Mechanism of Action of Prazosin
Prazosin works by selectively blocking alpha-1 adrenergic receptors, which causes vasodilation by relaxing vascular smooth muscle and reduces CNS sympathetic outflow in the brain. 1
Peripheral Vascular Effects
Prazosin selectively antagonizes postsynaptic alpha-1 adrenoceptors on arteriolar smooth muscle, causing vasodilation primarily at the level of resistance vessels (arterioles), which decreases total peripheral resistance and lowers blood pressure. 1, 2
The drug's selectivity for alpha-1 receptors (as opposed to alpha-2 receptors) preserves the local feedback control of noradrenergic transmitter release by pre-junctional alpha-2 adrenoceptors, which explains why prazosin causes less reflex tachycardia compared to non-selective alpha blockers. 3
Unlike conventional alpha-blockers and direct vasodilators, prazosin's antihypertensive action typically occurs without clinically significant changes in cardiac output, heart rate, renal blood flow, glomerular filtration rate, or plasma renin activity. 1, 4
Central Nervous System Effects
In the CNS, prazosin reduces sympathetic outflow throughout the brain by blocking alpha-1 adrenergic receptors, which regulates several phenomena implicated in PTSD pathogenesis, including sleep and nightmare mechanisms. 5, 6
This CNS alpha-1 blockade decreases nightmare frequency and intensity by reducing adrenergic activity rather than acting as a traditional sedative. 7
Pharmacokinetic Properties
Following oral administration, prazosin reaches peak plasma concentrations at approximately 3 hours with a plasma half-life of 2-3 hours, is highly protein-bound, and has approximately 90% bioavailability. 1
The drug undergoes extensive metabolism primarily through demethylation and conjugation, with excretion mainly via bile and feces. 1
Clinical Implications of Mechanism
The alpha-1 receptor blockade on urethral smooth muscle can cause relaxation of the urethra, which may lead to stress incontinence as a side effect, particularly in women. 8
The first-dose phenomenon—significant orthostatic hypotension after initial dosing—occurs due to the acute vasodilation from alpha-1 blockade, necessitating low starting doses (typically 1 mg at bedtime) with gradual titration. 9, 7