Table: Recommended Initial Agent in Patients with Concomitant Disease

* If CRI is due to decreased cardiac output, ACEI/ARB may be used with caution.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CHF, congestive heart failure; CRI, chronic renal insufficiency.

Coronary Artery Disease

In hypertensive patients with concomitant coronary artery disease manifested by angina, lowering blood pressure alone may improve anginal symptoms by decreasing myocardial oxygen demand. Beneficial agents include the non-ISA β-blockers, ACE inhibitors, ARBs, and calcium channel blockers. Care should be taken to avoid sudden drops in blood pressure to hypotensive levels. Patients with an acute coronary syndrome, unstable angina or non–ST-segment elevation myocardial infarction and hypertension should receive standard therapy for acute coronary syndrome (ie, intravenous heparin or low-molecular-weight heparin and nitroglycerin, aspirin, and β-blockers). This will usually lower blood pressure to a safe level. In patients with acute ST-segment elevation myocardial infarction complicated by hypertension, -blockers are the mainstay of therapy. Blood pressure should be reduced to < 140/90 mm Hg. Drastic reductions should be avoided because coronary perfusion pressure is directly related to mean arterial pressure; coronary vascular reserve is exhausted in the peri-infarction area, and further ischemia or infarction could result. β-Blockers have been clearly demonstrated to decrease postmyocardial infarction mortality and ischemic event rates. 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 in patients with acute coronary syndromes. The mechanisms are as yet to be delineated.

Heart Failure

In patients with reduced LV systolic function (from any cause), elevated blood pressure may contribute to further signs and symptoms of heart failure. Even normal levels of blood pressure may be too high in patients with moderate-to-severe LV systolic dysfunction. The goal of therapy should be to lower systolic blood pressure as low as possible without symptoms (< 110 mm Hg and lower if tolerated). ACEIs have proved very useful in reducing blood pressure and symptoms of heart failure and improving survival rates in such patients (see Table 13–3). Diuretics augment the antihypertensive effects of ACEI and are useful additions for the hypertensive patient with or without congestive heart failure. When starting an ACEI in a patient who is already taking a diuretic, the dose of the ACEI should be reduced and the diuretic should be withheld or given at a reduced dose that day to avoid hypotension. ARBs may be substituted in ACEI-intolerant patients.

β-Blockade has been definitively shown to improve symptoms, LV systolic function, and longevity in patients with heart failure when added to ACEI or alone. Metoprolol, bisoprolol, and carvedilol are the agents that have been used in the major heart failure trials.

It is not yet clear as to the most beneficial way to treat patients with preserved systolic function heart failure. The cornerstone of therapy is to reduce the invariably present hypertension to the usual target levels. These patients respond similarly to other hypertensive patients. Clinicians should be careful to not reduce preload too much with diuretics.

Cerebrovascular Disease

Patients with symptomatic or otherwise evident cerebrovascular disease coexistent with hypertension should receive antihypertensive therapy. Such patients tend to be older and therefore respond similarly to other older patients. Acute cerebrovascular accidents are frequently accompanied by hypertension, which is sometimes severe. Rapid reduction of blood pressure in patients with acute stroke is associated with increased morbidity and mortality and should be avoided during the acute phase. In fact, unless the diastolic blood pressure is greater than 115 mm Hg, treatment should either be withheld or instituted slowly and with great caution until the patient has stabilized. Because cerebrovascular disease and coronary artery disease frequently coexist, antihypertensive therapy should be instituted judiciously in patients with stroke and evidence of ischemia or heart failure.

Renal Insufficiency

Effective antihypertensive therapy will halt or slow the progression of renal insufficiency in most hypertensive patients (see Table Recommended Initial Agent in Patients with Concomitant Disease). In patients with established renal insufficiency, ACEI therapy may be very effective and improve renal function but should be used carefully, with frequent monitoring of renal function and serum potassium during initiation and titration of therapy. Patients with renovascular hypertension may have rapid worsening of renal function when treated with ACE inhibitors. Such patients must be monitored carefully during initiation of antihypertensive therapy for worsening of renal function or the development of hyperkalemia. Potassium supplementation or potassium-sparing diuretics should be avoided in patients with even moderate renal insufficiency. Even a modest decrease in renal function could cause serious or fatal hyperkalemia. Most patients with renal insufficiency and hypertension respond well to all types of antihypertensive therapy, however. Such patients tend to have volume-dependent hypertension and respond well to loop diuretics, although higher doses must be used as renal function deteriorates.

Diabetes Mellitus

Diabetic patients are known for their almost universal incidence of vascular disease and increased susceptibility to cardiovascular complications. The coexistence of diabetes and hypertension markedly increases the risk of coronary artery disease, stroke, and renal failure. If dyslipidemia is also present, the risk is even greater. Hypertension should be treated aggressively in diabetic patients, using agents that are renal-protective and do not further aggravate glucose intolerance or adversely affect lipids (see Table Recommended Initial Agent in Patients with Concomitant Disease). ACE inhibitors, β-blockers, and ARBs are extremely useful in both controlling blood pressure and preventing or slowing the onset of proteinuria and renal failure in diabetic patients. The Hypertension Optimal Treatment Trial (HOT) established that lowering diastolic blood pressure in diabetic patients to levels below 80 mm Hg decreases the risk of major cardiovascular events and mortality compared with lowering diastolic blood pressure to “normal” (< 90 mm Hg) levels. The goal for systolic blood pressure is < 130 mm Hg. β-Blockers, ACEI, and ARBs, which are effective in diabetic patients, are glucose- and lipid-beneficial or neutral. It is recommended that an ACEI be used as the first agent in all diabetic patients. ARBs appear to have the same renal protective effects in diabetic patients as ACE inhibitors. No clear-cut superiority of ACEI compared with ARBs in diabetic patients has been demonstrated. Due to the much higher cost of ARBs and the proven efficacy of ACE inhibitors, diabetic patients should start on an ACEI and ACEI-intolerant patients should use ARBs.

Hypertensive Emergencies

Patients with severe hypertension (> 220/120 mm Hg) and signs and symptoms of encephalopathy, acute myocardial ischemic syndromes, stroke, pulmonary edema, or aortic dissection should be treated emergently to achieve rapid reduction of their blood pressure (Table Antihypertensive Therapy for Hypertensive Emergencies). Because of its rapid onset and short duration of therapy, which allow for smoother titration of blood pressure, intravenous sodium nitroprusside is the treatment of choice. Patients should be admitted to the intensive care unit and monitored closely during therapy. The aim is to reduce blood pressure very quickly within the first hour or two after presentation but to avoid hypotension. Patients must be monitored for thiocyanate toxicity if therapy is prolonged. An alternative is intravenous fenoldopam, a selective dopamine-1 receptor agonist. It has a similar antihypertensive profile to nitroprusside with a rapid predictable onset of action, short half-life (9.8 min), and few side effects at effective doses. There is a linear correlation between fenoldopam infusion rate and blood pressure lowering. Its use still requires monitoring in the intensive care unit.

Table: Antihypertensive Therapy for Hypertensive Emergencies

If aortic dissection is present, a short-acting β-blocker such as esmolol should be added to decrease shear forces in the aorta. Intravenous labetalol is highly effective and can also be used. Oral immediate-release clonidine and ACEI are effective in rapidly reducing blood pressure and can be added orally. Oral immediate-release nifedipine may cause unpredictable hypotension and should not be used.

Hypertensive urgencies (defined as patients who have severe hypertension but with minimal or no symptoms) may be treated more slowly, achieving a significant reduction in blood pressure within the first 24 hours. Intravenous labetalol is particularly useful in these patients.

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.

*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

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.

Table: Selective classes of antihypertensive agents

The Joint National Commission (JNC) also emphasized the need to recognize and treat systolic hypertension, which is associated with a higher degree of risk of MI in patients older than 45 years. Systolic hypertension is more difficult to treat than diastolic hypertension and frequently requires multiple drugs acting via different mechanisms.

The JNC-7 report and other recent studies recommend thiazide diuretics as the first-line agent for the treatment of hypertension in most cases (Table The Joint National Committee on hypertension has defined four categories of hypertension). This conservative approach is based on data supporting the fact that these agents decrease morbidity and mortality in clinical trials. The other agents that should be considered for initial monotherapy include the beta blockers, the renin-angiotensin system inhibitors (either ACE inhibitors or ARBs), a-adrenoreceptor antagonists, calcium-channel antagonists, and arterial vasodilators. All have been shown to reduce blood pressure by 10-15 mm Hg.

Table: The Joint National Committee on hypertension has defined four categories of hypertension

Diuretics

Diuretics cause an initial reduction in blood pressure by facilitating loss of Na⁺ and water. This leads to a decrease in cardiac output and blood pressure. However, after 8 weeks, cardiac output returns to normal while blood pressure remains reduced. This is thought to be caused by a reduction in the vasocon-strictive activities of Na⁺ on vascular smooth muscles that include elevation of intracellular Ca²⁺ via the Ca ²⁺/Na⁺ antiporter. Thiazide diuretics, which reduce the activity of a specific Na⁺Cl^- cotransporter (NCC2) in the distal convoluted tubule, are the class of diuretics most often used for hypertension. In refractory cases or in patients with concomitant edema, loop diuretics can be used with caution. Loop diuretics reduce Na⁺ reabsorption in the ascending limb of the loop of Henle by reducing the activity of another Na⁺-K⁺-2Cl^- cotransporter (NKCC) and can produce a profound loss of Na⁺ and K⁺. Both thiazides and loop diuretics can cause hypokalemia and hyponatremia. A common complaint associated with diuretic use is the increased frequency of urination. Spironolactone and eplerenone are antagonists of the aldosterone receptor and are weakly diuretic. Eplerenone is much more specific for the alososterone receptor compared to spironolactone.

Beta (β) Blockers

Use of β-adrenoreceptor blockers for hypertension relies on decreasing cardiac output and decreasing peripheral vascular resistance. The various drugs in this class vary in their potency on β₁ receptors; metoprolol is more than 1000 times more potent in blocking β₁ compared to β₂ receptors, giving this drug a relative cardioselectivity. Blockade of β₁-adrenoreceptors in the JGA of the kidney reduces renin secretion, and this reduces the production of angiotensin II. Nonselective beta blockers such as propranolol cause a number of predictable adverse effects including bronchoconstriction (contraindicating use in asthmatics); a decrease in the production of insulin (contraindicating use in diabetics); and central nervous system (CNS) effects including depression, insomnia, and a decline in male potency. In addition, the nonselective agents increase both triglycerides and low-density lipoprotein (LDL). These effects are reduced but not eliminated with the more P_:-selective agents.

Alpha₁ (α₁) Blockers

Prazosin, doxazosin, and terazosin reduce blood pressure by antagonizing α₁-adrenoreceptors in vascular smooth muscle. Blockade of this receptor reduces intracellular cyclic adenosine monophosphate (cAMP) and leads to a reduction in intracellular Ca²⁺. Orthostatic hypotension is common on initiation of therapy but diminishes. Dizziness and headache are also adverse effects. α₁-Blockers appear to reduce LDL cholesterol. Alpha blockers are used primarily for hypertension in patients who also have symptomatic prostatic hyperplasia. Because of excess cases of congestive heart failure in users of alpha blockers, these agents should not be used as first-line therapy in hypertension.

Calcium Channel Blockers

Calcium channel (Ca²⁺-channel) blockers are useful antihypertensives and can reduce blood pressure by 10-15 mm Hg. These agents exert their anti-hypertensive effect by blocking L-type (voltage-sensitive) Ca²⁺ channels.

By blocking the entry of Ca²⁺ into the cell, less is available to activate the contractile apparatus, and within vascular smooth muscle, this produces a reduction in vascular tone. Three distinct chemical classes comprise the Ca²⁺-channel antagonists, dihydropyridines include nifedipine, diphenylalky-lamines include verapamil, and benzothiazepines include diltiazem. All are approved for treating hypertension. Nifedipine and the other dihydropyridines have less of an effect on the heart than verapamil and diltiazem. Verapamil has the greatest effect on the heart and can significantly reduce contractility. Because of its effect on the heart, verapamil can be used to treat supraventricular arrhythmias as well as variant angina. Depression of cardiac function is the greatest adverse effect of the Ca²⁺-channel blockers, and this is markedly diminished with the dihydropyridines. Dihydropyridines can induce a reflex tachycardia in response to their blood pressure-lowering effect. However, clinical trials with short-acting nifedipine suggested that there was an increase in the risk of MI in patients treated for hypertension, and these agents should not be used to treat the disease.

Renin-Angiotensin System Inhibitors

Inhibitors of the renin-angiotensin system, both ACE inhibitors and ARBs are effective for hypertension monotherapy. ACE inhibitors block the conversion of the inactive angiotensin I to the potent angiotensin II. Angiotensin II acts to increase blood pressure in several ways. In vascular smooth muscle it increases intracellular Ca²⁺ and produces pronounced vasoconstriction. At peripheral nerve endings and in the adrenal medulla it increases the amount of catecholamines released on stimulation. In the zona glomerulosa of the adrenal cortex it acts to stimulate the biosynthesis of aldosterone, which increases renal Na⁺ and water retention. Adverse effects include hypotension, dizziness, and fatigue; rarely, hyperkalemia may occur. A dry cough and angioedema may occur as a result of the reduction in degradation of bradykinin that is brought about by these drugs.

Aliskiren (Tekturna) reduces the activity of renin; this in turn causes a reduction in the production of angiotensin II. Clinical experience is lacking for aliskiren, but it appears about as effective as ACE inhibitors and has fewer side effects. During clinical trials, headache, dizziness, and some gastrointestinal events were the most common side effects, and angioedema was observed in a few patients.

Angiotensin II acts through AT-1 and AT-2 receptors, which in turn couple to numerous signal transduction pathways. The hypertensive actions of angiotensin II are mediated by AT-1 receptors. Losartan, valsartan, and other AT-1 receptor blockers are also effective in reducing blood pressure by 10-15 mm Hg. The adverse-effect profile is similar to the ACE inhibitors but without the cough or angioedema.

Direct Arterial Vasodilators

Arterial vasodilators act by increasing the efflux of potassium from the cell. This causes hyperpolarization across the plasma membrane that diminishes the activity of the voltage-regulated L-type calcium channel. In vascular smooth muscle cells this produces a reduction in vascular tone. Minoxidil and hydralazine are the two most commonly used oral vasodilators used to treat hypertension. Both have pronounced effects on the resistance vessels and little effect on veins. Because of their predominant effect on arterioles, these agents provoke the baroreceptor reflex that includes tachycardia, vasoconstric-tion, and the release of renin. For this reason, these agents are usually combined with a beta blocker and a diuretic.

Centrally Acting Agents

Centrally acting vasodilators such as clonidine and methyldopa act as α₂-adrenergic receptor agonists in the vasomotor center within the medulla. These agents decrease sympathetic outflow and thereby decrease vascular tone and cardiac output. The use of these agents as antihypertensives has been overshadowed by the introduction of ACE inhibitors and ARBs and Ca²⁺-channel blockers. This is largely a result of the adverse effects, which are mostly in the CNS and include sedation, depression, and dry mouth. However, they are still used in cases of refractory hypertension.

Peripheral Sympathetic Inhibitors

Peripheral sympatholytic agents used for hypertension include guanethidine and reserpine. Guanethidine enters sympathetic nerve terminals by transport and replaces norepinephrine in transmitter vesicles. Release of norepinephrine is thereby diminished. Reserpine blocks the uptake and storage of biogenic amines, and this diminishes the amount of transmitter released on stimulation. Because of much higher rates of adverse effects, these agents are rarely used to treat simple hypertension but may be combined in the treatment of refractory hypertension.

What is the mechanism of action of metoprolol?

What is the mechanism of action of thiazide diuretics?

What electrolyte abnormalities commonly occur with thiazide diuretics?

Answers to case: Antihypertensive agents

Summary: A 50-year-old man with inadequately controlled hypertension is prescribed a thiazide diuretic.

Mechanism of action of metoprolol: β₁-Selective adrenoreceptor antagonist.

Mechanism of action of thiazide diuretics: Inhibit active reabsorption of NaCl in the distal convoluted tubule by interfering with a specific Na⁺/Cl^- cotransporter.

Electrolyte abnormalities seen with thiazide diuretics: Hypokalemia, hyponatremia, hypochloremia.

Clinical correlation

Thiazide diuretics are the recommended first-line agents for most people with hypertension. They are frequently used in combination with other classes of antihypertensives. Thiazides inhibit the active reabsorption of Na⁺. This causes an increase in the excretion of Na⁺, Cl^-, and K⁺. They also reduce the excretion of Ca²⁺ by increasing its absorption. The excretion of sodium and water reduces intravascular volume and contributes to their antihypertensive effect. Thiazides are used as single agents primarily in mild to moderate hypertension. They are often added as second agents when other drugs alone cannot control a patient’s hypertension. The electrolyte abnormalities caused by thiazides can be clinically important. Hypokalemia occurs frequently, especially when higher doses of thiazides are used. Patients need to be instructed to follow a high potassium diet and frequently require potassium supplementation. Thiazides can also elevate serum uric acid levels, which can precipitate gout in susceptible individuals.

Approach to pharmacology of antihypertensive agents

Objectives

1. Know the classes of antihypertensive medications and their mechanisms of action.

2. Know the common side effects of the antihypertensive agents.

Definitions

Hypertension: Blood pressure continuously elevated to levels greater than 120/80 mm Hg. Pressures of 130/90 mm Hg are considered prehypertensive.

Essential hypertension: Hypertension of unknown etiology makes up approximately 90 percent of hypertensive patients.

Pharmacology pearls

The ALLHAT clinical trial (Antihypertensive and lipid-lowering treatment to prevent heart attack) compared amlodipine, a dihydropyridine Ca²⁺-channel blocker, lisinopril, an ACE inhibitor, doxazosin, an α₁-adrenergic antagonist with chlorthalidone, a thiazide diuretic.

Thiazide diuretics are the preferred initial therapy for hypertension in most cases.

Beta-blocking agents can cause depression, insomnia, male impotency, bronchoconstriction, and decreased production of insulin.

Questions

[1] The inclusion of spironolactone with a thiazide diuretic in a regimen to treat hypertension is done to achieve which of the following?

A. Reduce hyperuricemia

B. Reduce Mg⁺ loss

C. Decrease the loss of Na⁺

D. Reduce K⁺ loss

[2] Which of the following drugs would be the best to treat moderate hypertension in a diabetic patient with mild proteinuria?

A. Enalapril

B. Propranolol

C. Hydrochlorothiazide D Nifedipine

[3] A 33-year-old man is diagnosed with essential hypertension. He is started on a blood pressure medication, and after 6 weeks, he notes fatigue, rash over his face, joint aches, and effusions. A serum antinu-clear antibody (ANA) test is positive. Which of the following is the most likely agent?

A. Hydralazine

B. Propranolol

C. Thiazide diuretic

D. Nifedipine

E. Enalapril

Answers

[1] D. Spironolactone is a “potassium-sparing” diuretic that reduces K⁺ excretion in the collecting duct. It diminishes the K⁺-wasting effects of thiazide diuretics.

[2] A. ACE inhibitors, such as enalapril, have been shown to reduce the progressive loss of renal function that is often seen in diabetic patients. The nonselective beta blocker, propranolol, would worsen the diabetes.

[3] A. Hydralazine is associated with a lupus-like presentation, with pho-tosensitivity, malar rash, joint pain, and sometimes pericardial effusion or pleura! effusion.

Continuation: Antihypertensive agents. Class

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 oflipophilicity, 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 β-blockers are much shorter, once-daily administration still maybe 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 blood pressure. 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 concentrations.

Hypertension during pregnancy is the second leading cause of maternal death, accounting for 15% of pregnancy-associated mortality in the United States. Approximately 8% of pregnancies are complicated by hypertension. Maternal complications of untreated hypertension during pregnancy include hepatic failure, acute renal failure, cerebral hemorrhage, abruptio placentae, and disseminated intravascular coagulation.Neonatal manifestations include prematurity, intrauterine growth retardation, spontaneous abortion, and stillbirth. Maternal mortality is less than 1%, whereas fetal mortality is approximately 9%. With the development of superimposed preeclampsia, mortality approaches 16% — 41%.

Pharmacological treatment of moderate to severe hypertension in pregnancy is necessary and has been proven to decrease both maternal and fetal complications. In mild hypertension, however, pharmacological treatment is controversial. There is also controversy regarding when to initiate pharmacotherapy,which agents to choose,and whether to maintain therapy during the first trimester in patients already on effective regimens. The National High Blood Pressure Education Program (NHBPEP) Working Group on High Blood Pressure in Pregnancy has combined reviews of clinical trials in women with hypertension of pregnancy and consensus documents from clinicians to summarize recommendations for diagnosing and treating hypertension in pregnancy. Classification of the hypertensive subtypes during pregnancy are listed in TABLE 1.

TABLE 1: Classification of Hypertension in Pregnancy

Chronic Hypertension

Chronic hypertension is defined as hypertension present or diagnosed prior to the 20th week of gestation. This includes patients with hypertension prior to pregnancy. Patients are diagnosed using an absolute level of blood pressure (140/90 mmHg or greater) or by an increase in blood pressure from preconception or first trimester levels (systolic blood pressure increase >25 mmHg and/or diastolic blood pressure increase >15 mmHg). Most women with mild chronic hypertension of pregnancy (systolic blood pressure of 140 — 179 mmHg or diastolic blood pressure of 90 — 109 mmHg) are considered at low risk for cardiovascular complications within the short time frame of pregnancy. According to the Working Group, these women are candidates for nonphar-macologic therapy.There is a normal physiologic decrease in diastolic blood pressure that occurs in the first trimester, thus averting the need for pharmacologic intervention in the mildly hypertensive woman. Also, clinical trials have failed to show improved maternal or neonatal outcomes in mildly to moderately hypertensive women. Failure to improve outcomes is generally attributed to problems in study design.

For hypertensive patients who have been treated for several years, or have evidence of target organ damage, or are on a regimen of multiple antihypertensive agents, medication dosage sizes may be reduced on the basis of blood pressure readings. These medications should be maintained, however, if they are needed to control blood pressure. Systolic blood pressures >160 mmHg, diastolic blood pressures >110 mmHg, left ventricular hypertrophy, and renal insufficiency all warrant reinitiation of pharmacologic treatment during pregnancy.

Methyldopa is generally recommended as first-line therapy because it does not compromise uteroplacental blood flow and fetal hemodynamics (TABLE 2). Methyldopa is an antihypertensive agent that stimulates the central inhibitory alpha-adrenergic receptors. Oral doses are 500 — 750 mg per day to a maximum of 2 — 3 g/day in divided doses; IV doses are 250 — 500 mg at six-hour intervals to a maximum of 1 g every six hours. Blood pressure control occurs within 3 — 6 hours. Approximately 50% of an oral dose is absorbed, and the elimination half-life is 7 — 16 hours. Fifty percent of the dose is metabolized via hepatic mechanisms. Hemolytic anemia, hepatitis, and myocarditis are rare but potentially fatal adverse effects of methyldopa. The most common adverse effects include lightheadedness, dizziness, headache, and postural hypotension, which occur in 15% of patients and are the most common causes for treatment discontinuation. Dose-dependent sedation, sleep disturbances, nasal congestion, and dry mouth are other common adverse effects. Drug-induced depression is also common and must be monitored, especially in pregnant patients, since depression can have adverse effects on the fetus as well.

TABLE 2: Current Drug Therapy Recommedations

If methyldopa cannot be tolerated, labetalol is recommended. A selective alpha-blocking and nonselective beta-adrenergic blocking agent with weak intrinsic sympathomimetic activity, labetalol has no membrane-stabilizing activity and moderate lipid solubility. The usual initial doses in hypertension are 100 mg orally twice a day, increasing gradually to maintenance doses of 200 — 400 mg twice a day. Intravenous bolus dosing consists of 20 mg infused over two minutes, with repeated doses of 40 mg or 80 mg given in 10-minute intervals. Alternatively, labetalol may be administered via continuous intravenous infusion at the rate of 2 mg per minute, with the effective dose usually within 50 — 200 mg. Oral labetalol is rapidly absorbed, producing hypotensive effects in one hour. It is metabolized in the liver, with 50% — 60% of the dose excreted in the urine and the remainder excreted in the bile. The half-life is 5 — 8 hours. Common adverse effects include hypotension, dizziness, and nausea. Aggravation of airway obstruction has been reported in asthmatic patients. Positive tests for antinuclear antibodies and a lupus-like illness have occurred. Severe hepatic injury is reported rarely. Hepatic necrosis and death have been reported but are also rare. During beta-blocker therapy, monitoring parameters include fetal and neonatal heart rate, serum blood glucose, respiratory rate, liver function tests, and fetal growth rate. Labetalol therapy should be discontinued in patients who develop laboratory or clinical signs of liver injury.

Labetalol has both alpha- and beta-blocking properties. It has been shown to be as effective as methyldopa for acute blood pressure control. Labetolol has a more rapid onset of action and a smoother control of blood pressure versus hydralazine. It has also been effectively used to treat hypertensive emergencies and to attenuate intubation-induced hypertensive responses in patients with preeclampsia. Beta-blockers have been shown to be no different in efficacy, with fewer adverse effects from methyldopa. Yet NHBPEP guidelines suggest that beta-blockers be reserved for use in the latter stages of pregnancy.

Another controversy involves the use of diuretic agents during pregnancy. Theoretically, diuretics may decrease plasma volume, resulting in decreased uteroplacental perfusion. Regardless, diuretics have been shown to be effective in controlling blood pressure for patients with hypertension of pregnancy in randomized controlled trials. A meta-analysis of nine randomized trials involving >7,000 subjects receiving diuretics revealed a reduced tendency among treated women to develop edema, hypertension, or both, and confirmed no increased incidence of adverse effects to the mother or fetus.

One option in treating chronic hypertension in pregnancy is to maintain an already effective regimen, provided the regimen does not contain an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blockers (ARBs). ACE inhibitors have been associated with fetal growth retardation, oligohydramnios, neonatal renal failure, and possibly, abnormal fetal morphology when administered to patients in the second and third trimesters. The effects of ARBs are thought to be similar to those of ACE inhibitors; thus, ARBs are also not recommended during pregnancy. There is much controversy on the use of atenolol during pregnancy since atenolol may decrease fetal birth weight.

Preeclampsia

Preeclampsia is defined as a pregnancy-specific syndrome of reduced organ perfusion related to vasospasm and activation of the coagulation cascade. In this syndrome, elevated blood pressure is only one sign that typically occurs after 20 weeks gestation.Classic symptoms of preeclampsia include increased blood pressure with proteinuria. Even if proteinuria is absent, any or all of the following suggest the development of preeclampsia: headache, blurred vision, abdominal pain, low platelet counts, or abnormal liver enzymes. The major maternal abnormalities occur in kidneys, liver, brain and coagulation systems. Consequently, the ensuing multi-organ failure impairs uteroplacental blood flow and may cause fetal growth retardation or intrauterine death.

Preeclampsia is associated with maternal adverse effects. The maternal disease is characterized by activation of the coagulation system, vasospasm, and changes in neurohormonal mechanisms related to blood pressure control. These pathophysiologic changes are ischemic, affecting the placenta, kidney, liver, and brain. The main difference between preeclampsia and chronic or gestational hypertension is that preeclampsia is a life-threatening systemic syndrome, even when blood pressure is only mildly elevated.Lowering blood pressure is only one aspect of managing preeclampsia, however. Maternal and fetal monitoring is essential to assess worsening preeclampsia or impending fetal demise, which may necessitate premature delivery.

Low-dose aspirin, calcium supplementation,and fish oil supplementationhave all been unsuccessful in preventing preeclampsia/eclampsia. Vitamin C and vitamin E supplementation, however, were associated with a decrease in preeclampsia,but further studies are needed.

The drugs most widely used to lower blood pressure acutely in pregnancy include nifedipine, labetalol, and hydralazine.Ketanserin, a specific serotonin S2 receptor antagonist, is not currently marketed in the U.S., but is considered to be an effective alternative to hydralazine, though there is no clear consensus on this issue. Blood pressure >170 per 110 mmHg should be lowered to protect the mother against risk of stroke or eclampsia (convulsions in a person with preeclampsia). In addition to the above antihypertensives, magnesium sulfate is used to prevent and treat convulsions. It may lower blood pressure, but is generally inadequate to treat severe hypertension in pregnancy.

Chronic Hypertension with Preeclampsia

When preeclampsia is superimposed on chronic hypertension, the prognosis is much worse for both mother and fetus.A sudden increase in proteinuria in a pregnant woman with preexisting hypertension prior to 20 weeks gestation is the main clinical diagnostic criterion. Others include a sudden increase in proteinuria or a sudden increase in blood pressure in a woman whose hypertension has been otherwise well controlled. Hospitalization for the duration of pregnancy is indicated upon onset of severe gestational hypertension or preeclampsia. This permits intensive maternal and fetal surveillance to determine platelet count, serum liver enzyme levels, renal function, and urinary protein excretion. At gestational week 33 — 34 the fetus may benefit from corticosteroid administration. Delivery is the only curative treatment for preeclampsia.

Gestational Hypertension

Gestational hypertension is diagnosed when women have blood pressure elevations for the first time after mid-pregnancy without proteinuria. Gestational hypertension can be an early manifestation of preeclampsia. It may also be an early sign of unrecognized chronic hypertension. Patients with gestational hypertension must be monitored closely for signs and symptoms of worsening. The point at which to initiate pharmacotherapy for patients with gestational hypertension is not clear at this time and is currently left to clinical judgment. Pharmacotherapy along with counseling, restricted activity, diet, and home blood pressure monitoring are the mainstays of the treatment of hypertension of pregnancy. Effective blood pressure control must be achieved with minimal adverse effects while maintaining normal uterine perfusion. Minimal long-term adverse effects on the fetus remain the long-term goal of treatment.

Dear Sukas,

Assuming she has essential hypertension, i.e. no other reason for high blood pressure, and has already lost weight, avoided salt and actively exercised, a second agent might be considered to lower her blood pressure to 160/90 or less. Other well tolerated drugs include ACE inhibitors (Capoten, Vasotec, Zestril), diuretics (Hydrodiuril), alpha blockers (Minipress, Hytrin, Cardura), and calcium channel blockers (Norvasc, Cardizem, Procardia, Plendil, Calan).

If her heart rate is still higher than 70 beats per minute, she may also be able to tolerate a higher dose of Tenormin, but this must be reviewed with her physician.

Thank you for your question.

Strengths

Our study has two strengths: it is based on observations of actual prescribing practices rather than on reported practices, and it has documented thoroughly patients’ clinical conditions. To our knowledge, only two other studies have considered comorbidity as an explaining factor, and, in those studies, the authors did not identify any relationship between associated conditions and prescribing practices. They do not report clearly, however, which clinical factors were considered, which hampers comparison with our findings.

Limitations

This study has limitations. Only one clinical setting was studied and the number of patients was small. A retrospective approach to data collection has shortcomings. Were all hypertensive patients identified? How valid are medical records as a source of information on patient care? In 1994, researchers estimated that about 15% of hypertensive patients were not identified correctly by their doctors. Perhaps as many as 20% to 80% of patients who visit physicians do not have their blood pressure measured. The objective of our study, however, was not to estimate the prevalence of hypertension in our practice. There is no reason to suspect that underidentification of hypertension is associated with a systematic bias in estimating the prescribing choices of physicians. Underidentification could lead to underestimating the number of patients not treated, if this phenomenon is associated preferentially with mild hypertension. Some studies on the validity of medical records as sources of information allow us to be confident in the data obtained from the charts. In a classic study, Romm and Putnam observed that information in medical records corroborated transcripts of actual encounters at 92% for the chief complaint, 71% for description of current illness, and 73% for diagnosis. To further validate our observations, we excluded all charts for which data were either insufficient (three) or did not support a diagnosis of hypertension (11). We suggest that there is no systematic association between potentially missing information and the type of pharmacologic treatment prescribed. Finally, the fact that the study clinic is a teaching setting can be considered a limitation also. The physicians, however, appear to share the prescribing practices of most North American physicians. The proportion of patients receiving monotherapy in our study (about 50%) is comparable to that observed in larger cohorts.

Our patient population consisted mostly of elderly women. It is possible that we did not have a sufficient number of young and middle-aged men to reveal specific prescribing tendencies for them. In a Canadian study, Vanasse et al observed that diuretics and β-blockers tended to be prescribed more frequently to patients older than 60 years. Other studies did not report any association between age and sex of patients and prescribing practices. New research results can modify treatment guidelines; our observations and all previous results were reported before the Stone study, which suggested that long-acting nifedipine (eg, Adalat) might help reduce complications from cerebrovascular disease.

Clinical practice guidelines

There seems to be a problem with implementing clinical practice guidelines on the pharmacologic treatment of hypertension. The right drugs are not necessarily given to the right patients. Our results suggest, however, that some recommendations are being followed. The contraindications to β-blockers appear to be well known, as is their indication for patients who have had myocardial infarctions. Still, we should be concerned that p-blockers were not the preferred choice for patients with coronary disease and that ACE inhibitors, although prescribed for most patients, were not prescribed for most diabetics, for whom they are the first choice. It is unlikely that socioeconomic factors can be blamed because, in Quebec, at the time of the study, elderly people and those on social welfare, who constituted a large part of our cohort, did not pay for drugs.

Interestingly, the trend in favour of calcium channel blockers and ACE inhibitors is not as strong in Europe, Australia, or New Zealand. Aggressive marketing of these new classes of medication (relying strongly on the bad publicity about the side effects of the first β-blockers) and lack of marketing of P-blockers probably explain the trend. Still, recent studies of second-generation p-blockers do not support the bad press that these medications receive. The pharmaceutical industry appears to be more effective at disseminating its messages than guideline developers are.

Key points

Family physicians prescribed diuretics most frequently, followed by ACE inhibitors, and then β-blockers. Enalapril (eg, Vasotec) was the most commonly prescribed medication, although only one third of diabetics received it. β-Blockers appear to be underused.

We cannot generalize our findings, but they suggest that some guideline recommendations are implemented well. Part of the discrepancy between practice and clinical guidelines might be due to the guidelines’ complexity. Emphasizing all recommendations equally could have hampered communication of a clear message. Too many recommendations might be as bad as too few. A better understanding of the problem could help focus the messages on the most questionable prescribing behaviours. We need studies such as this one on a larger scale and in various settings if we are to plan effective continuing medical education to improve physicians’ prescribing practices for hypertension.

Of the 183 patients, 15 (8.2%) received no medication, 103 (56.3%) received one medication, and 65 (35.5%) received combined therapy (seven received three medications). We observed modifications to the therapeutic regimen for only 11 patients (6%). Enalapril (eg, Vasotec) was the most frequently prescribed drug (15% of all prescriptions), followed by the combination of hydrochlorothiazide and triamterene, Diazide and others (11.5%). Regrouped as classes of medications, however, diuretics ranked first (45.9%), followed by ACE inhibitors (28.4%), calcium channel blockers (26.2%), and β-blockers (18.0%). Figure 1 shows the distribution of antihypertensive medications for patients on monotherapy and combined therapy. The distribution of medications is comparable for both groups. Angiotensin-converting enzyme inhibitors and calcium channel blockers were preferred to β-blockers as monotherapy.

Figure 1. Distribution of prescriptions according to medication class for patients receiving monotherapy (n = 103) and for the complete sample of patients receiving pharmacotherapy (n = 168)

Only 20% of patients with coronary artery disease were receiving β-blockers; 32% of diabetics were receiving ACE inhibitors. Table 3 shows the results of logistic regression analyses. Age, sex, duration of hypertension, and blood pressure readings were not associated with any class of medication and do not appear in the table. Prescription of p-blockers was strongly associated with antecedents of myocardial infarction, but not with diagnosis of angina pectoris.

As expected, patients with contraindications to β-blockers were less likely to receive them and more likely to receive calcium channel blockers. Patients with target organ damage were less likely to receive thiazide diuretics, but more likely to receive ACE inhibitors (P= 0.09).

Some studies, however, suggest that physicians, particularly in North America, do not apply these guidelines. Diuretics are the most frequently prescribed drugs, but angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers, which are more expensive, are prescribed more often than is recommended as first-choice therapy. For example, Psaty et al, in a study of prescribing trends, observed that newly treated hypertensive patients were about half as likely as previously treated patients to receive diuretics or β-blockers and about twice as likely to receive calcium channel blockers or ACE inhibitors.

Although hypertension treatment guidelines are remarkably consistent, they are also remarkably complex. First-choice drugs might be contraindicated because of associated medical conditions. Because hypertension often is associated with myriad other chronic diseases, it is possible that only a few patients actually are able to take diuretics or β-blockers, making it difficult to ascertain how widely clinical practice strays from the guidelines.

Few studies have reported on factors associated with the choice of antihypertensive medication. Many of those studies are surveys of reported prescribing practices rather than descriptive studies based on chart review or database analysis. Some authors have reported that younger patients tend to receive ACE inhibitors more frequently than older ones, but this has not been observed consistendy. In a survey conducted in Sweden, female and older physicians chose diuretics as first-line therapy more often than younger male physicians did. Some authors suggest that general practitioners choose less expensive treatment strategies more frequently than specialists, an observation that does not take into consideration the difference in case severity between the two groups of physicians. We found only two studies where comorbidity was ascertained. One was conducted in a health management organization; the other was based on a study of a community of residents older than 65 years. In neither study was comorbidity associated with choice of therapy.

Our study aims to evaluate the appropriateness of prescribing antihypertensive drugs according to the latest recommendations of the Canadian Hypertension Society, in a cohort of patients followed for at least 2 years in a family medicine unit in Montreal.

Method

Setting

The study took place in a teaching unit affiliated with the Family Medicine Program at the University of Montreal. The clinic, which opened in 1988, serviced a mostly French-speaking population and was located in a poor socioeconomic area of Montreal. (At that time, the Quebec provincial government paid the full cost of prescription drugs for disadvantaged and elderly people.) The unit had 13 regular staff physicians, nine of whom practiced full time at the teaching unit, and 13 family medicine residents on rotation for 2 years. In 1994, the clinic entered all its patient records into a computerized register. Two fourth-year medical students (functioning as clinical clerks at the externship level) effected the transfer under the supervision of one of the authors. We reviewed records of the previous 2 years’ visits to establish an active problem list, which we captured in the computerized database.

Study population

To be eligible, patients registered as having hypertension had to be regular patients of the clinic (not walk-in patients), who had consulted at least once a year between 1993 and 1995 and who had been treated for hypertension by a family physician at the clinic rather than by a specialist at the hospital. Charts were excluded if diagnosis of hypertension was not supported by chart review; if charts contained insufficient information; if patients were pregnant or younger than 18 years; or if patients were suffering from secondary hypertension and presenting with complex medical conditions, such as severe cardiac failure, a trial fibrillation with anticoagulant therapy, and metastatic cancer. Of the 350 patients registered since 1988,183 met the eligibility criteria. Reasons for exclusion appear in Table 1.

Variables

Variables were extracted from the charts by the same person, who had been trained by the two other authors. Interobserver agreement was not measured formally, but periodic checks of the data abstraction process were conducted during the study. As previously mentioned, to be included in the analysis, charts had to contain information on patients’ problems, blood pressure readings, and medications. Only three charts were excluded, which illustrates the high quality of the clinic’s charts.

All visits were reviewed to ascertain treatment modifications and occurrence of new health problems. The dependent variable was the antihypertensive medication. Mean blood pressure reading was considered an outcome variable and readings at each visit as independent variables that could explain treatment modifications. Other independent variables were age and sex of patients, duration of hypertension, total number of visits and number of visits for hypertension during the study period, number of physicians consulted at the clinic, number of consultations with specialists, associated medical conditions, diagnosis of target organ damage, and associated medications.

Analysis

χ² and Student’s t tests were used for nominal and continuous variables, respectively. Logistic regression analysis was performed to evaluate factors associated with the probability of receiving each major class of medication (diuretics, β-blockers, calcium channel blockers, and ACE inhibitors). Control variables were medical conditions considered indications or contraindications, age and sex of patients, presence of target organ damage, duration of hypertension, and systolic and diastolic blood pressure.