Download sedative-hypnotic

SEDATIVE-HYPNOTIC
Sedative: A substance that induces sedation by reducing irritability and excitement.
Hypnotic: A drug which induces a state of drowsiness.
Sedative-hypnotics are drugs which depress or slow down the body’s functions. Often
these drugs are referred to as tranquilizers and sleeping pills or sometimes just as sedatives. Their
effects range from calming down anxious people to promoting sleep. Both tranquilizers and
sleeping pills can have either effect, depending on how much is taken. At high doses or when
they are abused, many of these drugs can even cause unconsciousness and death.
Treatment:
Benzodiazepines: Diazepam, midazolam, alprazolam and triazolam
Benzodiazepines exert their effect by selectively binding to GABAA receptors and
enhancing its inhibitory effect on the CNS. GABA receptor contains more than one isoform each
with different subunits:
1. α1-subunit→ sedation, amnesia and possibly antiseizure effects.
2. α 2 -subunit → anxiolytic and muscle relaxing action.
3. α5-subunit→ memory impairment.
Benzodiazepines bind to many isoforms of the GABA receptor at different areas of the
brain. The GABA receptor is a pentameric receptor consisting from five subunits in variant
isoforms. The major isoform is composed of five subunits comprising of 2α, 2β, and one γ
subunits.
Pharmacokinetics: The rate of oral absorption varies depending on each drug’s lipophilicity.
Diazepam and the active metabolite of clorazepate have more rapid absorption than other
benzodiazepines. Absorption of triazolam is extremely rapid. Benzodiazepines bind strongly to
plasma proteins. They also accumulate in body fats with high volume of distribution.
Benzodiazepines are metabolized by oxidation and hydroxylation by cytochrome P450 especially
isoform CYP3A4 (phase I). The metabolites are subsequently conjugated (phase II) to form
glucuronides that are excreted in the urine. All sedative-hypnotics cross the placental barrier
during pregnancy. They are also detectable in breast milk. The metabolism of diazepam,
midazolam, and triazolam is affected by inhibitors and inducers of hepatic P450 isozymes.
Side effects: Drowsiness, confusion, amnesia, decrease in motor coordination, and decrease in
psychomotor performances.
Pharmacological Effects: Reduction of anxiety & aggression, Sedation, Hypnotic.
Barbiturates: Phenobarbitone, mephobarbitone, secobarbitone, pentobarbitone, thiopentone,
hexobarbitone.
Barbiturates are able to enhance the action of GABA by prolonging the duration of
chloride channel opening. At high doses, barbiturates can actually act directly on GABA’s
receptor. They have a depressant effect similar to general anesthetics due to their broad
inhibitory effect on various CNS receptors.
Pharmacokinetics: Barbiturates are absorbed rapidly into the blood following their oral
administration. Their metabolic pathway involves oxidation by hepatic enzymes to form
substances which appear in the urine as glucuronide conjugates. Phenobarbital is the only
barbiturate excreted unchanged in the urine (20–30%), and its elimination rate can be increased
significantly by alkalinization of the urine where it is considered a weak acid.
Adverse Effects: Barbiturates induce the hepatic cytochrome P450 inducing increased metabolic
degradation. Barbiturates, in relation to benzodiazepines, are more likely to causes
cardiovascular and respiratory depression. Also, barbiturates do aggravate porphyria crisis.
Zolpidem: The hypnotic zolpidem is not a benzodiazepine in structure, but it acts on a subset of
the benzodiazepine receptor. Zolpidem has no anticonvulsant or muscle-relaxing properties. It
Shows little withdrawal affects, and exhibits minimal rebound insomnia, and little or no
tolerance occurs with prolonged use. Zolpidem is rapidly absorbed from the gastrointestinal tract,
and it has a rapid onset of action and short elimination half-life. Zolpidem undergoes hepatic
oxidation by the cytochrome P450 system to inactive products.
Adverse effects: Agitation, nightmares, headache, gastrointestinal upset, dizziness, and daytime
drowsiness.
Zaleplon: Zaleplon causes fewer residual effects on psychomotor and cognitive functions
compared to zolpidem or the benzodiazepines. This may be due to its rapid elimination, with a
half-life that approximately 1 hour. The drug is metabolized by CYP3A4.
Eszopiclone: Eszopiclone is an oral non-benzodiazepine hypnotic and is also used for treating
insomnia. Eszopiclone is rapidly absorbed, extensively metabolized by oxidation and
demethylation via the cytochrome enzyme system and mainly excreted in the urine. Elimination
half-life is approximately 6 hours.
Adverse effects: Dry mouth, anxiety, headache, peripheral edema, somnolence, and unpleasant
taste.
Ramelteon: It is a selective agonist at the MT1 and MT2 subtypes of melatonin receptors.
Normally, light stimulating the retina transmits a signal to the supra chiasmatic nucleus (SCN) of
the hypothalamus, that in turn relays a signal via a lengthy nerve pathway to the pineal gland that
inhibits the release of melatonin from the gland.
Adverse effects: Fatigue, dizziness, and somnolence.
Chloral hydrate: Chloral hydrate is a trichlorinated derivative of acetaldehyde that is converted
to the active metabolite trichloroethanol in the body. The drug is an effective sedative and
hypnotic that induces sleep in about 30 minutes and the duration of sleep is about 6 hours.
Chloral hydrate is irritating to the gastrointestinal tract and causes epigastric distress. It also
produces an unusual, unpleasant taste sensation. It synergizes with ethanol.
Antihistamines:
Nonprescription
antihistamines
with
sedating
properties,
such
as
diphenhydramine and doxylamine, are effective in treating mild types of insomnia. However,
these drugs are usually ineffective for all but the milder forms of situational insomnia.
Ethanol: Ethyl alcohol (Ethanol) has anxiolytic and sedative effects, but its toxic potential
outweighs its benefits. Alcoholism is a serious medical and social problem. Ethanol is a CNS
depressant, producing sedation and, ultimately, hypnosis with increasing dosage. It is readily
absorbed orally and has a volume of distribution close to that of total body water. Ethanol is
metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenase and then to
acetate by aldehyde dehydrogenase. Elimination is mostly through the kidney, but a fraction is
excreted through the lungs.
Disulfiram: Disulfiram blocks the oxidation of acetaldehyde to acetic acid by inhibiting
aldehyde dehydrogenase. This results in the accumulation of acetaldehyde in the blood, causing
flushing, tachycardia, hyperventilation, and nausea.
Naltrexone: It is a long-acting opiate antagonist. It is better tolerated than disulfiram and does
not produce the aversive reaction that disulfiram does.