SEDATIVA HYPNOTICS
Basic Pharmacology
An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming
effect. A hypnotic drug should produce drows iness and encourage the onset and
maintenance of a state of sleep.
Pharmacokinetics
Absorption and distribution: A hypnotic drug should produce drows iness and
encourage the onset and maintenance of a state of sleep. Lipid solubility plays a
major role in determining the rate at which a particular sedative-hypnotic enters the
central nervous system. For example, the absorption of triazolam is extremely rapid.
All sedative-hypnotics cross the placental barrier during pregnancy. Sedativehypnotics are also detectable in breast milk and may exert depressant effects in the
nursing infant.
Biotransformation:
Benzodiazepines - Hepatic metabolism accounts for the clearance of all
benzodiazepines. Most benzodiazepines undergo microsomal oxidation (phase I
reactions), including N- dealkylation and aliphatic hydroxylation catalyzed by cyto
chrome P450 isozymes, especially CYP3A4. The metabolites are subsequently
conjugated (phase II reactions) to form glucuronides that are excreted in the urine.
Barbiturates - — With the exception of phenobarbital, only insignificant quantities of
the barbiturates are excreted unchanged. The major metabolic pathways involve
oxidation by hepatic enzymes to form alcohols, acids, and ketones, which appear in
the urine as glucuronide conjugates.
Excretion
The water-soluble metabolites of sedative-hypnotics, mostly formed via the
conjugation of phase I metabolites, are excreted mainly via the kidney
Pharmacodynamics
The benzodiazepines, the barbiturates, zolpidem, zaleplon, eszopi clone, and many
other drugs bind to molecular components of the GABA A receptor in neuronal
membranes in the central nervous system. This receptor, which functions as a
chloride ion channel, is activated by the inhibitory neurotransmitter GABA.
A major isoform of the GABA A receptor that is found in many regions of the brain
consists of two α1, two β2, and one γ2 subunits. In this isoform, the two binding sites
for GABA are located between adjacent α1 and β2 subunits, and the binding pocket
for benzodiazepines (the BZ site of the GABA A receptor) is between an α1 and the
γ2 subunit. In contrast to GABA itself, benzodiazepines and other sedative hypnotics
have a low affinity for GABA B receptors, which are acti vated by the spasmolytic
drug baclofen.
Barbiturates also facilitate the actions of GABA at multiple sites in the central
nervous system, but—in contrast to benzodiazepines—they appear to increase the
duration of the GABA-gated chloride channel openings. At high concentrations, the
barbiturates may also be GABA-mimetic, directly activating chloride channels.
Barbiturates are less selective in their actions than benzodiazepines, because they
also depress the actions of the excitatory neurotransmitter glu tamic acid via binding
to the AMPA receptor. This multiplicity of sites of action of barbiturates may be the
basis for their ability to induce full surgical anesthesia and for their more pronounced
central depressant effects.
Benzodiazepine Binding Site Ligands
Agonists facilitate GABA actions, and this occurs at multiple BZ binding sites in the
case of the benzodiazepines.
Antagonists are typi fied by the synthetic benzodiazepine derivative flumazenil,
which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem
but does not antagonize the actions of barbiturates, mep robamate, or ethanol.
Inverse agonists act as negative allosteric modula tors of GABA-receptor function
Their interaction with BZ sites on the GABA A receptor can produce anxiety and sei
zures, an action that has been demonstrated for several compounds, especially the
β-carbolines, eg, n- butyl-β-carboline-3-carboxylate (β-CCB). In addition to their
direct actions, these molecules can block the binding and the effects of
benzodiazepines.
Organ Level Effects
Sedation - — Benzodiazepines, barbiturates, and most older sedative-hypnotic
drugs exert calming effects with concomitant reduction of anxiety at relatively low
doses.
Hypnosis - all of the sedative-hypnotics induce sleep if high enough doses are
given. The effects of sedative hypnotics on the stages of sleep depend on several
factors, including the specific drug, the dose, and the frequency of its administration.
Anesthesia - high doses of certain sedative-hypnotics depress the central nervous
system to the point known as stage III of general anesthesia. Among the
barbiturates, thiopental and methohexital are very lipid-soluble, penetrating brain
tissue rapidly following intravenous administra tion, a characteristic favoring their use
for the induction of anes thesia.
Benzodiazepines—including diazepam, lorazepam, and midazolam—are used
intravenously in anesthesia. In large doses, they could cause postanesthetic
respiratory depression due to their long half life and formation of active metabolites.
This actions are however reversible with flumazenil.
Anticonvulsant effects - — Many sedative-hypnotics are capable of inhibiting the
development and spread of epileptiform electrical activity in the central nervous
system. Several benzodiazepines—including clonazepam, nitrazepam, lorazepam,
and diazepam—are sufficiently selective to be clinically useful in the management of
seizures. Of the barbiturates, phenobarbital and metharbital (converted to
phenobarbital in the body) are effective in the treatment of generalized tonic-clonic
seizures, though not the drugs of first choice.
Muscle relaxation - Some sedative-hypnotics, particularly members of the carbamate
(eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on
polysynaptic reflexes and inter nuncial transmission and at high doses may also
depress transmis sion at the skeletal neuromuscular junction.
Effects on respiration and cardiovascular function - — At hypnotic doses in healthy
patients, the effects of sedative-hypnotics on respiration are comparable to changes
during natural sleep. However, even at therapeutic doses, sedative-hypnotics can
pro duce significant respiratory depression in patients with pulmonary disease.
Effects on respiration are dose-related, and depression of the medullary respiratory
center is the usual cause of death due to overdose of sedative-hypnotics.
Benzodiazepine Antagonist: Flumazenil
Flumazenil has high affinity for the benzodiazepine binding site on the GABA A
receptor that act as competitive antagonists. It blocks many of the actions of
benzodiazepines, zolpidem, zaleplon, and eszopiclone, but does not antagonize the
central nervous system effects of other sedative-hypnotics, ethanol, opioids, or
general anesthetics.
Clinical uses of sedative-hypnotics.
For relief of anxiety
For insomnia
For sedation and amnesia before and during medical and surgical procedures
For treatment of epilepsy and seizure states
As a component of balanced anesthesia (intravenous administration)
For control of ethanol or other sedative-hypnotic withdrawal states
For muscle relaxation in specific neuromuscular disorders
As diagnostic aids or for treatment in psychiatry
Clinical toxicology of sedative hypnotics
Relatively low doses may lead to drowsiness, impaired judgment, and diminished
motor skills, sometimes with a significant impact on driving ability, job performance,
and personal relationships.
Benzodiazepines may cause a significant dose-related anterograde amnesia; they
can significantly impair ability to learn new information, particularly that involving
effortful cognitive processes, while leaving the retrieval of previously learned
information intact.
Because barbiturates enhance porphy rin synthesis, they are absolutely
contraindicated in patients with a history of acute intermittent porphyria, variegate
porphyria, hereditary coproporphyria, or symptomatic porphyria. Hypersensitivity
reactions, including skin rashes, occur only occa sionally with most drugs of this
class.
Drug interactions
The most common drug interactions involving sedative-hypnotics are interactions
with other central nervous system depressant drugs, leading to additive effects.
🌙 Newer Hypnotics
Examples:

Eszopiclone

Zaleplon

Zolpidem
Mechanism of Action:

Selectively bind to a subgroup of GABA

Act like benzodiazepines → enhance membrane hyperpolarization.
𝑨 receptors.
Clinical Features:

Rapid onset of hypnosis.

Minimal amnesia.

Low risk of next-day psychomotor depression or somnolence.

Indicated for sleep disorders, especially difficulty initiating sleep.
Pharmacokinetics:

Orally active.

Short half-lives.

Metabolized via CYP enzymes.
Toxicity & Interactions:

Extensions of CNS depressant effects.

Dependence liability.

Additive CNS depression with ethanol and other depressants.
🌌 Melatonin Receptor Agonist
Example:

Ramelteon
Mechanism of Action:

Activates MT1 and MT2 receptors in the suprachiasmatic nucleus of the
CNS.
Clinical Features:

Rapid onset of sleep.

Minimal rebound insomnia or withdrawal symptoms.

Indicated for sleep-onset insomnia.

Not a controlled substance.
Pharmacokinetics:

Orally active.

Forms active metabolite via CYP1A2.
Toxicity & Interactions:

Dizziness, fatigue, endocrine changes.

Fluvoxamine strongly inhibits metabolism.
🌐 5-HT Receptor Agonist
Example:

Buspirone
Mechanism of Action:

Partial agonist at 5-HT

Also has affinity for D2 receptors.

Exact mechanism of anxiolysis remains uncertain.
𝟏𝑨 receptors.
Clinical Features:

Slow onset (1–2 weeks) of anxiolytic effect.

Minimal psychomotor impairment.

No additive CNS depression with sedative-hypnotics.

Indicated for generalized anxiety disorder (GAD).
Pharmacokinetics:

Orally active.

Forms active metabolite.

Short half-life.
Toxicity & Interactions:

Tachycardia, paresthesias, gastrointestinal distress.

Interactions with CYP3A4 inducers and inhibitors.