Sedatives and hypnotics

Contents:Definition of sedatives and hypnotics, Insomnia and sleep, Classification of hypnotic & sedatives, Pharmacology of barbiturates ,Pharmacology of benzodiazepines, Pharmacology of non-benzodiazepine.

Sedatives:

A Drug that subdues excitement and calms the subject without inducing sleep. Drowsiness may be produced Decreased responsiveness Decrease in motor activity Hypnotics:

A drug that induced sleep, similar to normal arousable sleep .

The sedatives and hypnotics are more less general CNS depressants which differ in ; Dose action Time action The sedatives and hypnotics differ in;

Hypnotics sedativesQuicker onset Short duration

Steeper dose response curve

Slower acting drug

Flatter dose response curve

Insomnia & sleep. . .Treatment of insomnia is most important for the use of sedative and hypnotics. REM Sleep: rapid eye movement NON-REM sleep: non rapid eye movement Sleep: It is an architectured cyclic process. The following are stages of sleep. Stage 0: (awake) 1-2% Stage 1: (dosing) 3-6%Stage 2: (un equivocal) 40-50% Stage 3: (deep sleep transition) 5-8% Stage 4: (cerebral sleep) 10-20%

Classification of drugs: Barbiturates:

Long acting:

Short acting Ultra short acting

Phenobarbitone Butobarbitone Thiopentone

Pentobarbitone Methohexitone

Benzodiazepine: Diazepam Flurazepam Nitrazepam Alprazolam Triazolam Non benzodiazepine: Zopiclone Zolpidem zaleplon

Barbiturates:

These are prototype of CNS depressants. Barbiturate are substituted derivatives of barbituric acid(malonyl urea). Barbituric acid as such is not a hypnotic but compounds with alkyl or aryl substitution on C5. Replacement of O with S at C2 yields thiobarbiturate which are more lipid-soluble and more potent. They are insoluble in water but their sodium salts dissolve yielding highly alkaline solution.

Pharmacological actions:

Barbiturates are general depressants for all excitable cells.CNS is more sensitive. Effect is more global but certain areas are

suseptible.

CNS: They show dose-dependent effect. Hypnotic dose:(100-200mg of short acting barbiturate) Shortens the time taken to fall asleep , • increases sleep duration , • Night awakenings are reduced,• Hangover in the morning.

Sedative dose:

(Small dose of long acting barbiturate )• Drowsiness • Reduction in anxiety and excitability • Impaired learning short term memory, • Hyperalgesia and • euphoria addicts.

Mechanism of action: Barbiturates appear to act primarily at the GABA : BZD receptor –Cl channel complex.

• Potentiate GABAergic inhibition by increasing the lifetime of Cl channel opening induced by GABA.

•They do not bind to the BZD receptor, but bind to another site.

•The barbiturate site appears to be located on alpha &beta subunits.

Other systems:Respiration: It is depressed by relatively higher doses. Neurogenic, hypoxic drives to respiratory centre are depressed in succession. Barbiturates do not have antitussive action.

•Effects of barbiturates:

At high concentration, barbiturates directly Increase Cl conductanceInhibit Ca2+ dependent release of neurotransmitters. At very high concentrations, barbiturates Depress voltage sensitive Na+ & k+ channels.

CVS: Hypnotic doses of barbiturates produce a • slight decrease in BP & Heart rate, • Toxic doses produce marked fall in BP due to ganglionic blocked, •Vasomotor centre depression, •Decrease in cardiac contractility. •Reflex tachycardia can occur, though presser reflexes are pressed • The dose producing cardiac arrest is about 3 times larger than that causing respiratory failure.

Pharmacokinetics: Barbiturate are well absorbed from the G.I tract. They are widely distributed in the body.The rate of entry into CNS is dependent on lipid solubility. a)Redistribution: It important in case of highly lipid soluble thiophene & other. After their .v. injection, consciousness is regained in 6-10 min due to redistribution.

b)Metabolism: Short acting barbiturates are primilarly metabolized in liver by

oxidation,dealkylation&conjugation.

c)Excretion : Long acting agents are significantly excreted unchanged in

urine. Uses: Phenobarbitone used in epilepsy, Thiopentone in anaesthesia, The enzyme inducing property of phenobarbitone can be

utilized to hasten clearanceof congential nonhaemolytic jaundice .

Adverse effects: a. Idiosyncrasy. b. Hypersensitivity. c. Tolerance &dependence

Treatment:

1. Gastric lavage: 2. Supportive measures: 3. Alkaline diuresis:4. Haemodialysis & haemofusion There is no specific anti dote for Barbiturates. In the past, analeptics like metrazole, bemegride, have been

used as an attempt to awaken the patient. This is dangerous, may precipitate convulsions while the patient

is still comatose- mortality may be increased. The emphasis is now keeping the patent alive till the poison is

eliminated.

USES:

Phenobarbitone in epilepsy. Thiopentone in anaesthesia. Occasionally employed as adjuvants in psycosomatic disorders. Enzyme inducing property of phenobarbitone is utilised to hasten clearance of congenital non haemolytic jaundice and kernicturus. ADVERSE EFFECTS:

Side effects Idiosyncrasy Hypersensitivity •Tolerance and dependence Acute barbiturate poisoning is mostly susidal , some times accidental . Lethal dose depends on lipid solubility. It is 2-3g for the more lipid soluble agents and 5-10g for less lipid soluble.

Benzodiazepine:

•Chlorodiazepoxide & diazepam were introduced around 1960 as antianxiety drugs. • Since this class has gained popularity over barbiturates as hypnotic and sedative as well. •BZDs have a high therapeutic index. •Hypnotic doses do not affect respiration or cardiovascular functions.

•High doses produce mild respiratory depression & hypotension.

•BZDs cause less distortion of sleep architecture.

•BDZs do not alter disposition of other drugs by microsomal enzyme induction.

•They have lower abuse liability.

Why Do People Use Benzodiazepines?

To get away fromthis!

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Mechanism of action:BZDs act preferentially on mid brain ascending reticular formation and a limbic system .

Muscle relaxation is produced by a primary medullary site of action on cerebellum.

BZDs acts by enhancing pre/post synaptic inhibition through a specific BZD receptor which is an integral part of the GABA –A receptor cl channel complex.

It has α and β sub units which are required for GABA action and the binding site of GABA is present on β sub unit.

BZDs do not increase cl conductance they only have GABA facilitatory action but not GABA mimetic action.

For example,GABA antagonist bicuculline antagonizes BZD action in a non-competitive manner.

The competitive BZD-antagonist flumazenil blocks the sedative action of BZD as well as convulsant action of DMCM.

Pharmacokinetics:BZDs differ in lipid solubility by >54X .Oral absorption of some drugs is rapid while others is slow

DRUG t1/2 (hr) redistribution Hypnotic dose (mg)

Clinical indications

LONG ACTING:

Flurazepam 50-100 - 15-30 Chronic insomniadiazepam 30-60 + 5-10 Short term insomnia

nitrazepam 30 +/- 5-10 Frequent nocturnal awakening

SHORT ACTING

alprazolam 12 + 0.25-0.5 Sleep onset difficulty

temazepam 8-12 + 10-20

triazolam 2-3 +/- 0.125-0.25

ADRsDizzinessVertigoAtaxiaDisorientationAmnesiaProlongation of reaction timeINTERACTIONS

BZDsSynergize with alcohol and other CNS depressants.Concurrent use with sodium valproate has provoked psychotic symptoms .Cimetidine , isoniazide and oral contraceptives also retard BZD metabolism

Pharmacological actions:

ON CNS. . . The over all action of al BZDs is qualitatively similar to barbiturates. But differ in time selectivity and course of action. They significantly differ among different BZDs. They hasten onset of sleep and reduce intermittent awakening and increase total sleep time. Night terrors and body movements during sleep are reduced and subject wakes up with refreshing sleep.

Mild tolerance is seen. They produce centrally mediated skeletal muscle relaxation without impairing voluntary action. Ex: clonazepam and diazepam's: I.V diazepam causes analgesia. Diazepam decreases nocturnal gastric secretions and prevent stress ulcers. Short lasting coronary dilatation is produced by I.V diazepam.

NON BZD –HYPNOTICS:

ZOPICLONE: This is newer cyclopyrolone hypnotic at sub type of BZD receptor involved in hypnotic action .It does not alter REM sleep and tends to prolong stagses 3&4 sleep.T1/2 is 5-6 hrs .It is indcated for short term treatment for insomnia.

SIDE EFFECTS: Metalic taste Impaired jurdgementDry mouth.

ZOLPIDEM:

An imidazopyridine acts on alpha -1 sub unit.Sleep latency is shortened.Sleep duration is prolonged.Very less side effects.Plasma t1/2 is 2 hrs.

ZALIPLON:This is shortest acting newer non-BZD hypnotics that selectively act on a subset of BZD R’s containing the alpha -1 subunit which appear to mediate the hypnotic action.

Effective only in sleep- onset insomnia, reduce the no’s awakenings.

T1/2 is 1 hour.

Its efficacy is similar to zolpidem.

Summary:

Sedatives:BenzodiazepinesAntipsychotics

Hypnotics: (Non-pharmacological 1st)AntihistaminesZolpidemBenzodiazepines (rapid onset, short t1/2)

Anxiolytics:Benzodiazepines (acute)Antidepressants (chronic)

REFERENCES: K.D TRIPATHIROGER WALKERDIPIRO

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