These papers on the pharmacologic therapy of hypertension from the American Society of Hypertension (ASH) are written to provide a brief, expert, up-to-date review of current pharmacologic principles and approaches to hypertension for clinicians, especially designated hypertension specialists, or those who desire to be designated. The primary intent of these papers is to discuss, in a precise and concise manner, various classes of oral antihypertensive agents and chronic disease management. Overall, the authors address mechanisms of action, pharmacokinetics, and drug differentiation within areas of therapeutic classes. The emphasis was placed specifically on practical uses of the cornucopia of approved antihypertensive agents available today. After studying this series of papers, the hypertension specialist or any clinician who desires to become a designated specialist will better understand and recognize basic pharmacology, indications, variations in responses among specific patient types, and special situations for various drugs. Consistently, the authors include commentary on the combination of the highlighted drug class with other medications, when appropriate, with discussions of relevant drug interactions and adverse effects.
The first discussion concerns thiazide-type and loop diuretics by Drs Dominic A. Sica, Barry L. Carter, William C. Cushman, and L. Lee Hamm.1Consistently in major guidelines and in most expert practices, thiazide-type diuretics are appropriate first choices for a wide range of persons with hypertension. Dr Sica and colleagues, however, caution clinicians to avoid volume-depleting effects with overdiuresis. Nevertheless, they appropriately discuss the long history of safe and effective use of chlorthalidone, including multiple cardiovascular (CV) outcome studies for heart disease and stroke, including low-renin patient groups such as blacks, the elderly, and patients with diabetes. Clinical suggestions are offered on how to best manage complications that may arise from thiazide-type diuretics, including metabolic derangements, such as hypokalemia and glucose intolerance. Nevertheless, diuretic-based therapy, including concurrent administration with a wide range of agents, especially angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), can be effective and safe in most patients. Interestingly, an older thiazide-type diuretic, chlorthalidone, is increasingly being used to effectively control blood pressure (BP), especially in patients with more complicated scenarios. The authors also confirm the benefits of loop diuretics, although not as first-line therapy, in patients with significant fluid overload or renal disease.
In the article on aldosterone blockers and potassium-sparing diuretics,2 Drs Murray Epstein and David A. Calhoun propose that aldosterone blockers are now increasingly recognized as effective compounds for the treatment of hypertension, especially in patients with low-renin and salt-sensitive forms of hypertension. Furthermore, the authors suggest that the appropriate use of aldosterone blockers is a beneficial addition to the armamentarium for persons with resistant hypertension. Although spironolactone has been shown to benefit patients with heart failure and resistant hypertension, a newer, more selective aldosterone blocker, eplerenone, has been shown to have the additional benefit of reduced gynecomastia in men and fewer menstrual irregularities in women. Eplerenone, they suggest, may have somewhat less hyperkalemia than seen with spironolactone. Aldosterone blockers have proven CV benefits in the treatment of patients with severe heart failure, when combined with ACE inhibitors, digoxin, and loop diuretics. The authors also highlight the benefits of potassium-sparing diuretics (amiloride or triamterene) often used in combination with a thiazide-type diuretic.
Subsequently, β-adrenergic–blocking drugs are discussed by Drs William H. Frishman and Elijah Saunders.3 They note that, increasingly, modern reviews of the treatment of hypertension question the use of β-blockers as initial therapy, especially in elderly patients. However, this heterogeneous class of agents remains compelling, specifically for the treatment of patients who have concomitant ischemic heart disease, left ventricular dysfunction, heart failure, obstructive cardiomyopathy, or certain arrhythmias. Frishman and Saunders offer detailed tables and insights into how various pharmacologic effects of β-adrenergic blockers may impact their clinical use, including side effects and adverse reactions. β-Blockers are clearly different in the degree of β1 selectivity, pharmokinetics, and additional modes of activity (vasodilating β-blockers, such as labetalol, carvedilol, and nebivolol) for instance. Their detailed table of the pharmacolgy of these agents includes carvedilol with its peripheral vasodilating activity and additional α1-adrenergic–blocking activity, along with labetalol, with this agent also available for use in intravenous form for hypertensive emergencies. A unique β-blocker, nebivolol can augment vascular nitric oxide release, but the authors note it has not been approved for use beyond hypertensive therapy at this point.
Drs Richard H. Grimm and John M. Flack4 submitted the article on α receptor blockers. An older class of agents, α1 antagonists effectively lower BP, especially in combination with diuretics, and also reduce symptoms of lower urinary tract obstruction with benign prostatic hyperplasia. They note that the pharmacology of selective post-synaptic receptors includes various subtypes. Prazosin at one time was a widely used, beneficial addition to the antihypertensive armamentarium, with subsequent use of terazosin and its main advantage of a much longer half-life, allowing for a once-daily dosage. Nevertheless, in clinical use, quinazoline α1 antagonists cannot be recommended as initial monotherapy. According to Drs Grimm and Flack, despite the beneficial metabolic effects of doxazosin in controlled trials, the adverse CV outcomes, including heart failure in the Antihypertensive Lipid-Lowering in Heart Attack Trial (ALLHAT), with this agent vs chlorthalidone limit the use of this class as a primary agent to control hypertension. The authors argue that α1 antagonists remain useful as add-on therapy in multidrug, antihypertensive therapy.
Central sympatholytics are described by Drs Wanpen Vongpatanasin, Ronald G. Victor, Kazuomi Kario, and Steven A. Atlas.5 This older class of agent has limited clinical use because of side effects and no definitive evidence for benefit on CV outcomes. These agents reduce BP, mainly by stimulating central α2 adrenergic receptors in the brain centers, reducing sympathetic nerve activities. While recognizing their diminished use because of side effects such as drowsiness, fatigue, and dry mouth, the authors discuss how this class of drugs can be used as a fourth-line (or beyond) drug therapy. They specifically detail differences in the pharmacokinetics of central sympatholytic drugs and the need for hypertension specialists to be aware of the potential for rebound hypertension in nonadherent patients. Specific discussion of the central sympatholytic agents includes unique aspects of clonidine, guanfacine, and guanabenz. Dr Vongpatanasin and coauthors include a table to assist with better understanding the pharmacokinetic profiles of this class of drugs. Their illustration of the mechanisms underlying the CV effects of sympatholytic drugs will assist the expert in hypertension in understanding the development of systemic BP elevation itself.
Renin inhibitors, the newest class of antihypertensive agents, presently have only one member approved, aliskiren, for use in hypertension in the United States. Drs Naomi Fisher and Emma A. Meagher6 describe the pharmacology of aliskiren and the concept of oral renin inhibition. This agent is effective for treatment of hypertension either as monotherapy or in combination therapy and is well tolerated, although presently limited in its use by the lack of data to determine whether benefits in diabetic nephropathy will extend to protection with CV diseases. As a brief background, Drs Fisher and Meagher note the difficulty with previous low potency, poorly absorbed early molecules, but with modern molecular modeling via x-ray crystallography and reconstruction of the active renin site, more potent oral renin inhibitors are being produced. The authors note that the actions of oral renin inhibition are unique on the renin-angiotensin-aldosterone (RAAS) system and they also involve inhibiting activation of the pro-enzyme pro-renin. Since aliskiren is the sole oral renin inhibitor approved at this time, the authors primarily discuss its indications when used as monotherapy or in combination and the sustained BP-lowering effects of aliskiren. They include an excellent table that summarizes the presently available surrogate end point studies and ongoing clinical trials with aliskiren.
Drs Joseph L. Izzo, Jr and Matthew R. Weir7 detail aspects of ACE inhibitors, which are considered excellent for the effective lowering of BP and provision of CV protection in a wide range of patients. The authors discuss the mechanisms involved with blocking the conversion of angiotensin I to angiotensin II with subsequent lowering of systemic vascular resistance and protection against the deleterious effects of angiotensin II. They note that the expert use of these agents will lead to reduction in morbidity and mortality in patients with heart failure, reduced systolic function post-myocardial infarction, and slow progression of diabetic renal disease and nephrosclerosis. Dr Izzo and cohorts suggest that ACE inhibitors have effects beyond lowering BP alone and may actually prevent complications related to CV disease in high-risk patients, including in patients with diabetes. Because of the effect of ACE inhibitors outside of blocking the conversion of angiotensin I to angiotensin II, clinicians and specialists must be aware of the side effects of cough and angioedema. While not life-threatening, the cough that accompanies ACE inhibitors often can lead to poor adherence. On the other hand, angioedema has potentially serious consequences in a small subset of persons treated with ACE inhibitors, especially in black patients. While recognizing the benefit of ACE inhibitors, the authors note that their expert use must consider adverse effects including hypotension in volume-depleted patients and hyperkalemia, especially in patients with renal insufficiency, and/or using potassium supplements and acute renal failure in persons with bilateral renal artery stenosis.
Another class of RAAS-blocking agents, angiotensin receptor blockers (ARBs), is the subject of the chapter written by Drs Addison A. Taylor, Helmy Siragy, and Shawna D. Nesbitt.8 They discuss the pharmacology, efficacy, and safety of ARBs, the last major class of multiple available antihypertensive agents approved in the United States. They note that ARBs share the selective binding to angiotensin II receptors and are effective as monotherapy and in combination with a wide range of agents. Although there are pharmacologic actions common to all ARBS, the authors point out some unique properties, such as the potential peroxisome proliferator-activated receptor γ activity with telmisartan and uric acid reduction with losartan. An excellent table details the pharmacokinetic effects of the 7 ARBs available and includes protein binding, volume of distribution, and elimination half-life. Despite the lower incidence of cough and angioedema with ARBs vs ACE inhibitors, the authors caution that ARBs should be considered for persons who have experienced ACE inhibitor–related angioedema only if no alternatives are available and indications are compelling. Drs Taylor and colleagues review the increasing body of clinical studies and trials with surrogate markers of CV outcomes, including proteinuria, left ventricular hypertrophy, and the development of new-onset diabetes. An interesting brief review of the effects of central pressure and stiffness with this class of agents is included. The lack of benefits of ARBs combined with ACE inhibitors is noted, and specific data are reviewed related to cardiovascular and renal outcome studies.
Drs William J. Elliott and C. Venkata S. Ram9 discuss calcium channel blockers (CCBs), including their basic differences in pharmacology and characteristics, benefits as antihypertensive agents, and potential for treating conditions beyond uncomplicated hypertension, such as dysrhythmias. The authors note that a wide range of patients effectively respond to CCBs, including both sexes, various racial/ethnic groups, the elderly, and patients with excessive dietary sodium intake. The hypertension specialist should specifically recognize that CCBs are heterogeneous, including dihydropyridine, diltiazem, and verapamil, each with specific hemodynamic and pharmacologic effects. A comprehensive table is included, which lists the presently available CCBs, including their half-lives, unique effects, results of hypertension-related outcome trials, and dosages. The authors also discuss other Food and Drug Administration indications for CCBs beyond hypertension and off-label uses of this class of agents, including for patients with peripheral vasospasm (Raynaud’s phenomenon), migraine and cluster headaches, and high-altitude pulmonary edema. They also point out the use of CCBs with hypertension in persons taking cyclosporine and nonsteroidal anti-inflammatory drugs. In order to best utilize CCBs, specialists in hypertension must recognize the various CCB-related benefits and contraindications. Drs Elliott and Ram detail unique and important drug interactions with an often unappreciated wide range of other medications.
In “Potassium Channel Modulating Arterial Dilatators (hydralazine and minoxidil),” Drs Jay N. Cohn, Alexander Shepherd, and Gordon T. McInnes10 analyze how direct-acting vasodilators vary in their ability to affect large conduit arteries, small branch arteries, arterioles, and veins. These are older but still effective medications that directly dilate resistant arterioles and reduce peripheral resistance. Nitrates are not used routinely as antihypertensive agents, but the combination of a nitrate with an antioxidant hydralazine has been shown to be effective in heart failure when added to conventional medications. Nonetheless, clinicians should be aware that small, short-term studies with nitrates have demonstrated effective BP reduction. Although, not an oral compound or for long-term use, the authors discuss nitroprusside, infused intravenously and titrated in hypertensive crises. Hypertension specialists should recognize the headache and nausea common with this agent and cyanide toxicity with prolonged infusion.
As guest editor in chief for this issue, I have a few take-home messages. The expert understanding and treatment of hypertension will not be achieved by the random collection of facts or strict adherence to recommendations from various committees. This Compendium of Antihypertensive Therapy gives the opportunity for clinicians to use science and evidence-based studies to bolster their approaches to controlling this potent CV and renal risk factor. Simply knowing the data is not enough, and hopefully these insightful chapters will assist with application of that knowledge and better outcomes for patients.
Acknowledgment and Disclosure: These articles were reviewed by the American Society of Hypertension Writing Group Steering Committee: Barry J. Materson, MD, MBA, Chair; Henry R. Black, MD; Joseph L. Izzo, Jr, MD, Suzanne Oparil, MD, and Michael A. Weber, MD. The authors received no honoraria for their contribution to this issue.