alpha-1 agonist

MECHANISM: α1 receptors are Gq-coupled. Agonist binding activates phospholipase C, which cleaves PIP2 into IP3 and DAG. IP3 raises intracellular Ca2+ (released from the sarcoplasmic reticulum). Ca2+ binds calmodulin and activates myosin light-chain kinase (MLCK), causing smooth muscle contraction. DAG activates protein kinase C.

TISSUE EFFECTS: (1) Vascular smooth muscle: vasoconstriction, increased SVR and BP (arterioles and veins). (2) Eye, radial muscle of the iris: contraction, mydriasis without cycloplegia. (3) Bladder trigone/sphincter and prostate smooth muscle: contraction, urinary retention. (4) Liver: glycogenolysis and gluconeogenesis. (5) GI sphincters: contraction. (6) Male ejaculation: contraction of the vas deferens/seminal vesicles (this is why alpha blockers can cause ejaculatory dysfunction). (7) Pilomotor muscles: piloerection. (8) Sweat glands on palms: localized secretion.

HEMODYNAMIC PROFILE: A pure α1 agonist (phenylephrine) increases SVR and mean arterial pressure. Baroreceptor-mediated reflex bradycardia follows (vagal), so HR falls. There is no direct β1 inotropy or chronotropy. Afterload rises, so cardiac output may fall or stay unchanged. In a classic autonomic pharmacology question, phenylephrine causes increased MAP with decreased HR.

KEY DRUGS: - Phenylephrine: selective α1. Used for hypotension (anesthesia-induced, neurogenic shock, distributive shock), nasal decongestion, and mydriasis for eye exams. It is also used in SVT to induce reflex vagal tone, though this is less common now. - Midodrine: oral prodrug (active metabolite desglymidodrine). Used for orthostatic hypotension and hepatorenal syndrome (with octreotide and albumin). Adverse effect: supine hypertension. - Oxymetazoline and pseudoephedrine: topical/oral decongestants. Oxymetazoline is a topical α1/α2 agonist. Pseudoephedrine is an indirect sympathomimetic. Adverse effect: rebound congestion (rhinitis medicamentosa) with prolonged topical use. - Norepinephrine: α1, α2, and β1 agonist. First-line for septic shock. Vasoconstriction predominates. - Epinephrine: at high doses, α1 effects dominate. - Vasopressin acts through V1 receptors, not α1, but it is a similar vasoconstrictor. - Dopamine at high doses (>10 mcg/kg/min) has α1 effects.

CLINICAL ADVERSE EFFECTS: Hypertension (especially supine HTN with midodrine), reflex bradycardia, urinary retention (particularly in BPH), piloerection/"goosebumps," headache, tissue ischemia and necrosis with extravasation (treat with phentolamine, a nonselective α blocker, injected locally). Avoid in patients with severe hypertension, peripheral vascular disease, or urinary retention.

HIGH-YIELD COMPARISONS: - α1 agonists vs. α2 agonists: α2 agonists (clonidine, methyldopa, dexmedetomidine) are Gi-coupled presynaptic agents that decrease sympathetic outflow, which lowers BP. - α1 agonists vs. α1 antagonists (prazosin, doxazosin, terazosin, tamsulosin): the antagonists cause vasodilation, orthostatic hypotension, and reflex tachycardia, and are used for BPH and PTSD nightmares (prazosin). Tamsulosin is selective for α1A/D (prostate). - Phenylephrine vs. norepinephrine: norepinephrine also has β1 effects, so HR is less reduced. - Phenylephrine vs. isoproterenol: isoproterenol is a β agonist, so MAP may fall (β2 vasodilation) and HR rises.

CLASSIC BOARD PEARLS: - Following an α-blocker, epinephrine's pressor effect is reversed (epinephrine reversal), unmasking β2-mediated vasodilation. - Phenylephrine eye drops dilate the pupil without affecting accommodation (cycloplegia needs a muscarinic antagonist like tropicamide). - In pheochromocytoma, α blockade (phenoxybenzamine) comes before β blockade to prevent unopposed α stimulation and hypertensive crisis. - In neurogenic shock (loss of sympathetic tone), phenylephrine or norepinephrine increases tone and counteracts hypotension with bradycardia. - Cocaine and amphetamines indirectly activate α1 receptors by increasing synaptic norepinephrine, producing hypertension, mydriasis, and vasoconstriction.