Mechanism of Action of Droperidol
Droperidol is a butyrophenone derivative that acts primarily as a potent dopamine D2 receptor antagonist in the central nervous system, while also occupying GABA receptors on postsynaptic membranes and producing mild alpha-adrenergic blockade peripherally. 1, 2
Primary Mechanisms
Central Dopaminergic Blockade
- Droperidol blocks postsynaptic dopaminergic D2 receptors in the brain, which is the primary mechanism responsible for its antiemetic, sedative, and antipsychotic effects 1, 3, 4
- This dopamine antagonism allows the drug to pass through the blood-brain barrier and produce marked tranquilization while maintaining reflex alertness 2, 3
GABAergic Modulation
- Droperidol occupies GABA receptors on postsynaptic membranes, contributing to its sedative and anxiolytic properties 1
- Research demonstrates that droperidol inhibits GABAA receptor activation by approximately 25% at therapeutic concentrations (IC50 of 12.6 nM), though this inhibition is submaximal 5
- At very high concentrations (100 μM), droperidol can directly activate GABAA receptors even without GABA present 5
Peripheral Alpha-Adrenergic Effects
- Droperidol produces mild alpha-adrenergic blockade, leading to peripheral vascular dilation and reduction of the pressor effect of epinephrine 1, 2
- This mechanism can result in hypotension and decreased peripheral vascular resistance, particularly at higher doses 2
Additional Receptor Interactions
Nicotinic Acetylcholine Receptor Inhibition
- Droperidol inhibits neuronal nicotinic acetylcholine receptors (particularly α7 nAChR) with an IC50 of 5.8 μM, which may contribute to its anesthetic properties 5
Cardiovascular Effects
- The drug may reduce pulmonary arterial pressure, especially when abnormally elevated 2
- It can reduce the incidence of epinephrine-induced arrhythmias, though it does not prevent other cardiac arrhythmias 2
Clinical Pharmacokinetics
- Onset of action occurs within 3-10 minutes following intravenous or intramuscular administration 1, 2, 4
- Peak effect may not be apparent for up to 30 minutes 2
- Duration of tranquilizing and sedative effects is typically 2-4 hours, though alteration of alertness may persist for up to 12 hours 1, 2, 4
Important Caveats
The submaximal GABA inhibition at therapeutic concentrations may paradoxically contribute to the anxiety, dysphoria, and restlessness (akathisia) that can occur with droperidol use, occurring in approximately 2.9% of patients 6, 5. This side effect profile limits the utility of high-dose droperidol anesthesia and should be anticipated when using the medication 5.