Systemic Hypertension: Treatment
The treatment of hypertension has evolved over the past four decades as knowledge of the natural history, pathophysiology, and risk factors for hypertension as well as the effects of therapy and the interactions of these factors has accumulated. The goal of treating high blood pressure is to reduce blood pressure and thereby prevent or reverse end-organ damage without causing significant side effects or requiring unacceptable changes in lifestyle. Many classes of antihypertensive agents that effectively lower blood pressure, either alone or in conjunction with an agent from another class of drugs, are available. Because of the potentially detrimental metabolic changes caused by some agents, their failure to reduce the incidence of myocardial infarction, and the multisystem involvement of hypertension, it is essential to choose a regimen that effectively lowers blood pressure without causing abnormalities. The following recommendations incorporate data from large long-term trials and experimental evidence from human and animal studies.
Nonpharmacologic therapy and coronary risk factor reduction should be initiated in all patients once the diagnosis of sustained hypertension is made. Individuals with stage 1 hypertension can be treated with nonpharmacologic therapy for 3–6 months. If this fails to reduce blood pressure to below 140/90 mm Hg within that time, pharmacologic therapy should be initiated. If end-organ damage is already present at diagnosis, or if other major coronary risk factors such as diabetes or dyslipidemia are present, pharmacologic therapy should be initiated once the diagnosis has been made. Individuals with severe hypertension (systolic blood pressure higher than 160 mm Hg; diastolic higher than 100 mm Hg) should have both nonpharmacologic and drug therapy initiated once the diagnosis is confirmed.
Nonpharmacologic Therapy
Nonpharmacologic therapy should be encouraged in all hypertensive patients. The approaches of proven benefit are weight reduction especially in obese patients; moderate aerobic exercise in sedentary patients; a reduction in alcohol consumption in all patients who drink; and a reduction of salt intake in some patients.
Obesity
Obesity (more than 10% over ideal weight) is associated with hypertension, diabetes, hyperlipidemia, and excess coronary mortality. In obese patients, a decrease of as much as 2 mm Hg of diastolic blood pressure can be achieved for every 3 lbs of weight loss. The benefits of weight reduction start early in the course, with a loss of as little as 10–15 lb. Although all obese patients should be encouraged to lose weight, the process is usually difficult and frequently requires extensive support and sometimes a financial investment. The use of all “stimulant” type weight reduction therapies should be strictly avoided because they tend to elevate blood pressure. The fat substitutes or avoidance therapies do not raise blood pressure but have their own side effects.
Exercise
Regular exercise in a previously sedentary individual may reduce diastolic blood pressure as much as 10 mm Hg. The level of exercise should be that required to raise the heart rate to 50–60% of the maximal predicted heart rate. Walking briskly for 45 minutes three to five times per week should suffice for most previously sedentary individuals. Increasing the amount of exercise in a previously active individual, however, seldom decreases blood pressure.
Alcohol Consumption
Alcohol consumption causes acute increases in blood pressure and can cause sustained hypertension in a significant proportion of individuals. Hypertensive patients should be encouraged to limit their alcohol consumption to 1 oz of ethanol per day, the equivalent of 2 oz of 100-proof hard liquor, 8 oz of wine, or 24 oz of beer. Even this level of alcohol consumption is associated with increased overall mortality. Alcohol decreases cardiovascular mortality and appears to decrease the onset of diabetes by improving insulin resistance. The best data for these benefits are for wine. Beer with its even higher carbohydrate load should be avoided in diabetic patients.
Sodium Reduction
Reducing sodium in the diet has been shown to reduce blood pressure in most people to a modest degree. Hypertensive patients, older individuals, and blacks tend to be more salt-sensitive, and achieve larger reductions in blood pressure with salt restriction. Hypertensive patients should be encouraged to keep sodium chloride consumption to less than 4–6 g/d.
Stress
Stress has long been known to raise blood pressure acutely and has been implicated in the genesis of sustained hypertension, even though no clear relationship has been demonstrated. Reducing stress would seem to be a reasonable form of nonpharmacologic therapy, but no controlled studies have demonstrated significant improvement in blood pressure with stress avoidance or relaxation therapy.
Pharmacologic Therapy
Table Common Oral Antihypertensive Agents lists the available antihypertensive medications. Although all of these classes of agents have been shown to be roughly equal in their ability to lower blood pressure in large population studies, they are not equally effective in all demographic groups or in preventing all complications. The initial choice for a given patient should take age, race, metabolic side effects, other cardiac risk factors and, most importantly, concomitant diseases into consideration. The report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure recommends monotherapy with diuretics or -blockers as initial therapy. Calcium channel blockers, ACEIs, and ARBs, are alternative first-line agents. The report does recognize special populations, such as diabetic patients and patients with coronary disease, which need special consideration.
Table: Common Oral Antihypertensive Agents.
| Drug | Total Daily Dose* (mg) | Frequency |
|---|---|---|
| Adrenergic inhibitors | ||
| α-Blockers | ||
| Doxasosin | 1–16 | Once daily |
| Prazosin | 1–20 | Two or three times daily |
| Terazosin | 1–20 | Once daily |
| β-Blockers | ||
| Atenolol | 25–100 | Once daily |
| Betaxolol | 5–40 | Once daily |
| Bisoprolol | 5–20 | Once daily |
| Carvedilol | 3.125–25 | Twice daily |
| Metoprolol | 25–200 | Twice daily |
| Nadolol | 20–240 | Twice daily |
| Propranolol (long-acting) | 60–240 | Once daily |
| Timolol | 20–40 | Once daily |
| β-Blockers with ISA | ||
| Acebutolol | 200–1200 | Once daily |
| Carteolol | 2.5–10 | Once daily |
| Penbutolol | 20–80 | Once daily |
| Pindolol | 10–60 | Twice daily |
| α-β-Blockers | ||
| Labetalol | 200–1200 | Once or twice daily |
| ACE inhibitors | ||
| Benazepril | 10–40 | Once or twice daily |
| Captopril | 25–50 | Three times daily |
| Enalapril | 10–40 | Once or twice daily |
| Fosinopril | 10–40 | Once or twice daily |
| Lisinopril | 10–40 | Once or twice daily |
| Moexipril | 7.5–30 | Once or twice daily |
| Perindopril | 4–16 | Once daily |
| Quinapril | 10–80 | Once or twice daily |
| Ramipril | 2.5–20 | Once or twice daily |
| Trandolapril | 1–8 | Once daily |
| Angiotensin receptor blockers | ||
| Candesartan | 2–32 | Once daily |
| Eprosartan | 600–800 | Once or twice daily |
| Irbesartan | 75–300 | Once daily |
| Losartan | 25–100 | Once or twice daily |
| Telmisartan | 20–80 | Once daily |
| Valsartan | 80–320 | Once daily |
| Drug | Total Daily Dose* (mg) | Frequency |
|---|---|---|
| Calcium channel blockers | ||
| Diltiazem (SR) | 120–160 | Twice daily |
| (CD, XR) | 120–160 | Once daily |
| Verapamil | 80–480 | Two or three times daily |
| (long-acting) | 120–480 | Once or twice daily |
| Dihydropyridines | ||
| Amlodipine | 2.5–10 | Once daily |
| Felodipine | 5–20 | Once daily |
| Isradipine | 2.5–10 | Twice daily |
| Nifedipine (GITS) | 30–120 | Once daily |
| Diuretics | ||
| Thiazide–type | ||
| Bendroflumethiazide | 2.5–5 | Once daily |
| Benzthiazide | 12.5–50 | Once daily |
| Chlorthalidone | 12.5–50 | Once daily |
| Chlorthiazide | 12.5–50 | Once daily |
| Hydroclorthiazide | 12.5–50 | Once daily |
| Indapamide | 2.5–5 | Once daily |
| Metolazone | 1.25–5 | Once daily |
| Methyclothiazide | 2.5–5 | Once daily |
| Polythiazide | 1.0–4 | Once daily |
| Trichlormethiazide | 1.0–4 | Once daily |
| Loop diuretics | ||
| Bumetanide | 0.5–5 | Twice daily |
| Furosemide | 10–300 | Twice daily |
| Torsemide | 2.5–10 | Once daily |
| Potassium-sparing agents | ||
| Amiloride | 5–10 | Once or twice daily |
| Spironolactone | 25–100 | Two or three times daily |
| Triamterene | 50–150 | Once or twice daily |
| Centrally acting agents | ||
| Clonidine | 0.1–1.2 | Once or twice daily |
| Transdermal | 0.1–0.3 | Once a week |
| Guanabenz | 4–64 | Twice daily |
| Methyldopa | 250–2000 | Twice daily |
| Peripheral vasodilators | ||
| Hydralazine | 50–200 | Once or twice daily |
| Minoxidil | 2.5–80 | Once or twice daily |
*The total daily dose should be given in divided doses at the frequency specified. The initial dose should be the smallest listed.
ISA, intrinsic sympathomimetic activity.
Until the most recent JNC7 recommendations, the traditional initial approach, known as monotherapy, was to start with one drug and titrate it to blood pressure control or limiting side effects. The main advantage of starting with a diuretic or β-blocker (JNC6 recommendations) is that it is both moderately effective and reasonably inexpensive. The main drawback of monotherapy is that blood pressure is controlled to recommended levels in only a small number of patients; most patients require two or more medications.
Initial therapy should take concomitant diseases and ethnicity into consideration. Individual patient responsiveness is also very important. Blood pressure should be checked at home in the morning and at night and reported to the physician, since antihypertensive medications may lose efficacy late in the day, resulting in high morning pre-dose hypertension. An additional evening dose may be required for some “once daily” medications.
The use of -blockers as initial therapy has been called into question by several large clinical trials, and the UK’s National Institute of Health and Clinical Excellence (NICE) revised its guidelines to move β-blockers to fourth-line initial therapy. Their initial recommendation is to start with calcium channel blockers in all hypertensive patients older than 55 years and in all black patients.
Table Response by Demographic Group lists the generalized response to antihypertensive therapy based on demographic groups. It is important to note that gender does not appear to affect the response in any group. Such data can serve as a starting point in picking initial antihypertensive agents, but they provide only an indication of the likelihood of response in an individual patient. Concomitant diseases should be a major influence in the decision-making process. Demographics cannot predict individual responses and therefore should not be used to exclude consideration of any class of agents in a given patient (eg, ACEI for a black patient). Because pharmaceutical agents are quite costly, the economic burden must also factor into the decision-making process. If a patient cannot afford to buy his or her medications, it is unlikely that the patient will purchase it and hence that medication will be ineffective.
Table: Response by Demographic Group
| Group | Effective Agents | Ineffective Agents |
|---|---|---|
| Young white | ACEI, calcium channel blocker, β-blocker | Diuretics |
| Older white | Calcium channel blocker, diuretic | |
| Young black | Calcium channel blocker | ACEI, β-blocker |
| Other black | Calcium channel blocker, diuretic | ACEI, β-blocker |
| Isolated systolic hypertension | Diuretic, calcium channel blocker | ACEI |
ACEI, angiotensin-converting enzyme inhibitor.
Concomitant Diseases
Other diseases occurring along with hypertension clearly must influence the choice of initial and subsequent antihypertensive agents. In patients with diabetes, inhibitors of the renin-angiotensin-aldosterone system (RAAS) decrease hypertension-related nephropathy and should be used as initial antihypertensive agents unless contraindicated. In such patients, diuretics may exacerbate glucose intolerance and should be added to RAAS blockers only if they are needed to reach target levels or to manage fluid accumulation.
Because thiazide diuretics raise plasma triglycerides and LDL cholesterol, they worsen the already present dyslipidemias prevalent in diabetics. The current recommendations are to only use low-dose diuretics, which will avoid some of the deleterious side effects but tend to be less effective when used as monotherapy.
β-Blockers may exacerbate heart block and reactive airway disease. They may also increase plasma triglyceride levels and decrease HDL cholesterol, thereby potentially increasing atherosclerosis (see section on β-Adrenergic Blocking Agents). Nonetheless, β-blockers are a good choice for patients with hypertension and angina and are recommended for all patients with known coronary artery disease. They effectively treat both conditions and can simplify patient care without sacrificing efficacy. β-Blockers decrease mortality following myocardial infarction and should therefore not be withheld in such patients because of fears of increased atherogenesis or heart failure. Calcium channel blockers are also very effective in patients with combined hypertension and angina. RAAS blockers have been shown to improve survival in patients with dilated cardiomyopathy from any cause and with postmyocardial infarction systolic dysfunction.
Diuretics
When used as monotherapy, diuretics are effective in approximately 30–40% of patients and are especially effective in lowering systolic blood pressure. They are extremely inexpensive. Several studies and meta-analyses have shown diuretic therapy to significantly decrease cardiac and stroke mortality rates. Diuretics are particularly effective antihypertensive agents in the elderly.
The adverse side effects of diuretics are urinary frequency and metabolic disturbances. They cause loss of potassium, which can precipitate cardiac dysrhythmias, renal insufficiency, and resistance to antihypertensive agents. Thiazide diuretics may induce gout in gout-prone individuals. Low doses (eg, 12.5–25 mg/day of hydrochlorothiazide) usually prevent hypokalemia and may reduce the metabolic alterations in glucose and lipids.
The shorter acting loop diuretics, such as furosemide, are poor antihypertensive agents and should be used for managing fluid overload. No outcome data are available for these agents in hypertension.
Spironolactone inhibits aldosterone and is a weak diuretic. It may be used in conjunction with a thiazide or loop diuretic to conserve potassium if hypokalemia occurs. Serum potassium should be monitored especially carefully when spironolactone is used with other potassium-sparing agents such as RAAS blockers. Aldosterone blockers are also indicated in patients with New York Heart Association (NYHA) class III and IV heart failure and are useful in addition to ACE inhibitors and ARBs and β-blockers in patients with hypertension and heart failure.
Angiotensin-Converting Enzyme Inhibitors
These agents block the conversion of inactive angiotensin I to the potent vasoconstrictor substance angiotensin II. The use of this group of agents is rapidly increasing as first-line therapy, especially in the young white population, due to the low incidence of associated side effects. The success rate is 40–50% as monotherapy and when used in combination with a low-dose diuretic, β-blocker, or calcium channel blocker, ACEIs are highly effective in controlling blood pressure in more than 80% of patients. Some of the additional benefits thought to be achieved with ACEIs are related to the reduction of the potent vasoconstrictor and mitogen effects of angiotensin II on cardiac and vascular tissue. They produce no adverse effect on glucose metabolism or lipid profile and have a potent renal-protective effect in diabetic patients. ACEIs preserve renal function and avoid or delay the onset of microalbuminuria and slow or prevent the progression to proteinuria and end-stage renal disease. ACEIs work by inhibiting the renin-angiotensin-aldosterone system and may cause mild elevations of serum potassium. If supplemental potassium is concomitantly administered, life-threatening hyperkalemia may result. Renal function and potassium levels should be monitored during initiation and titration of ACEI therapy in all patients, especially those with preexisting renal insufficiency. Of special note, ACEI may cause life-threatening fetal abnormalities and should be avoided in pregnant women. A chronic nonproductive cough develops in 5–15% of patients treated with an ACEI and may be bothersome enough to cause discontinuation of the agent. Recently, a rare potentially fatal side effect of angioedema has been described with ACEI use. This side effect should be aggressively treated, and the patient should not be rechallenged with an ACE inhibitors.
The antihypertensive efficacy of ACEI may be attenuated by concomitant administration of nonsteroidal antiinflammatory agents (including aspirin and over-the-counter ibuprofen, naproxen, etc), which should therefore be avoided.
Angiotensin Receptor Blockers
These agents selectively block the vascular angiotensin II (AT1) receptors, causing vasodilation similar to the ACEI. They are as effective and very well tolerated with a side-effect profile similar to that of ACEI. ARBs appear to have the same renal protective effects in diabetic patients as ACEI. No large head-to-head trials of ACEIs and ARBs in diabetic patients are available. Due to the much higher cost of ARBs and the proven efficacy of ACEIs, diabetic patients should start on an ACE inhibitor, and patients intolerant of ACEI should use ARBs. The incidence of cough with ARBs is less than that observed with ACEI (< 5%) but is much higher in those patients who have already had an ACEI-associated cough. Angioedema has also been described with ARB use although it is significantly less frequent than with ACEI. If a patient has had angioedema with an agent in either of the two classes, the other class should be avoided.
β-Adrenergic Blocking Agents
β-Blockers are effective monotherapy in 50–60% of patients, especially those with an activated renin-angiotensin system. They lower blood pressure by decreasing both heart rate and cardiac contractility and thus cardiac output. All β-blockers are similar in antihypertensive efficacy, regardless of whether they are cardioselective (1-specific) or nonselective (β1 and β2) receptor blockers; possess intrinsic sympathomimetic activity (ISA); or are lipid-soluble. The side-effect profile does differ, however, and is based on these properties. β1-Selective agents cause less bronchial constriction at lower doses but are similar to nonselective β-blockers at high doses. Agents with ISA produce less resting bradycardia than do those without. Lipid solubility determines whether the agent will cross into the brain. Lipid-soluble β-blockers, which cross the blood-brain barrier, may cause more central nervous system disturbances, including nightmares and confusion. All β-blockers depress LV systolic function, tend to reduce cardiac output, and may cause impotence. Fatigue is a frequent side effect and may limit use in young active patients. β-Blockers also cause the alterations in lipid profile mentioned earlier; the HDL depression is less significant with cardioselective β-blockers at low doses (eg, metoprolol, 25–50 mg twice daily) and insignificant with the ISA β-blockers. The clinical significance of these abnormalities has not been established and the concomitant use of appropriate lipid therapy probably makes this a moot point.
Calcium Channel Blockers
Calcium channel blockers are very well tolerated and effective as monotherapy in 50–60% of patients in all demographic groups. The mechanism of antihypertensive action is vasodilatation with all such agents and a decrease in heart rate and cardiac output with the nondihydropyridines agents (verapamil and diltiazem). Because of the negative inotropic effects in all but the newest dihydropyridines agents, calcium channel blockers should not be used in patients with cardiac failure. All calcium channel blockers are now available in formulations that can be taken once or twice daily, a regimen that greatly improves compliance. Immediate-release preparations of short-acting agents have no place in the antihypertensive armamentarium. Combinations of calcium channel blockers and a -blocker, an ACEI, or ARB are very effective in lowering blood pressure. Concomitant use of a β-blocker and a calcium channel blocker with significant sinus and atrioventricular node-slowing properties (eg, diltiazem, verapamil) should be done with caution to avoid profound bradycardia or heart block. Other side effects include peripheral edema (dihydropyridines) and constipation (verapamil).
In several large meta-analyses, calcium channel blockers have been shown to be highly effective in lowering blood pressure but have a 25% excess incidence of acute myocardial infarction and heart failure. The mechanisms are as yet to be delineated. Until this is resolved, use of calcium channel blockers as monotherapy for hypertension is not encouraged in patients with known coronary artery disease.
α-Receptor Blockers
α-Blockers act at vascular postsynaptic α-receptors to produce arterial and venous dilatation. Because the α-blockers do not reduce cardiac output, they do not adversely affect exercise tolerance. The major side effect of this group is postural hypotension, especially after the first dose, a problem that can be minimized by taking the first dose at bedtime. α-Blockers increase HDL cholesterol and reduce LDL cholesterol and may thereby decrease coronary risk. The LDL-cholesterol-lowering effect of doxazosin is similar in magnitude to that of 10 mg of lovastatin. It is therefore surprising that the α-blocker arm of the ALLHAT trial, a large randomized trial comparing the major antihypertensive classes, was stopped early due to a 25% higher incidence of major cardiac events in hypertensive patients treated primarily with α-blockers compared with diuretics. The reasons for these unexpected results are unclear. α-Blockers should therefore not be used as initial therapy and should be relegated to the status of add-on therapy until more data clarify the reasons for this increased risk.
Centrally Acting Agents
The group of agents with central sympatholytic action includes methyldopa, clonidine, and guanabenz. This class of drugs acts by stimulating central 1-adrenergic receptors, which exert an inhibitory effect on peripheral sympathetic outflow and is moderately effective as monotherapy in lowering blood pressure. The predominant side effects of this class are sedation, postural hypotension, dry mouth, and fatigue. Rebound hypertension may be a significant problem if the agent is withdrawn suddenly following high-dose therapy, especially with clonidine. Gradual reduction of the dose will avoid the rebound effect. This class of agents is now used infrequently because of its significant and often limiting side effects. The transcutaneous patch formulation of clonidine, which is applied once a week, is useful in enhancing compliance in selected patients or in patients unable to take oral therapy.
Direct Arteriolar Dilators
Agents such as hydralazine and minoxidil that lower blood pressure by relaxing vascular smooth muscle do so by direct arteriolar dilation. The resulting decrease in peripheral resistance induces a reflex tachycardia and inotropic cardiac stimulation. Because fluid retention develops almost universally, diuretics must usually be used concomitantly. Vasodilators should be avoided in patients with coronary artery disease because the reflex tachycardia may induce angina. These agents are used almost exclusively as additional agents in patients whose blood pressure is extremely difficult to control with more commonly used agents.
Combination Therapy
Combining antihypertensive medications from different classes may be even more effective than expected from their individual responses. Many experts now recommend combination therapy to enhance efficacy and reduce side effects. This synergistic result frequently allows lower doses of each agent to be used with fewer side effects. A low-dose thiazide diuretic, for example, will significantly augment the antihypertensive efficacy of an ACE inhibitor, an ARB, an α-blocker, a β-blocker, or a vasodilator. β-Blockers will enhance the blood pressure-lowering effects of a vasodilator and reduce any reflex increase in heart rate. The use of lower dose combinations is highly effective and is likely to produce fewer side effects.
Pharmaceutical companies have made fixed-dose combinations of two medications in the same pill. The combinations may or may not work for a given patient, so it is recommended that blood pressure be controlled initially with appropriate doses of two or more agents and then a fixed-dose combination that approximates the effective therapy be substituted. This strategy will improve compliance.
Direct Renin Inhibitors
Aliskiren (Tekturna), the first member of this new class of antihypertensive agents, was recently approved by the FDA. The drug inhibits the ability of renin to form angiotensin I and reduces plasma renin activity. Aliskiren appears to be safe and does not produce rebound hypertension on withdrawal. It appears to be effective in all patient groups but as with all RAAS inhibitors, is less effective in blacks. Second-generation renin inhibitors are under development.
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