Mechanism of Action of Prazosin
Prazosin works by selectively blocking postsynaptic alpha-1 adrenergic receptors, causing vasodilation primarily at the arteriolar level (resistance vessels) without triggering reflex tachycardia or significantly affecting cardiac output. 1
Peripheral Vascular Effects
Prazosin's primary mechanism is selective alpha-1 receptor blockade on vascular smooth muscle, which decreases total peripheral resistance and lowers blood pressure in both supine and standing positions. 1
The vasodilator effect occurs mainly at the resistance vessel level (arterioles), causing a balanced reduction in both arteriolar and venous tone. 1, 2
Unlike non-selective alpha blockers, prazosin preserves presynaptic alpha-2 receptor function, which maintains negative feedback control of norepinephrine release from sympathetic nerve terminals—this explains why it doesn't cause reflex tachycardia or increase plasma renin activity. 3, 2
Central Nervous System Effects
In the CNS, prazosin blocks alpha-1 adrenergic receptors throughout the brain, reducing sympathetic outflow and regulating mechanisms implicated in PTSD pathogenesis, including sleep and nightmare generation. 4
The drug decreases nightmare frequency and intensity by reducing adrenergic activity rather than acting as a traditional sedative. 4
Hemodynamic Profile
Prazosin lowers blood pressure (most pronounced on diastolic pressure) without clinically significant changes in cardiac output, heart rate, renal blood flow, or glomerular filtration rate. 1
There is no measurable negative chronotropic effect, and the drug does not increase plasma renin activity in clinical use. 1
Important Clinical Consideration
The "first-dose phenomenon"—significant orthostatic hypotension after initial dosing—occurs due to acute vasodilation from alpha-1 blockade, necessitating low starting doses (typically 1 mg at bedtime) with gradual titration. 5, 4
This selective alpha-1 blockade without alpha-2 effects distinguishes prazosin from classical alpha-blockers and explains its therapeutic success in hypertension where previous non-selective agents failed. 3