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Sedative and hypnotic drugs

Created: 21/4/2006
Updated: 21/3/2006
 
a. Define and distinguish: sedation, hypnosis, anxiolysis, tolerance, REM and non-REM sleep, physical and psychological dependence.

b. Identify the major chemical classes of sedatives, hypnotics and anxiolytics.

c. Describe the pharmcodynamics of the barbiturate and non-barbiturate
sedatives.

d. Describe the pharmacokinetics of commonly used barbiturates and
benzodiazepines and indicate how differences between them may be applied clinically.

e. Describe individual sedative-hypnotic agents.

Ethanol

  • Clear colourless liquid, miscible with water
  • Usually given orally, can be administered IV
  • Some is metabolized by gastric alcohol dehydrogenase (more in men)
  • Small Vd = 0.7 l/kg
  • Metabolized in the liver to acetaldehyde and acetic acid

- Alcohol dehydrogenase active at low BAC (< 0.10)
- Microsomal oxidation at high BAC
- Limited by NAD+, NADP+ availability
- Zero-order kinetics (~8 g/h)

  • Dissolves in membranes decreasing viscosity and affecting many receptors and ion channels

- CNS depression (many complex actions)
- Decreased cardiac contractility, smooth muscle tone, uterine contraction, platelet aggregation
- Teratogenic

  • Long term effects are difficult to separate from confounding variables (nutrition, smoking, social status, premorbid problems)
  • Interacts with other drugs acutely by reducing hepatic metabolism and with chronic use by inducing hepatic metabolism
  • Tolerance mainly results from cellular adaption, not increased metabolism
  • Cross-tolerance with other sedatives
  • Little therapeutic use: acute methanol poisoning, prevention of withdrawal
  • Dose: 10g per standard drink
  • Dependent users 100-750 g/day
Thiopentone
  • 0.5 g in 20 ml glass ampoule
  • Yellow power, sodium salt
  • Stabilized with anhydrous sodium carbonate 60 mg/g
  • Prepared with water or saline to 25 mg/ml solution
  • pH 11-12. Precipitates in neutral or acid solution
  • Administered IV
  • Rapid onset of effect in CNS followed by redistribution
  • Hepatic metabolism
  • Binds GABA receptors, increasing the duration of Cl- channel opening

Forumula of Thiopentone

Methohexitone
  • 500 mg in 50 ml glass ampoule
  • White/yellow powder, sodium salt
  • Stabilized with anhydrous sodium carbonate
  • Mostly aL and aD isomers. ß isomers increase involuntary movement.
  • Prepared with water or saline
  • pH 10.6-11.6
  • Pharmacokinetics and actions similar to thiopentone
Phenobarbitone
  • 200 mg in 1 ml ampoule
  • 30 mg tablets
  • The oldest anticonvulsant
  • pKa = 7.4
  • Undergoes hepatic oxidation of the C5 functional groups and conjugation with renal
  • clearance. 25% is excreted unchanged
  • t1/2ß = 4 days
  • Binds GABA receptors increasing Cl- conductance, AMPA receptors blocking glutamate transmission
  • Sedative and anticonvulsant
Propofol
  • 10 mg/ml in 20, 50 and 100 ml ampoules
  • White aqueous isotonic emulsion
  • Solubilized with 2.25% glycerol, 1% soybean oil, 1% purified egg phospholipid
  • Previously solubilized in Cremaphor EL which caused anaphylaxis
  • pH 6.0 to 8.5
  • Administered IV
  • Rapid onset of effect in CNS followed by redistribution
  • Rapid metabolism in liver (t1/2ß 0.5-1.5 h)
Diazepam
  • Diazemuls

1 ml of 5 mg/ml glass ampoule
Solubilized in soybean oil

  • Diazepam USP

2 ml of 5 mg/ml brown glass ampoule
Clear yellow solution
Dissolved in 40% propylene glycol, 10% ethyl alcohol, 5% Na benzoate

Midazolam
  • 5 ml of 1 mg/ml or 1, 3 or 10 ml of 5 mg/ml glass ampoules
  • Clear aqueous solution
  • Buffered to pH 3.3
  • Precipitates in strongly alkaline solutions
Clonazepam
  • 1 mg in 1 ml glass ampoule
  • 2.5 mg/ml oral solution
  • 0.5 mg and 2 mg tablets
  • Long t1/2ß ~36 h
Zopiclone
  • 7.5 mg tablets
  • Structurally unrelated to benzodiazepines, but binds at the same site on the GABA receptor
Chloral hydrate
  • No longer on the Australian market
  • Prodrug metabolized to trichloroethanol
  • Non-specific membrane stabilizer
  • Hepatic metabolism produces trichloroacetic acid which accumulates
  • Possibly carcinogenic
  • Dose 0.5-1.0 g (of 100 mg/ml solution)
Chlormethiazole
  • 8 mg/ml oral solution
  • 192 mg capsules
  • 5-20% bioavailability
  • 65% protein bound
  • pKa 3.2
  • Related to vitamin B1
  • ?GABAergic, unknown mechanism
Agents affecting CMR and CBF

CBF CMR ICP Autoregulation
N2O Increase Decrease Increase 0
Halothane Increase Decrease Increase Decrease
Enflurane Increase Decrease Increase Decrease
Isoflurane 0.5 MAC Decrease Decrease 0 0
Isoflurane 2 MAC Increase Decrease Increase Decrease
Barbiturates Decrease Decrease Decrease 0
Benzodiazepines Decrease Decrease 0 0
Ketamine Increase 0 Increase 0

f. Describe the anticonvulsant and proconvulsant properties of the agents.

Kindly provided by Dr James Mitchell from his pharmacodynamics series

ArticleDate:20060421
SiteSection: Article
 
   
    
                                            
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