Reserpine

Reserpine is an alkaloid extracted from the root of the climbing shrub Rauwolfia serpentina. The whole root had been used in India for centuries to treat fever and snakebite, but the drug’s ability to lower BP was described in published Indian research in 1931, and the alkaloid extract was introduced to modern Western medicine in the mid-1940s. Reserpine was 1 of the earliest drugs used widely to treat hypertension. It binds to the storage vesicles in adrenergic neurons and inhibits the uptake of norepinephrine and dopamine, which leads to their degradation by cytoplasmic monoamine oxidase. Recovery of sympathetic function requires the formation of new storage vesicles, which takes days to weeks after discontinuation of the drug. Reserpine reduces cardiac output and peripheral resistance and produces little postural hypotension. Reserpine’s antihypertensive effect is due primarily to effects on peripheral nerves, but its primary side effects, sedation and depression, are due to effects on the central nervous system (CNS).

Reserpine is a very effective antihypertensive agent as part of a 2- or 3-drug regimen and has outcomes data attesting to its effectiveness. Reserpine was used in the landmark Veterans Administration Cooperative Study (VACS), the first adequately designed, placebo-controlled, randomized clinical trial of drug treatment in patients with diastolic BPs of 115 to 129 mm Hg. Active treatment included hydrochlorothiazide (50 mg twice daily), reserpine (0.1 mg twice daily), and hydralazine (50 mg 3 times daily), all used concurrently. The reduction from prerandomization BP averaged 43 mm Hg systolic and 29.7 mm Hg diastolic using these agents. The study was terminated early after only 1.5 years of treatment because of excessive morbidity and mortality in the placebo group (21 vs 1 event). The second part of this VACS examined patients with diastolic BPs of 90 to 114 mm Hg. Using the same active regimen, it again demonstrated significant reduction in BP, averaging 27.2 mm Hg systolic and 17.4 mm Hg diastolic, and significant reductions in fatal and nonfatal events, especially stroke, with treatment.

Because of such results, the first Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure, in 1977, recommended thiazide diuretics as first-step drugs in the “stepped care” approach to hypertension treatment, with reserpine among the agents added in the second step. The later recommendation was based on evidence from clinical trials combining reserpine with thiazide diuretics. Studies from the 1960s to the 1990s documented the efficacy of this combination and demonstrated average reductions of 20 to 23 mm Hg in systolic BP and 17 to 19 mm Hg in diastolic BP. Indeed, reserpine was included as 1 of the optional step 2 agents in the recent Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT compared initial treatment with the calcium channel blocker amlodipine or the ACE inhibitor lisinopril to the thiazide-like diuretic chlorthalidone in reducing cardiovascular events. Reserpine, atenolol, and clonidine were the medications available for step 2 therapy if BP was not adequately controlled on monotherapy. At 5 years, reserpine was used by 4.3% of subjects.

Despite its effects on BP, particularly when added to a diuretic, reserpine use has decreased dramatically. This was attributed in part to reserpine’s side effects, including lethargy, depression, nightmares, sexual dysfunction, and anxiety. Gastrointestinal side effects are also common. In the second VACS, 20 of 186 subjects in the treatment arm reported side effects thought to be reserpine related (depression in 7 subjects, peptic ulcer disease in 6 subjects, and other side effects in 7 subjects). However, 10 subjects in the placebo arm reported similar side effects. The incidence of serious side effects has never been a problem in any of the controlled trials. In the VACS, reserpine did not cause any serious adverse events. Lower doses tend to produce fewer side effects, and although the initial standard dose of reserpine was 0.25 mg/day, doses of 0.125 mg and 0.05 mg produced 90% and 82% of the BP reduction of the standard dose when all doses were combined with chlorthalidone 25 or 50 mg.

The most serious concern with reserpine was carcinogenicity. Three case comparison studies in the early 1970s suggested an association between reserpine and breast cancer. Subsequent case comparison studies failed to confirm an association, and the Hypertension Detection and Follow-Up Program (HDFP), including 2,529 women, 1,036 of whom were treated with reserpine, concluded that there was no evidence that reserpine caused breast cancer.

Consequently, reserpine, especially in low doses and combined with a diuretic, is a potentially useful antihypertensive medicine for modern practice. Patients do need to be warned of, and observed for, psychological side effects, but reserpine when used in combination has outcome data, produces significant BP reductions, and has a very long duration of action, so missing a dose is less of a problem than with shorter acting agents.

Methyldopa

Methyldopa is a prodrug that is converted to the centrally acting antihypertensive agent α-methyl-norepinephrine. The latter replaces norepinephrine in the neurosecretory vesicles of adrenergic neurons. When released, α-methyl-norepinephrine inhibits central α-adrenergic receptors and reduces CNS sympathetic outflow. Methyldopa reduces vascular resistance, with little change in the cardiac output. Renal blood flow is maintained and significant postural hypotension is unusual because methyldopa attenuates, but does not completely block, baroreceptor-mediated vasoconstriction. It is rapidly absorbed orally and has a short half-life of 2 hours, but its peak effect is 6 to 8 hours later, probably because of the time required for transport to the CNS. Its duration of action is approximately 24 hours, which permits once or twice daily dosing at doses of 250 to 3,000 mg/day.

Methyldopa’s side effects include those common to centrally acting drugs that reduce sympathetic outflow, such as sedation, dry mouth, and impotence. However, methyldopa produces other adverse effects not related to its pharmacologic action. These include autoimmune hemolytic anemia and hepatotoxicity. Transient elevations on liver function tests are seen in 5% of patients, but serious hepatotoxicity is rare. Positive Coombs test results occur in 20% of patients with long-term use, but hemolytic anemia is rare. A febrile reaction is occasionally seen and can rarely lead to serious illness. Methyldopa should be avoided in patients with hepatic disease. Salt and water retention can occur with prolonged use of methyldopa, and the use of a diuretic is often needed.

Methyldopa was widely used as a second-line antihypertensive agent, with approximately 20 million patients in the United States in the 1960s and 1970s. A large multiclinic retrospective study evaluated methyldopa’s efficacy and tolerability in 435 patients who had received methyldopa as their first nondiuretic antihypertensive for ≥1 and up to 10 years. Methyldopa was added to diuretic therapy in 73% of patients, methyldopa and a diuretic were started simultaneously in 19%, and 8% received methyldopa alone. BP decreased within 2 weeks and was maintained over the 4.5 years of the efficacy analysis. Mean sitting BP decreased from 171/108 to 143/90 mm Hg at 4.5 years. The average dose was 946 mg/day. Methyldopa was discontinued in 14 patients because of lack of response; in 73 because of adverse effects including dizziness, hypotension, impotence, drowsiness, or fatigue; and in 60 for unknown reasons. Several studies comparing methyldopa to β blockers failed to show differences in BP control, but in the elderly, methyldopa was more efficacious than oxprenolol (age 65 to 80 years) and better tolerated than propranolol (age >60 years).

Methyldopa is an effective antihypertensive agent alone or when given in conjunction with a diuretic, but its use is limited because of the frequent side effects. Outcomes data to support the use of methyldopa are not available. Nevertheless, it remains an option for hypertension treatment when other agents fail or are poorly tolerated, especially in older patients. Oral methyldopa was assigned to pregnancy category B; animal studies have failed to reveal evidence of fetal toxicity, but no controlled human data are available. However, given the safe and successful history of its use, methyldopa is considered by most experts to be the drug of choice in treating nonemergent hypertension in pregnancy.

Clonidine

Clonidine stimulates α ₂ -adrenergic receptors in the brainstem, thereby reducing sympathetic outflow from the CNS. Decreases in plasma concentrations of norepinephrine correlate directly with the hypotensive effect. BP is reduced by effects on cardiac output and vascular resistance. Some degree of orthostatic hypotension may occur, but symptomatic postural hypotension is uncommon without plasma volume depletion. Renal blood flow is maintained. Fluid retention can occur with clonidine, so almost all patients given this drug will also require a diuretic. Clonidine can be administered transdermally. It is best absorbed from the skin of the chest or upper arms and provides drug delivery for 7 days. Sedation, dry mouth, and impotence are common side effects. These are less frequent when the drug is used transdermally, possibly because high peak concentrations are avoided. Clonidine has a short half-life of about 12 hours so that sudden discontinuation may cause a withdrawal syndrome consisting of a profound increase in BP, headache, tremors, tachycardia, abdominal pain, and sweating. Rebound hypertension is significantly less frequent when discontinuing transdermal clonidine. The best way to treat this potentially life-threatening emergency is to reintroduce clonidine and taper more slowly. Overdose with clonidine can cause a paradoxical hypertension if peripheral α ₂ stimulation exceeds central α ₂ -adrenergic receptor stimulation and produces vasoconstriction.

Clonidine was 1 of the step 2 options in ALLHAT, and 10.6% of patients were taking clonidine at the 5-year end of the study. Clonidine is as effective as ACE inhibitors, β blockers, and hydrochlorothiazide in BP control as monotherapy. It reduces BP in diabetic patients and also decreases insulin resistance, microalbuminuria, and plasma fibrinogen levels. Clonidine has not been totally abandoned in the United States. It has proved efficacy but can be dangerous when not used properly. Transdermal application may be a best option for patients who miss or dislike daily dosing. Another α ₂ -adrenergic agonist, guanfacine, may be used as an alternative. Guanfacine has similar properties to clonidine but carries a milder risk for withdrawal syndrome because of its longer half-life. In the mid-1990s, moxonidine was introduced as a newer class of α ₂ -adrenergic agonists with a better side effect profile. A few years later, a large clinical trial of moxonidine in heart failure, the Moxonidine Congestive Heart Failure (MOXCON) trial, was stopped because of an increase in deaths in the moxonidine group, which prompted discontinuation of the drug from the United States market. It is still being used as an antihypertensive agent in Europe, however.

Guanethidine

Guanethidine is the prototype of drugs that inhibit the peripheral postganglionic adrenergic neurons. It is actively transported into the neuron, where it replaces norepinephrine in storage vesicles. Guanethidine is released by stimuli that normally release norepinephrine and exerts its effect by being an inactive transmitter. It decreases cardiac preload through venodilation, and inhibits sympathetic stimulation of the heart, reducing cardiac output. Renal blood flow is modestly reduced, and plasma volume often expands. The later can reduce the antihypertensive efficacy of guanethidine and requires concomitant diuretic administration. Guanethidine has some attractive characteristics. It does not enter the CNS and thus has no central activity. Its long half-life (5 hours) permits once daily dosing. In contrast, guanethidine can cause postural hypotension, sexual dysfunction with delayed or retrograde ejaculation, and diarrhea. Favorable clinical reports on the use of guanethidine in the treatment of hypertension were published in the late 1950s and early 1960s, but its use has traditionally been reserved for patients refractory to other drugs because of concern over side effects. However, in patients with stage 1 and the lower range of stage 2 hypertension, it is comparable to reserpine in BP reduction and tolerability. Guanethidine lacks outcome study results to support its use, although it was the step 4 drug in HDFP, and approximately 10% of participants in the stepped care arm were prescribed guanethidine at the end of 5 years. Guanethidine has been largely abandoned in the United States during the past 2 decades and as a result was recently discontinued from the United States market.

Chlorthalidone

Thiazides and thiazide-like diuretics are the most frequently used antihypertensive agents in the United States. Chlorothiazide and hydrochlorothiazide are benzothiadiazines (“thiazides”) and block Na ⁺ -Cl ⁻ transport in the distal collecting renal tubule. Chlorthalidone is a nonbenzothiadiazine diuretic with a mechanism of action similar to thiazides. Hydrochlorothiazide has always dominated chlorthalidone in the United States market. Most clinicians consider the 2 drugs at equivalent doses interchangeable, but they have different pharmacologic properties. The half-life of hydrochlorothiazide is 8 to 15 hours, compared to 45 to 60 hours for chlorthalidone. Chlorthalidone has a larger volume of distribution, possibly because chlorthalidone concentrates in erythrocytes and is slowly released from this compartment, and most studies suggest that chlorthalidone is ≥25% to 50% more potent than hydrochlorothiazide.

Most side effects of thiazide and thiazide-like diuretics are dose related and include hypokalemia and hyponatremia, increased blood triglyceride levels, hyperuricemia and gout, and impotence. Increased insulin resistance is also a known side effect; a post hoc subgroup analysis from ALLHAT showed that the risk for developing new diabetes was higher in the chlorthalidone group than the other groups. Despite this less favorable metabolic profile, clinical outcomes were similar between treatment groups. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure suggested “thiazide-like diuretics for most patients” with hypertension as initial therapy. These guidelines, however, do not distinguish among the thiazide diuretics and list several acceptable options, including chlorothiazide, chlorthalidone, hydrochlorothiazide, polythiazide, indapamide, and metolazone.

It is not clear whether the pharmacokinetic differences between chlorthalidone and hydrochlorothiazide translate into different BP and outcome effects. A single-blinded, randomized trial compared the antihypertensive effects of hydrochlorothiazide and chlorthalidone. Chlorthalidone 25 mg/day reduced 24-hour mean and nighttime mean systolic BP more than hydrochlorothiazide 50 mg/day (–12.4 vs −7.4 and −13.5 vs −6.4 mm Hg, respectively), although there was no difference in office BP measurements. Most major trials used either hydrochlorothiazide or chlorthalidone. Those trials with the more favorable outcomes used chlorthalidone as their diuretic. Specifically, the HDFP study used chlorthalidone as the step 1 drug; the Systolic Hypertension in the Elderly Program (SHEP) and ALLHAT used chlorthalidone exclusively, and the Multiple Risk Factor Intervention Trial (MRFIT) switched participants who initially received hydrochlorothiazide to chlorthalidone. In MRFIT, 8,012 men were randomized to either a risk factor special intervention program or to usual care. Therapy in the special intervention group with either hydrochlorothiazide (50 or 100 mg) or chlorthalidone (50 or 100 mg) had a favorable outcome and significantly reduced death from acute myocardial infarction, but 6 years into the trial, mortality was higher in the special intervention group than the usual care group in the 9 clinics predominately using hydrochlorothiazide, whereas the opposite was true in the 6 clinics predominantly using chlorthalidone. At the beginning, enrolled clinics were given the option to choose 1 or the other, but the protocol was changed near its end to exclusively use chlorthalidone, and mortality risk in the special intervention and usual care groups reversed in the 9 clinics that initially used hydrochlorothiazide.

Despite such intriguing observations, chlorthalidone is underused in treating hypertension, is not as readily available as hydrochlorothiazide, and in contrast to hydrochlorothiazide is available in only a few fixed-dose combination products. The reluctance to use chlorthalidone may be because many clinicians believe that chlorthalidone produces more hypokalemia, but this may relate to its greater potency per milligram and longer duration of action. The incidence of hypokalemia in ALLHAT was low; about 8% of the chlorthalidone group were receiving potassium supplementation at 5 years. Although it is difficult to change clinicians’ habits, it is likely that this inexpensive and effective drug will not remain neglected.

There has been some renewed interest in chlorthalidone use since ALLHAT, in which chlorthalidone was more effective than lisinopril at reducing systolic BP, especially in African Americans and in the first year of the trial. The Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial showed 20% more cardiovascular events in the benazepril-hydrochlorothiazide arm compared to the benazepril-amlodipine arm, challenging the “tradition-based” recommendation from the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure that a diuretic always be part of any 2-drug antihypertensive regimen. Some have speculated that had chlorthalidone rather than hydrochlorothiazide been the diuretic in the diuretic-benazepril arm of ACCOMPLISH, the benefit seen with benazepril-amlodipine would not have occurred. However, because the BPs were not different in the 2 arms of ACCOMPLISH, a hemodynamic explanation cannot explain the results. Recently, Woodman et al found that chlorthalidone decreases platelet aggregation, possibly because of differences in platelet carbonic anhydrase activity, and vascular permeability and promotes angiogenesis more effectively than bendroflumethiazide. Variations in these pleiotropic effects between thiazides and chlorthalidone could account for the discrepancy in reducing cardiovascular outcomes in patients with hypertension and are a more likely explanation as to why ACCOMPLISH might have had a different result had chlorthalidone been the diuretic studied. New fixed-dose combinations with chlorthalidone are soon to be marketed if approved by the United States Food and Drug Administration.

Spironolactone

Aldosterone binds to mineralocorticoid receptors in the renal distal tubules and collecting ducts, and activates Na ⁺ pumps, causing Na ⁺ and water retention and increased excretion of K ⁺ and H ⁺ . Spironolactone is an aldosterone antagonist that competitively inhibits the binding of aldosterone to the mineralocorticoid receptor. The clinical efficacy of spironolactone is hypothetically a function of endogenous levels of aldosterone. This idea, however, has been vigorously challenged as the use of and value of this agent has become apparent. Spironolactone has little or no effect on renal hemodynamics. It is partially absorbed through the gut (60% to 70%), extensively metabolized in the liver, undergoes enterohepatic recirculation, and has a short half-life (1.4 hours). Canrenone, however, is an active metabolite of spironolactone with a half-life of approximately 16.5 hours, allowing once daily use. As with other K ⁺ -sparing diuretics, spironolactone may cause severe and life-threatening hyperkalemia, especially in patients with renal insufficiency or who are also taking ACE inhibitors, angiotensin receptor blockers, or direct renin inhibitors. Spironolactone, because of its steroid structure, may cause gynecomastia, impotence, decreased libido, hirsutism, and menstrual irregularities. It may also cause diarrhea, gastritis, and peptic ulcers, as well as CNS side effects such as drowsiness and headache. Early studies demonstrating the antihypertensive efficacy of spironolactone were mostly small single-center trials comparing spironolactone to thiazide diuretics. BP reductions were similar. Spironolactone is often coadministered with thiazides to reduce the hypokalemia of the thiazides, but it is also useful when added to other drugs in resistant hypertension. This effectiveness may be due to the recent recognition that mineralocorticoid excess may be present frequently, even if measurements of plasma or urinary aldosterone levels are not abnormally high. Up to 20% of patients with resistant hypertension may have primary hyperaldosteronism. However, spironolactone reduces BP similarly whether or not a patient has primary hyperaldosteronism. Furthermore, the BP response is not predicted by plasma aldosterone level, plasma renin activity, aldosterone/renin ratio, or 24-hour urinary aldosterone excretion, although patients with confirmed primary hyperaldosteronism require higher spironolactone doses. This suggests a broader role for aldosterone in resistant hypertension and an expanded role for aldosterone antagonists. Spironolactone has not been abandoned in the United States because it is used frequently in heart failure and also in patients with refractory hypertension. After the publication of the Randomized Aldactone Evaluation Study (RALES), the rates of prescriptions for spironolactone increased dramatically, as did hyperkalemia-related morbidity and mortality. Physicians should be aware of this fact and consider closer laboratory monitoring when prescribing this drug.

Ethacrynic acid

Ethacrynic acid was the first loop diuretic marketed. This class of diuretics inhibits the reabsorption of sodium and chloride in the ascending loop of Henle. It is mainly indicated to treat edema associated with congestive heart failure, hepatic cirrhosis, or renal disease, but is also used to treat hypertension. One feared adverse reaction is ototoxicity, generally associated with rapid intravenous administration or unusually high oral dosages (>100 mg/day). Unlike other diuretics of same or different class, ethacrynic acid is not a sulfa drug and thus can be useful to treat hypertension in patients who need a diuretic and who are allergic to sulfa drugs. Ethacrynic acid was neglected by clinicians for many years and was taken off the United States market because of the predominance of other loop diuretics such as furosemide and torsemide. However, it was reintroduced to the market shortly afterward because of the aforementioned advantage over these drugs in sulfa-allergic patients.