Benzodiazepines
Benzodiazepines are double-ringed positive allosteric modulators of the GABA receptors in the CNS. They:
- Bind to the α/γ interface of the receptor, increasing affinity of the receptor for GABA
- This leads to hyperpolarisation of the cell membranes and decreased neuronal transmission
The mechanism varies between receptors:- GABAA is a ligand gated post-synaptic Cl- ion channel
Activation increases Cl- conductance via increasing frequency of channel opening. - GABAB is a pre- and post-synaptic G-protein coupled receptor
Activation increases K+ conductance.
- GABAA is a ligand gated post-synaptic Cl- ion channel
Common Features of Benzodiazepines
| Property | Action |
|---|---|
| Uses | Sedation, anxiolysis, hypnotic, anticonvulsants, amnestic, muscle relaxation |
| Absorption | |
| Distribution | Highly lipid soluble and protein bound, very low VD |
| Metabolism | Generally active metabolites. |
| Elimination | Renal elimination of active and inactive metabolites. |
| Resp | ↓ VT, ↑RR, apnoea. |
| CVS | ↓ SVR, ↓SBP, ↓ DBP, ↑HR. Typically stable CO. |
| CNS | Hypnosis, sedation, anterograde amnesia, anticonvulsant, ↓ CBF. ↓ MAC. |
| MSK | Skeletal muscle relaxation. |
| Metabolic | ↓ Adrenergic stress response. |
Comparison of Benzodiazepines
| Property | Midazolam | Diazepam | Clonazepam |
|---|---|---|---|
| Physicochemical | pKa 6.5. Structure is dependent on surrounding pH - at a pH < 4 its ring structure opens and it becomes water soluble. | 40% propylene glycol. | |
| Route of Administration | PO/IV/IM. | PO/IV/IM. | PO. |
| Absorption | 50% PO bioavailability. | Good PO bioavailability. | |
| Distribution | VD 1.5L.kg-1, 95% protein bound. | 95% protein bound. | |
| Metabolism | Partially metabolised to oxazepam and 1-α-hydroxy-midazolam. Clearance ~7ml.kg-1.min-1. | Hepatic to all active metabolites including oxazepam, temazepam, and des-methyl-diazepam (has t1/2β up to 100 hours). | Hepatic to inactive metabolites. |
| Elimination | t1/2β 2-4 hours, prolonged with cirrhosis, CHF, obesity and in the elderly. | t1/2β 20-45 hours. |
References
- Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care. 4th Ed. Oxford University Press. 2011.
- Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
- Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
- Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale's Pharmacology. 6th Ed. Churchill Livingstone.