HYPERTENSION ANTIADRENERGIC AGENTS
Category: Cardiology Heart Health
Abstract : Antiadrenergic Agents Central Acting Drugs Methyldopa (Aldomet), clonidine (Catapres), guanfacine (Tenex), and guanabenz (Wytensin) are central alpha2-agonists. These agents decrease dopamine and norepinephrine production in the brain, resulting in a decrease in sympathetic nervous activity throughout the body. Blood pressure declines with the decrease in peripheral resistance. Methyldopa
Antiadrenergic Agents
Central Acting Drugs
Methyldopa (Aldomet), clonidine (Catapres), guanfacine (Tenex), and guanabenz (Wytensin) are central alpha2-agonists. These agents decrease dopamine and norepinephrine production in the brain, resulting in a decrease in sympathetic nervous activity throughout the body. Blood pressure declines with the decrease in peripheral resistance.
Methyldopa exhibits a unique adverse effect profile as it induces autoimmune disorders, such as those with positive Coombs and antinuclear antibody (ANA) tests, hemolytic anemia, and hepatic necrosis. The other agents produce sedation, dry mouth, and dizziness. Abrupt clonidine withdrawal may result in rebound hypertension. These drugs are good choices for patients with asthma, diabetes, high cholesterol, and peripheral vascular disease.
Peripheral Acting Drugs
Guanadrel (Hylorel), reserpine (Serpasil), and guanethidine (Ismelin) are peripheral antiadrenergic agents. Their mechanism of action is at the storage granule level of norepinephrine release. They are infrequently chosen because of their significant side effects, which include profound hypotension, sedation, depression, and impotence.
Beta-Blockers
ß-adrenergic blocking agents compete with ß-agonists for B1 receptors in cardiac muscles and B2 receptors in the bronchial and vascular musculature, inhibiting the dilator, inotropic, and chronotropic effects of ß-adrenergic stimulation. Clinical responses to ß-adrenergic blockade include decreased heart rate, cardiac output, blood pressure, renin production, and bronchiolar constriction; there is also an initial increase in total peripheral resistance, which returns to normal with chronic use. Beta-blockers are contraindicated for sinus bradycardia, secondor third-degree heart block, cardiogenic shock, cardiac failure, and severe COPD/asthma. The adverse effect profile of beta-blocking agents is partially dependent on their receptor selectivity. Acebutolol (Sectral), penbutolol (Levatol), carteolol (Cartrol), and pindolol (Visken) have intrinsic sympathomimetic activity (ISA), resulting in less effect on cardiac output and lipid profiles.
Betablockers without ISA slow the heart rate, decrease cardiac output, increase peripheral vascular resistance, and cause bronchospasm. Common adverse effects include fatigue, impotence, depression, shortness of breath, cold extremities, cough, drowsiness, and dizziness. The more lipid-soluble agents, such as propranolol and metoprolol, have a higher incidence of central nervous system (CNS) effects. In diabetic patients beta-blockers may mask the usual symptoms of hypoglycemia, such as tremor, tachycardia, and hunger.13 Increased triglycerides (30%) and decreased HDL cholesterol (1 - 20%) occur with non-ISA agents.15 Beta-blockers are effective agents in the young and white populations. Black patients may not respond as well to monotherapy because of their lower renin levels. Beta-blockers are good choices for patients with supraventricular tachycardia, high cardiac output, angina, recent myocardial infarction, migraine, and glaucoma. Caution should be exercised in those with diabetes, CHF, peripheral vascular disease, COPD/asthma, and an elevated lipid profile.
alpha1-Blockers
alpha1-Receptor blockers have an affinity for the alpha1-receptor on vascular smooth muscles, thereby blocking the uptake of catecholamines by smooth muscle cells. This action results in peripheral vasodilation. The currently available agents are prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura). There is a marked reduction in blood pressure with the first dose of these drugs. It is recommended that they be started with 1 mg at bedtime and titrate slowly upward over 2 to 4 weeks. When adding a second antihypertensive the alpha-blocker dose should be decreased and titrated upward again. Often a diuretic is added to alpha1-blocker therapy to reduce sodium and water retention.
The primary adverse effects of these three drugs are dizziness, sedation, nasal congestion, headache, and postural effects. They do not significantly affect lipids, glucose, electrolytes, or exercise tolerance. alpha1-Blockers are good choices for young active adults and patients with diabetes, renal insufficiency, CHF, peripheral vascular disease, COPD/asthma, or elevated lipids. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was initiated in 1994 to evaluate the impact of various classes of antihypertensives on outcomes. In early 2000 the doxazosin treatment arm was discontinued because a twofold higher incidence of CHF was noted compared to those on chlorthalidone.
Vasodilators
The two direct vasodilators, hydralazine (Apresoline) and minoxidil (Loniten), dilate peripheral arterioles, resulting in a significant fall in blood pressure. A sympathetic reflex increase in heart rate, renin and catecholamine release, and venous constriction occur. The renal response includes sodium and water retention. The patient often experiences tachycardia, flushing, and headache. Addition of a diuretic and a beta-blocker relieves the major adverse effects of the vasodilators. Hydralazine may cause a lupuslike reaction with fever, rash, and joint pain. Chronic use of minoxidil often results in hirsutism with increased facial and arm hair. These drugs are third- or fourth-line agents because of their adverse side-effect profile.
Quality-of-Life Issues
The need for lifestyle changes and probable drug therapy increases the possibility that the patients quality of life will be altered. The adverse physical, mental, and metabolic effects of antihypertensive therapy results in significant nonadherence to prescribed regimens. In 1982 Jachuck and associates17 investigated the effect of medications on their patients by asking them, their closest relatives, and their physicians a series of questions concerning their quality of life since starting the blood pressure medications.
The physicians and patients thought there was either no change or improvement, whereas 99% of the relatives thought the patients were worse. They cited side effects such as memory loss, irritability, decreased libido, hypochondria, and decreased energy as major problems.17 Other studies during the 1980s confirm that nonselective beta-blockers, diuretics, and methyldopa compromised quality of life to a far greater extent than ACE inhibitors or calcium entry antagonists.17 - 19 Further research in this area is necessary to assist the physician in determining the optimum strategy for blood pressure control to improve adherence and quality of life.
Antihypertensive Selection
It is important to consider the patients lifestyle, economic status, belief systems, and concerns about treatment when selecting an antihypertensive agent. Therapy should be initiated with one drug in small doses to minimize adverse effects. It is important to educate the patient about the long-term benefits of therapy, including the decreased incidence of stroke and renal and cardiac disease. Adequate follow-up visits are scheduled to assess adherence and adverse effects. During these visits the patient is asked to describe the mental, physical, and emotional changes that have occurred as a result of therapy.
If adverse effects are bothersome, consider an alternative selection from a different drug class and attempt to maintain monotherapy. If a second drug is needed, agents can be combined that improve efficacy without significantly altering the adverse-effect profile (e.g., adding a diuretic to an ACE inhibitor). There are some special considerations when prescribing medications. Concomitant disease states must be considered and drugs selected that either improve or at least maintain the current clinical condition. Hypertension is a major risk factor for thrombotic and hemorrhagic strokes; smoking, CHF, diabetes, and coronary artery disease increase the risk. Patients with coronary artery disease may benefit from a calcium entry antagonist or beta-blocker with ISA to decrease anginal pain while resulting in minimal changes in lipid profiles.
CHF and hypertension respond well to ACE inhibitors and diuretic therapy. Diabetes may be adversely affected by thiazide diuretics and beta-blockers. ACE inhibitors, calcium entry antagonists, and central 2-agonists are appropriate choices. Patients with severe renal disease are most effectively treated with loop diuretics, whereas ACE inhibitors and CEAs may decrease proteinuria and slow the progress of renal failure. As renal function declines, ACE inhibitors must be used with some caution as increased potassium and decreased renal perfusion may occur. A few agents such as methyldopa, clonidine, atenolol, nadolol, and captopril need dosage reduction in the presence of renal failure.
Asthma and COPD patients may be effectively treated with calcium entry antagonists, central alpha2-agonists, and alpha1-blockers. Betablockers and possibly diuretics should be avoided because they might exacerbate bronchospasm. The elderly are of special concern when selecting an antihypertensive. They have decreased receptor sensitivity, changing baroreceptor response, atherosclerosis, decreased myocardial function, declining total body water, decreased renal function, and memory loss. Blood pressure should be lowered cautiously using smaller than normal doses that are slowly titrated upward. Calcium entry antagonists, ACE inhibitors, and diuretics are possible choices for the elderly. Beta-blockers are effective in the elderly especially in conjunction with diuretics. Larger doses may result in declining mental function, depression, fatigue, and impotence. alpha1-Blockers and central alpha2-agonists may be used with caution. First-dose syncope and sedation are the major concerns.
Black patients may not respond as well to ACE inhibitors or betablockers as other races, perhaps due in part to low renin, salt/ volume-dependent hypertension. Thiazide diuretics may adversely affect diabetes, gout, and lipids. Calcium entry antagonists, alpha1-blockers, central alpha2-agonists, and ACE inhibitors are possible choices. Young women with hyperdynamic hypertension may respond best to a beta-blocker to slow the heart rate and relieve symptoms of stress. An active young man would be better served with an ACE inhibitor, calcium entry antagonist, or alpha-blocker, as beta-blockers and diuretics may cause impotence and exercise intolerance.
Severe Hypertension and Emergencies
Patients with a diastolic blood pressure (DBP) over 115 mm Hg must be treated upon diagnosis. The blood pressure should be lowered in 5- to 10-mm Hg increments with a goal of lowering it to less than 100 mm Hg after several weeks of therapy. Often more than one drug must be used initially to control the blood pressure. A hypertensive emergency exists if the DBP is over 130 mm Hg and evidence of end-organ damage exists, such as retinal hemorrhage, encephalopathy, pulmonary edema, myocardial infarction, or unstable angina.
Drugs available for treatment in this situation include sodium nitroprusside, nitroglycerin, hydralazine, phentolamine, labetalol, and methyldopa. Patients must be hospitalized for appropriate monitoring. Hypertensive urgency exists when the DBP is over 115 mm Hg without evidence of end-organ damage. Oral agents such as clonidine, captopril, and minoxidil may be used to lower the DBP 10 to 15 mm Hg over several hours.1 Nifedipine should not be used in this situation as many serious adverse events have been reported including severe hypotension, acute myocardial infarction, and death.
Conclusion
Pharmacologic management of hypertension challenges the physician to understand the patients social, psychological, and economic status in order to select an antihypertensive regimen that effectively lowers the blood pressure, alleviates concomitant disease states, and allows easy adherence to the regimen. Continual assessment of therapy is necessary to determine the effectiveness of the regimen, adverse side effects, and the patients quality-of-life issues.
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