HYPERTENSION

 Hypertension is defined by persistent elevation of arterial blood pressure (BP)

PATHOPHYSIOLOGY

Hypertension is a heterogeneous disorder that may result either from a specific cause (secondary hypertension) or from an underlying pathophysiologic mechanism of unknown etiology (primary or essential hypertension).
Other conditions causing secondary hypertension include pheochromocytoma, Cushing’s syndrome, hyperthyroidism, hyperparathyroidism, primary aldosteronism, pregnancy, obstructive sleep apnea, and coarctation of the aorta.
Some drugs that may increase BP include corticosteroids, estrogens, nonsteroidal antiinflammatory drugs (NSAIDs), amphetamines, sibutramine, cyclosporine, tacrolimus, erythropoietin, and venlafaxine.
Humoral abnormalities involving the renin-angiotensin-aldosterone system, natriuretic hormone, or hyperinsulinemia; ✓ A pathologic disturbance in the CNS, autonomic nerve fibers, adrenergic receptors, or baroreceptors; ✓ Abnormalities in either the renal or tissue autoregulatory processes for sodium excretion, plasma volume, and arteriolar constriction; ✓ A deficiency in the local synthesis of vasodilating substances in the vascular endothelium, such as prostacyclin, bradykinin, and nitric oxide, or an increase in production of vasoconstricting substances such as angiotensin II and endothelin I; ✓ A high sodium intake and increased circulating natriuretic hormone inhibition of intracellular sodium transport, resulting in increased vascular reactivity and a rise in BP; and ✓ Increased intracellular concentration of calcium, leading to altered vascular smooth muscle function and increased peripheral vascular resistance.



CLINICAL PRESENTATION


Patients with secondary hypertension may complain of symptoms suggestive of the underlying disorder. Patients with pheochromocytoma may have a history of paroxysmal headaches, sweating, tachycardia, palpitations, and orthostatic hypotension. In primary aldosteronism, hypokalemic symptoms of muscle cramps and weakness may be present. 

DIAGNOSIS

Frequently, the only sign of primary hypertension on physical examination is elevated BP. The diagnosis of hypertension should be based on the average of two or more readings taken at each of two or more clinical encounters. • As hypertension progresses, signs of end-organ damage begin to appear, chiefly related to pathologic changes in the eye, brain, heart, kidneys, and peripheral blood vessels. • The funduscopic examination may reveal arteriolar narrowing, focal arteriolar narrowing, arteriovenous nicking, and retinal hemorrhages, exudates, and infarcts. The presence of papilledema indicates hypertensive emergency requiring rapid treatment. • Cardiopulmonary examination may reveal an abnormal heart rate or rhythm, left ventricular (LV) hypertrophy, precordial heave, third and fourth heart sounds, and rales. • Peripheral vascular examination can detect evidence of atherosclerosis, which may present as aortic or abdominal bruits, distended veins, diminished or absent peripheral pulses, or lower extremity edema. • Patients with renal artery stenosis may have an abdominal systolic-diastolic bruit.

TREATMENT NONPHARMACOLOGIC THERAPY

• All patients with prehypertension and hypertension should be prescribed lifestyle modifications, including (1) weight reduction if overweight, (2) adoption of the Dietary Approaches to Stop Hypertension eating plan, (3) dietary sodium restriction ideally to 1.5 g/day (3.8 g/day sodium chloride), (4) regular aerobic physical activity, (5) moderate alcohol consumption (two or fewer drinks per day), and (6) smoking cessation. 


PHARMACOLOGIC THERAPY

 • Initial drug selection depends on the degree of BP elevation and the presence of compelling indications for selected drugs. • Most patients with stage 1 hypertension should be treated initially with a thiazide diuretic, angiotensin-converting enzyme (ACE) inhibitor, angio-
tensin II receptor blocker (ARB), or calcium channel blocker (CCB) (Fig. 10-1). Combination therapy is recommended for patients with stage 2 disease, with one of the agents being a thiazide-type diuretic unless contraindications exist. • There are six compelling indications where specific antihypertensive drug classes have shown evidence of unique benefits (Fig. 10-2). • Diuretics, ACE inhibitors, ARBs, and CCBs are primary agents acceptable as first-line options based on outcome data demonstrating CV risk reduction benefits (Table 10-2). β-Blockers may be used either to treat a specific compelling indication or as combination therapy with a primary antihypertensive agent for patients without a compelling indication. • α1-Blockers, direct renin inhibitors, central α2-agonists, peripheral adrenergic antagonists, and direct arterial vasodilators are alternatives that may be used in select patients after primary agents 


Diuretics
• Thiazides are the preferred type of diuretic for treating hypertension, and all are equally effective in lowering BP. • Potassium-sparing diuretics are weak antihypertensives when used alone but provide an additive hypotensive effect when combined with thiazide or loop diuretics. Moreover, they counteract the potassium- and magnesiumlosing properties and perhaps glucose intolerance caused by other diuretics. • Aldosterone antagonists (spironolactone, eplerenone) are also potassium-sparing diuretics but are more potent antihypertensives with a slow onset of action (up to 6 weeks with spironolactone). • Acutely, diuretics lower BP by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and, consequently, BP. The initial drop in cardiac output causes a compensatory increase in peripheral vascular resistance. With chronic diuretic therapy, the extracellular fluid volume and plasma volume return almost to pretreatment levels, and peripheral vascular resistance falls below its pretreatment baseline. The reduction in peripheral vascular resistance is responsible for the long-term hypotensive effects. Thiazides lower BP by mobilizing sodium and water from arteriolar walls, which may contribute to decreased peripheral vascular resistance. • When diuretics are combined with other antihypertensive agents, an additive hypotensive effect is usually observed because of independent mechanisms of action. Furthermore, many nondiuretic antihypertensive agents induce salt and water retention, which is counteracted by concurrent diuretic use. • Side effects of thiazides include hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia, and sexual dysfunction. Loop diuretics have less effect on serum lipids and glucose, but hypocalcemia may occur. • Hypokalemia and hypomagnesemia may cause muscle fatigue or cramps. Serious cardiac arrhythmias may occur, especially in patients receiving digitalis therapy, patients with LV hypertrophy, and those with ischemic heart disease. Low-dose therapy (e.g., 25 mg hydrochlorothiazide or 12.5 mg chlorthalidone daily) rarely causes significant electrolyte disturbances. • Potassium-sparing diuretics may cause hyperkalemia, especially in patients with chronic kidney disease or diabetes, and in patients receiving concurrent treatment with an ACE inhibitor, ARB, NSAID, or potassium supplement. Eplerenone has an increased risk for hyperkalemia and is contraindicated in patients with impaired renal function or type 2 diabetes with proteinuria. Spironolactone may cause gynecomastia in up to 10% of patients, but this effect occurs rarely with eplerenone. Angiotensin-Converting Enzyme Inhibitors • ACE facilitates production of angiotensin II, which has a major role in regulating arterial BP. ACE is distributed in many tissues and is present in several different cell types, but its principal location is in endothelial cells. Therefore, the major site for angiotensin II production is in the blood vessels, not the kidney. ACE inhibitors block the conversion of angiotensin


I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion. ACE inhibitors also block the degradation of bradykinin and stimulate the synthesis of other vasodilating substances including prostaglandin E2 and prostacyclin. The fact that ACE inhibitors lower BP in patients with normal plasma renin activity suggests that bradykinin and perhaps tissue production of ACE are important in hypertension. • Starting doses of ACE inhibitors should be low with slow dose titration. Acute hypotension may occur at the onset of ACE inhibitor therapy, especially in patients who are sodium- or volume-depleted, in heart failure exacerbation, very elderly, or on concurrent vasodilators or diuretics. Patients with these risk factors should start with half the normal dose followed by slow dose titration (e.g., 6-week intervals). • All 10 ACE inhibitors available in the United States can be dosed once daily for hypertension except captopril, which is usually dosed two or three times daily. The absorption of captopril (but not enalapril or lisinopril) is reduced by 30% to 40% when given with food. • ACE inhibitors decrease aldosterone and can increase serum potassium concentrations. Hyperkalemia occurs primarily in patients with chronic kidney disease or diabetes and in those also taking ARBs, NSAIDs, potassium supplements, or potassium-sparing diuretics. • Acute renal failure is a rare but serious side effect of ACE inhibitors; preexisting kidney disease increases the risk. Bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on efferent arterioles, making these patients particularly susceptible to acute renal failure. • The GFR decreases in patients receiving ACE inhibitors because of inhibition of angiotensin II vasoconstriction on efferent arterioles. Serum creatinine concentrations often increase, but modest elevations (e.g., absolute increases of less than 1 mg/dL) do not warrant changes. Therapy should be stopped or the dose reduced if larger increases occur. • Angioedema is a serious potential complication that occurs in less than 1% of patients. It may be manifested as lip and tongue swelling and possibly difficulty breathing. Drug withdrawal is necessary for all patients with angioedema, and some patients may also require drug treatment and/or emergent intubation. Cross-reactivity between ACE inhibitors and ARBs has been reported. • A persistent dry cough occurs in up to 20% of patients and is thought to be due to inhibition of bradykinin breakdown. • ACE inhibitors are absolutely contraindicated in pregnancy because of possible major congenital malformations associated with exposure in the first trimester and serious neonatal problems, including renal failure and death in the infant, from exposure during the second and third trimesters. Angiotensin II Receptor Blockers • Angiotensin II is generated by the renin-angiotensin pathway (which involves ACE) and an alternative pathway that uses other enzymes such as chymases. ACE inhibitors block only the renin-angiotensin pathway, whereas ARBs antagonize angiotensin II generated by either pathway. The ARBs directly block the angiotensin type 1 receptor that mediates the
ache, and peripheral edema occur more frequently with dihydropyridines than with verapamil or diltiazem. β-Blockers • The exact hypotensive mechanism of β-blockers is not known but may involve decreased cardiac output through negative chronotropic and inotropic effects on the heart and inhibition of renin release from the kidney. • Even though there are important pharmacodynamic and pharmacokinetic differences among the various β-blockers, there is no difference in clinical antihypertensive efficacy. • Atenolol, betaxolol, bisoprolol, and metoprolol are cardioselective at low doses and bind more avidly to β1-receptors than to β2-receptors. As a result, they are less likely to provoke bronchospasm and vasoconstriction and may be safer than nonselective β-blockers in patients with asthma, chronic obstructive pulmonary disease, diabetes, and PAD. Cardioselectivity is a dose-dependent phenomenon, and the effect is lost at higher doses. • Acebutolol, carteolol, penbutolol, and pindolol possess intrinsic sympathomimetic activity (ISA) or partial β-receptor agonist activity. When sympathetic tone is low, as in resting states, β-receptors are partially stimulated, so resting heart rate, cardiac output, and peripheral blood flow are not reduced when receptors are blocked. Theoretically, these drugs may have advantages in patients with heart failure or sinus bradycardia. Unfortunately, they do not reduce CV events as well as other β-blockers and may increase risk after MI or in those with high coronary disease risk. Thus, agents with ISA are rarely needed. • There are pharmacokinetic differences among β-blockers in first-pass metabolism, serum half-lives, degree of lipophilicity, and route of elimination. Propranolol and metoprolol undergo extensive first-pass metabolism. Atenolol and nadolol have relatively long half-lives and are excreted renally; the dosage may need to be reduced in patients with moderate to severe renal insufficiency. Even though the half-lives of the other βblockers are much shorter, once-daily administration still may be effective. β-Blockers vary in their lipophilic properties and thus CNS penetration. • Side effects from β-blockade in the myocardium include bradycardia, AV conduction abnormalities, and acute heart failure. Blocking β2-receptors in arteriolar smooth muscle may cause cold extremities and aggravate PAD or Raynaud’s phenomenon because of decreased peripheral blood flow. • Abrupt cessation of β-blocker therapy may produce unstable angina, MI, or even death in patients with coronary disease. In patients without heart disease, abrupt discontinuation of β-blockers may be associated with tachycardia, sweating, and generalized malaise in addition to increased BP. For these reasons, it is always prudent to taper the dose gradually over 1 to 2 weeks before discontinuation. • Increases in serum lipids and glucose appear to be transient and of little clinical importance. β-Blockers increase serum triglyceride levels and decrease high-density lipoprotein cholesterol levels slightly. β-Blockers with α-blocking properties (carvedilol and labetalol) do not affect serum lipid concentration