Cardiac Output.

Cardiac output is influenced by four factors: (1) heart rate, (2) myocardial contractility (force of contraction), (3) blood volume, and (4) venous return of blood to the heart. An increase in any of these will increase cardiac output, thereby causing BP to rise. Conversely, a decrease in these factors will make BP fall. Hence, to reduce BP, we might give a beta blocker to reduce cardiac output, or a diuretic to reduce blood volume, or a venodilator to reduce venous return.

Peripheral Vascular Resistance.

Vascular resistance is increased by arteriolar constriction. Accordingly, we can reduce BP with drugs that promote arteriolar dilation.

Sympathetic Baroreceptor Reflex.

The sympathetic nervous system employs a reflex circuit—the baroreceptor reflex—to keep BP at a preset level. This circuit operates as follows:

The baroreceptor reflex frequently opposes our attempts to reduce BP with drugs. Opposition occurs because the “set point” of the baroreceptors is high in people with hypertension. That is, the baroreceptors are set to perceive excessively high BP as “normal” (i.e., appropriate). As a result, the system operates to maintain BP at pathologic levels. Consequently, when we attempt to lower BP using drugs, the reduced (healthier) pressure is interpreted by the baroreceptors as below what it should be, and, in response, signals are sent along sympathetic nerves to “correct” the reduction. These signals produce reflex tachycardia and vasoconstriction—responses that can counteract the hypotensive effects of drugs. Clearly, if treatment is to succeed, the regimen must compensate for the resistance offered by this reflex. Taking a beta blocker, which will block reflex tachycardia, can be an effective method of compensation. Fortunately, when BP has been suppressed with drugs for an extended time, the baroreceptors become reset at a lower level. Consequently, as therapy proceeds, sympathetic reflexes offer progressively less resistance to the hypotensive effects of medication.

Renin-Angiotensin-Aldosterone System.

The RAAS can elevate BP, negating the hypotensive effects of drugs. The RAAS is discussed in Chapter 36 and reviewed briefly here.

The RAAS elevates BP beginning with the release of renin from juxtaglomerular cells of the kidney. These cells release renin in response to reduced renal blood flow, reduced blood volume, reduced BP, and activation of beta₁-adrenergic receptors on the cell surface. After its release, renin catalyzes the conversion of angiotensinogen into angiotensin I, a weak vasoconstrictor. After this, angiotensin-converting enzyme (ACE) acts on angiotensin I to form angiotensin II, a compound that constricts systemic and renal blood vessels. Constriction of systemic blood vessels elevates BP by increasing peripheral resistance. Constriction of renal blood vessels elevates BP by reducing glomerular filtration, which causes retention of salt and water, which in turn increases blood volume and BP. In addition to causing vasoconstriction, angiotensin II causes release of aldosterone from the adrenal cortex. Aldosterone acts on the kidney to further increase retention of sodium and water.

Because drug-induced reductions in BP can activate the RAAS, this system can counteract the effect we are trying to achieve. We have five ways to cope with this problem. First, we can suppress renin release with beta blockers. Second, we can prevent conversion of angiotensinogen to angiotensin I with a direct renin inhibitor (DRI). Third, we can prevent the conversion of angiotensin I into angiotensin II with an ACE inhibitor. Fourth, we can block receptors for angiotensin II with an angiotensin II receptor blocker (ARB). And fifth, we can block receptors for aldosterone with an aldosterone antagonist.

Renal Regulation of Blood Pressure.

As discussed in Chapter 34, the kidney plays a central role in long-term regulation of BP. When BP falls, glomerular filtration rate (GFR) falls too, thereby promoting retention of sodium, chloride, and water. The resultant increase in blood volume increases venous return to the heart, causing an increase in cardiac output, which in turn increases arterial pressure. We can neutralize renal effects on BP with diuretics.

8b—Renin.

Inhibition of renin decreases conversion of angiotensinogen into angiotensin I and thereby suppresses the entire RAAS. The result is peripheral vasodilation, renal vasodilation, and suppression of aldosterone-mediated volume expansion.

8c—Angiotensin-Converting Enzyme.

Inhibitors of ACE suppress formation of angiotensin II. The result is peripheral vasodilation, renal vasodilation, and suppression of aldosterone-mediated volume expansion.

8d—Angiotensin II Receptors.

Blockade of angiotensin II receptors prevents the actions of angiotensin II. Hence blockade results in peripheral vasodilation, renal vasodilation, and suppression of aldosterone-mediated volume expansion.

8e—Aldosterone Receptors.

Blockade of aldosterone receptors in the kidney promotes excretion of sodium and water and thereby reduces blood volume.

Thiazide Diuretics.

Thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone) are first-line drugs for hypertension. They reduce BP by two mechanisms: reduction of blood volume and reduction of arterial resistance. Reduced blood volume is responsible for initial antihypertensive effects. Reduced vascular resistance develops over time and is responsible for long-term antihypertensive effects. The mechanism by which thiazides reduce vascular resistance has not been determined.

Of the thiazides available, hydrochlorothiazide is used most widely. In fact, hydrochlorothiazide is used more widely than any other antihypertensive drug. Nonetheless, other thiazides, especially chlorthalidone, may be more effective.

The principal adverse effect of thiazides is hypokalemia. This can be minimized by consuming potassium-rich foods and using potassium supplements or a potassium-sparing diuretic. Other side effects include dehydration, hyperglycemia, and hyperuricemia.

Thiazides are superior to calcium channel blockers (CCBs) and ACE inhibitors as monotherapy and therefore are preferred.

Loop Diuretics.

Loop diuretics (e.g., furosemide) produce much greater diuresis than the thiazides. For most individuals with chronic hypertension, the amount of fluid loss that loop diuretics can produce is greater than needed or desirable. Consequently, loop diuretics are not used routinely for hypertension. Rather, they are reserved for (1) patients who need greater diuresis than can be achieved with thiazides and (2) patients with a low GFR (because thiazides won’t work when GFR is low). Like the thiazides, the loop diuretics lower BP by reducing blood volume and promoting vasodilation.

Most adverse effects are like those of the thiazides: hypokalemia, dehydration, hyperglycemia, and hyperuricemia. In addition, loop diuretics can cause hearing loss.

Potassium-Sparing Diuretics.

The degree of diuresis induced by the potassium-sparing agents (e.g., spironolactone) is small. Consequently, these drugs have only modest hypotensive effects. However, because of their ability to conserve potassium, these drugs can play an important role in an antihypertensive regimen. Specifically, they can balance potassium loss caused by thiazides or loop diuretics. The most significant adverse effect of the potassium-sparing agents is hyperkalemia. Because of the risk for hyperkalemia, potassium-sparing diuretics must not be used in combination with one another or with potassium supplements. Also, they should not be used routinely with ACE inhibitors, ARBs, or aldosterone antagonists, all of which promote significant hyperkalemia.

Beta-Adrenergic Blockers.

Like the thiazides, beta blockers (e.g., metoprolol) are widely used antihypertensive drugs. However, despite their efficacy and frequent use, the exact mechanism by which they reduce BP is somewhat uncertain. Beta blockers are less effective in black people than in whites.

The beta blockers have at least four useful actions in hypertension. First, blockade of cardiac beta₁ receptors decreases heart rate and contractility, thereby causing cardiac output to decline. Second, beta blockers can suppress reflex tachycardia caused by vasodilators. Third, blockade of beta₁ receptors on juxtaglomerular cells of the kidney reduces release of renin and thereby reduces angiotensin II−mediated vasoconstriction and aldosterone-mediated volume expansion. Fourth, long-term use of beta blockers reduces peripheral vascular resistance—by a mechanism that is unknown. This action could readily account for most of their antihypertensive effects.

Three beta blockers have intrinsic sympathomimetic activity: pindolol, penbutolol, and acebutolol. That is, they can produce mild activation of beta receptors while blocking receptor activation by strong agonists (e.g., norepinephrine). As a result, heart rate at rest is slowed less than with other beta blockers. Accordingly, if a patient develops symptomatic bradycardia with another beta blocker, switching to one of these may help.

Beta blockers can produce several adverse effects. Blockade of cardiac beta₁ receptors can produce bradycardia, decreased atrioventricular (AV) conduction, and reduced contractility. Consequently, beta blockers should not be used by patients with sick sinus syndrome or second- or third-degree AV block—and must be used with care in patients with heart failure. Blockade of beta₂ receptors in the lung can promote bronchoconstriction. Accordingly, beta blockers should be used with caution in patients with asthma. If an asthmatic individual must use a beta blocker, a beta₁-selective agent (e.g., metoprolol) should be employed. Beta blockers can mask signs of hypoglycemia and therefore must be used with caution in patients with diabetes. Potential side effects of beta blockers include depression, insomnia, bizarre dreams, and sexual dysfunction; however, a review of older clinical trials has shown that the risk is small or nonexistent.

The basic pharmacology of the beta blockers is discussed in Chapter 14.