Hypnotics and Sedatives | Pharmacology

This article provides an overview on hypnotics and sedatives.

Hypnotics are drugs which produce drowsiness and facilitate the onset and maintenance of a state of sleep resembling natural sleep in its electroencephalogram (EEG) features and from which the recipient may be easily aroused. The effect produced by hypnotics is known as hypnosis.

Sedatives are the drug which moderately depress the central nervous system (CNS), moderate the excitement and calm the recipient. The effect produced by sedatives is known as sedation. All hypnotics in lower doses act as sedatives.

Both hypnotics and sedatives induce widespread depression of CNS, however, being mainly quantitative. All these agents are, thus, clinically employed as antianxiety, anti-epileptics, muscle relaxants and/or pre-anaesthetics. For understanding the effects of hypnotics or sedatives, basic physiology of sleep mechanism needs to be understood.

Reticular activating system (RAS) is responsible for wakefulness. Sleep and wakefulness are dependent on the release of neuro-humoral substances. Drugs that influence the activity of any one of the neurotransmitters would affect sleep process.

Serotoninergic neurons are richest in the raphe nuclei which are located in the midline areas of the pons and mid brain and are closely associated with the ascending reticular formation.

Many workers have reported that destruction of raphe nuclei cause insomnia in experimental animals similar to that as produced by the administration of p-chlorophenylalanine that prevents the synthesis of serotonin. Reduction, depression or inhibition of the activity of RAS results in sleep. Therefore, sleep can be encouraged by drugs that are known to inhibit transmission of impulses in reticular system.

Based on the EEG characteristics, mainly two stages of sleep are important:

Slow Wave Sleep (SWS):

During this stage, the eye balls remain motionless, muscles under chin are tense and EEG shows predominantly high voltage synchronous activity and subject is hard to arouse. Insomniacs generally have the normal SWS.

Rapid Eye Movement (REM) Sleep:

In REM sleep, the eye balls make rapid, jerky and irregular movements whereas the skeletal muscles completely relax. EEG shows no spindles. These two stages of sleep alternate throughout the sleep period; the REM sleep maximally making up to 25 per cent of the total sleep period. REM sleep is accompanied by dreams and 75 per cent of the dreams occur in REM sleep.

Classification of Hypnotics and Sedatives:

Depending on the chemicals nature the main groups are:

(a) Barbiturates;

(b) Benzodiazepine derivatives; and

(c) Miscellaneous agents

Barbiturates:

These are the derivatives of barbituric acid which is a condensation product of urea and malonic acid.

Depending on the duration of action, the barbiturates have been divided into 4 classes:

(i) Long Acting Barbiturates (8 hrs. or more): e.g. Phenobarbitone, barbitone, methyl-phenobarbitone and aprobarbitone.

(ii) Intermediate Acting Barbiturates (4-8 hrs.): e.g. Butobarbitone, mephobarbitone, cyclobarbitone and amylobarbitone.

(iii) Short Acting Barbiturates (< 4 hrs.): e.g. pentobarbitone, secobarbitone and quinalbarbitone.

(iv) Ultra-short Acting Barbiturates (< 30 min): e.g. thiopentone, thiamylal, hexobarbitone and methylhexitone.

The long, medium and short acting barbiturates are generally used as hypnotics and sedatives. Barbitone, phenobarbitone, methyl-phenobarbitone, butobarbitone, amebarbitone, and pentobarbitone are the most commonly used barbiturates.

Pharmacological Action:

All barbiturates have reversible depressant effect on the activity of all excitable cells, the central nervous system being more sensitive. Hypnotic doses, however, produce very little effects on cardiac, smooth or skeletal muscles.

Mechanism of Action:

Barbiturates primarily act at the GABA – Benzodiazepine receptor – CI^– channel complex arid potentiate GABAergic inhibition by augmenting the Cl^– conductance mediated by GABA.

Preparation and Dosage:

Barbitone Sodium:

It is not given by IV route as it paralyses the vital medullary centres. Administered by oral route. Used as hypnotic, sedative and anticonvulsant.

Dogs: 150-1000 mg/day

Cats: 100-300 mg/day

Amobarbitone Sodium:

Sedative and basal anaesthetic dose in all species of animal is 4-11 mg/kg.

Phenobarbitone Sodium:

Dogs: 7.5-15 mg/kg t.i.d.

Cats: 15-60 mg t.i.d.

Secobarbitone Sodium:

Dogs and Cats: 30-200 mg

Pentobarbitone Sodium:

For all species of animals, the oral sedative dose is 4. 4 mg/kg, however, IV dose is 1-1.5 mg/kg and is given to effect. However, it is generally used for anaesthetic purpose. In swine, it is given intramuscularly @ 2.2-6.6 mg/kg body weight.

Compared to short acting barbiturates, long acting barbiturates are better inducers of hepatomicrosomal enzymes. And, on molar basis, phenobarbitone is the most potent enzyme inducer. It may take up to 7 months for its complete disappearance in dogs.

Benzodiazepine Derivatives:

These are the most important sedatives and hypnotics because of their high therapeutic index, least adverse effects on the cardiopulmonary functions and these do not alter disposition of other drugs by microsomal enzyme induction. These are used as hypnotics, sedatives, tranquilizers and anticonvulsants in animals. All compounds of this class hasten the onset of sleep, reduce the intermittent awakening and increase the total sleep time.

Benzodiazepines produce relaxation, without affecting the voluntary activity.

Depending on the duration of action, these are divided into two groups:

(i) Long Acting Benzodiazepines: e.g. Diazepam, flurazepam, nitrazepam, flunitrazepam etc.

(ii) Short Acting Benzodiazepines: e.g. Midazolam, triazolam, timazepam, lorazepam, oxazepam.

Mechanism of Action:

Benzodiazepines act on mid-brain ascending reticular formation and limbic system. These potentiate the GABAergic neurotransmission. Activation of type II BZP receptors result in interaction with GABA receptor Cl^– ionophore complex and increased Cl^– conductance and hence decreased firing in these regions of CNS.

Preparation and Dosage:

Diazepam is commonly used in veterinary medicine. It can be administered by oral, intramuscular or intravenous routes for sedation, anticonvulsant and preanesthetic effects.

Dogs: 1 mg/kg with a maximum of 20 mg by IV or oral route.

Cats: 1 mg/kg with a maximum of 5mg by the same routes.

Goats: 0.88 mg/kg by IM route.

Cattle: 0.4 mg/kg by IV route.

Swine: 8.5 mg/kg by IM route.

In goats, diazepam has been reported to prolong the period of analgesia, increase muscle relaxation and prevents reflex movement of limbs.

Miscellaneous Agents:

(i) Chloralhydrate:

Chloralhydrate is one of the oldest and most important and dependable drug for induction of sedation in large animals. For sedative use, it is administered by IV or oral route, however, IV route is preferred over oral route. Perivascular leakage should be avoided.

In horses it is used to quieten the animals for shoeing or other procedures lasting for 30-60 minutes and in treatment of colic. The typical signs of chloralhydrate induced sedation in horses are: head drops, eyes may close, incoordination of the hind limbs; large doses may result in recumbency. Recovery take about 30-60 min.

Doses:

Horses: 22.5-30 g/454 kg by IV route; 60 g/454 kg orally by a stomach tube.

Cattle: 10.5-17.5 g/454kg by IV route; 15-45 g/454 kg by oral route.

Sheep and Pigs: 2-4 g by oral route.

Camel: 100 mg/kg by IV route.

(ii) Paraldehyde:

It is a rapidly acting hypnotic and is a polymer of acetaldehyde. It is devoid of analgesic action. Large doses produce cardiopulmonary depression. It is administered by rectal infusion and is used for the treatment of tetanus and strychnine poisoning.

(iii) Methaqualone:

It has hypnotic, analgesic, anticonvulsant, antispasmodic, local anaesthetic and weak antihistaminic properties.

(iv) Glutethimide:

Its pharmacological actions are similar to that of the barbiturates, however, cardiopulmonary depression is low.

(v) Xylazine Hydrochloride:

It is a potent α₂ adrenergic receptor agonist and classified as an analgesic, sedative and skeletal muscle relaxant. It is one of the most suitable sedatives for use in ruminants as these are most sensitive of all the domestic animals. The doses required for deep sedation and analgesia in cattle are l/10th of that required for horses, dogs and cats however, it is not effective in swine.

Intramuscular or IV injections of xylazine produce depressant effects on myocardial contractility, hypotension and bradycardia. It also sensitizes myocardium to the action of catecholamine’s. Thus, the general anaesthetics must be used very cautiously and the patient be continuously monitored following use of xylazine.

Doses:

Dogs and Cats: 1.1 mg/kg by IV route; 2.2 mg/kg by IMor SC route

Horses: 1.1 mg/kg by IV route; 2.2 mg/kg by IM route

Cattle: 0.1-0.35 mg/kg by IM route

Goats: 0.1 mg/kg by IV route.

(vi) Detomidine Hydrochloride:

It is a selective α₂ adrenoceptor agonist and has been developed as a sedative and analgesic for use in animals. It is not effective if administered orally and is thus given by IV or IM routes. It causes marked bradycardia and initial rise in blood pressure but subsequently, the BP falls i.e. biphasic effect on B.P. It is primarily used as a sedative -analgesic in horses. It is effective at very low concentrations/doses.

Doses:

Cattle and Horses: 10-30 µg/kg by IV route

Goats: 10-40 µg/kg by IM or IV route

Sheep: 30 µg/kg by IM or IV route.

(vii) Medetomidine Hydrochloride:

It is also a selective α₂ adrenoceptor agonist and is a mixture of two optical isomers, the dextrorotatory isomer being the active component. It is used in animals as a sedative, hypnotic, analgesic and premedicant; Cardiovascular effects like bradycardia, arterial hypertension followed by hypotension and reduced cardiac output are similar to that of detomidine. It is nonirritant and can be administered by IV, IM or SC routes. Like detomidine, it is also effective at very low doses.

Doses:

(viii) Phenothiazine Derivatives:

Drugs of this group are generally classified as neuroleptics or antipsychotics. These compounds have wide central and peripheral effects. The degree of sedation produced varies markedly between drugs. Sedation is an unwanted side effect in medical practice, however, in veterinary practice, phenothiazine derivatives are primarily used for this purpose.

Acepromazine:

It is probably the most extensively used phenothiazine in veterinary practice. Dose for most of the domestic animals is 0.025-0.1 mg/kg by IM route.

Propionylpromazine:

Horses: 0.15-0.25 mg/kg IM

Dogs: 0.2-0.3 mg/kg IM

Promazine:

Horses: 1 mg/kg

Triflupromazine:

Camel: 2 mg/kg IM