2. Overview of the chapter
🠶 Introduction (Sedatives, Hypnotics).
🠶 Salient features of Sedatives and Hypnotics.
🠶 Classification of Hypnotic- Sedatives
🠶 Barbiturates
🠶 Benzodiazepines (advantages over barbiturates, MOA)
🠶 Cloralhydrates
🠶 Paraldehyde
🠶 Methaqualone
🠶 Glutithimide
🠶 Xylazine hydrochloride
🠶 Detomidine hydrochloride
🠶 Medetomidine hydrochloride
3. Sedatives
Sedatives:
🠶 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.
🠶 On the basis of the type of effect produced by sedatives, it can be
classified into two major groups:
Hypnotic – Sedative
Tranquillizers- Sedative
4. 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.
5. 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
6. 🠶 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.
7. 🠶 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.
8. 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
10. 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
11. 🠶 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 .
12. 🠶 Benzodiazepines are commonly used as sedatives or hypnotics in man and dog.
🠶 These compounds have several advantages over barbiturates as hypnotic and
sedatives. ---
o Benzodiazepines have high therapeutic index. Ingestion of even 20
hypnotic doses does not usually endanger life—there is no loss of
consciousness.
o Hypnotic doses do not affect respiration or cardiovascular function.
o BZDs have practically no action on other body systems. Only on i.v.
injection the BP falls and cardiac contractibility decreases.
o BZDs do not alter disposition of other drugs by microsomal enzyme
induction.
o Their toxicity (due to higher dosage) can be overcome by giving specific
benzodiazepine receptor antagonist flumazenil.
Benzodiazepines
14. Mechanism of Action of Benzodiazepines
Fig: GABAA Benzodiazepines
receptor-Cl-
channel complex
Source: Book : Essentials of
Medical Pharmacology
15. 🠶 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.
16. 🠶 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.
17. 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.
18. 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.
19. 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.
21. 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.
