Drugs for Hypertension 2012

Treatment Guidelinesfrom The Medical Letter®

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Drugs for Hypertension

Tables1. Diuretics Page 22. Renin-Angiotensin System Inhibitors Pages 3-43. Calcium Channel Blockers Page 54. Beta-Adrenergic Blockers Page 65. Alpha-Adrenergic Blockers and Other Page 7

Antihypertensives6. Some Combination Products Page 8


Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication

Volume 10 (Issue 113) January 2012www.medicalletter.org

Drugs available in the US for treatment of chronichypertension, with their dosages and adverse effects,are listed in the tables that begin on page 2.Combination products are listed on page 8. Drugs fortreatment of hypertensive emergencies are not dis-cussed here. They were reviewed previously.1,2

DIURETICS

Thiazide-type diuretics are the first-line therapy formany patients with hypertension. Chlorthalidone andhydrochlorothiazide (HCTZ) are often prescribedat a dose of 12.5-25 mg once daily. Chlorthalidoneis, however, 1.5-2 times more potent than HCTZ andhas a longer duration of action that persists through-out the nighttime hours.3 In a study that measured24-hour ambulatory blood pressure (BP), chlorthali-done 25 mg was more effective than HCTZ 50 mg inlowering BP.4

HCTZ is by far the most widely used thiazide-typediuretic, even though no outcomes data are availablefor the most commonly used doses; studies docu-menting the effectiveness of HCTZ in reducingclinical outcomes used doses of >25 mg/day.5 Moststudies that have shown outcome benefits of thi-azide-type diuretics have used chlorthalidone. In adouble-blind, randomized controlled trial (ALLHAT)in more than 30,000 men and women >55 years oldwith hypertension and at least one risk factor for coro-nary heart disease, chlorthalidone 12.5-25 mg/day wasas effective as the calcium channel blocker amlodipineor the angiotensin-converting enzyme (ACE) inhibitorlisinopril in preventing fatal coronary heart disease ornonfatal myocardial infarction. At the end of 5 years,about 40% of patients had required at least one addi-tional drug to achieve the BP goal of 140/90 mm Hg.6,7

The number of fixed-dose combination productscontaining chlorthalidone as the diuretic is smaller

RECOMMENDATIONS: In many patients, a thi-azide diuretic remains a reasonable choice forinitial treatment of hypertension. Chlorthalidoneappears to be more effective than hydrochloro-thiazide (HCTZ) in lowering blood pressure (BP)and has been shown to be as effective as a calciumchannel blocker or an angiotensin-convertingenzyme (ACE) inhibitor in preventing cardiovas-cular events in hypertensive patients with coronaryrisk factors. An ACE inhibitor, an angiotensinreceptor blocker (ARB) or a calcium channelblocker would also be a good choice for initialtherapy. In black patients, diuretics and calciumchannel blockers are more effective than ACEinhibitors or ARBs. The choice of antihypertensiveagents for some patients may be dictated by con-comitant conditions and their treatment.

Generally, if the first drug chosen is ineffective,a drug with a different mechanism of actionshould be substituted or added. The addition of asecond drug with a different mechanism of actionis usually more effective in decreasing BP thanraising the dose of the first drug and often allowsfor use of lower doses of both drugs, improvingtolerability. If an ACE inhibitor or an ARB wasused initially, it would be reasonable to add adiuretic such as chlorthalidone. For patients withresistant hypertension, adding spironolactone canbe helpful.

Most patients eventually require 2 or more drugs toachieve their blood pressure goals. When baselineBP is >20/10 mm Hg above goal, many expertswould begin therapy with 2 drugs. The use offixed-dose combinations may facilitate adherence.

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Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012

than the number containing HCTZ. A fixed-dosecombination of chlorthalidone and azilsartan(Edarbyclor) has been approved by the FDA.8

Metolazone may be effective in patients with impairedrenal function when the other thiazides are not, butdata are lacking. Indapamide with or without the ACEinhibitor perindopril was effective in one study in eld-erly patients (>80 years old) in reducing death fromstroke or any cause.9

2

Loop diuretics such as furosemide are more effectivethan thiazides in lowering BP in patients with moder-ate to severe renal insufficiency (CrCl <30 mL/min).In patients with normal renal function, they are lesseffective than thiazides for treatment of hypertension.Ethacrynic acid can be used in patients allergic tosulfonamides (thiazide and other loop diuretics containsulfonamide moieties).

Potassium-sparing agents such as amiloride and tri-amterene are generally used with other diuretics to

Usual DailySome Oral Maintenance Pregnancy Frequent or Severe

Drug Formulations Dosage Category2 Adverse Effects3

Thiazide-Type

Chlorthalidone – 12.5-50 mg once Bgeneric 25, 50 mg tabsThalitone (Monarch) 15 mg tabs

Chlorothiazide – 125-500 mg once Cgeneric 250, 500 mg tabsDiuril (Salix) 250 mg/5mL susp

Hydrochlorothiazide – 12.5-50 mg once Bgeneric4 12.5 mg caps;

12.5, 25, 50 mg tabsMicrozide (Watson) 12.5 mg caps

Indapamide – 1.25, 2.5 mg tabs 1.25-5 mg once Bgeneric4

Metolazone – generic 2.5, 5, 10 mg tabs 1.25-5 mg once BZaroxolyn (UCB Pharma)

Loop

Bumetanide – generic4 0.5, 1, 2 mg tabs 0.5-2 mg in C2 doses

Ethacrynic acid – 25 mg tabs 25-100 mg in BEdecrin (Aton Pharma) 2 or 3 doses

Furosemide – generic4 20, 40, 80 mg tabs; 20-320 mg in C10 mg/mL, 40 mg/5 mL soln 2 doses

Lasix (Sanofi) 20, 40, 80 mg tabs

Torsemide – generic 5, 10, 20, 100 mg tabs 5-20 mg in BDemadex (Meda) 1 or 2 doses

Potassium-Sparing

Amiloride – generic 5 mg tabs 5-10 mg in B Hyperkalemia, GI disturbances, Midamor (Paddock) 1 or 2 doses rash, headache

Eplerenone – generic 25, 50 mg tabs 25-100 mg in B Hyperkalemia, hyponatremiaInspra (Pfizer) 1 or 2 doses

Spironolactone – generic4 25, 50, 100 mg tabs 12.5-100 mg in D Hyperkalemia, hyponatremia, Aldactone (Pfizer) 1 or 2 doses mastodynia, gynecomastia, men-

strual abnormalities, GI disturb-ances, rash

Triamterene – 50-150 mg in C Hyperkalemia, GI disturbances, Dyrenium (WellSpring) 50, 100 mg caps 1 or 2 doses nephrolithiasis

1. Diuretics are not recommended for treatment of gestational hypertension.2. FDA pregnancy categories: A = controlled studies show no risk; B = no evidence of risk; C = risk cannot be ruled out; D = positive evidence of risk;

X = contraindicated in pregnancy3. In addition to the adverse effects listed, antihypertensive drugs may interact adversely with other drugs.4. A 30-day supply of some strengths is available for $4 at some discount pharmacies.

Table 1. Diuretics1

Dehydration, circulatory collapse,hypokalemia, hyponatremia, hypomagnesemia, hypergly-cemia, metabolic alkalosis, hyperuricemia, blood dyscrasias,rash, hypercholesterolemia, hypertriglyceridemia

Hyperuricemia, hypokalemia,hypomagnesemia, hyperglycemia,hyponatremia, hypercalcemia, hypercholesterolemia, hyper-triglyceridemia, pancreatitis, rash and other allergic reactions, sexual dysfunction in men, photo-sensitivity reactions



prevent or correct hypokalemia. These drugs can causehyperkalemia, particularly in patients with renalimpairment and in those taking ACE inhibitors,angiotensin receptor blockers (ARBs), beta blockers ordirect renin inhibitors.

Spironolactone, a mineralocorticoid receptor antago-nist also used as a potassium-sparing diuretic, has beeneffective as an add-on in patients with resistant hyper-tension.10 Eplerenone, a selective mineralocorticoidreceptor antagonist,11 is less likely than higher doses ofspironolactone to cause gynecomastia. Aldosteroneantagonism may provide cardiovascular benefitsbeyond minimizing hypokalemia.12 Both spironolac-tone and eplerenone have been shown to reducemortality in patients with heart failure when added tostandard therapy.13

ANGIOTENSIN-CONVERTING ENZYME(ACE) INHIBITORS

ACE inhibitors are effective in treating hypertensionand are well tolerated. They are less effective in blackpatients and others with low-renin hypertension,

unless combined with a thiazide diuretic or calciumchannel blocker. ACE inhibitors have been shown toprolong survival in patients with heart failure or leftventricular dysfunction after a myocardial infarction,reduce mortality in patients without heart failure orleft ventricular dysfunction who are at high risk forcardiovascular events, and reduce proteinuria inpatients with either diabetic or non-diabetic nephropa-thy.14 In an open-label trial (ANBP2) among morethan 6000 mostly white patients with a low incidenceof diabetes, ACE inhibitor-treated male patients hadan 11% lower incidence of cardiovascular events orall-cause mortality than those treated with variousdoses of thiazide diuretics, despite similar reductionsin BP.15 However, among 15,700 mostly whitepatients in the double-blind ALLHAT study, treatmentof hypertension with an ACE inhibitor did notimprove cardiovascular outcomes compared tochlorthalidone 12.5-25 mg. In black hypertensiveparticipants in ALLHAT, the ACE inhibitor regimenwas less effective than the diuretic in lowering BP andless effective in reducing the incidence of stroke andcardiovascular events.6

3

Table 2. Renin-Angiotensin System InhibitorsUsual Daily

Some Oral Maintenance Pregnancy Frequent or Severe Drug Formulations Dosage Category1,2 Adverse Effects3

Benazepril – generic4 5, 10, 20, 40 mg tabs 10-80 mg in DLotensin (Novartis) 1 or 2 doses

Captopril – generic4 12.5, 25, 50, 100 mg 12.5-150 mg in C/DCapoten (Par) tabs 2 or 3 doses

Enalapril – generic4 2.5, 5, 10, 20 mg tabs 2.5-40 mg in C/DVasotec (Valeant) 1-2 doses

Fosinopril – generic 10, 20, 40 mg tabs 10-80 mg in C/DMonopril (BMS) 1 or 2 doses

Lisinopril – generic4 2.5, 5, 10, 20, 30, 5-40 mg once C/DPrinivil (Merck) 40 mg tabsZestril 5(AstraZeneca)

Moexipril – generic 7.5, 15 mg tabs 7.5-30 mg in C/D Univasc (UCB Pharma) 1 or 2 doses

Perindopril – generic 2, 4, 8 mg tabs 4-8 mg in DAceon (Abbott) 1 or 2 doses

Quinapril – generic 5, 10, 20, 40 mg tabs 5-80 mg in C/D Accupril (Pfizer) 1 or 2 doses

Ramipril – generic 1.25, 2.5, 5, 10 mg caps 1.25-20 mg in C/D Altace (King) 1 or 2 doses

Trandolapril – generic 1, 2, 4 mg tabs 1-8 mg in C/DMavik (Abbott) 1 or 2 doses

1. ACE inhibitors, ARBs and aliskiren are rated category C during the first trimester and category D during the second and third trimesters. Drugs thatact on the renin-angiotensin system can cause fetal and neonatal morbidity and death.

2. FDA pregnancy categories: A = controlled studies show no risk; B = no evidence of risk; C = risk cannot be ruled out; D = positive evidence of risk;X = contraindicated in pregnancy

3. In addition to the adverse effects listed, antihypertensive drugs may interact adversely with other drugs.4. A 30-day supply of some strengths is available for $4 at some discount pharmacies.5. Not available as 2.5 or 30 mg tablets.

Angiotensin-Converting Enzymes (ACE) Inhibitors

Cough, hypotension (particularly with diuretic use or volume deple-tion), rash, acute renal failure inpatients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, angioedema, hyperkalemia (particularly if also taking potassium supplements or potassium-sparing diuretics),mild-to-moderate loss of taste, hepatotoxicity, pancreatitis, blood dyscrasias and renal damage (particularly in patients with renal dysfunction), increased fetal mal-formations and mortality with usein pregnancy



ANGIOTENSIN RECEPTOR BLOCKERS(ARBs)

ARBs are as effective as ACE inhibitors in loweringBP, and appear to be equally reno- and cardioprotec-tive, with fewer adverse effects. Like ACE inhibitors,they are less effective in black patients and others withlow-renin hypertension, unless combined with a thi-azide diuretic or calcium channel blocker. Irbesartantreatment delayed development of overt diabeticnephropathy in hypertensive patients with type 2diabetes.16 In diabetic patients who already had overtnephropathy, irbesartan and losartan slowedprogression of the renal disease.17,18 In patients withhypertension and left ventricular hypertrophy, with orwithout diabetes (LIFE), losartan was more effectivein decreasing stroke, than the beta blocker atenolol, butnot in black patients.19 The ARBs valsartan and can-desartan have been shown to slow disease progressionin patients with chronic heart failure (Val-HeFT,VALIANT, CHARM).20-22 Telmisartan was as effec-tive as the ACE inhibitor ramipril in preventingcardiovascular events in high-risk hypertensivepatients with diabetes or vascular disease(ONTARGET); the combination of an ACE inhibitorand an ARB provided no additional benefit on cardio-vascular or renal outcomes compared to either agentalone, but was more effective in lowering BP.23

4

DIRECT RENIN INHIBITOR

Aliskiren, a direct renin inhibitor (DRI), is FDA-approved alone or in combination with otherantihypertensive drugs for treatment of hyperten-sion.24 Whether aliskiren offers any advantage overACE inhibitors or ARBs remains to be determined,and no outcomes data are available for aliskiren. In an8-week study, concurrent use of aliskiren and the ARBvalsartan was significantly more effective in loweringBP than either agent alone.25

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers are a structurally and func-tionally heterogeneous class of drugs. They all causevasodilatation, which decreases peripheral resistance.The cardiac response to decreased vascular resistanceis variable; with some dihydropyridines (felodipine,nicardipine, nisoldipine and immediate-releasenifedipine), an initial reflex tachycardia usuallyoccurs, but isradipine, sustained-release nifedipineand amlodipine generally cause little increase in heartrate. The non-dihydropyridines verapamil and dilti-azem slow heart rate, can affect atrioventricular (AV)conduction and should be used with caution in patientsalso taking a beta blocker.

Table 2. Renin-Angiotensin System Inhibitors (continued)

Usual Daily Some Oral Maintenance Pregnancy Frequent or Severe

Drug Formulations Dosage Category1,2 Adverse Effects3

Angiotensin Receptor Blockers (ARBs)

Azilsartan – Edarbi (Takeda) 40, 80 mg tabs 80 mg once C/D Candesartan – 4, 8, 16, 32 mg tabs 8-32 mg once

Atacand (AstraZeneca)Eprosartan – 400, 600 mg tabs 400-800 mg in C/D

Teveten (Abbott) 1 or 2 dosesIrbesartan – Avapro 75, 150, 300 mg tabs 150-300 mg once C/D

(BMS/Sanofi)Losartan – generic 25, 50, 100 mg tabs 25-100 mg in C/D

Cozaar (Merck) 1 or 2 dosesOlmesartan – Benicar 5, 20, 40 mg tabs 20-40 mg once C/D

(Daiichi Sankyo)Telmisartan – Micardis 20, 40, 80 mg tabs 40-80 mg once C/D

(Boehringer Ingelheim)Valsartan – Diovan (Novartis) 40, 80, 160, 320 mg tabs 80-320 mg once D

Direct Renin Inhibitor (DRI)

Aliskiren – Tekturna (Novartis) 150, 300 mg tabs 150-300 mg once C/D

1. ACE inhibitors, ARBs and aliskiren are rated category C during the first trimester and category D during the second and third trimesters. Drugs thatact on the renin-angiotensin system can cause fetal and neonatal morbidity and death.


3. In addition to the adverse effects listed, antihypertensive drugs may interact adversely with other drugs.

Similar to ACE inhibitors, includ-ing increased fetal mortality with use in pregnancy, but do not cause cough and only rarely cause angioedema, loss of taste and hepatotoxicity; rarely rhab-domyolysis

Same as ARBs, but can alsocause GI effects such as diarrhea



In one meta-analysis, the risk of heart failure washigher in patients treated with calcium channel block-ers compared to those treated with ACE inhibitors,beta blockers or diuretics.26 One large double-blindtrial (VALUE Trial) in more than 15,000 high-riskpatients found similar rates of cardiovascular events

with amlodipine and the ARB valsartan.27 In one largeoutcomes trial, a combination of the ACE inhibitorbenazepril with the calcium channel blocker amlodip-ine was more effective in preventing adversecardiovascular outcomes than benazepril with HCTZ12.5-25 mg.28

5



Dihydropyridines

Amlodipine3 – generic 2.5, 5, 10 mg tabs 2.5-10 mg once CNorvasc (Pfizer)

Felodipine – generic 2.5, 5, 10 mg ER tabs 2.5-10 mg once CPlendil (AstraZeneca)

Isradipine – generic 2.5, 5 mg caps 5-10 mg in C2 doses Dizziness, headache, peripheral

extended-release edema (more than with verapa-DynaCirc CR (GSK) 5, 10 mg ER tabs 5-10 mg once mil and diltiazem, more com-

Nicardipine – generic 20, 30 mg caps 60-120 mg in C mon in women), flushing, 3 doses tachycardia, rash, gingival

extended-release 30, 60 mg ER caps 60-120 mg in hyperplasiaCardene SR (EKR) 2 doses

Nifedipine – extended-release 30, 60, 90 mg ER tabs 30-90 mg once C

genericAdalat CC (Bayer)Procardia XL (Pfizer)

Nisoldipine – generic 8.5, 17, 20, 25.5, 30, 17-40 mg once C34, 40 mg ER tabs

Sular (Shionogi) 8.5, 17, 25.5, 34 mg ER tabs 17-34 mg once

Non-Dihydropyridines

Diltiazem 4

generic (extended-release) 120, 180, 240, 300, 120-540 mg once CCardizem LA (Abbott) 360, 420 mg ER tabsgeneric (sustained-release) 120, 180, 240, 300, 360 120-540 mg onceTaztia XT 5 (Watson) mg ER capsTiazac6 (Forest)generic (continuous-delivery)120, 180, 240, 300, 120-360 mg onceCardizem CD (Valeant) 360 mg ER caps Dizziness, headache, edema,Cartia XT7 (Watson) constipation (especially verapa-Dilt-CD7 (Apotex) mil), AV block, bradycardia,

Verapamil (extended-release)4 heart failure, lupus-like rash generic (tabs) 120, 180, 240 mg ER tabs 120-480 mg C with diltiazemgeneric (caps) 120, 180, 240, 360 mg in 1 or 2 doses

ER capsCalan SR (Pfizer) 120, 180, 240 mg ER tabsIsoptin SR (Ranbaxy) 120, 180, 240 mg ER tabsextended-release (once/day)

Covera-HS (Pfizer) 180, 240 mg ER tabs 180-540 mg once Verelan (Elan) 120, 180, 240, 360 mg 120-480 mg once

ER capsVerelan PM 100, 200, 300 mg 100-400 mg once

(Elan) ER caps1. FDA pregnancy categories: A = controlled studies show no risk; B = no evidence of risk; C = risk cannot be ruled out; D = positive evidence of risk;

X = contraindicated in pregnancy2. In addition to the adverse effects listed, antihypertensive drugs may interact adversely with other drugs.3. Amlodipine is also available in combination with atorvastatin (Caduet – Pfizer).4. A 30-day supply of some strengths is available for $4 at some discount pharmacies.5. Diltia XT and Dilacor XR (both manufactured by Watson) are also ER capsules (available in 120, 180, 240 mg ER capsules).6. Also available in 420 mg ER caps.7. Not available in 360 mg ER caps.

Table 3. Calcium Channel Blockers





Atenolol3 – generic4 25, 50, 100 mg tabs 25-100 mg in DTenormin (AstraZeneca) 1 or 2 doses

Betaxolol3 – generic 10, 20 mg tabs 5-40 mg once C

Bisoprolol3 – generic 5, 10 mg tabs 5-20 mg once CZebeta (Teva)

Metoprolol3 – generic4 25, 50, 100 mg tabs 50-200 mg in CLopressor (Novartis) 1 or 2 doses

extended-release 50, 100 mg tabsToprol-XL (AstraZeneca) 25, 50, 100, 200 mg 25-400 mg once

ER tabsNadolol – generic4 20, 40, 80 mg tabs 20-320 mg once C

Corgard (Pfizer)Propranolol – generic4 10, 20, 40, 60, 40-240 mg in C

Inderal (Akrimax) 80 mg tabs 2 dosesextended-release 60, 80, 120, 160 mg 60-240 mg once

generic ER capsInderal LA (Akrimax)InnoPran XL (GSK) 80, 120 mg 80-120 mg at

ER caps bedtimeTimolol – generic 5, 10, 20 mg tabs 10-60 mg in C

2 doses

Beta Blockers with Intrinsic Sympathomimetic Activity

Acebutolol3 – generic 200, 400 mg caps 200-1200 mg in BSectral (Dr. Reddy’s Labs) 1 or 2 doses Similar to other beta-adrenergic

blocking drugs, but with less rest-Penbutolol – Levatol 20 mg tabs 10-80 mg once C ing bradycardia and lipid changes,

(UCB Pharma) acebutolol has been associatedwith a positive antinuclear anti-

Pindolol – generic 5, 10 mg tabs 10-60 mg in B body test and occasional drug-2 doses induced lupus

Beta Blockers with Alpha-Blocking Activity

Carvedilol – generic4 3.125, 6.25, 12.5, 12.5-50 mg in CCoreg (GSK) 25 mg tabs 2 doses Similar to other beta-adrenergic

extended-release blocking drugs, but more ortho-Coreg CR (GSK) 10, 20, 40, 80 mg 20-80 mg once static hypotension; hepatotoxicity

ER tabsLabetalol – generic 100, 200, 300 mg tabs 200-1200 mg in C

2 dosesTrandate (Prometheus) 100, 200 mg tabs

Beta Blockers with Vasodilating Nitric-Oxide-Mediated Activity

Nebivolol – Bystolic 2.5, 5, 10, 20 mg tabs 5-40 mg once C Similar to other beta-adrenergic (Forest) blocking drugs but may not

cause impotence and may improve erectile dysfunction.


2. In addition to the adverse effects listed, antihypertensive drugs may interact adversely with other drugs.3. Cardioselective4. A 30-day supply of some strengths is available for $4 at some discount pharmacies.

Table 4. Beta-Adrenergic Blockers

Fatigue, depression, bradycar-dia, erectile dysfunction, decr-eased exercise tolerance, heart failure, worsening ofperipheral arterial insuffi-ciency, may aggravate allergicreactions, bronchospasm, may mask symptoms of and delay recovery from hypoglycemia, Raynaud’s phenomenon, in-somnia, vivid dreams or hallu-cinations, acute mental disor-der, increased serum triglyc-erides, decreased HDL choles-terol, increased incidence of diabetes, sudden withdrawal may lead to exacerbation of angina and myocardial infarc-tion



BETA-ADRENERGIC BLOCKERS

A beta blocker may be a good choice for treatment ofhypertension in patients with another indication for abeta blocker, such as migraine, angina pectoris,myocardial infarction or heart failure. In other high-risk patients, large cardiovascular outcome trials have

found a beta blocker less effective in preventingcardiovascular events (especially stroke) than an ACEinhibitor, an ARB, a calcium channel blocker or adiuretic.29,30 Two guideline panels have recommendednot using a beta blocker for initial therapy of hyperten-sion.31,32 Like ACE inhibitors and ARBs, beta blockersare less effective in black patients.

7

Usual DailySome Maintenance Pregnancy Frequent or Severe


Alpha-Adrenergic BlockersDoxazosin – generic3 1, 2, 4, 8 mg 1-16 mg once4 C Syncope with first dose (less likely

Cardura (Pfizer) tabs with terazosin and doxazosin), diz-Prazosin – generic3 1, 2, 5 mg 1-20 mg in C ziness and vertigo, headache, pal-

Minipress (Pfizer) caps 2 or 3 doses4 pitations, fluid retention, drowsiness, weakness, anticholinergic effects,

Terazosin – generic3 1, 2, 5, 10 mg 1-20 mg once4 C priapism, thrombocytopenia, atrial Hytrin (Abbott) caps fibrillation

Central Alpha-Adrenergic Agonists

Clonidine – generic3 0.1, 0.2, 0.3 mg 0.1-0.6 mg in C CNS reactions similar to methyldopa,Catapres tabs 2 or 3 doses but more sedation and dry mouth;(Boehringer Ingelheim) bradycardia, heart block, rebound transdermal – generic 0.1, 0.2, 0.3 mg one patch weekly hypertension (less likely with patch),

Catapres TTS (transdermal) patches (0.1 to 0.3 mg/day) contact dermatitis from patch

Guanfacine – generic3 1, 2 mg tabs 1-3 mg once B Similar to clonidine, but milder

Methyldopa – generic3 250, 500 mg tabs 250 mg-2 g in B Sedation, fatigue, depression, dry 2 doses mouth, orthostatic hypotension,

bradycardia, heart block, autoim-mune disorders (including colitis, hepatitis), hepatic necrosis, Coombs-positive hemolytic anemia, lupus-like syndrome, thrombocy-topenia, red cell aplasia, impotence

Direct Vasodilators

Hydralazine – generic3 10, 25, 50, 100 mg 40-200 mg in C Tachycardia, aggravation of angina,tabs 2-4 doses headache, dizziness, fluid retention,

nasal congestion, lupus-like synd-rome, hepatitis

Minoxidil – generic 2.5, 10 mg tabs 2.5-40 mg in C Tachycardia, aggravation of angina,1 or 2 doses marked fluid retention, pericardial

effusion, hair growth on face and body

Peripheral Adrenergic Neuron Antagonists

Reserpine – generic 0.1, 0.25 mg tabs 0.05-0.1 mg once C Nasal stuffiness, drowsiness, GIdisturbances, bradycardia, depression, nightmares with high doses, tardive dyskinesia


2. In addition to the adverse effects listed, antihypertensive drugs may interact adversely with other drugs.3. A 30-day supply of some strengths is available for $4 at some discount pharmacies.4. The first dose is 1 mg at bedtime.

Table 5. Alpha-Adrenergic Blockers and Other Antihypertensives

Table 6. Some Combination Products



Pindolol, acebutolol, penbutolol and carteolol haveintrinsic sympathomimetic activity (ISA). Beta block-ers without ISA are preferred in patients with angina ora history of myocardial infarction.

8

Labetalol combines beta blockade with alpha-adrenergicreceptor blockade. Carvedilol is another beta blockerwith alpha-blocking properties; compared to metopro-lol, it is less likely to interfere with glycemic control in

Drug Strengths (mg)ACE Inhibitors and Diuretics

Benazepril/HCTZ 5/6.25, 10/12.5,generic 20/12.5, 20/25 tabsLotensin HCT (Novartis)

Captopril/HCTZ 25/15, 25/25, 50/15,generic 50/25 tabsCapozide (Apothecon)

Enalapril/HCTZ 5/12.5, 10/25 tabsgeneric1

Vaseretic (Biovail)Fosinopril/HCTZ 10/12.5, 20/12.5 tabs

genericLisinopril/HCTZ 10/12.5, 20/12.5,

generic1 20/25 tabsPrinzide2 (Merck)Zestoretic (AstraZeneca)

Moexipril/HCTZ 7.5/12.5, 15/12.5,generic 15/25 tabsUniretic (UCB)

Quinapril/HCTZ 10/12.5, 20/12.5, generic 20/25 tabs

Accuretic (Pfizer)

Angiotensin Receptor Blockers and Diuretics

Candesartan/HCTZ 16/12.5, 32/12.5, 32/25 tabsAtacand HCT (AstraZeneca)

Eprosartan/HCTZ 600/12.5, 600/25 tabsTeveten HCT (Abbott)

Irbesartan/HCTZ 150/12.5, 300/12.5 tabsAvalide (BMS)

Losartan/HCTZ 50/12.5, 100/12.5, Hyzaar (Merck) 100/25 tabs

Olmesartan/HCTZ 20/12.5, 40/12.5, Benicar HCT (Daiichi Sankyo) 40/25 tabs

Telmisartan/HCTZ 40/12.5, 80/12.5,Micardis HCT (Boehringer 80/25 tabsIngelheim)

Valsartan/HCTZ 80/12.5, 160/12.5, 160/25Diovan HCT (Novartis) 320/12.5, 320/25 tabs

ARB and Direct Renin InhibitorValsartan/aliskiren 160/150, 320/300 tabs

Valturna (Novartis)

Direct Renin Inhibitor and Diuretic

Aliskiren/HCTZ 150/12.5, 150/25,Tekturna HCT (Novartis) 300/12.5, 300/25 tabsBeta-Adrenergic Blockers and Diuretics

Atenolol/chlorthalidone 50/25, 100/25 tabsgeneric1

Tenoretic (AstraZeneca)Bisoprolol/HCTZ 2.5/6.25, 5/6.25,

generic1 10/6.25 tabsZiac (Duramed)

Drug Strengths (mg)Beta-Adrenergic Blockers and Diuretics (cont)

Metoprolol/HCTZ 25/50, 25/100,generic 50/100 tabsLopressor HCT (Novartis) 25/50, 25/100 tabs

Nadolol/bendroflumethiazide 40/5, 80/5 tabsgenericCorzide (King)

Calcium Channel Blockers and ACE Inhibitors

Amlodipine/benazepril 2.5/10, 5/10, 5/20, 5/40Lotrel (Novartis) 10/20, 10/40 caps

Verapamil ER/trandolapril 180/2, 240/1, Tarka (Abbott) 240/2, 240/4 tabs

Calcium Channel Blockers and ARBsAmlodipine/telmisartan – 5/40, 5/80, 10/40,

Twynsta (Boehringer Ingelheim) 10/80 tabs

Amlodipine/valsartan 5/160, 5/320, 10/160,Exforge (Novartis) 10/320 tabsAmlodipine/olmesartan 5/20, 5/40, 10/20,Azor (Daiichi Sankyo) 5/40 tabs

Calcium Channel Blockers and Direct Renin InhibitorAmplodipine/aliskiren 5/150, 10/150, 5/300, Tekamlo (Novartis) 10/300 tabs

Diuretic Combinations

HCTZ/spironolactone 25/25 tabsgenericAldactazide (Pfizer) 25/25, 50/50 tabs

HCTZ/triamterene 25/37.5, 25/50, generic1 50/75 tabs, capsDyazide (GSK) 25/37.5 capsMaxzide (Mylan) 25/37.5, 50/75 tabs

HCTZ/amiloride 50/5 tabs generic1

Direct Vasodilator and Diuretic

Hydralazine/HCTZ 25/25, 50/50 caps Hydra-Zide (Par)

Central Alpha Adrenergic Agonist and DiureticClonidine/chlorthalidone 0.1/15, 0.2/15, Clorpres (Mylan) 0.3/15 tabs

Triple Drug CombinationsAliskiren/amlodipine/HCTZ 150/5/12.5, 300/5/12.5,Amturnide (Novartis) 300/5/25, 300/10/12.5,

300/10/25 tabsValsartan/amlodipine/HCTZ 160/5/12.5, 160/5/25,Exforge HCT (Novartis) 160/10/12.5, 160/10/25,

320/10/25 tabsOlmesartan/amlodipine/HCTZ 20/5/12.5, 40/5/12.5,Tribenzor (Daiichi Sankyo) 40/5/25, 40/10/12.5,

40/10/25 tabs

1. A 30-day supply of some strengths is available for $4 at some discount pharmacies.2. Only available in 10/12.5 and 20/12.5 mg tabs


Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012 9

patients with type 2 diabetes and hypertension.33

Nebivolol does not have alpha-blocking properties butdoes have nitric-oxide-mediated vasodilating activity.34

ALPHA-ADRENERGIC BLOCKERS

Prazosin, terazosin and doxazosin cause lesstachycardia than direct vasodilators (hydralazine,minoxidil), but more frequent postural hypotension,especially after the first dose. Treatment of essentialhypertension with doxazosin has been associated withan increased incidence of heart failure, stroke andcombined cardiovascular disease compared to treat-ment with a diuretic (ALLHAT). Alpha-blockersprovide symptomatic relief from prostatism in men,but may cause stress incontinence in women and pos-tural hypotension in elderly patients.

CENTRAL ALPHA-ADRENERGIC AGONISTS

Drugs such as clonidine, guanfacine and methyldopadecrease sympathetic outflow, but do not inhibit reflexresponses as completely as sympatholytic drugs thatact peripherally. They do, however, frequently causesedation, dry mouth and erectile dysfunction.Clonidine is often used for treatment of hypertensiveurgencies. Due to its short half-life (~7 hours), it mustbe taken 2 to 3 times a day for adequate long-termmanagement of chronic hypertension. Once dailyguanfacine (half-life ~17 hours) is more convenient fortreatment of chronic hypertension; at doses of 1 mg,which provide all or most of the drug’s blood pressure-lowering effect, it is generally well tolerated.

DIRECT VASODILATORS

Direct vasodilators frequently produce reflex tachycar-dia and rarely cause orthostatic hypotension. Theyshould usually be given with a beta blocker or a cen-trally-acting drug to minimize the reflex increase inheart rate and cardiac output, and with a diuretic toavoid sodium and water retention. They should gener-ally be avoided in patients with coronary arterydisease. Hydralazine maintenance dosage should belimited to 200 mg per day to decrease the possibility ofa lupus-like reaction. Minoxidil, a potent drug thatrarely fails to lower blood pressure, should be reservedfor severe hypertension refractory to other drugs. Itcauses hirsutism and tachycardia and can also causesevere fluid retention.

PERIPHERAL ADRENERGIC NEURONANTAGONISTS

Reserpine is an effective antihypertensive but is sel-dom used now because (in doses much higher than cur-

rently recommended) it can cause severe depression.35

Guanadrel (no longer available in the US) decreasescardiac output and may lower systolic pressure morethan diastolic; postural and exertional hypotensionoccur commonly and are aggravated by vasodilatationcaused by heat, exercise or alcohol.

COMBINATION THERAPY

Most patients with hypertension eventually need morethan one drug to control their BP. Patients with a BP>20/10 mm Hg at baseline may benefit from initiatingtherapy with 2 drugs.36 By combining drugs with dif-ferent mechanisms of action, lower doses can be usedto effectively reduce BP and decrease the incidence ofadverse effects.37 Fixed-dose combination products(see Table 6) are widely available and may improveadherence. Three triple combination products are nowavailable containing hydrochlorothiazide (12.5-25 mg)and amlodipine added to either aliskiren, olmesartan orvalsartan.38,39

COST

Many of the drugs commonly used to treat hyperten-sion are available generically. Some of these areavailable in large discount pharmacies for $4-10 for a30-day supply.

1. Clevidipine (Cleviprex) for IV treatment of severe hypertension. MedLett Drugs Ther 2008; 50:73.

2. Cardiovascular drugs in the ICU. Treat Guidel Med Lett 2002; 1:19.3. BL Carter et al. Hydrochlorothiazide versus chlorthalidone: evidence

supporting their interchangeability. Hypertension 2004; 43:4.4. ME Ernst and M Moser. Use of diuretics in patients with hypertension.

N Engl J Med 2009; 361:2153.5. FH Messerli and S Bangalore. Half a century of hydrochlorothiazide:

facts, fads, fiction and follies. Am J Med 2011; 124:896.6. ALLHAT Officers and Coordinators for the ALLHAT Collaborative

Research Group. Major outcomes in high-risk hypertensive patients ran-domized to angiotensin-converting enzyme inhibitor or calcium channelblocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatmentto Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981.

7. JT Wright Jr et al. ALLHAT Collaborative Research Group. ALLHATfindings revisited in the context of subsequent analyses, other trials, andmeta-analyses. Arch Intern Med 2009; 169:832.

8. Azilsartan medoxomil (Edarbi) - the eighth ARB. Med Lett Drugs Ther2011; 53:39.

9. NS Beckett et al. Treatment of hypertension in patients 80 years of ageor older. N Engl J Med 2008; 358:1887.

10. DA Calhoun et al. Resistant hypertension: diagnosis, evaluation, andtreatment: a scientific statement from the American Heart AssociationProfessional Education Committee of the Council for High BloodPressure Research. Circulation 2008; 117:e510.

11. Eplerenone (Inspra). Med Lett Drugs Ther 2003; 45:39.12. GS Francis and WH Tang. Should we consider aldosterone as the pri-

mary screening target for preventing cardiovascular events? J Am CollCardiol 2005; 45:1249.

13. Drugs for treatment of chronic heart failure. Treat Guidel Med Lett2009; 7:53.

14. R Kunz et al. Meta-analysis: effect of monotherapy and combinationtherapy with inhibitors of the renin angiotensin system on proteinuria in

http://secure.medicalletter.org/TML-article-1295a

http://secure.medicalletter.org/TG-article-4a

http://www.ncbi.nlm.nih.gov/pubmed/14638621





http://secure.medicalletter.org/TML-article-1364c





http://secure.medicalletter.org/TG-article-83a




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EDITOR IN CHIEF: Mark Abramowicz, M.D.EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., Weill Medical College

of Cornell University EDITOR: Jean-Marie Pflomm, Pharm.D.ASSISTANT EDITOR, DRUG INFORMATION: Susan Morey, Pharm.D.CONTRIBUTING EDITOR: Eric J. Epstein, M.D. Albert Einstein College of MedicineCONTRIBUTING EDITOR, DRUG INTERACTIONS: Philip D. Hansten, Pharm.D.,

University of WashingtonADVISORY BOARD:Jules Hirsch, M.D., Rockefeller UniversityDavid N. Juurlink, BPhm, M.D., PhD, Sunnybrook Health Sciences CentreRichard B. Kim, M.D., University of Western Ontario Gerald L. Mandell, M.D., University of Virginia School of MedicineHans Meinertz, M.D., University Hospital, Copenhagen Dan M. Roden, M.D., Vanderbilt University School of Medicine F. Estelle R. Simons, M.D., University of Manitoba Neal H. Steigbigel, M.D., New York University School of MedicineSENIOR ASSOCIATE EDITORS: Donna Goodstein, Amy FaucardASSOCIATE EDITOR: Cynthia Macapagal CoveyEDITORIAL FELLOW:Lauren K. Schwartz, M.D., Mount Sinai School of MedicinePRODUCTION COORDINATOR: Cheryl BrownASSISTANT MANAGING EDITOR: Liz DonohueMANAGING EDITOR: Susie Wong

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Copyright and Disclaimer: The Medical Letter is an independent nonprofit organ-ization that provides healthcare professionals with unbiased drug prescribing rec-ommendations. The editorial process used for its publications relies on a review ofpublished and unpublished literature, with an emphasis on controlled clinical trials,and on the opinions of its consultants.The Medical Letter is supported solely by sub-scription fees and accepts no advertising, grants or donations.

No part of the material may be reproduced or transmitted by any process in whole orin part without prior permission in writing.The editors do not warrant that all the mate-rial in this publication is accurate and complete in every respect.The editors shall notbe held responsible for any damage resulting from any error, inaccuracy or omission.

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EDITOR IN CHIEF: Mark Abramowicz, M.D.EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School

EDITOR: Jean-Marie Pflomm, Pharm.D.ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D.,Blaine M. Houst, Pharm.D., Corinne E. Zanone, Pharm.D.

CONSULTING EDITORS: Brinda M. Shah, Pharm.D., F. Peter Swanson, M.D.

CONTRIBUTING EDITORS:Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and SurgeonsVanessa K. Dalton, M.D., M.P.H., University of Michigan Medical SchoolEric J. Epstein, M.D., Albert Einstein College of MedicineJules Hirsch, M.D., Rockefeller UniversityDavid N. Juurlink, BPhm, M.D., PhD, Sunnybrook Health Sciences CentreRichard B. Kim, M.D., University of Western Ontario Hans Meinertz, M.D., University Hospital, Copenhagen Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of MedicineDan M. Roden, M.D., Vanderbilt University School of Medicine F. Estelle R. Simons, M.D., University of Manitoba Jordan W. Smoller, M.D., Sc.D., Harvard Medical SchoolNeal H. Steigbigel, M.D., New York University School of MedicineArthur M.F.Yee, M.D., Ph.D., F.A.C.R, Weill Medical College of Cornell University

SENIOR ASSOCIATE EDITORS: Donna Goodstein, Amy FaucardASSOCIATE EDITOR: Cynthia Macapagal Covey

EDITORIAL FELLOW: Esperance A. K. Schaefer, M.D., M.P.H., Harvard Medical School

MANAGING EDITOR: Susie WongASSISTANT MANAGING EDITOR: Liz DonohuePRODUCTION COORDINATOR: Cheryl Brown

EXECUTIVE DIRECTOR OF SALES: Gene CarbonaFULFILLMENT AND SYSTEMS MANAGER: Cristine RomatowskiDIRECTOR OF MARKETING COMMUNICATIONS: Joanne F. ValentinoVICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy

Founded in 1959 byArthur Kallet and Harold Aaron, M.D.

Coming Soon in Treatment Guidelines:Drugs for Asthma Drugs for Inflammatory Bowel Disease

renal disease. Ann Intern Med 2008; 148:30.15. LM Wing et al. A comparison of outcomes with angiotensin-convert-

ing--enzyme inhibitors and diuretics for hypertension in the elderly. NEngl J Med 2003; 348:583.

16. HH Parving et al. The effect of irbesartan on the development of dia-betic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870.

17. EJ Lewis et al. Renoprotective effect of the angiotensin-receptor antag-onist irbesartan in patients with nephropathy due to type 2 diabetes. NEngl J Med 2001; 345:851.

18. BM Brenner et al [RENAAL]. Effects of losartan on renal and cardio-vascular outcomes in patients with type 2 diabetes and nephropathy. NEngl J Med 2001; 345:861.

19. B Dahlöf et al. Cardiovascular morbidity and mortality in the LosartanIntervention For Endpoint reduction in hypertension study (LIFE): arandomised trial against atenolol. Lancet 2002; 359:995.

20. JN Cohn, G Tognoni, Valsartan Heart Failure Trial Investigators. A ran-domized trial of the angiotensin-receptor blocker valsartan in chronicheart failure. N Engl J Med 2001; 345:1667.

21. MA Pfeffer et al. Valsartan, captopril, or both in myocardial infarctioncomplicated by heart failure, left ventricular dysfunction, or both. NEngl J Med 2003; 349:1893.

22. JB Young et al. Mortality and morbidity reduction with candesartan inpatients with chronic heart failure and left ventricular systolic dysfunc-tion: results of the CHARM low-left ventricular ejection fraction trials.Circulation 2004; 110:2618.

23. S Yusuf et al. Telmisartan, ramipril, or both in patients at high risk forvascular events. N Engl J Med 2008; 358:1547.

24. Aliskiren (Tekturna) for hypertension. Med Lett Drugs Ther 2007;49:29.

25. S Oparil et al. Efficacy and safety of combined use of aliskiren and val-sartan in patients with hypertension: a randomised, double-blind trial.Lancet 2007; 370:221.

26. Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects ofdifferent blood-pressure-lowering regimens on major cardiovascularevents: results of prospectively-designed overviews of randomised tri-als. Lancet 2003; 362:1527.

27. S Julius et al. Outcomes in hypertensive patients at high cardiovascu-lar risk treated with regimens based on valsartan or amlodipine: theVALUE randomised trial. Lancet 2004; 363:2022.

28. K Jamerson et al. Benazepril plus amlodipine or hydrochlorothiazidefor hypertension in high-risk patients. N Engl J Med 2008; 359:2417.

29. CS Wiysonge et al. Beta-blockers for hypertension. Cochrane DatabaseSyst Rev 2007; 24 (1):CD002003.

30. BM Psaty et al. Health outcomes associated with various antihyperten-sive therapies used as first-line agents: a network meta-analysis. JAMA2003; 289:2534.

31. National Clinical Guideline Centre, National Institute for Health andClinical Excellence. Hypertension: The clinical management of pri-mary hypertension in adults: Clinical Guideline 127. www.nice.org.uk/nicemedia/live/13561/56007.pdf. Accessed December 16, 2011.

32. G Mancia et al. Reappraisal of European guidelines on hypertensionmanagement: a European Society of Hypertension Task Force docu-ment. J Hypertens 2009; 27:2121.

33. GL Bakris et al. Metabolic effects of carvedilol vs metoprolol inpatients with type 2 diabetes mellitus and hypertension: a randomizedcontrolled trial. JAMA 2004; 292:2227.

34. Nebivolol (Bystolic) for hypertension. Med Lett Drugs Ther 2008;50:17.

35. HB Slim et al. Older blood pressure medications — do they still havea place? Am J Cardiol 2011; 108:316.

36. TA Kotchen. Expanding role for combination drug therapy in the initialtreatment of hypertension? Hypertension 2011; 58:550.

37. DS Wald et al. Combination therapy versus monotherapy in reducingblood pressure: meta-analysis on 11,000 participants from 42 trials. AmJ Med 2009; 122:290.

38. In brief: another three drug combination for hypertension. Med LettDrugs Ther 2011; 53:28.

39. Tribenzor for hypertension. Med Lett Drugs Ther 2010; 52:70.

2011 Year-End Index:For an electronic copy of the 2011 Index, go to:www.medicalletter.org/downloads/tgindex2011.pdf


















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1. Most studies that have shown outcome benefits of a diuretic intreating hypertension have used:

a. hydrochlorothiazideb. chlorthalidonec. metolazoned. furosemide

Issue 113

2. A 64-year-old man with fairly well-controlled hypertension andchronic heart failure who is being treated with hydrochlorothiazidehas developed hypokalemia. One reasonable option would be toadd:

a. chlorthalidone b. furosemidec. spironolactoned. none of the above

Issue 113

3. Which of the following antihypertensive drugs are less effective inblack patients?

a. ACE inhibitorsb. ARBsc. beta blockersd. all of the above

Issue 113

4. One advantage of ARBs over ACE inhibitors for treatment ofhypertension is that they:

a. are more effectiveb. are safer for use in pregnancyc. have fewer adverse effectsd. all of the above

Issue 113

5. A 53-year-old woman with hypertension being treated with anARB is told by her next-door neighbor, who also has hyperten-sion, that she is being treated with aliskiren, which is more effec-tive and safer. Which of the following statements about aliskiren istrue?

a. It has been shown to be more effective than an ARB in low-ering blood pressure.

b. It has fewer side effects than an ARB.c. It has been shown to lead to better outcomes than ARBs.d. Whether it offers any advantage over ACE inhibitors or ARBs

remains to be determined.Issue 113

6. Use of a beta blocker to treat hypertension has been found lesseffective in preventing cardiovascular events than:

a. an ACE inhibitorb. a diureticc. a calcium channel blockerd. all of the above

Issue 113

7. Among calcium channel blockers, an initial reflex tachycardia is tobe expected with:

a. felodipineb. verapamilc. diltiazemd. all of the above

Issue 113

8. Alpha-adrenergic blockers are especially likely to cause:a. rashb. postural hypotensionc. coughd. hepatic toxicity

Issue 113

9. Minoxidil is highly effective in lowering blood pressure, but it cancause:

a. hirsutismb. tachycardiac. edemad. all of the above

Issue 113

10. The diuretic found in most antihypertensive combination productsis:

a. hydrochlorothiazideb. chlorthalidonec. furosemided. spironolactone

Issue 113

11. The 3 triple drug combinations available in the US for hyperten-sion all contain:

a. an ACE inhibitorb. an ARBc. a calcium channel blockerd. all of the above

Issue 113

12. Use of 2 drugs with different mechanisms of action for treatmentof hypertension:

a. is usually more effective in decreasing BP than raising thedose of a single drug

b. often allows for use of lower doses of both drugsc. should be considered for initial therapy in patients with a

baseline BP >20/10 mm Hg above goald. all of the above

Issue 113

DO NOT FAX OR MAIL THIS EXAMTo take this exam, go to:

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Issue 113 Questions

ACPE UPN: 379-0000-11-113-H01-P; Release: December 2011, Expire: December 2012

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Documents

Drugs for Hypertension 2012