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Complete Explanation of Sedative-Hypnotics

Sedative: 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. Hypnotic A drug that induces and/or maintains sleep, similar to normal arousable sleep. This is not to be confused with ‘hypnosis’ meaning
a trans-like state in which the subject becomes passive and highly suggestible. The sedatives and hypnotics are more or less global CNS depressants with somewhat 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 a lower dose may act as a sedative.

Thus, sedation—hypnosis—general anaesthesia may be regarded as increasing grades of CNS depression. Hypnotics given in high doses can produce general anaesthesia. However, benzodiazepines (BZDs) cannot be considered nonselective or global CNS depressants like barbiturates and others. Treatment of insomnia is the most important use of this class of drugs. Alcohol and opium have been the oldest hypnotics and continue to be used for this purpose as self-medication by people. Bromides introduced in 1857 are now obsolete, so
are chloral hydrate (1869) and paraldehyde (1882).

Fischer and von Mering introduced barbitone in 1903 and phenobarbitone in 1912. Barbiturates reigned supreme till the 1960s when benzodiazepines started eroding their position and have now totally replaced them. In the meantime, a number of other sedative-hypnotics (glutethimide, methyprilon, methaqualone) were introduced but none was significantly different from barbiturates; all are redundant now. Some nonBZD hypnotics have become available over the past two decades, and a novel melatonin receptor agonist ramelteon has been introduced.
Sleep. The duration and pattern of sleep vary considerably among individuals. Age has an important effect on the quantity and depth of sleep. It has been recognized that sleep is an architectured cyclic process. The different phases of sleep and their characteristics are— Stage 0 (awake) From lying down to falling asleep and
occasional nocturnal awakenings; constitutes 1–2% of sleep time. EEG shows α activity when eyes are closed and β activity when eyes are open.

Eye movements are irregular or slowly rolling. Stage 1 (dozing) α activity is interspersed with θ waves.
Eye movements are reduced but there may be bursts of rolling. Neck muscles relax. Occupies 3–6% of sleep time.

Stage 2 (unequivocal sleep) θ waves with interspersed spindles, K complexes can be evoked on sensory stimulation; little eye movement; subjects are easily arousable. This comprises 40–50% of sleep time.

Stage 3 (deep sleep transition) EEG shows θ, δ and spindle activity, K complexes can be evoked with strong stimuli only. Eye movements are few; subjects are not easily arousable;
comprises 5–8% of sleep time.

Stage 4 (cerebral sleep) δ activity predominates in EEG, K complexes cannot be revoked. Eyes are practically fixed; subjects are difficult to arouse. Night terror may occur at this time. It comprises 10–20% of sleep time.
During stage 2, 3 and 4 heart rate, BP and respiration are steady and muscles are relaxed. Stages 3 and 4 together are called slow-wave sleep (SWS). REM sleep (paradoxical sleep) EEG has waves of all
frequency, K complexes cannot be elicited. There are marked, irregular and darting eye movements; dreams and nightmares The EEG waves have been divided into—

α: high amplitude, 8–14 c.p.s. (cycles per second)
β: low amplitude, 15–35 c.p.s.
θ: low amplitude, 4–7 c.p.s.
δ: high amplitude, 0.5–3 c.p.s.
K complex: deep negative wave followed by the positive wave

Heart rate and BP fluctuate; respiration is irregular. Muscles are fully relaxed, but irregular body movements occur occasionally. Erection occurs in males. About 20–30% of sleep time is spent
in REM. Normally stages 0 to 4 and REM occur in succession over a period of 80–100 min. Then stages 1–4–REM are repeated cyclically.

CLASSIFICATION

1. Barbiturates

  • Long-acting
  • Short-acting
  • Ultra-short acting
  • Phenobarbitone
  • Butobarbitone
  • Thiopentone
  • Pentobarbitone
  • Methohexitone

2. Benzodiazepines

  • Hypnotic Antianxiety Anticonvulsant
  • Diazepam Diazepam Diazepam
  • Flurazepam Chlordiazepoxide Lorazepam
  • Nitrazepam Oxazepam Clonazepam
  • Alprazolam Lorazepam Clobazam
  • Temazepam Alprazolam
  • Triazolam

3. Newer nonbenzodiazepine hypnotics

  • Zopiclone
  • Zolpidem
  • Zaleplon

Chloral hydrate, Triclophos, Paraldehyde, Glutethimide, Methyprylon, Methaqualone and Meprobamate are historical sedative-hypnotics no longer used. They are described in earlier editions of this book.
In addition some antihistaminics (promethazine, diphenhydramine), some neuroleptic/antidepressants
(chlorpromazine, amitriptyline), some anticholinergic (hyoscine) and opioids (morphine, pethidine) have significant sedative action but are not reliable for the treatment of insomnia.

BARBITURATES

Barbiturates have been popular hypnotics and sedatives of the last century up to 1960s, but are
not used now to promote sleep or to calm patients. However, they are described first because they
are the prototype of CNS depressants. Barbiturates 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 are. Replacement of O with S at C2 yields thiobarbiturates which are more lipid-soluble and more potent. Barbiturates have
variable lipid solubility, the more soluble ones are more potent and shorter acting. They are insoluble in water but their sodium salts dissolve yielding highly alkaline solution.

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