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Hypertension is most commonly associated with an increase in vascular resistance caused by narrower or stiffer blood vessels; but other mechanisms, including increased cardiac output, large blood volume, or excess venous return, are possible. These factors are the targets of antihypertensive agents, which can be grouped into several categories:
– Diuretics, which promote sodium and water excretion by the kidneys and thereby decrease blood volume.
– Medications that inhibit the sympathetic nervous system or the renin-angiotensin system.
– And vasodilators, which dilate blood vessels, and thereby decrease vascular resistance.
Of the three classes of diuretics used for treating hypertension, thiazides are the most commonly prescribed. Thiazides act on the distal tubule of nephrons, which reabsorbs only a small portion of the sodium load, so their diuretic effect is less powerful than that of loop diuretics, which act on the thick ascending limb of the loop of Henle. However, thiazides also have a vasodilation effect by an unknown mechanism. The two classes produce similar side effects, but the side effects are more severe with loop diuretics.
Potassium-sparing diuretics act mainly in the collecting duct and have only a mild diuretic effect, but they can compensate for the potassium loss induced by other diuretics, and are therefore commonly used in conjunction with thiazide or loop diuretics.
Sympathetic inhibitors, or sympatholytics, act on adrenergic receptors to block sympathetic activity. There are beta-blockers, alpha-blockers, mixed alpha and beta-blockers, and central sympatholytics.
Beta blockers are typical first-line treatment for hypertension. They reduce heart rate and cardiac contractility and thus decrease cardiac output.
Alpha-1 blockers are effective in reducing sympathetic vasoconstriction, but their action can lead to an excessive baroreceptor-mediated reflex that increases heart rate and produces tachycardia.
Non-selective adrenergic antagonists block both alpha and beta receptors. By inhibiting beta receptors in the heart, they are able to lower blood pressure without inducing reflex tachycardia.
Central sympatholytics stimulate alpha-2 receptors in the brainstem to reduce sympathetic tone. They reduce heart rate, contractility and vasoconstriction, but may also cause sedation.
Renin-angiotensin system blockers include ACE inhibitors and angiotensin receptor blockers.
ACE inhibitors are commonly used as first-line treatment for hypertension. They block the conversion of angiotensin-I to angiotensin-II, which in turn leads to a reduction in aldosterone. Their action reduces systemic vasoconstriction and increases sodium and water excretion by the kidneys.
Angiotensin receptor blockers inhibit the effects of angiotensin-II. Their indications are similar to those of ACE inhibitors.
Vasodilators include calcium channel blockers, direct arterial vasodilators and nitrodilators.
Calcium channel blockers inhibit L-type calcium channels that are responsible for smooth muscle contraction, cardiac myocyte contraction, and action potential generation in cardiac nodal tissue.
The dihydropyridine class acts on peripheral blood vessels. They are powerful vasodilators but their action can lead to reflex tachycardia and increased cardiac contractility.
Non-dihydropyridine agents, on the other hand, primarily act to decrease heart rate, contractility and cardiac conduction speed; and are less effective on peripheral vessels. By having cardiac depressant effect, they can reduce blood pressure without producing reflex cardiac stimulation. However, they should not be used for patients with systolic heart failure.
The mechanisms of direct arterial vasodilators are not entirely clear. They can cause reflex tachycardia and are only used for short-term treatment of refractory hypertension.
Nitrodilators act by releasing nitric oxide, a powerful vasodilator. They are administered intravenously to manage hypertensive crises and to control blood pressure during surgery.
