Saturday, 13 December 2014

Pharmacology and chemistry of sedative & hypnotics

Sedatives & hypnotics are terms which have similarity but pharmacological meaning is different of the both. In this article, this topic is discussed in detail for the GPAT aspirants.

Sedative: This is the class of drug which decrease the excitement and calms down the patient. There will be a decreased response to any stimulation.

Hypnotics: Hypnotics are used for inducing sleep in the patient.

Sleep cycle

Sleep cycle
REM sleep (Paradoxical sleep):
  • There will be all waves in EEG.
  • Marked, irregular & darting eye movement.
  • Dreams & nightmares occur which can be recalled.
  • Heart rate & BP fluctuates.
  • Respiration irregular.
  • Muscles are fully relaxed.

Sleep cycle
  • One sleep cycle is of 80-100 minutes then it repeats.
  • There are four EEG wave ( [α - high amplitude- 8-14cps] [β - low amplitude- 15-35 cps] [ Q - low amplitude - 4-7 cps] [ δ - high amplitude .5-3 cps]
  • K complex: Deep negative wave followed by positive wave.
  • On the whole sleep cycle can be summarised as Stage 0------> NREM -------> REM------> NREM--------> REM ( NREM - 90 minutes & REM 20 minutes).

Sleep Factors

1. Neurotransmitter/ Neuromodulators: If a neurotransmitter is involved in wakefulness then it produce REM sleep. Similarly, its antagonist produce NREM sleep.

a) Catecholamines: Catecholamine transmission system is needed for the REM sleep.
  • α1 agonist (Methoxamine) : Decrease REM sleep.
  • α antagonist: REM sleep.
  • β blocker (Propanol): Insomania
b) Serotonin: Earlier it was believed that serotonin promotes sleep but now from studies, it has been evolved sleep occurs when this system becomes inactive.
  • 5HT1, 5HT2 & 5HT3 agonists: Wakefulness
  • 5HT2 antagonists (Ritanserin): Increase NREM sleeep.
c) Histamine: H1 antagonists (Diphenyl hydramine) & H3 antagonists; Induce sleep.
  • H2 receptors has little effect on the sleep.
d) Adenosine: A1 receptors causes hypnosis. Methoxamine act by A1 blocking & hence causes alertness.

e) GABA:  Inhibitory neurotransmitter and hence agonists of GABAa receptor induces sleep.

2. Neurohumoral modulators: 

a) Growth hormone & Prolactin: Growth hormone secreted during NREM sleep whereas prolactin secreted at the onset of sleep.

b) Melatonin: Hormone of darkness (MT1- sleep, MT2- Circadian rhythm, M3- Unknown).

c) CNS peptides: Hypocretins (Hcrt-1 & Hcrt-2) induces sleep.

Classification of sedatives-hypnotics
Classification of sedative-hypnotic

 Individual pharmacology & Chemistry of each class

1. Barbiturates: 

General synthesis of barbiturates

  • They were popular earlier but not used now due to toxicity.
  • Dose dependent action: Sedation ----> Sleep -----> Anesthesia -----> Coma.
  • Tolerance develops after sometime
Mechanism of action: Act at benzodiazepine + GABA receptor + Chlorine complex & increase GABAergic inhibition by increasing the lifetime of chlorine.

  • Further increasing dose, they directly increase chlorine conductance.
  • This is the main difference between benzodiazepine & barbiturates where benzodiazepines act as GABA facilitating only but barbiturates can act as GABA mimetic also.
Drug interactions:

  • Drug inducers: Lowers the plasma concentration of warfarin, steroids (including contraceptives), tolbutamide, griseofulvin, theophylline & Chloramphenicol.
  • Additive action: Alcohol, Opoids, Antihistamines.
  • Na valproate increase concentration of phenobarbitone.
  • Decrease absorption of griseofulvin from the GIT.
Structural activity relationships:

SAR of barbiturates
  • 5,5 disubstituted barbituric acid, 5,5 disubstituted thiobarbituric acid & 1,5,5 trisubstituted barbituric acids are active.
  • Active drugs are slightly basic in nature.
  • More the lipophilicity lesser will be duration of action.
  • 5,5 disubstitution: Aromatic substitution decrease lipophilicity.                                                                                   Branching, alkyl substitution, halogen to alkyl group increase lipophilicity.
  • Substitution on Nitrogen: Substitution at N1 increase lipophilicity.                                                                                         Large substitution at N1 gives convulsant property.                                                                       N1 & N3 substitution in same drug results in inactivity.
  • Modification at C2: Replacement by Sulphur of Oxygen at C2 decrease lipophilicity.
Metabolism of barbiturates: 

Metabolism of barbiturates

2. Benzodiazepines:

  • They act as GABA facilitating agents with no GABA mimetic action.
  • Mainly metabolized by dealkylation & Hydroxylation.
  • Benzodiazepine competitive antagonist- Flumazenil.
  • Benzodiazepine non-competitive antagonist- Bicculine.
  • Benzodiazepine inverse agonist- β-Carboline (DMCM- Dimethyl-carbomethoxy-β-Carboline.
3. Non benzodiazepine hypnotics: Zoplicone, Zolpidem, Zolepon.

  • Zolepon is the shortest acting among these.

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