A. Treatment with antihypertensives is usually initiated if the patient’s blood pressure (BP) is greater than 140/90 mm Hg.
1. Essential hypertension is of multifactorial origin (genetic plus environmental).
It disproportionately affects older people, men, and blacks.
2. Arterial blood pressure ⴝ cardiac output (CO) ⴛ peripheral resistance. CO depends on heart rate and stroke volume (which depends on contractility, pre-load, and afterload).
3. There are two interconnected BP control systems in the body:
a. Baroreceptors, which increase sympathomimetic stimulation and decrease parasympathomimetic stimulation in response to a decrease in BP (rapid response).
b. Renin–Angiotensin–Aldosterone System (RAAS). The kidney releases renin in response to decreased perfusion.
i. Renin cleaves angiotensinogen to angiotensin I (AT I), which is in turn cleaved to angiotensin II (AT II) by the angiotensin-converting enzyme (ACE).
ii. AT II is a potent vasoconstrictor. It also reduces renin release and stim-ulates release of aldosterone. Increased aldosterone leads to sodium and water retention and an increase in BP (Figure 5-1).
iii. The primary clinical use of angiotensin is to increase blood pressure. It induces fewer cardiac arrhythmias than the catecholamines.
4. Treatment of hypertension has been demonstrated to decrease the incidence of a. Stroke
b. Heart failure
c. Myocardial infarction d. Coronary artery disease III
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e. Renal failure f. Arterial dissections
B. TREATMENT for hypertension is initiated with lifestyle changes (e.g., weight loss, decreased consumption of salt).
C. If this is insufficient to control blood pressure, a thiazide diuretic (e.g., hydrochlorothiazide [Esidrix, HydroDIURIL]) can be given.
1. Thiazides are useful in hypertension because they are cheap, convenient, and have few side effects.
2. Thiazides initially increase sodium and water loss.
a. This effect is compensated for by the mechanisms illustrated in Figure 5-2.
b. Later, the blood pressure is reduced as a result of direct vasodilation, which decreases peripheral resistance.
c. High salt intake leads to water retention, which will reduce the effectiveness of the thiazides.
d. The onset of the antihypertensive action is slow, taking 2–4 weeks to develop.
e. Side effects can occur, including:
i. Hypokalemia. To avoid hypokalemia, combine thiazide diuretics with potas-sium supplements or potaspotas-sium-sparing diuretics (e.g., spironolactone).
ii. Hyperglycemia.
iii. Small increases of LDL and small decreases of HDL cholesterol.
3. Loop diuretics should only be used if the thiazides do not induce diuresis.
Plasma volume BP
Na
Sympathetic tone (β-receptors)
Na+ retention
Aldosterone release BP
Renin release Angiotensinogen
Angiotensin I
Angiotensin II
Angiotensin III Vasoconstriction
Prorenin
Converting enzyme X
X X
Figure 5-1 Renin–angiotensin aldosterone system.
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D. BETA-BLOCKERS (e.g., propranolol [Inderal]) can be given as a first-line alternative to thiazide diuretics.
1. ββ-Blockers have many effects on blood pressure. The mechanism may be related to a. Decreased heart rate and contractility
b. Decreased renin release
c. Decreased CNS sympathetic output
d. Blockade of presynaptic ββ-adrenoceptors, resulting in decreased norepi-nephrine (NE) release
2. The side effects are described in Table 2-6. Additional concerns include increased LDL cholesterol, increased triglycerides, and reduced high-density lipoprotein (HDL) cholesterol; however, these changes are small.
3. When combined with other antihypertensives, propranolol decreases the reflex sympathetic activation of the heart and the reflex sympathetic activation of renin release.
4. Metoprolol is cardioselective; thus, it induces less bronchoconstriction in asthmatics and less masking of hypoglycemia in diabetics than propranolol. The β-selectivity is relative, however, and tends to disappear at high dosages.
E. ANGIOTENSIN-CONVERTING ENZYME (ACE) can be inhibited by several drugs.
1. The effects of ACE inhibition include:
a. Reduced conversion of angiotensin I to angiotensin II b. Reduced blood pressure
c. Reduced aldosterone levels, which increases sodium and water excretion d. Increased plasma renin levels, due to reduced feedback inhibition on renin
release
e. Dilation of efferent renal arterioles, which are regulated by angiotensin II, thus reducing renal perfusion pressure
f. Decreased vasoconstriction
g. Increased bradykinin levels due to decreased breakdown of bradykinin by ACE, which leads to additional vasodilation
2. The indications for ACE inhibitors are a. Hypertension.
b. Congestive heart failure. ACE inhibitors have been shown to decrease mor-tality in CHF patients.
c. Prevention and treatment of diabetic nephropathy.
d. Patients who have had a recent MI.
Initially, thiazide diuretics
increase sodium and water loss BV
Sympathetic reflexes Compensatory increase in BP
These drugs later cause a direct vasodilation that decreases peripheral resistance.
CO
BP
Renin release
Figure 5-2 Effects of the thiazides that reduce blood pressure and activate homeostatic mechanisms. BV ⫽ blood volume. CO ⫽ cardiac output. BP ⫽ blood pressure.
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3. The side effects include:
a. Hyperkalemia, due to reduced aldosterone levels.
b. Hypotension.
c. Coughing, due to increased bradykinin.
d. Skin rashes and angioedema.
e. Fetal toxicity. ACE inhibitors should not be used during pregnancy.
f. Excessive reduction of pressure in the glomerulus due to dilation of the efferent renal arterioles. ACE inhibitors should be avoided in patients with renal artery stenosis.
4. Captopril (Capoten) is the prototype ACE inhibitor.
a. It reduces angiotensin synthesis and lowers blood pressure by i. Vasodilation
ii. Reduction of aldosterone release, which increases the loss of water b. There are no autonomic effects and no changes in LDL cholesterol.
5. Enalapril (Vasotec) and lisinopril (Prinivil, Zestril) have the same effects as capto-pril, but they have longer durations of action.
F. AT1 ANGIOTENSIN II RECEPTORS can be inhibited by angiotensin II receptor blockers (ARBs) such as losartan (Cozaar) and candesartan (Atacand).
1. Effects are similar to those from ACE inhibitors. ARBs can therefore be used to treat CHF or hypertensive patients who cannot tolerate ACE inhibitors.
2. Coughing is less common because ACE is not inhibited and bradykinin levels do not rise.
3. However, ARBs are also fetotoxic and should not be used in pregnancy.
G. CALCIUM CHANNEL BLOCKERS (e.g., amlodipine [Norvasc]) vasodilate arterioles and reduce blood pressure.
1. They have no autonomic side effects and do not change LDL cholesterol.
2. There is an increased risk of heart attack or stroke with the short-acting dihy-dropyridines such as nifedipine.
H. THE SECOND LINE of drugs includes the sympathetic blockers. These drugs can be used alone but are usually combined with a first line drug.
1. Peripheral sympathetic blockers that can be used in hypertension include:
a. Prazosin (Minipress), an α1-blocker
b. Labetalol (Trandate, Normodyne), an α1- and β-blocker
2. Several drugs act on the CNS to reduce the efferent sympathetic tone (output) to the cardiovascular system.
a. Methyldopa (Aldomet) is metabolized in CNS adrenergic neurons to αα-methyl-dopamine and αα-methylnorepinephrine (αα-methylNE).
i. αα-MethylNE acts on α2-adrenoceptors and decreases the sympathetic out-flow from the medulla.
ii. The site of action appears to be the nucleus tractus solitarius.
b. Clonidine (Catapres) and guanabenz (Wytensin) are αα2-adrenoceptor ago-nists that act like α-methylNE in the medulla.
c. Side effects from the CNS active sympathetic blockers include:
i. Drowsiness.
ii. Sodium and water retention. This can be decreased by coadministration of a diuretic.
iii. Positive Coombs’ test (increased risk for hemolytic anemia) with methyldopa.
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iv. Acute rebound hypertension with clonidine. Clonidine should be with-drawn slowly.
I. DIRECT VASODILATORS (e.g., hydralazine [Apresoline], minoxidil [Loniten]) are use-ful in combination regimens for severe hypertension.
1. Vasodilation of arterioles leads to a fall in blood pressure.
2. Homeostatic mechanisms (e.g., sympathetic reflexes) are induced, which com-pensate for the fall in blood pressure and make the arteriolar vasodilators ineffec-tive when used alone. The homeostatic mechanisms include increases in
a. Sympathetic vasoconstrictor tone to blood vessels b. Heart rate
c. Myocardial contractility
d. Renin release, leading to increased fluid retention
3. The vasodilators are usually combined with diuretics and sympathetic blockers, which will dampen homeostatic compensatory mechanisms.
4. Side effects of these drugs include:
a. Palpitations.
b. Flushing.
c. Headache.
d. Lupus-like syndrome with hydralazine, especially in patients who are slow acetylators. This effect is reversible if the drug is discontinued.
e. Hirsutism with minoxidil. In fact, minoxidil is used topically (as Rogaine) to treat baldness.
f. Pericardial effusion with minoxidil.
J. HYPERTENSIVE CRISIS is a severe rise in blood pressure that has either already caused organ damage (hypertensive emergency) or has the potential to cause organ damage (hypertensive urgency).
1. Hypertensive crisis may be caused by secondary mechanisms. If hypertension is due to elevated catecholamines, a phentolamine test can be used for diagnosis.
a. Phentolamine (Regitine) is an α-antagonist. It will rapidly reduce blood pres-sure that has been elevated due to
i. Pheochromocytoma
ii. Monoamine oxidase inhibitors iii. Sympathomimetics or cocaine
iv. Clonidine withdrawal
b. Measurement of urinary catecholamine metabolites is also diagnostic.
c. Treatment of hypertensive crisis due to elevated catecholamines involves the administration of
i. αα- and ββ-blockers ii. Labetalol
iii. Metyrosine, an inhibitor of tyrosine hydroxylase
2. Hypertensive crises due to other causes will not respond as dramatically to phentolamine and are treated with rapid-acting antihypertensives, usually admin-istered intravenously.
a. Sodium nitroprusside (Nitropress), like the nitrates, dilates venules and arterioles.
i. The onset of action is very rapid, within minutes.
ii. The half-life is very short, which makes the antihypertensive effect very controllable, but requires regular monitoring and administration by con-tinuous infusion.
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iii. Side effects include:
(a) Hypotension.
(b) Toxicity from thiocyanate and cyanide, which are by-products of nitroprusside metabolism. Cyanide toxicity can be treated with sodium thiosulfate.
b. Fenoldopam (Corlopam), is a D1-dopamine receptor agonist that
i. Dilates peripheral arterioles, especially renal and mesenteric arterioles ii. Has a rapid onset after IV infusion
iii. Has a very short half-life
c. Nitroglycerin IV has actions similar to nitroprusside, although venous dilation is more pronounced than arterial dilation.
d. Diazoxide (Hyperstat IV), like hydralazine, dilates only arterioles.
i. Side effects include:
(a) Palpitations (b) Hyperglycemia ii. Can aggravate angina.
e. Labetalol (Normodyne, Trandate), when administered intravenously, has a rapid antihypertensive action.