Renin-Angiotensin-Aldosterone System

Renin-Angiotensin-Aldosterone System

• Renin converts angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme (ACE)
• Angiotensin II is a potent circulating vasoconstrictor, constricting both arterioles and veins, and increasing renal sodium reabsorption and blood volume, leading to an increase in blood pressure

Regulation of Blood Pressure

• The sympathetic system and kidneys work together to maintain arterial blood pressure within a narrow range when a person is at rest
• They adjust blood pressure appropriately in response to postural changes and physical activity
• In normotensive individuals, an increase in blood pressure leads to a proportional increase in sodium and water excretion by the kidneys, reducing blood volume and blood pressure
• In hypertensive patients, the set point at which blood pressure is controlled is higher than normal, and an increase in blood pressure is not followed by a proportional increase in sodium and water excretion

Treatment Strategies

• The four major categories of antihypertensive drugs are diuretics, sympatholytic drugs, angiotensin inhibitors, and vasodilators
• These drugs lower blood pressure through actions at the kidneys, sympathetic nervous system, renin-angiotensin-aldosterone axis, or vascular smooth muscle
• The goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality
• Antihypertensive therapy is indicated for individuals with systolic blood pressure ≥150 mm Hg or diastolic blood pressure ≥90 mm Hg, particularly those 60 years or older

Hypertension Overview

• Hypertension is defined as a sustained systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg
• Untreated hypertension damages blood vessels, accelerates atherosclerosis, and produces left ventricular hypertrophy, contributing to ischemic heart disease, stroke, heart failure, and renal failure
• Hypertension results from increased peripheral vascular arteriolar smooth muscle tone, leading to increased arteriolar resistance and reduced capacitance of the venous system
• In most cases, the cause of increased vascular tone is unknown
• Elevated blood pressure is a common disorder, affecting approximately 30% of adults
• Chronic hypertension can lead to heart disease and stroke, but early diagnosis and proper treatment can significantly decrease morbidity and mortality

Diuretics

• Thiazide diuretics decrease blood pressure by reducing sodium content of arteriolar smooth muscle cells, which decreases muscle contraction in response to vasopressor agents
• Hydrochlorothiazide is a commonly used thiazide diuretic, reducing blood pressure by 10-15 mm Hg
• Indapamide and chlorthalidone have similar efficacy, and indapamide has the additional benefit of causing vasodilation via calcium channel blockade
• Thiazide diuretics are often used in combination with other antihypertensive agents
• Adverse effects of thiazide diuretics include hypokalemia, which may contribute to cardiac arrhythmias and muscle weakness, as well as elevated plasma levels of glucose, uric acid, and lipids

Beta-Blockers

• Selective blockers of β1 receptors, such as metoprolol and atenolol, are commonly prescribed β-blockers
• Nebivolol is a selective blocker of β1 receptors that also increases nitric oxide production, leading to vasodilation
• β-blockers are beneficial in hypertensive patients with other cardiovascular diseases, such as coronary heart disease, heart failure, and myocardial infarction
• Adverse effects of β-blockers include hypotension, bradycardia, fatigue, insomnia, decreased libido, and erectile dysfunction
• Noncardioselective β-blockers may disturb lipid metabolism and impair glycemic control

Angiotensin Receptor Blockers

• ARBs selectively block angiotensin AT1 receptors, reducing vasoconstriction, aldosterone secretion, sodium reabsorption, and norepinephrine release
• ARBs are often effective as monotherapy and can be combined with a diuretic, CCB, or other antihypertensive agent when greater blood pressure reduction is needed
• Adverse effects of ARBs are similar to those of ACE inhibitors, although the risks of cough and angioedema are decreased
• ARBs should not be combined with an ACE inhibitor for the treatment of hypertension due to similar mechanisms and adverse effects
• ARBs are contraindicated during pregnancy

Renin Inhibitor

• Aliskiren is a selective renin inhibitor available for the treatment of hypertension
• Aliskiren directly inhibits renin, acting earlier in the renin-angiotensin-aldosterone system than ACE inhibitors or ARBs
• Aliskiren should not be combined with an ACE inhibitor or ARB in the treatment of hypertension
• Adverse effects of aliskiren include diarrhea, cough, and angioedema, but less often than ACE inhibitors
• Aliskiren is contraindicated during pregnancy and is metabolized by CYP3A4, with many drug interactions

Vasodilators

• Vasodilators include CCBs and other agents such as hydralazine, minoxidil, and nitroprusside
• CCBs are used to treat hypertension, angina pectoris, peripheral vascular disorders, and cardiac arrhythmias
• CCBs are useful in hypertensive patients with diabetes or stable ischemic heart disease