Adrenergic Modulators

Blood pressure is controlled by cardiac output (CO) and peripheral resistance (TPR). CO is governed by heart rate and force of contraction — both regulated by the autonomic nervous system (ANS). TPR is controlled by sympathetic tone on vascular smooth muscle. Additional regulators include blood volume (kidney/RAAS), blood viscosity, and endothelial mediators (NO, prostacyclins, thromboxane).

Baroreceptors in the carotid sinus and aortic arch sense mean arterial blood pressure (MABP) via wall distension and send afferent signals to the CVS centre in the medulla oblongata. The CVS centre sends efferent signals to the heart and vasculature. Sympathetic stimulation (cardiac accelerator nerve) releases noradrenaline (NA) acting on beta-1 adrenergic receptors — increasing heart rate (chronotropy) and force of contraction (inotropy). Parasympathetic stimulation (vagus nerve) releases ACh acting on muscarinic receptors — decreasing HR (negative chronotropy).

Adrenergic receptors are GPCRs. Alpha-1 and alpha-2 receptors mediate vasoconstriction. Alpha-1 activates Gq → phospholipase C → increased Ca2+. Alpha-2 activates Gi → inhibits adenylate cyclase → decreased cAMP. Beta-1 and beta-2 receptors activate Gs → adenylate cyclase → increased cAMP → PKA activation → downstream effects including Ca2+ influx in the heart.

Catecholamines (adrenaline, noradrenaline, dopamine) are the endogenous agonists. Adrenoreceptors are found in: the heart (primarily beta-1, some alpha-1 and beta-2); lungs (beta-2); kidneys (beta-1); smooth muscle of arteries and veins (alpha-1, alpha-2, beta-2); and nerve terminals (alpha-2 for presynaptic feedback).

Doxazosin is a selective alpha-1 antagonist. It relaxes arterial and venous smooth muscle, reduces TPR, decreases MABP, and increases venous capacitance. Key ADRs: postural hypotension, drowsiness, nasal stuffiness, urinary incontinence. Used as 2nd/3rd line for hypertension.

Beta-blockers: metoprolol (selective beta-1, strong inverse agonist — decreases baseline adenylate cyclase activity); propranolol (non-selective beta-1 and beta-2, lipid-soluble — crosses BBB); carvedilol (blocks beta-1, beta-2, and alpha-1 — vasodilation + cardiac blockade, very weak inverse agonist).

Clonidine and alpha-methyldopa are alpha-2 agonists that enter the vasomotor centre of the brainstem, mimic NA at presynaptic alpha-2 receptors, reduce sympathetic outflow, decrease CO and TPR. Alpha-methyldopa is used in pregnancy (eclampsia) as it does not cross the placenta. ADRs include postural hypotension, sedation, and dry mouth.

The RAAS is activated by sympathetic stimulation of beta-1 receptors in juxtaglomerular cells → renin release → angiotensinogen → angiotensin I → ACE → angiotensin II. Angiotensin II is a vasoconstrictor, profibrotic agent, and maintains sodium levels — a major therapeutic target in hypertension.