2012 jan (113): treatment guidelines - drugs for hypertension

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Drugs available in the US for treatment of chronic RECOMMENDATIONS: In many patients, a thi-
hypertension, with their dosages and adverse effects, azide diuretic remains a reasonable choice for are listed in the tables that begin on page 2.
initial treatment of hypertension. Chlorthalidone Combination products are listed on page 8. Drugs for appears to be more effective than hydrochloro- treatment of hypertensive emergencies are not dis- thiazide (HCTZ) in lowering blood pressure (BP) cussed here. They were reviewed previously.1,2 and has been shown to be as effective as a calciumchannel blocker or an angiotensin-converting DIURETICS
enzyme (ACE) inhibitor in preventing cardiovas-cular events in hypertensive patients with coronary Thiazide-type diuretics are the first-line therapy for
risk factors. An ACE inhibitor, an angiotensin many patients with hypertension. Chlorthalidone and
receptor blocker (ARB) or a calcium channel hydrochlorothiazide (HCTZ) are often prescribed
blocker would also be a good choice for initial at a dose of 12.5-25 mg once daily. Chlorthalidone therapy. In black patients, diuretics and calcium is, however, 1.5-2 times more potent than HCTZ andhas a longer duration of action that persists through- channel blockers are more effective than ACE out the nighttime hours.3 In a study that measured inhibitors or ARBs. The choice of antihypertensive 24-hour ambulatory blood pressure (BP), chlorthali- agents for some patients may be dictated by con- done 25 mg was more effective than HCTZ 50 mg in comitant conditions and their treatment.
Generally, if the first drug chosen is ineffective, HCTZ is by far the most widely used thiazide-type a drug with a different mechanism of action diuretic, even though no outcomes data are available should be substituted or added. The addition of a for the most commonly used doses; studies docu- second drug with a different mechanism of action menting the effectiveness of HCTZ in reducing is usually more effective in decreasing BP than clinical outcomes used doses of >25 mg/day.5 Most raising the dose of the first drug and often allows studies that have shown outcome benefits of thi- for use of lower doses of both drugs, improving azide-type diuretics have used chlorthalidone. In a tolerability. If an ACE inhibitor or an ARB was double-blind, randomized controlled trial (ALLHAT) used initially, it would be reasonable to add a in more than 30,000 men and women >55 years old diuretic such as chlorthalidone. For patients with with hypertension and at least one risk factor for coro- resistant hypertension, adding spironolactone can nary heart disease, chlorthalidone 12.5-25 mg/day was as effective as the calcium channel blocker amlodipineor the angiotensin-converting enzyme (ACE) inhibitor Most patients eventually require 2 or more drugs to lisinopril in preventing fatal coronary heart disease or achieve their blood pressure goals. When baseline nonfatal myocardial infarction. At the end of 5 years, BP is >20/10 mm Hg above goal, many experts about 40% of patients had required at least one addi- would begin therapy with 2 drugs. The use of tional drug to achieve the BP goal of 140/90 mm Hg.6,7 fixed-dose combinations may facilitate adherence.
The number of fixed-dose combination productscontaining chlorthalidone as the diuretic is smaller Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines.
Drugs for Hypertension
Table 1. Diuretics1
Usual Daily
Some Oral
Maintenance Pregnancy
Frequent
Formulations
Category2
Adverse Effects3
Thiazide-Type
hypomagnesemia, hypergly-cemia, metabolic alkalosis, Potassium-Sparing
mastodynia, gynecomastia, men-strual abnormalities, GI disturb-ances, rash 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; 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.
than the number containing HCTZ. A fixed-dose Loop diuretics such as furosemide are more effective
combination of chlorthalidone and azilsartan than thiazides in lowering BP in patients with moder- (Edarbyclor) has been approved by the FDA.8 ate to severe renal insufficiency (CrCl <30 mL/min).
In patients with normal renal function, they are less Metolazone may be effective in patients with impaired
effective than thiazides for treatment of hypertension.
renal function when the other thiazides are not, but Ethacrynic acid can be used in patients allergic to
data are lacking. Indapamide with or without the ACE
sulfonamides (thiazide and other loop diuretics contain inhibitor perindopril was effective in one study in eld- erly patients (>80 years old) in reducing death from Potassium-sparing agents such as amiloride and tri-
amterene are generally used with other diuretics to
Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
prevent or correct hypokalemia. These drugs can cause unless combined with a thiazide diuretic or calcium hyperkalemia, particularly in patients with renal channel blocker. ACE inhibitors have been shown to impairment and in those taking ACE inhibitors, prolong survival in patients with heart failure or left angiotensin receptor blockers (ARBs), beta blockers or ventricular dysfunction after a myocardial infarction, reduce mortality in patients without heart failure orleft ventricular dysfunction who are at high risk for Spironolactone, a mineralocorticoid receptor antago-
nist also used as a potassium-sparing diuretic, has been
cardiovascular events, and reduce proteinuria in effective as an add-on in patients with resistant hyper- patients with either diabetic or non-diabetic nephropa- tension.10 Eplerenone, a selective mineralocorticoid
thy.14 In an open-label trial (ANBP2) among more receptor antagonist,11 is less likely than higher doses of than 6000 mostly white patients with a low incidence spironolactone to cause gynecomastia. Aldosterone of diabetes, ACE inhibitor-treated male patients had antagonism may provide cardiovascular benefits an 11% lower incidence of cardiovascular events or beyond minimizing hypokalemia.12 Both spironolac- all-cause mortality than those treated with various tone and eplerenone have been shown to reduce doses of thiazide diuretics, despite similar reductions mortality in patients with heart failure when added to in BP.15 However, among 15,700 mostly white patients in the double-blind ALLHAT study, treatmentof hypertension with an ACE inhibitor did not ANGIOTENSIN-CONVERTING ENZYME
improve cardiovascular outcomes compared to (ACE) INHIBITORS
chlorthalidone 12.5-25 mg. In black hypertensiveparticipants in ALLHAT, the ACE inhibitor regimen ACE inhibitors are effective in treating hypertension was less effective than the diuretic in lowering BP and and are well tolerated. They are less effective in black less effective in reducing the incidence of stroke and patients and others with low-renin hypertension, Table 2. Renin-Angiotensin System Inhibitors
Usual Daily
Some Oral
Maintenance
Pregnancy
Frequent or Severe
Formulations
Category1,2
Adverse Effects3
Angiotensin-Converting Enzymes (ACE) Inhibitors
tion), rash, acute renal failure inpatients with bilateral renal artery taking potassium supplements or potassium-sparing diuretics), dysfunction), increased fetal mal-formations and mortality with use Trandolapril – generic 1, 2, 4 mg tabs 1-8 mg in 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 that act 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; 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.
Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
Table 2. Renin-Angiotensin System Inhibitors (continued)
Usual Daily
Some Oral
Maintenance
Pregnancy Frequent or Severe
Formulations
Category1,2 Adverse Effects3
Angiotensin Receptor Blockers (ARBs)
Direct Renin Inhibitor (DRI)
Aliskiren – Tekturna (Novartis) 150, 300 mg tabs 1. ACE inhibitors, ARBs and aliskiren are rated category C during the first trimester and category D during the second and third trimesters. Drugs that act 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; 3. In addition to the adverse effects listed, antihypertensive drugs may interact adversely with other drugs.
ANGIOTENSIN RECEPTOR BLOCKERS
DIRECT RENIN INHIBITOR
Aliskiren, a direct renin inhibitor (DRI), is FDA-
ARBs are as effective as ACE inhibitors in lowering approved alone or in combination with other BP, and appear to be equally reno- and cardioprotec- antihypertensive drugs for treatment of hyperten- tive, with fewer adverse effects. Like ACE inhibitors, sion.24 Whether aliskiren offers any advantage over they are less effective in black patients and others with ACE inhibitors or ARBs remains to be determined, low-renin hypertension, unless combined with a thi- and no outcomes data are available for aliskiren. In an azide diuretic or calcium channel blocker. Irbesartan
8-week study, concurrent use of aliskiren and the ARB treatment delayed development of overt diabetic valsartan was significantly more effective in lowering nephropathy in hypertensive patients with type 2 diabetes.16 In diabetic patients who already had overt
nephropathy, irbesartan
and losartan
CALCIUM CHANNEL BLOCKERS
progression of the renal disease.17,18 In patients withhypertension and left ventricular hypertrophy, with or Calcium channel blockers are a structurally and func- without diabetes (LIFE), losartan was more effective tionally heterogeneous class of drugs. They all cause in decreasing stroke, than the beta blocker atenolol, but vasodilatation, which decreases peripheral resistance.
not in black patients.19 The ARBs valsartan and can-
The cardiac response to decreased vascular resistance desartan have been shown to slow disease progression
in patients with chronic heart failure (Val-HeFT,
is variable; with some dihydropyridines (felodipine,
VALIANT, CHARM).20-22 Telmisartan was as effec-
nicardipine, nisoldipine and immediate-release
tive as the ACE inhibitor ramipril in preventing nifedipine), an initial reflex tachycardia usually
cardiovascular events in high-risk hypertensive occurs, but isradipine, sustained-release nifedipine
patients with diabetes or vascular disease and amlodipine generally cause little increase in heart
(ONTARGET); the combination of an ACE inhibitor rate. The non-dihydropyridines verapamil and dilti-
and an ARB provided no additional benefit on cardio- azem slow heart rate, can affect atrioventricular (AV)
vascular or renal outcomes compared to either agent conduction and should be used with caution in patients alone, but was more effective in lowering BP.23 Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
Table 3. Calcium Channel Blockers
Usual Daily
Some Oral
Maintenance Pregnancy
Frequent
Formulations
Category1
Adverse Effects2
Dihydropyridines
genericAdalat CC (Bayer)Procardia XL (Pfizer) 8.5, 17, 25.5, 34 mg ER tabs 17-34 mg once Non-Dihydropyridines
generic (sustained-release) 120, 180, 240, 300, 360 generic (continuous-delivery)120, 180, 240, 300, 1. 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; 2. 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.
In one meta-analysis, the risk of heart failure was with amlodipine and the ARB valsartan.27 In one large higher in patients treated with calcium channel block- outcomes trial, a combination of the ACE inhibitor ers compared to those treated with ACE inhibitors, benazepril with the calcium channel blocker amlodip- beta blockers or diuretics.26 One large double-blind ine was more effective in preventing adverse trial (VALUE Trial) in more than 15,000 high-risk cardiovascular outcomes than benazepril with HCTZ patients found similar rates of cardiovascular events Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
Table 4. Beta-Adrenergic Blockers
Usual Daily
Some Oral
Maintenance
Pregnancy
Frequent or Severe
Formulations
Category1
Adverse Effects2
dia, erectile dysfunction, decr-eased exercise tolerance, Beta Blockers with Intrinsic Sympathomimetic Activity
acebutolol has been associatedwith a positive antinuclear anti- Beta Blockers with Alpha-Blocking Activity
Beta Blockers with Vasodilating Nitric-Oxide-Mediated Activity
blocking drugs but may not cause impotence and may improve erectile dysfunction.
1. 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; 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.
Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
Table 5. Alpha-Adrenergic Blockers and Other Antihypertensives
Usual Daily
Maintenance
Pregnancy
Frequent or Severe
Formulations
Category1
Adverse Effects2
Alpha-Adrenergic Blockers
Doxazosin – generic3
pitations, fluid retention, drowsiness, weakness, anticholinergic effects, Central Alpha-Adrenergic Agonists
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
marked fluid retention, pericardial effusion, hair growth on face and body Peripheral Adrenergic Neuron Antagonists
disturbances, bradycardia, depression, nightmares with high doses, tardive dyskinesia 1. 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; 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.
BETA-ADRENERGIC BLOCKERS
found a beta blocker less effective in preventingcardiovascular events (especially stroke) than an ACE A beta blocker may be a good choice for treatment of inhibitor, an ARB, a calcium channel blocker or a hypertension in patients with another indication for a diuretic.29,30 Two guideline panels have recommended beta blocker, such as migraine, angina pectoris, not using a beta blocker for initial therapy of hyperten- myocardial infarction or heart failure. In other high- sion.31,32 Like ACE inhibitors and ARBs, beta blockers risk patients, large cardiovascular outcome trials have are less effective in black patients.
Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
Table 6. Some Combination Products
Strengths (mg)
Drug Strengths (mg)
ACE Inhibitors and Diuretics
Beta-Adrenergic Blockers and Diuretics (cont)
Calcium Channel Blockers and ACE Inhibitors
Calcium Channel Blockers and ARBs
Calcium Channel Blockers and Direct Renin Inhibitor
Angiotensin Receptor Blockers and Diuretics
Diuretic Combinations
Direct Vasodilator and Diuretic
Central Alpha Adrenergic Agonist and Diuretic
ARB and Direct Renin Inhibitor
Triple Drug Combinations
Direct Renin Inhibitor and Diuretic
Beta-Adrenergic Blockers and Diuretics
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 Pindolol, acebutolol, penbutolol and carteolol have
Labetalol combines beta blockade with alpha-adrenergic
intrinsic sympathomimetic activity (ISA). Beta block- receptor blockade. Carvedilol is another beta blocker
ers without ISA are preferred in patients with angina or with alpha-blocking properties; compared to metopro- lol, it is less likely to interfere with glycemic control in Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
patients with type 2 diabetes and hypertension.33 rently recommended) it can cause severe depression.35 Nebivolol does not have alpha-blocking properties but
Guanadrel (no longer available in the US) decreases
does have nitric-oxide-mediated vasodilating activity.34 cardiac output and may lower systolic pressure morethan diastolic; postural and exertional hypotension ALPHA-ADRENERGIC BLOCKERS
occur commonly and are aggravated by vasodilatationcaused by heat, exercise or alcohol.
Prazosin, terazosin and doxazosin cause less
tachycardia than direct vasodilators (hydralazine,
COMBINATION THERAPY
minoxidil), but more frequent postural hypotension,especially after the first dose. Treatment of essential Most patients with hypertension eventually need more hypertension with doxazosin has been associated with than one drug to control their BP. Patients with a BP an increased incidence of heart failure, stroke and >20/10 mm Hg at baseline may benefit from initiating combined cardiovascular disease compared to treat- therapy with 2 drugs.36 By combining drugs with dif- ment with a diuretic (ALLHAT). Alpha-blockers ferent mechanisms of action, lower doses can be used provide symptomatic relief from prostatism in men, to effectively reduce BP and decrease the incidence of but may cause stress incontinence in women and pos- adverse effects.37 Fixed-dose combination products tural hypotension in elderly patients.
(see Table 6) are widely available and may improveadherence. Three triple combination products are now CENTRAL ALPHA-ADRENERGIC AGONISTS
available containing hydrochlorothiazide (12.5-25 mg)and amlodipine added to either aliskiren, olmesartan or Drugs such as clonidine, guanfacine and methyldopa
decrease sympathetic outflow, but do not inhibit reflexresponses as completely as sympatholytic drugs that act peripherally. They do, however, frequently causesedation, dry mouth and erectile dysfunction.
Many of the drugs commonly used to treat hyperten- Clonidine is often used for treatment of hypertensive sion are available generically. Some of these are urgencies. Due to its short half-life (~7 hours), it must available in large discount pharmacies for $4-10 for a be taken 2 to 3 times a day for adequate long-term management of chronic hypertension. Once daily guanfacine (half-life ~17 hours) is more convenient for treatment 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. They should usually be given with a beta blocker or a cen- trally-acting drug to minimize the reflex increase in heart rate and cardiac output, and with a diuretic to avoid sodium and water retention. They should gener- ally be avoided in patients with coronary artery disease. Hydralazine maintenance dosage should be
limited to 200 mg per day to decrease the possibility of a lupus-like reaction. Minoxidil, a potent drug that
rarely fails to lower blood pressure, should be reserved for severe hypertension refractory to other drugs. It causes hirsutism and tachycardia and can also cause PERIPHERAL ADRENERGIC NEURON
ANTAGONISTS
Reserpine is an effective antihypertensive but is sel-
dom used now because (in doses much higher than cur- Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
Drugs for Hypertension
2011 Year-End Index:
For an electronic copy of the 2011 Index, go to: Coming Soon in Treatment Guidelines:
EDITOR IN CHIEF: Mark Abramowicz, M.D.
EDITOR IN CHIEF:
EXECUTIVE EDIT Mark Abramo
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Jean-Marie Pflomm, Pharm.D.
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CONTRIBUTING EDITOR: Eric J. Epstein, M.D. Albert Einstein College of Medicine
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Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012
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Issue 113 Questions
1. Most studies that have shown outcome benefits of a diuretic in 7. Among calcium channel blockers, an initial reflex tachycardia is to 2. A 64-year-old man with fairly well-controlled hypertension and 8. Alpha-adrenergic blockers are especially likely to cause: chronic heart failure who is being treated with hydrochlorothiazide has developed hypokalemia. One reasonable option would be to 9. Minoxidil is highly effective in lowering blood pressure, but it can 3. Which of the following antihypertensive drugs are less effective in 10. The diuretic found in most antihypertensive combination products 4. One advantage of ARBs over ACE inhibitors for treatment of c. have fewer adverse effectsd. all of the above 11. The 3 triple drug combinations available in the US for hyperten- 5. A 53-year-old woman with hypertension being treated with an ARB 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 is a. It has been shown to be more effective than an ARB in low- 12. Use of 2 drugs with different mechanisms of action for treatment b. It has fewer side effects than an ARB.
a. is usually more effective in decreasing BP than raising the c. It has been shown to lead to better outcomes than ARBs.
d. Whether it offers any advantage over ACE inhibitors or ARBs b. often allows for use of lower doses of both drugs c. should be considered for initial therapy in patients with a 6. Use of a beta blocker to treat hypertension has been found less effective in preventing cardiovascular events than: a. an ACE inhibitorb. a diureticc. a calcium channel blockerd. all of the above ACPE UPN: 379-0000-11-113-H01-P; Release: December 2011, Expire: December 2012
Treatment Guidelines from The Medical Letter • Vol. 10 ( Issue 113) • January 2012

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