Hypnotic - Sedative Dr.Kumari Anjana Assistant

Hypnotics:
A drug that induces and/or maintains sleep, similar to normal arousable sleep.
Hypnosis is derived from ‘Hypnos’, the Greek god of sleep.
Effect produced by hypnotics – hypnosis.
These drugs produces drowsiness and facilitate the onset and maintenance of a state of sleep.<br>

Salient features of Sedatives and Hypnotics:

The Sedatives and Hypnotics are more or less general CNS depressants with some what differing time-action and dose action relationships.

Those with quicker onset, shorter duration and steeper dose-response curves are preferred as hypnotics while more slowly acting drugs with flatter dose-response curves are employed as sedatives.

However, there is considerable overlap; a hypnotic at lower dose may act as sedatives. Hypnotic- Sedatives<br>

Thus, sedation-hypnosis-general anesthesia may be regarded as increasing grades of CNS depression.
Both Sedatives and Hypnotics do not possess analgesic property, but dull the perception of pain sensation.

Hypnotics given in high doses can produce general anesthesia.

Hypnotics in higher doses cause deep sleep (narcosis) and hence are also called as narcotics.

Treatment of insomnia is the most important use of this class of drugs.<br>

The difference between sedatives and tranquillizers is also indistinct except that the tranquillizers produce a state of calmness with less drowsiness.

Tranquillized animals are usually easy to handle, but they may be aroused by and respond to stimuli in a normal way (biting, scratching and kicking).

In veterinary medicine Sedatives are generally used to restrain, to facilitate handling and transport, and to modify behavior of animals.

Sedatives are commonly included in pre- anesthetic medication and are also used to facilitate minor surgery or diagnostic procedures.<br>

Dose response curve of sedative and hypnotics Drug A
Barbiturates
Steeper DRC
Narrow margin of safety

Drug B
Benzodiazepines
Flatter DRC
Wide margin of safety<br>

Classification of Hypnotic- Sedatives<br>

Barbiturates Derivative of barbituric acid (A condensation product of urea and malonic acid).

Classification of barbiturates based on duration of action:
Long acting-(4-6 hr) - Barbitone, Phenobarbitone, methylphenobarbitone,
aprobarbitone
Intermediate acting (2-4 hr) - Pentobarbitone, Butobarbitone

Short acting (1-2 hr) - Secobarbitone, Pentobarbitone, quinalbarbitone

Ultra Short acting (20-40 min.) - Thiopentone, Thiamylal, hexobarbitone, methylhexitone<br>

MOA of barbiturates: potentiate GABAergic inhibition.

The long, medium and short acting barbiturates are generally used as hypnotics and sedative.

Barbitone, Phenobarbione, methylphenobarbione, butobarbitone, Pentobarbitone and Amobarbitone are the most commonly used barbiturates.

All barbiturates have reversible depressant effect on the activity of all excitable cells, the CNS being more sensitive.

At hypnotic doses, it produce very little effects on cardiac smooth or skeletal muscle.

Long acting barbiturates are better inducer of hepato-microsomal enzymes in comparison to short acting barbiturates .<br>

Benzodiazepines are commonly used as sedatives or hypnotics in man and dog.
These compounds have several advantages over barbiturates as hypnotic and sedatives. ---
Benzodiazepines have high therapeutic index. Ingestion of even 20 hypnotic doses does not usually endanger life—there is no loss of consciousness.
Hypnotic doses do not affect respiration or cardiovascular function.
BZDs have practically no action on other body systems. Only on i.v. injection the BP falls and cardiac contractibility decreases.
BZDs do not alter disposition of other drugs by microsomal enzyme induction.
Their toxicity (due to higher dosage) can be overcome by giving specific benzodiazepine receptor antagonist flumazenil. Benzodiazepines<br>

Hypnotic- Diazepam,
Flurazepam,
nitrazipam
flunitrazepam
Anxiolytics:- Diazepam,
Chlordiazepoxide,
Oxazepam
Lorazepam.
Anticonvulsants-Diazepam,
Clonazepam Classification of Benzodiazepines<br>

Mechanism of Action of Benzodiazepines Fig: GABAA Benzodiazepines receptor-Cl- channel complex

Source: Book : Essentials of Medical Pharmacology<br>

Benzodiazepines preferentially act on mid brain ascending reticular formation (maintains sleep-wakefulness cycle) and on limbic system (thought and mental functions).

Their mechanism of action is through enhancing presynaptic or postsynaptic inhibition of specific benzodiazepine receptor which is an integral part of GABAA receptor-Cl- channel complex.

The subunit of this complex form a pentameric transmembrane anion channel gated by the primary ligand (GABA), and modulated by secondary ligands BZDs.<br>

Only the α and β subunits are required for GABA action, and most likely the binding site for GABA is located on the β subunits, while the α /γ subunit interface carries the BZDs binding site.

The modulatory BZD receptor increases the frequency of CI- channel opening induced by submaximal concentrations of GABA. The BZDs also enhance binding of GABA to GABAA receptor.

It is noteworthy that, the BZDs do not themselves increase CI- conductance, these exert only GABA facilitation, but not GABA mimetic action.

GABA modulates activation of Cl-channels within the neuronal membrane of excitable neurons.<br>

Pharmacokinetics: Oral absorption of benzodiazepines differs due to their variation in lipid solubility.

These drugs due to lipid solubility gain access into CNS.

Benzodiazepines are metabolized in liver through Most of the benzodiazepine drugs have active metabolites (glucuronide conjugates) are excreted through urine.

Most of the benzodiazepine drugs have active metabolites (chlordiazepoxide, desmethyldiazepam, diazepam, flurazepam etc.) which undergo enterohepatic recycling (have long half-lives).

Chlorazepine is metabolically activated to desmethyldiazepine, which is further metabolically activated to oxazepam.<br>

Miscellaneous agents Chloral hydrates:
It is one of the oldest and most important drug for induction ofsedation in large animals.
For sedation it is administered IV or oral route, however, IV route is preferred.
Horse: It is used to quiten the animals for shoeing or other procedures and it is also used in treatment of colic.
Horses: 22.5-30 g /450kg by IV route.
60g /450kg by stomach tube.
Cattle: 10.5- 17.5 g /450kg by IV route
15- 45 g /450kg by oral route.
Sheep and Pigs: 2-4 g by oral route.
Camel: 100mg/kg by IV route.<br>

Xylazine hydrochloride Xylazine is classified as an analgesic as well as a sedative and skeletal muscle relaxant.
It is not a neuroleptic or tranquillizer nor an anaesthetic agent.
Xylazine is a potent a2-adrenergic agonist.
Through its central stimulation of a2-adrenergic receptors, xylazine has potent antinociceptive or analgesic activity.
It is most suitable sedative for use in ruminants. In cattle, doses that produce deep sedation and analgesia are 1/10th those required in horses, dogs and cats.
It is not effective in swine.<br>

Doses:
Dog & cat : 1.1 mg/kg I.V. route ; 2.2 mg/kg I.M. or SC route.
Horse: 1.1 mg/kg I.V. route ; 2.2 mg/kg I.M. or route.
Cattle: 0.1 – 0.35 mg/kg I.M. route.
Goat: 0.1 mg/kg I.V. or route.<br>

Detomidine hdrochloride:
It is selective a2-adrenergic agonist, developed as sedative and analgesic for use in animals.
It produces biphasic response on BP, (initial rise in BP but subsequently, BP falls).
It is effective in very low concentration.
Cattle and Horse: 10-30 µ g/kg I.V. route.
Goat: 10-40 µ g/kg I.V. or route.
Sheep : 30 µ g/kg I.V. or route.

Medetomidine hydrochloride:
It is also selective a2-adrenergic agonist.
It is a mixture of two optical isomers, the dextrorotatory isomer being the active components.
It is used in animals as a sedative hypnotic analgesic and as pre-anesthetic medication.<br>

Uses :
As chemical restraints.
To induce sleep.
As preanaesthetics.<br>

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