Reserpine: A New Consideration of an Old Drug for Refractory Hypertension

Refractory hypertension is a phenotype of antihypertensive treatment failure whereby all forms of appropriate medications and doses fail to control blood pressure to a desirable level. It has been defined by the failure to control blood pressure with five or more different classes of antihypertensive medication in their highest tolerated doses, which would include a long acting thiazide diuretic and a mineralocorticoid receptor antagonist.1 It should not be confused with resistant hypertension which is defined as inadequately controlled blood pressure with three or more appropriately dosed medications, including a diuretic, or blood pressure control which requires four or more appropriately dosed medications.2 Most prior estimates of resistant hypertension included refractory hypertension. Buhnerkempe et al.3 published the only national probability sample population estimates of resistant and refractory hypertension (over 8 National Health and Examination Survey cycles), and noted that 6.2% of patients with resistant hypertension actually had refractory hypertension instead. Interestingly, unlike clinical studies, these patients did not have higher heart rate. Although refractory hypertension is infrequent, it is a disturbing clinical phenotype that vexes clinicians who appreciate the need to better control the blood pressure to avoid cardiovascular events. The pipeline of new drugs to control both resistant and refractory hypertension are limited, and no major breakthroughs have occurred despite the introduction of endothelin receptor antagonists, neutral endopeptidase–angiotensin converting enzyme (ACE) inhibitors, and renal denervation. Some authors have suggested that resistant hypertension is related to volume excess,2 whereas refractory hypertension may represent a disorder of inadequately controlled sympathetic nervous system activity.1,4,5 Regardless of the theories, the proof of concept study in this edition of the journal by Siddiqui et al.6 provides important new understanding as to not only the pathogenesis of refractory hypertension, but may also provide some hope that an old drug could be repurposed for the treatment of this refractory blood pressure phenotype. Reserpine is a drug that was used for many years in the treatment of hypertension, usually in combination with a thiazide diuretic or a vasodilator.7 Large clinical trials have demonstrated that combined treatment with reserpine plus a thiazide diuretic reduces mortality in people with hypertension.8–10 It was first approved by the FDA in 1955. It was recommended to be used with a thiazide diuretic or vasodilator in patients who did not achieve adequate blood pressure control with a first line treatment (thiazide diuretic). Interestingly, reserpine-hydrochlorothiazide was the seventeenth most commonly prescribed combination anti-hypertensive therapy utilized in 2012.11 The main effect of the drug is to deplete catecholamines from peripheral sympathetic nerve endings.12 Catecholamines are normally involved in regulating heart rate, as well as myocardial inotropy and peripheral vascular resistance. The usual doses were 0.05–0.2 mg per day. It was described as being well tolerated with the most common adverse effects being nasal stuffiness.13 It was also used to treat psychotic symptoms. Other side effects include bradycardia and worsening of asthma with higher doses of 0.5 mg or greater and there are reports of drowsiness, nightmares, and fatigue. Reserpine was recommended as an alternate drug for treating hypertension by the JNC 8 Committee,14 and a 2016 Cochrane review found reserpine to be as effective as other first line antihypertensive drugs for lowering blood pressure.15 However, with the introduction of many new classes of medications over the past two decades, its use has declined substantially, and it is no longer commercially available in the United States in pill form but can be obtained in bulk form. The proof of concept trial by Siddiqui et al.6 provides a fascinating look at an old-fashioned, yet potent, way of attacking the sympathetic nervous system with a discarded medication. The idea behind the study makes perfect sense, as this drug has powerful antiadrenergic effects and its catecholamine depleting mechanism from peripheral sympathetic nerve endings is an ideal strategy for targeting hypertension which is largely driven by this sympathetic nervous system. Intriguingly, efforts to utilize renal denervation in patients with more complicated forms of hypertension felt to be due to the sympathetic nervous system over activity have yielded results that are not as consistent as those seen in this pilot study.16 Granted, the renal denervation technique may be incomplete in some circumstances, but why consider an invasive procedure when a low dose of an old generic medication may serve a similar purpose and possibly even more effective? The authors were very careful in their design of this small clinical trial. They purposely excluded other sympatholytic medications such as clonidine or guanfacine before starting the reserpine. They utilized reserpine in a 0.1 mg daily dose which is approximately half of the fully titrated dose. They were also careful to evaluate patients in the office with automated blood pressure readings, as well as with 24-hour ambulatory blood pressure monitoring measurements. Also important in the clinical trial design was the use of chlorthalidone and a mineralocorticoid receptor antagonist as part of the five or more drug regimen to control blood pressure in these patients thus, the patients were truly refractory. It is possible that higher doses of chlorthalidone or spironolactone may help lower blood pressure, but these drugs may not always be well tolerated in some patients. Despite only having six patients who completed the trial based on the many important inclusion and exclusion criteria the observations were impressive. The automated office systolic blood pressure reduction was nearly 30 mmttg, and mean the 24 hour systolic and diastolic ambulatory blood pressure measures were reduced by 21.8 and 15.3 mmttg, respectively. One would have to wonder how much more blood pressure reduction might have occurred had they used a 0.2 mg dose or possibly titrated the doses of the diuretic support or the mineralocorticoid receptor antagonist. From a clinical perspective, one has to wonder why someone has not thought of giving reserpine to patients with suspected hyperadrenergic hypertension before? We can agree with the importance of thiazide diuretics, particularly in higher dose, to facilitate blood pressure control in many different types of patients, especially those with chronic kidney disease. We can agree that the Pathway-2 study17 demonstrated important opportunity with mineralocorticoid receptor blockade, in low doses to facilitate better blood pressure control in resistant hypertensives. Yet, no major focus has been on the sympathetic nervous system except for renal denervation studies. The importance of greater sympathetic tone in patients with both resistant and refractory hypertension may be important areas of both current and future treatment considerations. This may be especially important with patients with increased heart rate and refractory hypertension which has been largely unresponsive to beta blockade. Overall, this proof of concept study adds importantly to the literature on the topic of refractory hypertension. The enrolled patients were appropriately phenotyped and clearly had refractory hypertension based on automated office readings and ambulatory blood pressure monitoring. They also had medication serum measurements to indicate compliance. The results are truly remarkable and should raise awareness that reserpine should be tested in larger clinical trials of patients with both refractory and resistant hypertension. This may also provide the impetus for a pharmaceutical company to start making this medication in the pill form again, so that it would be available to clinicians. Importantly, the 0.1 mg dose of reserpine was well tolerated in this small clinical trial. Reserpine was also reasonable well tolerated in clinical trials in older literature when studied as part of a multi-drug regimen. There is broad experience with reserpine in large scale clinical trial such as the Hypertension Detection and Follow up Program,9 the Veterans Administration Cooperative Study Group for Anti-hypertensive Agents and the Systolic Hypertension in the Elderly Program.10 Siddiqui et al. should be congratulated on this important addition to the literature, and providing new insight into the pathogenesis of this vexing clinical phenotype and how we may best consider future treatment approaches. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (R01DK 066013, U01DK106102, and U01DK116095) and National Heart, Lung, and Blood Institute (R01HL127422 and R01HL132732). Scientific Advisor: Janssen, Astra, BI, MSD, Akebia, Relypsa, Boston Scientific, Lexicon, Bayer, Vifor. The author declared no conflict of interest.