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• Benzodiazepines (e.g.,diazepam (Valium), midazolam (Versed), clonazepam (Klonopin)

• Barbiturates (amobarbital, pentobarbital (Nembutal), thiopental (Pentothal))

• Miscellaneous agents (e.g. paraldehyde (Paral), meprobamate (Miltown), ethchlorvynol (Placidyl))

Possible biochemical mechanism of action of anxiolytics, sedatives and hypnotics especially barbiturates and benzodiazepines.

Benzodiazepines

•  Benzodiazepines act on GABA_A receptors

•  GABA receptor: a pentameric protein, consists of several subunits designated alpha (mainly responsible for the pharmacology of the receptor) ,beta and  gamma which is required for high affinity benzodiazepine binding. 

  • Electrophysiological Effects: Benzodiazepines enhance GABA-activated hyperpolarizing chloride currents.

Barbiturates

• Barbiturates activate inhibitory GABA_A while inhibiting excitatory AMPA (amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptors. 

  • Ionotropic glutamate receptors (iGluR) include: the N-methyl-d-aspartate (NMDA), kainate (KA) and
     (AMPA) subtypes

  • AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate.

• Barbiturates interact differently than benzodiazepines at GABA receptors. For example, the gamma subunit is not required for barbiturate activity.

• The combination of these receptor effects may result in the profound central nervous system depression that occurs with higher barbiturate doses.

Ethanol

• Several sites and mechanisms may be responsible for ethanol-mediated CNS depression:

• Direct membrane effects:

  •  Dissolves into lipid membranes affecting the function of membrane proteins, such as receptors and ion channels.

  •  Decreases GABA-receptor mediated synaptic inhibition

  •  Inhibits the NMDA glutamate receptor (inhibits an excitatory effect)

  •  Potentiates the action of serotonin (5-HT) at excitatory 5-HT₃ receptors.

  •  Since these receptors are often localized on inhibitory interneurons, ethanol-enhanced activation results in increased inhibition.

[Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 361-383.]

Cardiovascular System

• Except in overdosage, cardiovascular effects of benzodiazepines in normal subjects are minor.

• If used as preanesthetic medication, benzodiazepines decrease blood pressure and increase heart rate.

Respiratory System

• At pharmacological hypnotic doses, benzodiazepines do not affect respiration in normal subjects.

• Severely benzodiazepine-intoxicated patients may require assistance in breathing if other CNS depressant drugs have been taken

• If a patient, however, has a sleep-related breathing syndrome such as obstructive sleep apnea (OSA), benzodiazepines may be contraindicated.

  • In patients with obstructive sleep apnea, hypnotic doses of benzodiazepines may decrease muscle tone in the upper airway and accentuate or worsen the impact of  apneic episodes on alveolar hypoxia, pulmonary hypertension and cardiac demand.

• At higher doses, such as those used for endoscopy or when given as preanesthetic medication, benzodiazepines somewhat depress alveolar ventilation causing a respiratory acidosis secondary to a decrease in hypoxic drive (rather than a decrease in hypercapnic drive, which driven by a  high concentration of carbon dioxide in the blood secondary to  hypoventilation.). 

  •  These effects are more severe in patients with COPD (chronic obstructive pulmonary disease) and maybe sufficiently detrimental to induce alveolar hypoxia and/or CO₂ narcosis.

Central Nervous System

• With increasing doses, benzodiazpines can progressive cause sedation, then hypnosis and then stupor.

• Benzodiazepines do not cause general anesthesia since awareness persists.

• These agents have anti-anxiety / sedative-hypnotic properties.

• Some benzodiazepines (clonazepam (Klonopin)) are effective muscle relaxants, whereas most others are not.  

[Hibbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 364-367.]

• In sedative or doses for pharmacological hypnosis, barbiturates have minimal cardiovascular effects.

•   When thiopental is used in general anesthesia, following pre-anesthetic medication:

  • Plasma renal flow decreases

  • Cerebral blood flow decreases

  • CSF pressure decreases

•  Significant depression of myocardial contractility occurs in barbiturate poisoning.

Central Nervous System

• Barbiturates depress respiratory drive

• At doses somewhat (three times) higher than required for pharmacological hypnosis, neurogenic is abolished and the hypoxic respiratory drive is reduced and the chemoreceptor drive is attenuated.

• At still higher doses, the hypoxic drive is abolished.

[Hibbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 377.]

Advantages and disadvantages of each class relative to the others (Benzodiazepines vs Barbiturates)

• Benzodiazepines have proven far safer than barbiturates for pharmacological hypnosis and both safer and more effective in management of generalized anxiety disorder.

•  The use of barbiturates therefore has declined as a result of more favorable pharmacological properties associated with benzodiazepines.

  • Tolerance to barbiturates occurs more often than that observed with benzodiazepines

  • Barbiturate abuse liability is greater than with benzodiazepines.

  • Barbiturate use may be accompanied by significant drug-drug interaction.

  • Barbiturates lack CNS specificity

• Prominent barbiturate use:

  • Barbiturates are used as therapeutic/diagnostic aids in psychiatry

  • Barbiturates also are effective in  reducing cerebral edema following surgery, head injury or cerebral ischema.

  • Barbiturates are also effective antiepileptic medications

[Hobbs, W.R, Rall, T.W., and Verdoorn, T.A., Hypnotics and Sedatives: Ethanol In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 379-380.]