SEDATIVES AND HYPNOTICS

Sedatives:- A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced.

Hypnotics:- A drug that induces and/or maintains sleep, similar to normal arousalable sleep.

These are more or less general CNS depressant with differing time-action and dose -action relationships.

·         Those with quicker onset, shorter duration and steeper dose response curve are preferred as hypnotics.

·         more slowly acting drugs with flatter dose response curves are preferably used as sedatives.

·         However, a hypnosis at lower dose may act as sedative. Thus, sedation - hypnosis - general anaesthesia may be regarded as increasing grades of CNS depression. All hypnotics given in higher dose can produce general anaesthesia.

USE:    Sedatives and hypnotics are mostly used in insomnia (loss of sleep).

CLASSIFICATION OF SEDATIVES AND HYPNOTICS

1. Barbiturates: According to duration of action divided into :

Long acting	Short acting	Ultra short acting
Phenobarbitone Mephobarbitone	Butobarbitone Secobarbitone Pentobarbitone	Thiopentone Hexobarbitone Methohexitone

2. Benzodiazepines: May be divided according to their primary use:

Hypnotics	Antianxiety	Anticonvulsant
Diazepam Flurazepam Nitrazepam Flunitrazepam Temazepam Triazolam Midazolam	Diazepam Chlordiazepoxide Oxazepam Lorazepam Alprazolam	Diazepam Clonazepam

3. Miscellaneous:

            Chloralhydrate, Glutethimide, Methyprylon, Paraldehyde, Methaqualone, Meprobamate.

4. Others:

            Some antihystaminics:             Promethazine, Diphenhydramine

            Some neuroleptics:                  Chlorpromazine, Triflupromazine

            Opioids;                                   Morphine, Pethidine

            Some anticholinergics:             Hyoscine

MODE OF ACTION of Barbiturates:

N.B.

            GABA = Gama Amino Butyric Acid

            GABA_A receptors in CNS ®   produce an increased chloride conductance.

            GABA_B receptors in CNS ®   reduce the calcium currents and increase K⁺ - permeability.

The GABA-benzodiazepine-chloride channel receptor complex:

·         This is receptor complex consisting of receptor sites for GABA and BZDs. The complex contains a chloride channel. when GABA binds with its site the chloride channel opens and an inhibitory signal is propagated through the neuron.

·         When BZD binds with its site the affinity of the GABA molecules for its own site is increased and vice versa; i.e. they are allosteric sites to each other.

·         BZD binds to its own site ® Affinity of GABA to its site is increased ® Chloride channel opens ® Inhibitory signals are propagated.

·         b-carboline 3-carboxylate (b-CCE) inhibits binding of BZD ® inhibits chloride channel opening by GABA ® so convulsant action is produced and anxiety precipitates.

Two state model

Benzodiazepine exists in two distinct conformations:

(i)     Conformation A can bind GABA molecule and open chloride channel.

(ii)   Conformation B cannot remain in equilibrium.

·         When BZD-agonist (e.g. diazepam) is not present, between these two conformations, sensitivity to GABA is present, but sub-maximal.

·         BZD-agonist (e.g. diazepam) binds to conformation A

            ® shifting the equilibrium in favour of A

            ® enhances GABA sensitivity

            ® more amount of GABA binds ® chloride channel open ® inhibitory impulse.

·         BZD-inverse agonist binds selectivity with conformation B

            ® shifting the equilibrium in favor of B and

            ® reduces GABA sensitivity

            ® less GABA binds (practically do not binds) ® Cl^- channels do not open

            ® anxiety and convulsion occurs.

MOA of Barbiturates

·         Barbiturates share the same BZD-GABA-Chloride channel ion receptor complex but they bind to a different site.

·         Barbiturate potentiate GABA-ergic inhibition by increasing the life-time of Cl^-channel opening induced by GABA

            (i) Barbiturates enhance BZD binding to its receptor.

            (ii) At high concentration barbiturates directly increases Cl^-  conductance i.e. GABA-mimetic           action.

            (iii) a very high concentration depress Na⁺ and K⁺ channels also.

Pharmacology of barbiturates

Barbiturates are general, non-specific depressants of all excitable cells. CNS is most sensitive.

1  CNS

Barbiturates produce dose dependent effects:

                        sedation ® sleep ® anaesthesia ® coma

(i)      Sedative dose: (i.e. smaller dose of a long acting barbiturate) given at day time produces drowsiness, reduction in anxiety and excitability.

(ii)   Hypnotic dose (100 - 200 mg of a short-acting barbiturate) shortens the time taken to fall asleep and increases the sleep duration. The sleep is arousable, but the subject may feel confused and unsteady if waken earl. REM and Stage 3 and 4 of NREM sleep decreases.

(iii) REM ad NREM sleep cycle is disrupted. S nightmare is reduced.

(iv) Longer acting (phenobarbitone) barbiturates have high anti-convulsant action which is independent of general CNS depression.

(v)   Barbiturate depresses all areas of the CNS, but the reticular activating  system is most sensitive, its depression is primarily responsible for inability to maintain normal wakefulness.

2 Respiration

At relatively higher dose they depresses the respiration-centre in the brain.

3. CVS

hypnotic dose produce slight decrease of blood pressure(BP) and heart rate.

toxic dose produce marked fall in BP due to

            ganglionic blockade

            vasomotor center depression and

            direct decrease in cardiac contractility.

Dose required to produce cardiac arrest is 3 times larger than that required for causing respiratory failure.

4. Smooth muscles

Hypnotic dose reduces the tone and motility of muscles of intestine. Action on other smooth muscles are not significant.

5. Kidney

Barbiturates tend to reduce urine flow by

                        decrease in BP

                        increase in ADH release (Anti-Diuretic Hormone).

Dose:

Drug	Dose	(mg)	Trade Names
	Hypnotic	Sedative
Phenobarbitone Butobarbitone Pentobarbitone Secobarbitone	60 to 100 100 to 200 100 100	15 to 30 15 to 60 30 30	GARDENAL/ LUMINAL SONERYL NEMBUTAL LIPATON

Uses:

1.      As hypnotic and to control mania and delirium (N.B.) now superseded by BZDs and phenothiazines).

2.      Sedatives: as adjuncts in chronic asthma, peptic ulcer, hyper tension, thyrotoxicosis etc.

3.      Anticonvulsant: used in epilepsy. It is also used intravenously for emergency control of continuous, but has slow action. Thiopentone may be used for quick action.

4.      Anaesthetic Thiopentone given intravenously.

5.      Preanaesthetics Pentobarbitone, secobarbitone or butabarbitone - long acting barbiturates are given before the anaesthesia to calm down the patient.

6.      Congenital non-haemolytic jaundice: Phenobarbitone induces conjugation of bilirubin and hastens the clearance of jaundice.

Mainly they are used in anaesthesia and in the treatment of epilepsy.

ADVERSE EFFECTS

1. Side effects:

hangover is common after the use of barbiturates as hypnotics, because they have long plasma half-life. On repeated use  they accumulate in the body - produce tolerance and dependence. Mental confusion, impaired performance and traffic accident may occur.

2 Idiosyncrasy

In some patients barbiturates produce excitement. This is more common in the elderly patients.

3 Hypersensitivity

Rashes, swelling of eye-lids, lips etc.

4. Tolerance and dependence

Barbiturates produce a high degree of tolerance and dependence.

On repeated use both cellular and pharmacokinetic tolerance occurs.

Cellular / Tissue tolerance       Higher dose is required at the site of action to produce the same effect                                                          that was produced initially.

Pharmacokinetic tolerance      production of lower blood concentration with prolonged usage.

MOA: Barbiturates strongly induce the synthesis of hepatic cytochrome P-450 and conjugating enzymes and this increases the rate of metabolic degradation of many other drugs, giving rise to a number of potentially troublesome drug interactions.

5. Dependence

After a prolonged treatment, if the treatment is stopped then anxiety, tremor, dizziness occurs. The withdrawal syndrome is intense in human - excitement, hallucinations, delirium, convulsive disorders.