment
• Psychiatric
• Anxiety
• Depressive mood
• Insomnia
• Withdrawal psychosis with transient optic,
auditory, or tactile hallucinations
•Treatment
• Dose tapering
• Withdrawal management
should be done in an
inpatient setting.
• Switch from multiple agents
to one, preferably diazepam.
• Discontinue gradually over a
period of 4–8 weeks.
• Reduce dose no more than
once a week
• Seizure prophylaxis
(e.g., carbamazepine)

23. Contraindications for benzodiazepines
•Hypersensitivity to benzodiazepines
•Narrow-angle glaucoma
•Respiratory depression (COPD, respiratory failure)
•Myasthenia gravis
•History of a substance use
disorder (e.g., alcohol, recreational drugs, prescription
medications), except in the treatment of
acute alcohol or sedative-hypnotic withdrawal
•Pregnancy (except for the management of
eclampsia following unsuccessful magnesium
sulfate therapy)

24. Agents
•Zolpidem (imidazopyridine): half-life ∼ 2 hours
•Zaleplon (pyrazolopyrimidine): half-life ∼ 1 hour
•Eszopiclone: half-life ∼ 6 hours
Mechanism of action
•Similar to benzodiazepines
•Selectivity for GABAA receptors with α1 subunits (corresponding to the BZ1 subtype)
•Short-acting due to fast metabolization by liver enzymes
Effects
•Sedation
•Hypnotic action
•Less effect on sleep architecture than benzodiazepines
•Less effective than benzodiazepines as an anticonvulsant and an anxiolytic
Nonbenzodiazepine hypnotics (Z-drugs)

25. Indications
•Insomnia
Adverse effects
•Ataxia
•Headaches
•Confusion, Psychomotor depression
•Amnesia
•Residual sedation
•Impaired cognitive functions
•Risk of overdose
• Symptoms are similar to those of benzodiazepine overdose.
• Can be treated with flumazenil as with benzodiazepines
•Tolerance and withdrawal [9]
• Risk profile is similar to that of benzodiazepines
• After long-term use, the daily dose should be tapered gradually (there is a risk of
developing withdrawal symptoms and memory impairment upon sudden cessation of
therapy).
•Risk of developing substance use disorder

26. Agents
•Ultra-short acting (half-life 15 minutes–3
hours): thiopental, methohexital
•Short-acting (half-life 3–6
hours): pentobarbital, secobarbital
•Intermediate-acting (half-life 6–12
hours): amobarbital, butalbital
•Long-acting (half-life 12–24
hours): phenobarbital, primidone
Barbiturate

27. Mechanism of action
•Bind to GABAA receptors → ↑ duration of the GABA-
gated chloride channel opening → ↑ intracellular Cl--flow
→hyperpolarization of postsynaptic neurons → ↓
neuronal excitability
•Additional, non-GABA-dependent, mechanisms of action
• ↓ Glutamate signaling
• Membrane effects similar to those of inhalational
anesthetics
•High lipid solubility of barbiturates leads to:
• Rapid onset of action
• Accumulation in skeletal and adipose tissue → prolonged
duration of action

28. Effects
•Dose-dependent effects
• Low dose: sedative
• Medium dose: hypnotic
• High dose: general anesthetic
Indications
•Ultra-short acting
• General anesthesia
• Status epilepticus
• Sedation for electroconvulsive therapy (methohexital)
• Reduction of intracranial pressure for brain
edema following trauma or surgery
•Short-acting and intermediate-acting
• Preanesthetic sedation
• Short-term treatment for insomnia or anxiety disorders
• Tension-type headache
•Long-acting
• Generalized-onset and focal-onset seizures Status
epilepticus
• Neonatal seizures
• Preanesthetic sedation
• Alcohol withdrawal
• Gilbert syndrome (to reduce hyperbilirubinemia)
• Primidone: essential tremor
Barbiturates are no longer used for sedation or long-
term treatment of insomnia due to their low safety
margin. They have been replaced by more
effective drugs with fewer side effects
(e.g., benzodiazepines).

29. Adverse effects
•Hypotension (dose-dependent)
•Respiratory depression and/or apnea (dose-dependent): Barbiturates have a narrower margin of safety
than benzodiazepines.
•Tolerance and withdrawal
•CNS depression, especially when used with other CNS depressants (e.g., benzodiazepines, alcohol)
•Toxicity
•Laryngospasm, bronchospasm (due to histamine release)
•Myoclonus
•Interactions: cytochrome P450 induction (leads to a variety of possible drug interactions)
Accidental intraarterial injection of barbiturates
•Etiology: incorrect injection of barbiturates
•Clinical features: tissue necrosis; gangrene (through vessel injury, spasm, and thrombosis)
•Treatment
• Intraarterial dilution with NaCl 0.9% and injection of heparin to prevent thrombosis
• Termination of vessel spasm
• Intraarterial administration of 5–10 mL of 1% lidocaine
• Axillary plexus or stellate ganglion block to block sympathetic nerve fibers that uphold the vessel spasm
): urine alkalinization and forced diuresis

30. Barbiturate overdose
•Clinical features
• Impaired consciousness, coma
• Respiratory failure
• Cardiovascular depression (potentially fatal)
•Management: mainly supportive as there is no
specific antidote
• Monitoring
• Secure airways, maintain adequate oxygenation,
and provide respiratory assistance, if necessary.
• Fluid resuscitation to maintain blood pressure
• ECG: Monitor for arrhythmia.
• ABG: Monitor for metabolic acidosis and increase
levels of serum lactic acid.
• In cases of suspected alcohol intoxication, measure
measure the alcohol and barbiturate levels in
serum.
• Sodium bicarbonate (NaHCO3
Contraindications
•Porphyria
•Severe anemia
•Myasthenia gravis
•Addison disease
•Liver or kidney disease
•Thyroid disorders
•Asthma

31. Agents
•Ramelteon
•Tasimelteon
•Agomelatine
Ramelteon, tasimelteon, and agomelatine
are melatonin receptor agonists.
Mechanism of action
•Activation of MT1
and MT2 receptors in suprachiasmatic nuclei of
the hypothalamus → quicker sleep onset
•Do not cause dependence
Indications
•Insomnia
•Circadian rhythm disorders
Adverse effects
•Headache
•Dizziness
•Fatigue
•Nausea
•Arthralgias
•Angioedema (rare)
•Interactions: CYP1A2 inhibitors
(e.g., fluvoxamine) increase blood
concentration.
Contraindications [11]
•Hypersensitivity reactions

32. Agents
•Suvorexant
Mechanism of action
•Antagonism of orexin (hypocretin) receptors → inhibits the
binding of neuropeptides orexin A and B → ↓ wakefulness and
arousal
Suvorex-ant is an orexin antagonist.
Indications
•Insomnia
Adverse effects
•Headache
•Sleep disturbances: abnormal dreams, nightmares, sleep terrors
Contraindications
•Liver disease
•Narcolepsy
Orexin antagonists