Overview
The pharmacologic management of hypertension has evolved significantly over the past few decades. In the past, thiazide diuretics and β-blockers were highly recommended as the only first-line therapies due to landmark evidence that demonstrated reduced risks of cardiovascular (CV) events. However, newer drug therapies have been introduced that include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs). These agents have been evaluated in outcomes-based trials and have been established as effective in preventing CV events. Moreover, newer evidence from outcomes trials has clarified the role of other agents, such as β-blockers and α-antagonists, in the treatment of hypertension.
Many important considerations influence the pharmacologic treatment of hypertension. These include selection of individual agents and drug classes and the choice of either monotherapy or combination therapy approaches when initiating therapy. Ongoing assessment of drug effectiveness and monitoring for adverse drug effects are also needed. Clinicians have the option of titrating and changing therapy through additions and/or modifications to achieve goal blood pressure (BP) values. Promoting and optimizing adherence to treatment are also essential to treat patients with hypertension optimally. All of these aspects of treatment are covered in this chapter.
Principles of Treatment
Evidence-Based Treatment
The prevailing guiding principle of hypertension management is to treat with the intent of reducing risk of CV events and thereby reducing CV morbidity and mortality. Outcomes trials have clearly established that a variety of antihypertensive drug therapies reduce risk of CV events. Moreover, results of comparative outcomes-based clinical trials and clinical trials in patients with concomitant cardiovascular disease (CVD) have enhanced the ability of clinicians to implement evidence-based drug therapy to manage hypertension.
Blood Pressure Goals
Most contemporary guidelines endorse a BP goal of less than 140/90 mm Hg for most patients with hypertension and less than 130/80 mm Hg for patients with diabetes or chronic kidney disease (CKD). Controversy surrounds whether this lower goal should extend to patients with coronary artery disease (CAD), noncoronary atherosclerotic vascular disease (ischemic stroke, peripheral arterial disease), and those with a 10-year risk of coronary heart disease according to a Framingham risk score of 10% or lower. The latter recommendation appeared in a 2007 American Heart Association (AHA) scientific statement but was modified and later rescinded in the recent American College of Cardiology Foundation (ACCF)/AHA/American Medical Association (AMA) Physician Consortium for Performance Improvement 2011 Performance Measures for Adults with Coronary Artery Disease and Hypertension Task Force report. Based on the lack of available trials that directly compare the clinical outcomes of CAD patients treated to different BP targets, and on the heterogeneity of outcomes in trials in which coronary patients with baseline BP below 140/90 mm Hg were treated with antihypertensive drugs, the Task Force recommended a more conservative BP goal below 140/90 mm Hg as a performance measure. They acknowledged that lower targets may be appropriate in some patients with CAD or other conditions but that it is unclear how such patients could be reliably identified for purposes of performance measurement.
Furthermore, current evidence has challenged whether aggressive BP goals—that is, those below 130/80 mm Hg—provide additional clinical benefit compared with the standard BP goal of less than 140/90 mm Hg in other patient groups, including those with uncomplicated hypertension, diabetes, CKD, and concomitant diabetes and CAD. Regardless of which goal clinicians select, BP reduction to a target goal is a clinically acceptable therapeutic strategy. Achieving target BP goals generally requires a combination of drug therapy and lifestyle modification.
Selecting Drug Therapy
Clinicians should select antihypertensive drug therapy that has been proven to reduce risk of CV events in addition to lowering BP. They should also consider the baseline CV risk of the hypertensive patient. Identifying whether the patient has compelling indications for a specific drug therapy, as summarized in Figure 29-1 , is the first step in selecting appropriate antihypertensive treatment. Clinicians should then consider effectiveness in lowering BP, minimizing risk for adverse events, and other patient-specific characteristics to help further guide and narrow selection of an individual drug, especially when more than one drug therapy option is identified.
Uncomplicated Hypertension
Many pharmacotherapeutic approaches are appropriate as first-line treatment options for patients with hypertension who have no comorbid condition that would dictate selection of specific antihypertensive drug therapy. Most guidelines have identified the following five drug classes as first-line choices for patients with uncomplicated hypertension: 1) thiazide diuretics, 2) β-blockers, 3) ACE inhibitors, 4) ARBs, or 5) CCBs. All these agents have been proven to reduce CV events in patients with hypertension. Moreover, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) recommends thiazide diuretics for most patients, if single-drug therapy is used, or as the first component of a two-drug combination. This recommendation was based on a number of randomized controlled trials, including the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared thiazide diuretic therapy to placebo or to other active treatments. Some guidelines and scientific statements have relegated β-blockers to the ranks of second-line therapy options in uncomplicated hypertension, based on evidence that indicates that although β-blockers reduce risk of CV events in hypertensive patients more effectively than placebo, they are not as effective as thiazide diuretics, ACE inhibitors, ARBs, or CCBs.
Patients with Compelling Indications
Compelling indications represent comorbid medical conditions other than hypertension for which specific antihypertensive drug therapy reduces risk of CV events and/or disease progression. Patients with compelling indications are at high risk for CV events and should receive other CV risk-reduction modalities—antiplatelet therapy, dyslipidemia therapy, smoking cessation, and obesity management—in addition to specific, targeted antihypertensive treatment.
Diabetes
Many patients with diabetes, either type 1 or type 2, have hypertension and require antihypertensive drug therapy. Most of these patients require at least two or three drugs to attain BP control. Many guidelines and expert statements recommend that patients with diabetes and hypertension be treated with either an ACE inhibitor or an ARB as first-line therapy because this has been proven to reduce the risk of CV events and kidney disease progression in patients with diabetes.
Other antihypertensive drugs should be added to ACE inhibitor or ARB therapy as needed to control BP. In particular, a diuretic is typically recommended as the first add-on therapy. Results from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study (ADVANCE) support the combination of an ACE inhibitor with a thiazide in reducing microvascular and macrovascular disease in patients with diabetes. Other data support the use of CCB therapy in patients with diabetes. CCBs do not have adverse metabolic effects and do not affect glycemic control in diabetes. Their use as an add-on therapy is typically effective and safe. Therefore, clinicians may choose a CCB over a thiazide diuretic as the first add-on therapy to treat patients with hypertension and diabetes. The American Society of Hypertension (ASH) recommends the use of dual CCB therapy, a dihydropyridine with a nondihydropyridine, as a possible option in diabetic patients with hypertension that is difficult to control, because this approach has been shown to provide additive antihypertensive effects.
When a diuretic is needed as add-on therapy in a patient with diabetes, a thiazide diuretic is typically recommended in patients with an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m 2 or higher. However, if eGFR is below 30 mL/min/1.73 m 2 , a loop diuretic should be considered. Moreover, the ASH identifies chlorthalidone as the suggested thiazide diuretic, because it is the diuretic used in clinical trials, and it forms the basis for the cardiovascular outcome data.
β-Blockers are also beneficial in the treatment of hypertension in patients with diabetes. A β-blocker should be considered as the third or perhaps fourth add-on agent for BP control in these patients. There is a risk of hyperglycemia with β-blocker therapy, but it is small and varies depending on the type of β-blocker used. For example, the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial demonstrated that carvedilol had no significant effect on glucose in patients with diabetes, but metoprolol did.
Chronic Kidney Disease
The JNC-7 considers CKD a compelling indication for either an ACE inhibitor or ARB therapy. For the purposes of identifying this compelling indication, CKD in general stage 3 or higher is defined as 1) an eGFR below 60 mL/min/1.73 m 2 (correlating to a serum creatinine >1.3 mg/dL in women or >1.5 mg/dL in men), or 2) albuminuria (>300 mg/day or >200 mg/g creatinine). In general, this is stage 3 or higher CKD. Treatment with an ACE inhibitor or ARB has been proven to reduce the rate of kidney disease progression and to lower BP in patients with CKD and proteinuria.
Diuretics are generally needed in hypertensive patients with CKD for both BP control and volume regulation. A thiazide or thiazide-like diuretic is recommended in CKD patients with an eGFR of 30 mL/min/1.73 m 2 or higher. When eGFR is below the 30 mL/min/1.73 m 2 threshold, or when the patient develops volume overload and edema, a loop diuretic should be used.
Coronary Artery Disease
Patients with CAD—that is, a prior history of myocardial infarction (MI), chronic stable angina, or acute coronary syndrome—are at high risk for recurrent CV events and CV death. CAD is considered a compelling indication for specific antihypertensive therapy that is proven to reduce risk of CV disease outcomes. β-Blocker treatment is the cornerstone of drug therapy for patients with hypertension and CAD because of proven long-term benefits. In patients with acute MI, β-blocker therapy reduces risk of death by more than 20%. In patients with CAD, β-blocker therapy reduces stimulation of the myocardium, balances myocardial oxygen supply and demand, and treats ischemic symptoms. Along with β-blocker therapy, patients should be treated with an ACE inhibitor or ARB to further reduce the risk of CV events, likely by preventing adverse cardiac remodeling. These benefits are present even if BP reduction is not needed.
Add-on therapy to a β-blocker plus ACE inhibitor (or ARB) regimen may both lower BP and reduce risk of CV events in patients with CAD. Thiazide or thiazidelike diuretics are proven add-on therapies. A CCB is also appropriate to treat ischemic symptoms. If added to a β-blocker, a dihydropyridine CCB should be chosen to avoid risk of excessive bradycardia, and even heart block, that is seen with β-blocker–nondihydropyridine CCB combinations. If a β-blocker cannot be used because of a contraindication or intolerable side effects, a nondihydropyridine CCB would be preferable owing to its ability to lower heart rate and reduce myocardial oxygen demand.
Left Ventricular Dysfunction
Antihypertensive drug therapy has been studied extensively in patients with left ventricular (LV) dysfunction or systolic heart failure, and it has been shown to improve LV function and to reduce related CV events, such as heart failure hospitalizations and CV death, at least in part by mechanisms other than BP lowering. Treatment with a “standard regimen” of a diuretic, ACE inhibitor or ARB, and an appropriate β-blocker has been proven to reduce the risk of CV events in patients with LV dysfunction. Diuretic therapy, most often with a loop diuretic, relieves or prevents fluid overload in addition to lowering BP and preventing CV events; ACE inhibitor (or ARB) and β-blocker therapies are used to reduce risk of CV events and risk of death. For patients with intolerance to ACE inhibitor therapy, an ARB is an acceptable alternative. Use of β-blocker therapy in combination with ACE inhibitor (or ARB) therapy both reduces risk of CV events and death and increases ejection fraction. However, β-blocker therapy should be initiated using recommended starting doses (low doses) titrated up appropriately to a target dose. Only metoprolol, carvedilol, and bisoprolol have been studied sufficiently to recommend their use in patients with LV dysfunction.
Beyond a standard regimen of a diuretic, ACE inhibitor or ARB, and an appropriate β-blocker, several add-on therapies have been studied. Addition of an aldosterone antagonist is proven to further reduce the risk of CV events in patients with both mild and severe heart failure and in those with recent MI. Another option is to add an ARB to a standard regimen that includes an ACE inhibitor. However, most clinicians prefer to add an aldosterone antagonist ahead of an ARB to a standard regimen that includes an ACE inhibitor, because the addition of an ARB has only been shown to reduce the risk of certain CV events, namely hospitalized heart failure, not death. Lastly, for African-American patients, addition of hydralazine in combination with isosorbide dinitrate is an option that has been shown to reduce the risk of CV events.
Previous Ischemic Stroke
History of stroke, specifically ischemic stroke, is a compelling indication for the use of a diuretic, with or without an ACE inhibitor, to reduce risk of a second stroke. A meta-analysis of seven randomized controlled trials showed that diuretics alone and in combination with ACE inhibitors, but not β-blockers or ACE inhibitors used alone, reduced risk of recurrent stroke, MI, and total CV events; however, no effect was seen on mortality rate. CCBs and ARBs were not evaluated in any of the included trials.
The Protection Against Recurrent Stroke Study (PROGRESS) confirmed that recurrent stroke can be reduced in patients with a history of ischemic stroke when a thiazide-type diuretic is added to an ACE inhibitor. Reduction in recurrent stroke was seen with this combination, even when pretreatment BP was below 140/90 mm Hg; however, recurrent stroke was not reduced with ACE inhibitor monotherapy in this study.
ARB therapy in patients with a history of stroke has not definitively been shown to reduce risk of recurrent stroke or CV events. The Morbidity and Mortality After Stroke: Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study demonstrated better reductions in recurrent stroke with ARB therapy compared with a dihydropyridine CCB, suggesting that CV endpoints are reduced with ARB therapy in patients with prior stroke. However, in the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial, patients with a history of ischemic stroke had similar rates of recurrent stroke and CV events with ARB therapy compared with placebo ; therefore the role of ARB therapy in secondary prevention of ischemic stroke has not been established.
Overview of Drug Classes
Many classes of drugs are available for the treatment of hypertension. The most frequently used antihypertensive drug classes are ACE inhibitors, ARBs, CCBs, and thiazide or thiazidelike diuretics. β-Blockers, aldosterone antagonists, and α-blockers are also commonly used as add-on therapy or for patients with compelling indications. These drug classes are summarized in Table 29-1 .
| CLASS | MECHANISM OF ACTION | ROLE IN THERAPY | AVOID USE | SITUATIONS WITH POTENTIALLY FAVORABLE EFFECTS | SITUATIONS WITH POTENTIALLY UNFAVORABLE EFFECTS |
|---|---|---|---|---|---|
| ACE inhibitors | Inhibition of ACE results in decreased production of angiotensin II, which causes decreased vasoconstriction, decreased aldosterone secretion, and sodium and water retention. Also results in decreased breakdown of bradykinin and other vasoactive peptides, which results in vasodilation and allergic responses. |
| Pregnancy, bilateral renal artery stenosis, history of angioedema | Low-normal potassium, prediabetes, albuminuria | High-normal potassium or hyperkalemia, volume depletion |
| Angiotensin receptor blockers | Blockade at the angiotensin II type 1 receptor results in decreased angiotensin II effects, which causes decreased vasoconstriction, decreased aldosterone secretion, and sodium and water retention. |
| Pregnancy, bilateral renal artery stenosis | Low-normal potassium, prediabetes | High-normal potassium or hyperkalemia, volume depletion |
| Dihydropyridine calcium channel blockers | Blocking of cellular calcium entry through the L-type channel results in reduced total peripheral resistance through arterial vasodilation. |
| Left ventricular dysfunction (all except amlodipine and felodipine) | Reynaud syndrome, elderly patients with isolated systolic hypertension, cyclosporine-induced hypertension | Peripheral edema, high-normal heart rate or tachycardia |
| Nondihydropyridine calcium channel blockers | Decreased cellular calcium entry through the L-type channel results in reduced total peripheral resistance through arterial vasodilation. Decreased myocardial contractility results in negative inotropic effects, and blocked AV nodal conduction results in decreased heart rate. |
| Second- or third-degree heart block, left ventricular dysfunction | Reynaud syndrome, migraine headache, arrhythmias, high-normal heart rate or tachycardia | Peripheral edema, low-normal heart rate |
| Thiazide diuretics | Initial transient effects cause natriuresis, resulting in reductions in cardiac output and decreased blood volume. Long-term persistent effects result in decreased peripheral vascular resistance. |
| Prior anaphylactic and/or Stevens-Johnson–type reactions to sulfa-type drugs (less extreme reactions are not an absolute contraindication), gout, hyponatremia, hypokalemia | Osteoporosis or at increased risk for osteoporosis, high-normal potassium | Gout, prediabetes, low-normal potassium, elevated fasting glucose |
| β-Blockers | Blockade of β-1 receptors results in reduced cardiac output and reduced heart rate. Also inhibits renin release, decreases adrenergic central nervous system effects, and reduces catecholamine release/response. |
| Second- or third-degree heart block, acute decompensated heart failure, severe bronchospastic disease | Migraine headache, tachyarrhythmia, high-normal heart rate or tachycardia, hyperthyroidism, essential tremor, preoperative hypertension | Bronchospastic disease, chronic obstructive pulmonary disease, symptoms of hypoglycemia, high physical activity |
| Aldosterone antagonists | Blockade of aldosterone receptor results in decreased vasoconstriction and decreased sodium/water retention. |
| Hypotension, dehydration, hyperkalemia | Low-normal potassium, chronic kidney disease | High-normal potassium |
Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors may be used as a first-line therapy for uncomplicated hypertension and are included in all first-line regimens for patients with compelling indications ( Table 29-2 ). They inhibit angiotensin-converting enzyme and result in decreased production of angiotensin II and decreased breakdown of bradykinin; thus they promote vasodilation. ACE inhibitor use is not accompanied by unfavorable compensatory changes such as sodium and water retention or increased heart rate. However, adding a thiazide, even in small doses, to ACE inhibitor therapy enhances the antihypertensive efficacy of the ACE inhibitor, because diuretic-induced sodium depletion activates the renin-angiotensin-aldosterone system and makes BP more angiotensin II dependent. Similarly, addition of either a dihydropyridine or a nondihydropyridine CCB enhances the BP-lowering effects of the ACE inhibitor. β-Blockers can also be given together with ACE inhibitors, although the incremental effect on BP lowering is minor. β-Blockade in this combination may be beneficial, because it blunts the reactive rise in plasma renin activity that accompanies ACE inhibitor therapy.
| DRUG | DOSE RANGE (MG/DAY) * | DAILY DOSES | SPECIAL CONSIDERATIONS † |
|---|---|---|---|
| Benazepril (Lotensin) | 10-80 | 1 or 2 |
|
| Captopril (Capoten) | 75-450 | 2 or 3 | |
| Enalapril (Renitec, Vasotec) | 5-40 | 1 or 2 | |
| Fosinopril (Monopril) | 10-80 | 1 or 2 | |
| Lisinopril (Prinivil, Zestril) | 10-80 | 1 | |
| Moexipril (Univasc) | 7.5-30 | 1 | |
| Perindopril (Aceon) | 4-16 | 1 or 2 | |
| Quinapril (Accupril) | 10-80 | 1 or 2 | |
| Ramipril (Altace) | 2.5-20 | 1 or 2 | |
| Trandolapril (Mavik) | 1-8 | 1 or 2 |
* Lists the typical starting and maximum daily doses for the management of hypertension.
ACE inhibitor therapy has benefits beyond BP lowering. Long-term ACE inhibitor therapy delays the onset of type 2 diabetes. Further, ACE inhibitor therapy can restore endothelial function in patients with endothelial dysfunction, and it can remodel blood vessels, and in the process, it improves vascular compliance. By blocking the effects of angiotensin II, ACE inhibitor therapy inhibits constriction of the efferent arteriole in the glomerulus. This pharmacologic effect has been used to explain the benefits of ACE inhibitors in slowing progression of kidney disease ; however, it is unclear whether these renal benefits of ACE inhibitors are independent of BP lowering.
ACE inhibitors are effective in lowering BP in most patients but are generally less effective as monotherapy in salt-sensitive, low-renin forms of hypertension—such as that often found in African-American, diabetic, and elderly hypertensive patients—unless administered in higher than usual doses. However, BP responses to ACE inhibitor therapy are variable, and some individuals in these groups experience significant BP reductions with usual doses. The dose-response curve for BP reduction is steep at low doses of ACE inhibitors but typically flattens at moderate to high doses. The antihypertensive effects of ACE inhibitors are linked to the patient’s volume status. When volume losses occur, both intentional (diuretic therapy) and unintentional (sweating/exercise), major decreases in BP and deterioration in renal function to the point of acute renal failure can result from ACE inhibitor therapy.
Adverse effects associated with ACE inhibitors include cough, angioedema, and a distinctive form of functional renal insufficiency. A dry cough can occur with ACE inhibitor therapy, likely owing to the decreased breakdown of peptide mediators, including substance P and bradykinin. If cough occurs with an ACE inhibitor, it is unlikely that switching to another ACE inhibitor will relieve this symptom, as it appears to be a class effect. If a patient experiences angioedema, future treatment with an ACE inhibitor is contraindicated. Under these circumstances, an ARB is a reasonable alternative, although angioedema has rarely been reported with ARBs.
The occurrence of functional renal insufficiency with an ACE inhibitor does not preclude future use of ACE inhibitor therapy, unless high-grade bilateral renal artery stenosis is present. Initiation of ACE inhibitor therapy often reduces GFR, owing to the decrease in angiotensin II–induced constrictor effects on the efferent arteriole. This effect is typically limited to an increase in serum creatinine of less than 30% and is not a reason to discontinue therapy.
Angiotensin Receptor Blockers
ARBs are first-line options for treatment of uncomplicated hypertension and are a reasonable alternative to ACE inhibitor therapy for many patients with compelling indications ( Table 29-3 ). The ARBs blunt the effects of angiotensin II via direct blockade of the angiotensin II type 1 receptor; they have no effect on generation of angiotensin II or breakdown of bradykinin or substance P. ARBs differ in bioavailability, rate of absorption, volume of distribution, and metabolism—that is, whether it metabolizes cytochrome (CY) P450—but these pharmacokinetic differences are of little practical consequence. Duration of receptor occupancy, a surrogate for the BP-lowering effect of the ARB class, is most relevant when low doses of ARBs are used. All ARBs are eliminated through some combination of renal and hepatic clearance. This distinguishes the ARBs from ACE inhibitors, which are predominantly renally cleared.
| DRUG | DOSE RANGE (MG/DAY) | DAILY DOSES | SPECIAL CONSIDERATIONS † |
|---|---|---|---|
| Azilsartan medoxomil (Edarbi) | 80 | 1 |
|
| Candesartan cilexetil (Atacand) | 16-32 | 1 | |
| Eprosartan mesylate (Teveten) | 600-800 | 1 or 2 | |
| Irbesartan (Avapro) | 150-300 | 1 | |
| Losartan potassium (Cozaar) | 50-100 | 1 or 2 | |
| Olmesartan medoxomil (Benicar) | 20-40 | 1 | |
| Telmisartan (Micardis) | 40-80 | 1 | |
| Valsartan (Diovan) | 80-320 | 1 |
Most ARBs are indicated for once-daily dosing, but at low doses, they may lose efficacy at the end of a dose interval, thereby necessitating twice-daily dosing. Similar to ACE inhibitors, certain patient groups are generally more responsive (high-renin and young hypertensive patients) or less responsive (low-renin, salt-sensitive, volume-expanded individuals, such as African Americans) to ARB monotherapy. Also similar to the ACE inhibitors, the effectiveness of an ARB in lowering BP is increased with addition of a diuretic or a CCB. On the basis of experience with ACE inhibitors, it can be expected that addition of a β-blocker to an ARB would have a minimal additional effect on BP but might be indicated to treat a compelling indication.
The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) compared the effects of ARB-based therapy to ACE inhibitor–based therapy and combination therapy with ARBs and ACE inhibitors on CV events in patients at high risk of CVD, the majority of whom had hypertension. The main finding was that the ACE inhibitors and ARBs were equally effective for lowering BP and preventing CV events, but the combination produced minimal additional BP lowering and no benefit in preventing CV events compared with either monotherapy. Further, adverse events occurred more frequently with the combination than with either drug therapy alone. Accordingly, ACE inhibitors with ARB combinations are not recommended for the treatment of uncomplicated hypertension.
ARBs are firmly established as an alternative and are arguably on par with ACE inhibitors for the compelling indications of diabetes, CKD, CAD (post MI), and LV dysfunction. However, results of outcome trials of ARBs for prevention of recurrent stroke are conflicting.
ARBs have a low rate of adverse effects and result in high adherence and persistence rates in patients with uncomplicated hypertension. Cough does not occur with ARBs, and angioedema is rarely a problem. Data from the prospective, randomized, placebo-controlled Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial indicate that patients with angioedema on ACE inhibitor therapy will not experience angioedema with an ARB.
Calcium Channel Blockers
The CCBs include two main subclasses of compounds: the dihydropyridines and the nondihydropyridines. These can be further subdivided into the benzothiazepines, such as diltiazem, and phenylalkylamines, such as verapamil. Although all CCBs block L-type calcium channels, and all have vasodilator effects, these subclasses have distinctly different structures and pharmacologic characteristics ( Table 29-4 ). CCBs can be used as first-line therapy for uncomplicated hypertension, and they have a compelling indication as add-on therapy for patients with diabetes and CAD. Several other uses are possible for dihydropyridine CCBs, such as cyclosporine-induced hypertension and Raynaud phenomenon, and for nondihydropyridine CCBs, including atrial fibrillation and migraine headache prevention. Because CCBs are not associated with metabolic side effects, patients who experience such effects from other antihypertensive drugs can be safely treated with CCBs.
| DRUG | DOSE RANGE (MG/DAY) * | DAILY DOSES | SPECIAL CONSIDERATIONS |
|---|---|---|---|
| Dihydropyridines | |||
| Amlodipine (Norvasc) | 2.5-10 | 1 |
|
| Felodipine (Plendil) | 2.5-10 | 1 | |
| Isradipine SR (Dynacirc SR) | 5-20 | 1 | |
| Nicardipine, sustained-release (Cardene SR) | 60-120 | 2 | |
| Nifedipine, long-acting (Adalat CC, Nifedical XL, Procardia XL) | 30-120 | 1 | |
| Nisoldipine (Sular) | 17-34 | 1 | |
| Nondihydropyridines | |||
| Diltiazem, sustained-release and extended-release (Cardizem CD, Cardizem LA, Cartia XT, Dilacor XR, Diltia XT, Tiazac, Taztia XT) | 120-540 | 1 |
|
| Verapamil, sustained-release (Calan SR, Isoptin SR, Verelan) | 120-480 | 1 or 2 | |
| Verapamil, controlled-onset, extended-release (Covera HS) | 180-480 | 1 | |
| Verapamil, sustained-release, slow-onset (Verelan PM) | 100-400 | 1 |
* Dose range lists the typical starting and maximum daily doses for the management of hypertension. The dosage range for diltiazem varies based on the product; refer to manufacturer recommendations for exact dose.
Dihydropyridine CCBs are potent arterial vasodilators that can elicit activation of the sympathetic nervous system and result in reflex tachycardia. Nondihydropyridine CCBs are less potent arterial vasodilators but have major effects on the heart, and they have clinically significant negative inotropic effects; second-generation dihydropyridine CCBs, such as amlodipine or felodipine, are selective for the vasculature and have little, if any, effect on cardiac contractility. CCBs do not have adverse metabolic effects.
The adverse effects of CCBs are predictable based on their pharmacologic properties. With all CCBs, blockade of L-type calcium channels can decrease lower esophageal sphincter pressure and cause gastroesophageal reflux. Typically this is not a treatment-limiting effect. All CCBs can slow gastrointestinal transit time and increase risk of constipation; verapamil has the highest incidence of this adverse effect. Rarely CCBs can cause gingival hyperplasia or polyuria. Because of their potent arterial dilation, dihydropyridine CCBs frequently cause flushing, headache, and peripheral edema; the peripheral edema is caused by a selective decrease in arteriolar resistance, whereby precapillary hydrostatic pressures increase and favor a fluid shift into the interstitial compartment. CCB-related edema is dose dependent and is more common in women and older people. Peripheral edema can be a treatment- or dose-limiting side effect of dihydropyridine CCBs that can be slow to resolve without intervention but is mitigated by reducing the dihydropyridine dose, by adding an ACE inhibitor or ARB, and by encouraging the patient to elevate the lower extremities whenever possible. Diuretic therapy is relatively ineffective in reducing CCB-induced edema and is not recommended as a management strategy. For bothersome peripheral edema that does not resolve with dose reduction or addition of ACE inhibitor or ARB therapy, the CCB must be discontinued.
Nondihydropyridine CCBs can cause atrioventricular (AV) block and resultant bradycardia, particularly when administered in high doses or with sympatholytic drugs such as β-blockers, and they are contraindicated in patients with LV dysfunction because of the risk of heart failure exacerbation as a result of their negative inotropic effects. Verapamil and diltiazem inhibit the CYP450 3A4 isoenzyme system and can result in drug interactions, such as with cyclosporine and simvastatin.
The availability of sustained-release delivery systems for CCBs, particularly the dihydropyridines, has enhanced their use because of a reduced side-effect profile and more sustained BP reduction. Short-acting dihydropyridine CCBs reduce BP abruptly, activating the sympathetic nervous system and potentially inciting coronary ischemia. This process does not occur with long-acting dihydropyridine CCBs, which lower BP gradually and smoothly.
All patient groups are to some degree responsive to CCB monotherapy. Low-renin, salt-sensitive, volume-expanded patients, such as diabetic and African-American patients, are more often responsive to a CCB than to an ACE inhibitor or a β-blocker. Elderly patients are also highly responsive to the vasodilator and BP-lowering effects of CCBs; however, these are generalizations that may not reliably predict the magnitude of BP reduction in individual patients.
Diuretics: Thiazides
Thiazide and thiazide-like diuretics are widely used in the treatment of hypertension ( Table 29-5 ). They are recommended as first-line agents for uncomplicated hypertension and in patients with compelling indications such as LV dysfunction, although loop diuretics are commonly needed in this situation, and previous ischemic stroke. Thiazide and thiazide-like diuretics have been shown in numerous controlled clinical trials to decrease hypertension-associated morbidity and mortality. They are particularly effective in lowering BP in African Americans and the elderly. Diuretics combine well with nearly every other antihypertensive drug class and are available in fixed-dose combinations with most other drug classes.
| DRUG | DOSE RANGE (MG/DAY) * | DAILY DOSES | SPECIAL CONSIDERATIONS |
|---|---|---|---|
| Thiazides | |||
| Chlorthalidone (Hydone, Hygroton, Thalitone) | 12.5-50 | 1 |
|
| Hydrochlorothiazide (Aquazide H, Carozide, Diaqua, Esidrix, Ezide, Hydro Par, HydroDIURIL. Hydrocot, Hydrokraft, Loqua, Oretic) | 12.5-50 | 1 | |
| Indapamide (Lozol) | 1.25-5 | 1 | |
| Loop | |||
| Furosemide (Lasix, Delone, Furocot, Lo-Aqua) | 20-600 | 2 | May be preferred over thiazides in patients with severe CKD or chronic heart failure |
| Torsemide (Demadex) | 5-10 | 1 | |
| Potassium Sparing | |||
| Amiloride (Midamor) | 5-20 | 1 |
|
| Triamterene (Dyrenium) | 37.5-75 | 1 |
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