SPECIAL ISSUETHE AMERICAN SOCIETY OF HYPERTENSION INC.

INTRODUCTION

A Compendium of Antihypertensive Therapy

Keith C. Ferdinand, MD, Guest Editor

From the Division of Cardiology, Emory University, Atlanta, GA, and Atlanta Clinical Research Center, Tucker, GA

These papers on the pharmacologic therapy of hyper-tension from the American Society of Hypertension(ASH) are written to provide a brief, expert, up-to-date review of current pharmacologic principles andapproaches to hypertension for clinicians, especiallydesignated hypertension specialists, or those whodesire to be designated. The primary intent of thesepapers is to discuss, in a precise and concise manner,various classes of oral antihypertensive agents andchronic disease management. Overall, the authorsaddress mechanisms of action, pharmacokinetics, anddrug differentiation within areas of therapeutic classes.The emphasis was placed specifically on practical usesof the cornucopia of approved antihypertensive agentsavailable today. After studying this series of papers,the hypertension specialist or any clinician who desiresto become a designated specialist will better under-stand 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 combinationof the highlighted drug class with other medications,when appropriate, with discussions of relevant druginteractions and adverse effects.

The first discussion concerns thiazide-type and loopdiuretics by Drs Dominic A. Sica, Barry L. Carter,William C. Cushman, and L. Lee Hamm.1Consis-tently in major guidelines and in most expert practices,thiazide-type diuretics are appropriate first choices fora wide range of persons with hypertension. Dr Sicaand colleagues, however, caution clinicians to avoidvolume-depleting effects with overdiuresis. Neverthe-less, they appropriately discuss the long history of safeand effective use of chlorthalidone, including multiplecardiovascular (CV) outcome studies for heart diseaseand stroke, including low-renin patient groups such asblacks, the elderly, and patients with diabetes. Clinicalsuggestions are offered on how to best manage compli-cations that may arise from thiazide-type diuretics,including metabolic derangements, such as hypokalemiaand glucose intolerance. Nevertheless, diuretic-basedtherapy, including concurrent administration with awide range of agents, especially angiotensin-convertingenzyme (ACE) inhibitors or angiotensin II receptor

blockers (ARBs), can be effective and safe in mostpatients. Interestingly, an older thiazide-type diuretic,chlorthalidone, is increasingly being used to effectivelycontrol blood pressure (BP), especially in patients withmore complicated scenarios. The authors also confirmthe benefits of loop diuretics, although not as first-linetherapy, in patients with significant fluid overload orrenal disease.

In the article on aldosterone blockers and potas-sium-sparing diuretics,2 Drs Murray Epstein andDavid A. Calhoun propose that aldosterone blockersare now increasingly recognized as effective com-pounds for the treatment of hypertension, especially inpatients with low-renin and salt-sensitive forms ofhypertension. Furthermore, the authors suggest thatthe appropriate use of aldosterone blockers is a benefi-cial addition to the armamentarium for persons withresistant hypertension. Although spironolactone hasbeen shown to benefit patients with heart failure andresistant hypertension, a newer, more selective aldoste-rone blocker, eplerenone, has been shown to have theadditional benefit of reduced gynecomastia in men andfewer menstrual irregularities in women. Eplerenone,they suggest, may have somewhat less hyperkalemiathan seen with spironolactone. Aldosterone blockershave proven CV benefits in the treatment of patientswith severe heart failure, when combined with ACEinhibitors, digoxin, and loop diuretics. The authorsalso highlight the benefits of potassium-sparing diuret-ics (amiloride or triamterene) often used in combina-tion with a thiazide-type diuretic.

Subsequently, b-adrenergic–blocking drugs are dis-cussed by Drs William H. Frishman and Elijah Saun-ders.3 They note that, increasingly, modern reviews ofthe treatment of hypertension question the use of b-blockers as initial therapy, especially in elderlypatients. However, this heterogeneous class of agentsremains compelling, specifically for the treatment ofpatients who have concomitant ischemic heart disease,left ventricular dysfunction, heart failure, obstructivecardiomyopathy, or certain arrhythmias. Frishman andSaunders offer detailed tables and insights into howvarious pharmacologic effects of b-adrenergic blockersmay impact their clinical use, including side effectsand adverse reactions. b-Blockers are clearly differentin the degree of b1 selectivity, pharmokinetics, andadditional modes of activity (vasodilating b-blockers,such as labetalol, carvedilol, and nebivolol) forinstance. Their detailed table of the pharmacolgy of

Address for correspondence: Keith C. Ferdinand, MD, Chief ScienceOfficer, Association of Black Cardiologists, 5355 Hunter Road, Atlanta,GA 30349E-mail: kferdinand@abcardio.org

DOI: 10.1111/j.1751-7176.2011.00506.x

636 The Journal of Clinical Hypertension Vol 13 | No 9 | September 2011 Official Journal of the American Society of Hypertension, Inc.

these agents includes carvedilol with its peripheral va-sodilating activity and additional a1-adrenergic–block-ing activity, along with labetalol, with this agent alsoavailable for use in intravenous form for hypertensiveemergencies. A unique b-blocker, nebivolol can aug-ment vascular nitric oxide release, but the authors noteit has not been approved for use beyond hypertensivetherapy at this point.

Drs Richard H. Grimm and John M. Flack4 sub-mitted the article on a receptor blockers. An olderclass of agents, a1 antagonists effectively lower BP,especially in combination with diuretics, and alsoreduce symptoms of lower urinary tract obstructionwith benign prostatic hyperplasia. They note that thepharmacology of selective post-synaptic receptorsincludes various subtypes. Prazosin at one time was awidely used, beneficial addition to the antihyperten-sive armamentarium, with subsequent use of terazo-sin and its main advantage of a much longer half-life, allowing for a once-daily dosage. Nevertheless,in clinical use, quinazoline a1 antagonists cannot berecommended as initial monotherapy. According toDrs Grimm and Flack, despite the beneficial meta-bolic effects of doxazosin in controlled trials, theadverse CV outcomes, including heart failure in theAntihypertensive Lipid-Lowering in Heart AttackTrial (ALLHAT), with this agent vs chlorthalidonelimit the use of this class as a primary agent to con-trol hypertension. The authors argue that a1 antago-nists remain useful as add-on therapy in multidrug,antihypertensive therapy.

Central sympatholytics are described by Drs Wan-pen Vongpatanasin, Ronald G. Victor, Kazuomi Kario,and Steven A. Atlas.5 This older class of agent has lim-ited clinical use because of side effects and no defini-tive evidence for benefit on CV outcomes. Theseagents reduce BP, mainly by stimulating central a2

adrenergic receptors in the brain centers, reducingsympathetic nerve activities. While recognizing theirdiminished use because of side effects such as drowsi-ness, fatigue, and dry mouth, the authors discuss howthis class of drugs can be used as a fourth-line (orbeyond) drug therapy. They specifically detail differ-ences in the pharmacokinetics of central sympatholyticdrugs and the need for hypertension specialists to beaware of the potential for rebound hypertension innonadherent patients. Specific discussion of the centralsympatholytic agents includes unique aspects of cloni-dine, guanfacine, and guanabenz. Dr Vongpatanasinand coauthors include a table to assist with betterunderstanding the pharmacokinetic profiles of thisclass of drugs. Their illustration of the mechanismsunderlying the CV effects of sympatholytic drugs willassist the expert in hypertension in understanding thedevelopment of systemic BP elevation itself.

Renin inhibitors, the newest class of antihyperten-sive 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 oralrenin inhibition. This agent is effective for treatmentof hypertension either as monotherapy or in combina-tion therapy and is well tolerated, although presentlylimited in its use by the lack of data to determinewhether benefits in diabetic nephropathy will extendto protection with CV diseases. As a brief background,Drs Fisher and Meagher note the difficulty with previ-ous low potency, poorly absorbed early molecules, butwith modern molecular modeling via x-ray crystallog-raphy and reconstruction of the active renin site, morepotent oral renin inhibitors are being produced. Theauthors note that the actions of oral renin inhibitionare unique on the renin-angiotensin-aldosterone(RAAS) system and they also involve inhibiting activa-tion of the pro-enzyme pro-renin. Since aliskiren is thesole oral renin inhibitor approved at this time, theauthors primarily discuss its indications when used asmonotherapy or in combination and the sustained BP-lowering effects of aliskiren. They include an excellenttable that summarizes the presently available surrogateend point studies and ongoing clinical trials withaliskiren.

Drs Joseph L. Izzo, Jr and Matthew R. Weir7 detailaspects of ACE inhibitors, which are considered excel-lent for the effective lowering of BP and provision ofCV protection in a wide range of patients. The authorsdiscuss the mechanisms involved with blocking theconversion of angiotensin I to angiotensin II with sub-sequent lowering of systemic vascular resistance andprotection against the deleterious effects of angiotensinII. They note that the expert use of these agents willlead to reduction in morbidity and mortality inpatients with heart failure, reduced systolic functionpost-myocardial infarction, and slow progression ofdiabetic renal disease and nephrosclerosis. Dr Izzo andcohorts suggest that ACE inhibitors have effectsbeyond lowering BP alone and may actually preventcomplications related to CV disease in high-riskpatients, including in patients with diabetes. Becauseof the effect of ACE inhibitors outside of blocking theconversion of angiotensin I to angiotensin II, cliniciansand specialists must be aware of the side effects ofcough and angioedema. While not life-threatening, thecough that accompanies ACE inhibitors often can leadto poor adherence. On the other hand, angioedemahas potentially serious consequences in a small subsetof persons treated with ACE inhibitors, especially inblack patients. While recognizing the benefit of ACEinhibitors, the authors note that their expert use mustconsider adverse effects including hypotension involume-depleted patients and hyperkalemia, especiallyin patients with renal insufficiency, and ⁄ or usingpotassium supplements and acute renal failure in per-sons with bilateral renal artery stenosis.

Another class of RAAS-blocking agents, angiotensinreceptor blockers (ARBs), is the subject of the chapterwritten by Drs Addison A. Taylor, Helmy Siragy, andShawna D. Nesbitt.8 They discuss the pharmacology,

Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 13 | No 9 | September 2011 637

A Compendium of Antihypertensive Therapy | Ferdinand

efficacy, and safety of ARBs, the last major class ofmultiple available antihypertensive agents approved inthe United States. They note that ARBs share the selec-tive binding to angiotensin II receptors and are effec-tive as monotherapy and in combination with a widerange of agents. Although there are pharmacologicactions common to all ARBS, the authors point outsome unique properties, such as the potential peroxi-some proliferator-activated receptor c activity with tel-misartan and uric acid reduction with losartan. Anexcellent table details the pharmacokinetic effects ofthe 7 ARBs available and includes protein binding,volume of distribution, and elimination half-life.Despite the lower incidence of cough and angioedemawith ARBs vs ACE inhibitors, the authors caution thatARBs should be considered for persons who haveexperienced ACE inhibitor–related angioedema only ifno alternatives are available and indications are com-pelling. Drs Taylor and colleagues review the increas-ing body of clinical studies and trials with surrogatemarkers of CV outcomes, including proteinuria, leftventricular hypertrophy, and the development of new-onset diabetes. An interesting brief review of theeffects of central pressure and stiffness with this classof agents is included. The lack of benefits of ARBscombined with ACE inhibitors is noted, and specificdata are reviewed related to cardiovascular and renaloutcome studies.

Drs William J. Elliott and C. Venkata S. Ram9 dis-cuss calcium channel blockers (CCBs), including theirbasic differences in pharmacology and characteristics,benefits as antihypertensive agents, and potential fortreating conditions beyond uncomplicated hyperten-sion, such as dysrhythmias. The authors note that awide range of patients effectively respond to CCBs,including both sexes, various racial ⁄ ethnic groups, theelderly, and patients with excessive dietary sodiumintake. The hypertension specialist should specificallyrecognize that CCBs are heterogeneous, includingdihydropyridine, diltiazem, and verapamil, each withspecific hemodynamic and pharmacologic effects. Acomprehensive table is included, which lists the pres-ently available CCBs, including their half-lives, uniqueeffects, results of hypertension-related outcome trials,and dosages. The authors also discuss other Food andDrug Administration indications for CCBs beyondhypertension and off-label uses of this class of agents,including for patients with peripheral vasospasm(Raynaud’s phenomenon), migraine and cluster head-aches, and high-altitude pulmonary edema. They alsopoint out the use of CCBs with hypertension inpersons taking cyclosporine and nonsteroidal anti-inflammatory drugs. In order to best utilize CCBs,specialists in hypertension must recognize the vari-ous CCB-related benefits and contraindications. DrsElliott and Ram detail unique and important drug

interactions with an often unappreciated wide rangeof other medications.

In ‘‘Potassium Channel Modulating Arterial Dilata-tors (hydralazine and minoxidil),’’ Drs Jay N. Cohn,Alexander Shepherd, and Gordon T. McInnes10 ana-lyze how direct-acting vasodilators vary in their abilityto affect large conduit arteries, small branch arteries,arterioles, and veins. These are older but still effectivemedications that directly dilate resistant arterioles andreduce peripheral resistance. Nitrates are not used rou-tinely as antihypertensive agents, but the combinationof a nitrate with an antioxidant hydralazine has beenshown to be effective in heart failure when added toconventional medications. Nonetheless, cliniciansshould be aware that small, short-term studies withnitrates have demonstrated effective BP reduction.Although, not an oral compound or for long-term use,the authors discuss nitroprusside, infused intravenouslyand titrated in hypertensive crises. Hypertension spe-cialists should recognize the headache and nauseacommon with this agent and cyanide toxicity withprolonged infusion.

As guest editor in chief for this issue, I have a fewtake-home messages. The expert understanding andtreatment of hypertension will not be achieved by therandom collection of facts or strict adherence to rec-ommendations from various committees. This Com-pendium of Antihypertensive Therapy gives theopportunity for clinicians to use science and evidence-based studies to bolster their approaches to controllingthis potent CV and renal risk factor. Simply knowingthe data is not enough, and hopefully these insightfulchapters will assist with application of that knowledgeand better outcomes for patients.

Acknowledgment and Disclosure: These articles were reviewed by theAmerican 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 nohonoraria for their contribution to this issue.

References1. Sica DA, Carter B, Cushman W, et al. Thiazide and loop diuretics.

J Clin Hypertens (Greenwich). 2011;13:639–643.2. Epstein M, Calhoun DA. Aldosterone blockers and potassium-

sparing diuretics. J Clin Hypertens (Greenwich). 2011;13:644–648.3. Frishman WR, Saunders E. Beta-adrenergic blockers. J Clin Hypertens

(Greenwich). 2011;13:649–653.4. GrimmRH,FlackJM.Alpha1adrenoreceptorantagonists.JClinHyper-

tens(Greenwich). 2011;13:654–657.5. Vongpatanasin W, Kario K, Atlas SA, et al. Central sympatholytic

drugs. J Clin Hypertens (Greenwich). 2011;13:658–661.6. Fisher NDL, Meagher EA. Renin inhibitors. J Clin Hypertens

(Greenwich). 2011;13:662–666.7. Izzo JL, Weir MR. Angiotensin-converting enzyme inhibitors. J Clin

Hypertens (Greenwich). 2011;13:667–675.8. Taylor AA, Siragy H, Nesbitt SD. Angiotensin receptor blockers:

pharmacology, efficacy and safety. J Clin Hypertens (Greenwich).2011;13:677–686.

9. Elliott WJ, Ram CVS. Calcium channel blockers. J Clin Hypertens(Greenwich). 2011;13:687–689.

10. Cohn JN, McInnes GT, Shepherd AM. Direct-acting vasodilators.J Clin Hypertens (Greenwich). 2011;13:690–692.

638 The Journal of Clinical Hypertension Vol 13 | No 9 | September 2011 Official Journal of the American Society of Hypertension, Inc.

A Compendium of Antihypertensive Therapy | Ferdinand