Wilkins Introduces Reserpine for the Treatment of High Blood Pressure

Date 1952

Robert Wallace Wilkins studied the unique ability of reserpine, prepared from the root of an Indian shrub, to lower blood pressure, providing clinical medicine with a versatile and effective tool against hypertension and related diseases.

Also known asRauwolfia serpentina; Serpalan

Locale Boston, Massachusetts

Key Figures

• Robert Wallace Wilkins (1906-2003), American physician and clinical researcher who pioneered drug therapies for vascular and mental disorders
• Walter E. Judson (b. 1916), colleague of Wilkins at Boston University who collaborated in the reserpine research

Summary of Event

Excessively elevated blood pressure, clinically known as hypertension, has long been recognized as a pervasive and serious human malady. In a few cases, hypertension is recognized as an effect brought about by discrete pathologies. Often, however, elevated blood pressure, or essential hypertension, occurs as the result of yet unknown specific causes. Despite this etiologic uncertainty, unattended hypertension leads to potentially dramatic health problems, including increased risk of kidney and heart disease and stroke. Risk is clearly related to the intensity of blood pressure elevation.

Recognizing the need to treat hypertension in a relatively straightforward and effective way, Robert Wallace Wilkins, a clinical researcher at Boston University’s School of Medicine and the head of Massachusetts Memorial Hospital’s Hypertension Clinic, began to experiment with reserpine in the early 1950’s. Initially, samples made available to Wilkins were crude and unpurified. Eventually, the purified drug, reserpine, was used without exceptional changes relative to those observed with crude preparations.

Reserpine has a long and fascinating history from use, both clinically and in folk medicine, in India. The source of reserpine is the root of the shrub Rauwolfia serpentina, first mentioned in Western medical literature in the 1500’s but virtually unknown or at least unaccepted outside India until the mid-twentieth century. Crude preparation of Rauwolfia serpentina had been used for a variety of ailments in India for centuries prior to its first mention in the West. Not until the purification of reserpine in 1952 and the serious clinical consideration of Wilkins and his associate Walter E. Judson did Rauwolfia serpentina become a meaningful adjunct in modern medical practice.

Wilkins’s work with the drug did not begin on an encouraging note, because reserpine’s actions do not take hold rapidly. This slowness of action had been known from the Indian literature. The standard observation in Western pharmacotherapy, however, was that most drugs work rapidly, within a few hours or days; if, for example, a week has elapsed without positive effects being shown by a drug, chances are not high that it will work at all. Additionally, physicians and patients alike, shouldered with the fear and uncertainty that accompanies difficult health problems, are looking for rapid improvement or at least indications that a turn for the better is nearing. Reserpine is deceptive in this temporal context.

Wilkins and colleagues nearly fell into the trap of time. First, in working with crude preparations of Rauwolfia serpentina, they were becoming quite pessimistic until a patient who had been treated for many consecutive days began to show symptomatic relief. Nevertheless, only after months of treatment did Wilkins become a strong believer in the drug’s beneficial effects. The tendency to expect quick breakthroughs is so powerful that a parallel series of events ensued when pure preparations of reserpine became available in 1952. At first, reserpine did not appear to be the active agent of crude preparations; doubts began to grow among the clinical staff. When heart rate and blood pressure began to drop after a few weeks, however, the investigators could see that reserpine was producing results that generally could not be distinguished from crude preparations. Reserpine is not the only drug to act slowly; the tricyclic antidepressants are notoriously slow in action, and the same uncertainties on the part of patients, investigators, and clinicians have also been observed with these drugs.

Once reserpine’s activity began, Wilkins observed a number of important and unique consequences. Whether using the crude drug preparation or pure reserpine, the two most meaningful measures of blood pressure were significantly reduced in trial patients at the Hypertension Clinic at the Massachusetts Memorial Hospital. These two parameters are known as systolic blood pressure and diastolic blood pressure. Systolic pressure represents the peak of produced pressure in the arteries following a contraction of the heart. Diastolic pressure is the low point determined while the heart is resting.

To lower the mean blood pressure in the system effectively, both of these contributory pressures must be reduced. Administration of low doses of reserpine produced an average drop in pressure of about 15 percent, a figure considered less than dramatic but still highly significant. A complex phenomenon such as blood pressure is determined by a multitude of factors, including the resistance of the arteries, the force of contraction of the heart, and the rate of the heart’s beating. Coincident with the overt lowering of blood pressure, reserpine also reduced heart rate by about 15 percent, providing an important auxiliary action.

In the early 1950’s, when reserpine was undergoing intense study by Wilkins, other therapeutic drugs were in use for hypertension. Noted examples included hexamethonium and the compound veratrum. Wilkins recognized almost immediately that reserpine’s major contribution was likely to be as a drug to add to this therapeutic cast as opposed to an agent that would be used alone. His studies established that reserpine, plus at least one of the drugs already in use, produced an additive effect in lowering blood pressure. Indeed, at times the drug combinations produced more than an additive effect, or synergism. This type of effect occurs when the combination of drugs produces an effect that exceeds the simple arithmetic addition of the expected results of the individual drugs when administered alone.

Wilkins also discovered that reserpine’s particular value as an adjunct with other agents was caused by its particular dose responsiveness in the therapeutic realm. Although the drug is rather potent (producing wanted effects at a low dose), as the dose is increased further, reductions in blood pressure are difficult to achieve. As the dose is moved upward, though, the probability of side effects does tend to increase in a predictable fashion. Remarkable among these adverse effects are weight gain, diarrhea, nasal congestion, occasional reports of impaired sexual activity in males, and infrequent cases of unusual mental effects. Thus, the best use of reserpine was when it could be used in a low dose to avoid its toxicity, but in combination with other drugs to produce additive therapeutic effects.

Wilkins believed that reserpine’s most unique effects were not those found directly in the cardiovascular system but those produced indirectly by the brain. Hypertension is often accompanied by neurotic anxiety, which is both a consequence of the justifiable fears of future negative health changes brought on by prolonged high blood pressure and contributory to the high blood pressure itself. Wilkins’s patients invariably felt better mentally, were less anxious, and were sedated, but in an unusual sense. Reserpine made patients drowsy, but typically would not produce sleep, or if sleep occurred, it was reversed easily.

These multiple mental effects are recognized now as characteristic of tranquilizing drugs, or antipsychotics; Wilkins attempted to control for these mental effects by using a traditional sedative-hypnotic drug, phenobarbital, in some of the patient groups under study. Phenobarbital, however, produced no observable antihypertensive effects versus placebo, while reserpine did. Although both drugs gave a type of sedation, the sedation was qualitatively different in the two cases. In effect, Wilkins had discovered, serendipitously, a new and important category of drugs, the tranquilizers.

Significance

Reserpine holds a vital position in the historical development of antihypertensive drugs for two main reasons: First, it was the initial drug discovered to have wide-ranging effects in blocking the consequences in nerves, both in the brain and in the peripheral nervous system, which utilize norepinephrine or its close relative dopamine as transmitter substances. Drugs that interfere with this part of nervous system activity include one of the four major categories of modern antihypertensive drugs; reserpine remains an important member of this drug group.

Second, reserpine was the first drug in any of the four groups to achieve broadly based clinical acceptance, use, and success. By 1950, many different drugs, some of them quite effective, were being used to treat hypertension. None, however, received massive support by physicians. Reserpine’s introduction provided the first central theme for therapeutic use because it gave at least some effectiveness in most patients. This near universal effectiveness is caused by the drug’s ability to act centrally and peripherally and to the central role the biogenic amines, especially norepinephrine, play in hypertension.

Since the 1950’s, medical science has rigorously explored the nature of cardiovascular function and diseases of the cardiovascular system such as hypertension. Many new factors have been identified in the genesis of hypertension. The role of salt balance, involvement of fatty substances such as cholesterol, hormonal action such as in the case of angiotensin, and the role of stress have all been recognized as vital components of a sophisticated physiological network. Nevertheless, despite all the new complications, cardiovascular activity is regulated at a basic level by the nervous system. Control of diet and lifestyle help tremendously in dealing with hypertension. Yet, without control of the nervous system, many cases of high blood pressure will remain problematic.

Reserpine, a refined drug from a bushy Indian plant, has become one of the world’s best-known drugs. This transition from crude natural product to the forefront of medical technology is grand testimony to the power of nature’s synthetic machinery that produces molecules of vast utility and intrigue.

Bibliography

Comroe, Julius H., Jr. Exploring the Heart: Discoveries in Heart Disease and High Blood Pressure. New York: W. W. Norton, 1983. Comroe, one of the twentieth century’s greatest cardiopulmonary physicians and researchers, has produced a philosophically sensitive, beautifully illustrated, and conceptually brilliant history of medicine’s attempts to better understand the heart and to control its various diseases. Although dated, still a good resource.

Gilman, Alfred G., et al., eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. Edited by Laurence L. Brunton et al. 11th ed. New York: McGraw-Hill, 2006. No book in the history of pharmacological study has made the impact of this tome, written for years by Gilman’s father and the renowned Louis Goodman. Reserpine’s basic actions, its clinical use in cardiovascular disease and psychiatry, in addition to parallel coverage of all other well-known drugs, are presented in exemplary fashion.

Lynch, James J. The Language of the Heart: The Body’s Response to Human Dialogue. New York: Basic Books, 1985. In nontechnical language, Lynch postulates how events in the psychosocial realm impact cardiovascular health and disease.

Trease, George Edward, and William Charles Evans. Trease and Evans, Pharmacognosy. 15th ed. Rev. ed. New York: W. B. Saunders, 2002. Contains not only the standard characterization of a natural product such as reserpine and related alkaloids but also the broadest spectrum available of drugs derived from nonsynthetic sources.

Wilkins, Robert W., et al. “Reserpine in the Treatment of Hypertension.” New England Journal of Medicine 250 (1954): 477-478. This short article specifically compares the effects of crude Rauwolfia serpentina with pure reserpine. This movement from crude natural product to pure drug occurs virtually without exception in the development of drugs from natural sources in the context of modern Western medicine.

Wilkins, Robert W., and Walter E. Judson. “The Use of Rauwolfia Serpentina in Hypertensive Patients.” New England Journal of Medicine 248 (1953): 48-53. Extensive results of clinical testing and comparison with drugs in use at the time and history are presented.