Primary Sedative - Anxiolytic Drugs
Drugs used to make children "more workable" and comfortable. Not sleepers. Particularly effective for noninvasive procedures or slightly painful procedures that do not require high immobilization and as adjuncts with analgesics for category 4.
Benzodiazepines (BNZs): Diazepam, Midazolam, Lorazepam
Pharmacodynamic Features
BNZs enhance gamma-aminobutyric acid (GABA) neurotransmission by binding to specific BNZ receptors on the GABAA receptor complex. They enhance chloride flux across ligand-gated chloride channels, resulting in membrane hyperpolarization and inhibition of the action potential.
Basics
The time of clinical onset and duration of action following single-dose administration is primarily related to lipid solubility.
| Benzodiazepine | Lipid Solubility* | Volume of distribution | Clearance (mL/kg/min) | Elimination half-life (hours) | Metabolism | Active Metabolite |
|---|---|---|---|---|---|---|
| Diazepam | +++ | 0.7-1.7 | 0.2-0.5 | <20-40 >40 (critically ill) |
Oxidation ↓ Conjugation |
Desmethyldiazepam (t 1/2 β=80-70 hours) |
| Midazolam | +++ | 1.1-1.7 | 6.4-11.1 | 2-4 >6-10 (critically ill) |
Oxidation ↓ Conjugation |
α-Hydroxymidazolam (t 1/2 β=1 hour) |
| Lorazepam | + | 1.1-1.8 | 0.7-1.0 | 10-20 >40 (neonates) |
Conjugation | - |
*Lipid Solubility: (+) low, (++) medium, (+++) moderate, (++++) high
- Diazepam and midazolam have active metabolites and require both oxidation and conjugation.
- Lorazepam does not have metabolites and requires only conjugation.
- All BNZs are highly protein-bound.
| Benzodiazepine | Dose | Repeat Dose | Onset | Duration |
|---|---|---|---|---|
| Diazepam | 0.1-0.15 mg/kg | 0.05-0.1 mg/kg q 3-5 min |
<60 sec | 15-30 min |
| Midazolam | 0.05-0.1 mg/kg | 0.05 mg/kg q 3-5 min |
<60 sec | 15-30 min |
| Lorazepam | 0.05 mg/kg | .025-.05 mg/kg q 10-15 min |
2-3 min | 1-2 hrs |
| Administer | Dose | Clinical Onset | (+) | (-) |
|---|---|---|---|---|
| Intranasal | 0.2 mg/kg | 10-15 min | faster effects | irritating |
| Rectal | 0.3-0.4 mg/kg | 15-20 min. | dependable | not older children |
| Oral | 0.3-0.5 mg/kg | 20-30 min | easy admin | variable onset, bad taste |
Clinical Use (Most Experience with Midazolam)
Used in procedures associated with mild to moderate discomfort not requiring high levels of immobility (Pediatrics 1992;89:631). *Benzodiazepines are not reliable hypnotic agents (Eur J Anaesth 1991;8:29). Useful as adjuncts with analgesics. Antegrade amnesia is one of the most important clinical effects of BNZs, particularly in children undergoing invasive procedures.