Major Antihypertensive Classes ACE Inhibitors Angiotensin-converting enzyme (ACE) inhibitors block the conversion of angiotensin I to angiotensin II, resulting in decreased aldosterone production with subsequent increased sodium and water excretion. Renin and potassium levels are usually increased as a result of this medication. The hemodynamic response includes decreased peripheral resistance, increased renal blood flow, and minimal changes in cardiac output and glomerular filtration rate. There is little change in insulin and glucose levels or in the lipid fractions.
The adverse effects of ACE inhibitors include cough (1–30%), headache, dizziness, first-dose syncope in salt- or volume-depleted patients, acute renal failure in patients with renal artery stenosis, angioedema (0.1–0.2%), and teratogenic effects in the human fetus. Thus, ACE inhibitors should not be used during the second and third trimesters of pregnancy. Captopril (Capoten) has a higher incidence of rash, dysgeusia, neutropenia, and proteinuria than the others due to a sulfhydryl group in the ring structure. The ACE inhibitors are good first-line agents for patients with diabetes, congestive heart failure, peripheral vascular disease, elevated lipids, and renal insufficiency. This class is effective in all races and ages, although black patients respond better with the addition of a diuretic.
Angiotensin Receptor Antagonists Angiotensin receptor antagonists, a newer class of antihypertensive agents, binds to the angiotensin II receptors, resulting in blockade of the vasoconstrictor and aldosterone-secreting effects of angiotensin II. In addition, bradykinin production is not stimulated. The first agent available in the United States was losartan (Cozaar). The physiologic effects of losartan include a rise in plasma renin and angiotensin II levels and a decrease in aldosterone production. There is no significant change in plasma potassium levels and no effect on glomerular filtration rate, renal plasma flow, heart rate, triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, or glucose. Losartan use does produce a small uricosuric effect with lowering of plasma uric acid levels.
These agents are effective antihypertensives in adults and the elderly. Blood pressure–lowering effects are not as significant in black patients. Adverse effects include muscle pain, dizziness, cough, insomnia, and nasal congestion. As with ACE inhibitors, angiotensin receptor antagonists should not be used during the second and third trimesters of pregnancy. At this time the role of angiotensin receptor antagonists is not completely defined. Further study of the hemodynamic effects in large populations is needed to determine the role in cardiac patients. These agents are an alternative antihypertensive agent for patients experiencing adverse effects from ACE inhibitors.
Calcium Entry Antagonists Calcium entry antagonists (CEAs) inhibit the movement of calcium across cell membranes in myocardial and smooth muscles. This action dilates coronary arteries, and additional peripheral arteriole dilation reduces total peripheral resistance, resulting in decreased blood pressure. Although the mechanism of action for lowering blood pressure is similar for these agents, structural differences result in varying effects on cardiac conduction and adverse effect profiles. Verapamil (Calan, Covera, Isoptin, Verelan) and diltiazem (Cardizem, Dilacor, Tiazac) slow atrioventricular (AV) node conduction and prolong the effective refractory period in the AV node.
Cardiac output is increased by nifedipine (Procardia), nicardipine (Cardene), isradipine (DynaCirc), and felodipine (Plendil). The calcium entry antagonists are contraindicated in patients with heart block, cardiogenic shock, or acute myocardial infarction. Common adverse effects include peripheral edema, dizziness, headache, asthenia, nausea, constipation, flushing, and tachycardia. Calcium entry antagonists have no significant impact on lipid profiles or glucose metabolism. These agents are effective at all ages and in all races. They are good choices for patients with diabetes, angina, migraine, chronic obstructive pulmonary disease (COPD)/asthma, peripheral vascular disease, renal insufficiency, and supraventricular arrhythmias.
Diuretics Thiazide, loop, and potassium-sparing diuretics have been the mainstay of antihypertensive therapy since the 1960s. They remain as firstline agents in the JNC VI approach, although the ACE inhibitors and calcium entry antagonists are rapidly replacing diuretics as monotherapy for hypertension. Thiazide diuretics increase renal excretion of sodium and chloride at the distal segment of the renal tubule, resulting in decreased plasma volume, cardiac output, and renal blood flow and increased renin activity. Potassium excretion is increased, and calcium and uric acid elimination is decreased. Thiazides adversely affect lipid metabolism by increasing the total cholesterol level 6% to 10% and the lowdensity lipoprotein (LDL) cholesterol 6% to 20%, and by causing a possible 15% to 20% rise in triglycerides. Plasma glucose levels increase secondary to a decrease in insulin secretion.
Clinical adverse effects include nausea, vomiting, diarrhea, dizziness, headache, fatigue, muscle cramps, gout attacks, and impotence. Thiazides are inexpensive choices for initial therapy, but caution must be exercised in patients with preexisting cardiac dysfunction, lipid abnormalities, diabetes mellitus, and gout. The lowest effective dose is recommended to minimize these potential adverse effects. Suggested daily doses are hydrochlorothiazide (HydroDIURIL) 25 mg, chlorthalidone (Hygroton) 25 mg, and indapamide (Lozol) 2.5 mg daily. Indapamide is unique among thiazides in that it has minimal effects on glucose, lipids, and uric acid. Thiazides are good choices for volume/saltdependent, low-renin hypertensives. Thiazides improve blood pressure control when added to ACE inhibitors, beta-blockers, vasodilators, and alpha-blockers.
The loop diuretics—furosemide (Lasix), torsemide (Demadex), and bumetanide (Bumex)—inhibit sodium and chloride reabsorption in the proximal and distal tubules and the loop of Henle. These diuretics are effective in patients with decreased renal function. The primary adverse effects include ototoxicity with high doses in patients with severe renal disease and in combination with an aminoglycoside, photosensitivity, excess potassium loss, increased serum uric acid, decreased calcium levels, and impaired glucose metabolism. Patients may experience nausea, vomiting, diarrhea, headache, blurred vision, tinnitus, muscle cramps, fatigue, or weakness.
Furosemide and bumetanide are utilized in patients with compromised renal function or congestive heart failure (CHF) and as adjuncts to volume-retaining agents such as hydralazine (Apresoline) and minoxidil (Loniten). The potassium-sparing diuretics spironolactone (Aldactone), triamterene (Dyrenium), and amiloride (Midamor) are useful for preventing potassium wastage from thiazide and loop diuretics. Spironolactone competitively inhibits the uptake of aldosterone at the receptor site in the distal tubule, thereby reducing aldosterone effects. It is used for treatment of primary aldosteronism, CHF, cirrhosis with ascites, hypertension, and hirsutism.
Triamterene is used in combination with hydrochlorothiazide as Dyazide or Maxzide and effectively prevents potassium loss. Amiloride inhibits potassium excretion at the collecting duct. Adverse reactions associated with spironolactone include gynecomastia, nausea, vomiting, diarrhea, muscle cramps, lethargy, and hyperkalemia. Triamterene and amiloride have adverse effects similar to those seen with the thiazide diuretics.
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