Sedative and Hypnotics
Prepared By: Priyanshi C Desai
M.PHARM (Pharmacology)
Sedative-Hypnotics
• Sedative A drug that subdues excitement and calms the subject without inducing sleep,
though drowsiness may be produced.
• Sedation refers to decreased responsiveness to any level of stimulation; is associated with
some decrease in motor activity and ideation.
• Sedation means decrease in alertness and a decreased responsiveness to any level of
stimulation without inducing sleep .
• Hypnotic A drug that induces and/or maintains sleep, similar to normal arousable sleep.
• hypnosis means a state that resembles natural sleep but the person can be aroused by
strong stimuli like pin prick or the sound of the alarm clock. .
Classification
• BENZODIAZEPINES
• Short Acting :Triazolam, Oxazepam, Midazolam TOM NLTEA CCDF
• Intermediate Acting :Alprazolam, Estazolam, Temazepam, Lorazepam, Nitrazepam
• Long Acting :Diazepam, Flurazepam, Clonazepam, Chlordiazepoxide
• NON-BENZODIAZEPINE HYPNOTICS :Zolpidem, Zaleplon, Zopiclone, Eszopiclone
• BARBITURATES
• Long Acting :Phenobarbital, Mephobarbital
• Short Acting :Pentobarbital, Amobarbital
• Ultra short Acting :Thiopental, Methohexital
• MISCELLANEOUS GROUP :Melatonin, Ramelteon, Triclophos, Hydroxyzine and
Promethazine
BENZODIAZEPINES (BZDs)
• Site of Action:
• Greater depressant action on limbic system compared to midbrain ascending RAS.Hence they
reduce anxiety at a dose which has little depressant effects on RAS, i.e., they elicit anxiolytic action
with less sedative effects. At higher doses, however, they depress RAS and induce sedative-
hypnotic action but this property differs qualitatively with individual drug.
• Muscle relaxation, Ataxia is due to their action on cerebellum.
• Mechanism of action : earlier discuss in detail.
• Pharmacokinetic Characteristics :
• Except for midazolam (given I.V. or I.M.), all can be given orally (though absorption varies).
• some of BZDs (diazepam, oxazepam and chlordiazepoxide) are more than 90% protein bound.
• They cross placental barrier (caution pregnancy).
• Most BZDs are metabolised by phase I metabolic processes and the resultant metabolites are
subsequently conjugated (phase II reactions) to form water-soluble metabolites that are excreted
in urine.
BENZODIAZEPINES (BZDs)
Therapeutic Uses:
• To Treat Anxiety Neuroses
• To Treat Insomnia:
• Transient insomnia: generally, lasts less than 7 days.
• Triazolam is effective in treating individuals who have difficulty in going to sleep; while
temazepam is useful for insomnia caused by inability to stay asleep. These drugs are used
intermittently rather than daily to avoid residual effects leading to rebound insomnia.
• Short-term insomnia: which lasts for one to three weeks.
• The patient may have induction difficulty, frequent nocturnal awakenings and/or early morning
awakening. Temazepam (15-30 mg) or flurazepam (15-30 mg) or estazolam (1-2 mg) at bed time
are more suited for this type of insomnia.
• Long-term chronic insomnia: which lasts longer than three weeks.
• Intermittent use (with a break after every third day) of longer acting BZD like flurazepam (15-30
mg) or nitrazepam (5-10 mg) at bed time is preferred because rebound insomnia and
withdrawal effects are less marked with these drugs.
BENZODIAZEPINES (BZDs)
• For Preanesthetic Medication and Induction of Anesthesia: Diazepam, lorazepam and
midazolam are generally used for this purpose. Midazolam (l.V.) is most frequently used as
it produces higher degree of amnesia, has a more rapid onset with shorter duration of
action.
• As Skeletal Muscle Relaxants: Diazepam is preferred for relaxant effects in skeletal muscle
spasticity of central origin
• As Anticonvulsants :Diazepam (slow l.V.) lorazepam (slow l.V.) and clonazepam (slow l.V.)
used. Clonazepam may also be used for myoclonic/petit mal seizures
• Treatment of Alcohol Withdrawal :Diazepam, oxazepam and chlordiazepoxide are also
used to control withdrawal effects of alcohol
BENZODIAZEPINES (BZDs)
• Adverse Effects:
• dose-dependent drowsiness, fatigue, disorientation, lethargy and impairment of psychomotor skills .
• fast I.V. injection can precipitate cardiac arrest.
• Tolerance to their sedative effects develops slowly, with only a little tendency to increase the dose.
• Dependence to BZDs is again mild but the risk factors Include continuous use, high doses, the use of BZDs
with shorter to medium half-life, use in patients with drug-dependent personality traits and the
development of tolerance. Nonetheless, their abuse liability is very low compared to barbiturates.
• BZD withdrawal includes anxiety, insomnia, impaired concentration, headache, irritability, tremors,
palpitation and vivid dreams (due to an increase in REM sleep) which may persist for some weeks after
withdrawal of BZDs.
• long-acting BZDs, if used regularly in elderly people, tends to increase with age resulting in increased
confusion and forgetfulness.
• Paradoxical stimulation (especially with flurazepam.)
• Flunitrazepam is one of the tasteless BZDs which has been misused, because of its sedative- amnestic effects,
in sexual assaults or so-called “date rapes”.
BENZODIAZEPINES (BZDs)
• Drug Interactions
• BZDs potentiate the effects of other CNS depressants, such as alcohol, hypnotics and
neuroleptics.
• Smoking decreases the activity of BZDs.
• Aminophylline antagonizes sedative effects of BZDs.
• Enzyme inhibitors like cimetidine and ketoconazole enhance BZD action.
Benzodiazepines are now preferred over barbiturates as hypnotic and sedative
as well, because:
• not provide anaesthesia even in high doses ,patient can be aroused. barbiturates provide
loss of consciousness and have lower margin of safety.
• not enzyme inducers hence do not lead to metabolic tolerance. Drug interactions are also
less. Barbiturates are potent enzyme inducers, exhibit metabolic tolerance and more drug
drug interactions.
• BZDs have a very low abuse liability while barbiturates not only exhibit tolerance but cause
both psychic and physical dependence.
• BZDs do not affect REM sleep and cause lesser distortion of normal hypnogram.
Barbiturates cause marked suppression of REM sleep, hence there is rebound increase in
REM sleep on withdrawal (nightmares). Hangover is also common.
Benzodiazepines are now preferred over barbiturates as hypnotic and sedative
as well, because:
• BZDs show no hyperalgesia while barbiturates exhibit hyperalgesic action and
may even increase the sensitivity to pain.
• BZDs exhibit amnesia but with no phenomenon of “automatism”. Barbiturates
are characterized by amnesia with automatism. The latter leads to accidental
poisoning; because due to loss of short-term memory, the patient forgets
whether he has taken the drug or not and takes it again.
• BZDs can be used as day time anxiolytic-sedative in sub-hypnotic doses. With
barbiturates, the accompanied drowsiness is unacceptable.
• Hypnotic doses of BZDs do not affect respiration or cardiovascular functions,
while barbiturates cause respiratory depression and hypotension.
• There are specific antagonists for BZDs (e.g.,flumazenir) which can be used in
case of poisoning; with barbiturates it is not possible.
NON-BENZODIAZEPINE HYPNOTICS
• act as agonist at the modulatory site of GABAA receptor to which BZDs bind.
• Two types of BZD receptor have been suggested: BZD receptor type I (BZ1) found
throughout the brain and in large concentrations in the cerebellum; and BZD receptor
type II (BZ2) found mainly in the cerebral cortex, hippocampus and spinal cord.
• It is the BZ1 receptor that is thought to be responsible for antianxiety, sedative and
hypnotic action while BZ2 receptor appears to be associated with muscle relaxation,
anticonvulsant action and amnesia.
• Most BZDs act on both BZ1and BZ2 receptors. Non- benzodiazepines such as zolpidem,
zaleplon, zopiclone and eszopiclone act on BZ1 receptor only; while 1-5-benzodiazepines
such as clobazam act preferably at BZ2 receptor to elicit muscle relaxant and
anticonvulsant actions.
NON-BENZODIAZEPINE HYPNOTICS
• Zolpidem, Zopiclone, Eszopiclone and Zaleplon :
• Act on BZ1 receptors and have hypnotic actions. As hypnotic, zolpidem (t½ 2-3 hrs) and
zaleplon (t½ 3-4 hrs) have faster onset of action with shorter duration of hypnotic effects while
zopiclone (t½ 6-8 hrs) and eszopiclone (t½ 6 hrs) are slightly longer acting.
• rebound insomnia (after withdrawal of the drug) is also minimal.
• Zolpidem (10-20 mg) and zaleplon (10-20 mg) at bed time are used to treat transient insomnia
while zopiclone (7.5 mg) and eszopiclone (1-3 mg) at bed time are used to treat short-term
insomnia. Their effects can be blocked by flumazenil, which is antagonist at both BZ1 and BZ2
receptors.
• The risk of tolerance and dependence is much less after their withdrawal as compared to BZDs.
Side effects and safety in overdoses are almost similar to BZDs.
• Dose reduction is needed in hepatic disease and in elderly patients.
• Headache, daytime drowsiness and nightmares can occur with higher doses.
BARBITURATES
• Mechanism of Action:
• Barbiturates act on the channel modulatory site of GABAA receptor and potentiate the GABA
mediated inhibitory effects by increasing the duration of chloride channel opening .At higher
concentrations, barbiturates directly increase chloride ion conductance, i.e., they exhibit a GABA
mimetic action and not a GABA facilitatory action (as exhibited by BZDs).
• Classification:
• Thiopental and methohexital are ultra-short-acting barbiturates with duration of action ranging from
15- 20 min. These are used by I. V. fast bolus injection to induce general anesthesia.
• Pentobarbital and amobarbital are Short-acting barbiturates and no more in use due to availability
of safer alternatives (benzodiazepine).
• Phenobarbital and mephobarbital (duration of action 12-24 hrs) are longer-acting barbiturates and
no more used as sedative and hypnotics but are used as anticonvulsant drugs
BARBITURATES
• Pharmacokinetics
• Absorption : rate depends on their lipid solubility.
• Distribution : widely distributed depending upon their lipid solubility and the regional blood flow.
• Metabolisim : by both phase-1 (liver microsomal oxidation) and phase-II (glucuronyl conjugation)
processes.
• prolonged use → induction of liver microsomal enzymes, which results in the development of
metabolic tolerance.
• Excretion : urine, these get readily reabsorbed from renal tubules. Alkalinization increases their
ionisation and therefore increases their renal excretion .
BARBITURATES
• Pharmacological Effects:
• The ultra-short- and short-acting barbiturates exhibit dose-dependent CNS depressant actions
starting from sedation → hypnosis → general anaesthesia to coma and death.
• The long-acting ones possess primarily sedative-anticonvulsant actions. However, their
anticonvulsant action has no relation with their sedative action, because even in sub-sedative
doses these drugs retain anticonvulsant actions whereas amphetamine though antagonises the
sedative action does not prevent their anticonvulsant actions.
• They disrupt the balance between REM: NON-REM sleep by decreasing the duration of REM
sleep. Hence on withdrawal, there is a rebound increase in REM sleep duration resulting into bad
dreams and nightmares with a feeling that “I didn’t sleep well”.
BARBITURATES
• Barbiturates may show hyperalgesic action, i.e., they may increase the reaction to painful stimuli.
• Sedative-hypnotic doses have no effect on CVS parameters. Higher doses decrease BP, HR and
depresses myocardium.
• Sedative-hypnotic doses do not affect respiration. Higher doses depress respiration, cause
shallow breathing and Cheyne-Stokes rhythm in breathing. Pulmonary oedema, laryngeal oedema
and bronchial pneumonia may also occur.
• Prolonged use increases the size and weight of smooth endoplasmic reticulum leading to enzyme
induction
• Higher doses have relaxant effects on GIT, bladder and uterus and decrease the urine flow from
kidneys (due to decrease in renal blood flow, increase in ADH release and relaxation of bladder)
BARBITURATES
• Therapeutic Uses :
• As sedative-hypnotics
• In anaesthesia, ultra-short-acting barbiturates (thiopental) are generally used as intravenous fast inducing agents .
• As anticonvulsants, usually long-acting barbiturates, such as phenobarbital, are used .
• To treat hyperbilirubinaemia of neonates, as they increase the activity of glucuronyl transferase enzyme by enzymatic induction. Hence
bilirubin gets conjugated faster and excreted through bile. These drugs also increase the bile flow.
• Adverse Effects :
• Repeated use of barbiturates leads to the development of metabolic tolerance due to enzymatic induction. This leads to various drug
interactions because of the accelerated metabolism of concomitantly administered drugs along with barbiturates.
• Barbiturates have considerable abuse liability and exhibit both psychic as well as physical dependence on withdrawal after prolonged use.
• Withdrawal symptoms include tremors, insomnia, headache, restlessness and delirium .
• They cause hangover, impairment of judgement and “drug automatism” .
• They cause respiratory depression, laryngeal oedema and hypersensitivity reactions (skin rash, swelling of lips and eyelids).
MISCELLANEOUS GROUP OF SEDATIVE-HYPNOTICS
• Melatonin is a hormone produced in the pineal gland from the amino acid tryptophan. involved in the protective
changes in skin colouration, but it is also secreted during hours of darkness and affects sleep pattern.
• Play an important role in entraining (synchronizing) the sleep-wakefulness cycle with the circadian rhythm.
• the light→ stimulates the retina and transmits signal through suprachiasmatic nucleus (SCN; of hypothalamus) to
pineal gland to inhibit release of melatonin.
• darkness→ promotes melatonin secretion from the pineal gland. It then stimulates MT1 and MT2 receptor
subtypes present in SCN to induce and promote sleep and to maintain the circadian rhythm of the normal “sleep-
awake” cycle.
• primarily used to alleviate symptoms of jet lag and other disorders resulting from delay of sleep .
• use might enable benzodiazepine therapy for insomnia to be discontinued, without impairing the quality of sleep.
• food enhances its bioavailability. It undergoes extensive first-pass metabolism and is excreted mainly by kidney. It
decreases serum luteinizing hormone and increases prolactin levels.
• contraindicated in persons taking corticosteroids like dexamethasone or prednisone.
• Ranielteon is a selective agonist at the MT1 and MT2 receptor subtypes of melatonin. approved for the treatment
of insomnia in which there is difficulty in falling asleep. There is yet no evidence of its abuse potential, dependence
or withdrawal but it can increase prolactin levels. Adverse effects include fatigue, dizziness and somnolence.
