Reserpine

The invention: A drug with unique hypertension-decreasing effects

that provides clinical medicine with a versatile and effective

tool.

The people behind the invention:

Robert Wallace Wilkins (1906- ), an American physician and

clinical researcher

Walter E. Judson (1916- ) , an American clinical researcher

Treating Hypertension

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 particular pathologies (diseases or disorders). Often,

however, hypertension occurs as the result of unknown causes.

Despite the uncertainty about its origins, unattended hypertension

leads to potentially dramatic health problems, including increased

risk of kidney disease, heart disease, and stroke.

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, the samples

that were made available to Wilkins were crude and unpurified.

Eventually, however, a purified version was used.

Reserpine has a long and fascinating history of 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

preparations of the shrub had been used for a variety of ailments in

India for centuries prior to its use in the West.

Wilkins’s work with the drug did not begin on an encouraging

note, because reserpine does not act rapidly—a fact that had been

noted in Indian medical literature. The standard observation in

Western pharmacotherapy, however, was that most drugs work

rapidly; if a week has elapsed without positive effects being shown

by a drug, the conventional Western wisdom is that it is unlikely

to work at all. Additionally, physicians and patients alike tend to

look for rapid improvement or at least positive indications. Reserpine

is deceptive in this temporal context, andWilkins and his

coworkers were nearly deceived. In working with crude preparations

of Rauwolfia serpentina, they were becoming very pessimistic,

when 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 believer in the drug’s

beneficial effects.





The Action of Reserpine



When preparations of pure reserpine became available in 1952,

the drug did not at first appear to be the active ingredient in the

crude preparations. When patients’ heart rate and blood pressure

began to drop after weeks of treatment, however, the investigators

saw that reserpine was indeed responsible for the improvements.

Once reserpine’s activity began, Wilkins observed a number of

important and unique consequences. Both the crude preparations

and pure reserpine significantly reduced the two most meaningful

measures of blood pressure. These two measures are systolic blood

pressure and diastolic blood pressure. Systolic pressure represents

the peak of pressure produced in the arteries following a contraction

of the heart. Diastolic pressure is the low point that occurs

when the heart is resting. To lower the mean blood pressure in the

system significantly, both of these pressures must be reduced. The

administration of low doses of reserpine produced an average drop

in pressure of about 15 percent, a figure that was considered less

than dramatic but still highly significant. The complex phenomenon

of blood pressure is determined by a multitude of factors, including

the resistance of the arteries, the force of contraction of the

heart, and the heartbeat rate. In addition to lowering the blood pressure,

reserpine reduced the heartbeat rate by about 15 percent, providing

an important auxiliary action.

In the early 1950’s, various therapeutic drugs were used to treat

hypertension. Wilkins recognized that reserpine’s major contribution

would be as a drug that could be used in combination with

drugs that were already in use. His studies established that reserpine,

combined with at least one of the drugs already in use, produced

an additive effect in lowering blood pressure. Indeed, at

times, the drug combinations produced a “synergistic effect,” which

means that the combination of drugs created an effect that was more

effective than the sum of the effects of the drugs when they were administered

alone. Wilkins also discovered that reserpine was most

effective when administered in low dosages. Increasing the dosage

did not increase the drug’s effect significantly, but it did increase the

likelihood of unwanted side effects. This fact meant that reserpine

was indeed most effective when administered in low dosages along

with other drugs.

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 hypertension and contributory to the hypertension itself.

Wilkins’s patients invariably felt better mentally, were less

anxious, and were sedated, but in an unusual way. Reserpine

made patients drowsy but did not generally cause sleep, and if

sleep did occur, patients could be awakened easily. Such effects

are now recognized as characteristic of tranquilizing drugs, or

antipsychotics. In effect, Wilkins had discovered a new and important

category of drugs: tranquilizers.



Impact



Reserpine holds a vital position in the historical development of

antihypertensive drugs for two reasons. First, it was the first drug

that was discovered to block activity in areas of the nervous system

that use norepinephrine or its close relative dopamine as transmitter

substances. Second, it was the first hypertension drug to be

widely accepted and used. Its unusual combination of characteristics

made it effective in most patients.

Since the 1950’s, medical science has rigorously examined cardiovascular

functioning and diseases such as hypertension. Many

new factors, such as diet and stress, have been recognized as factors

in hypertension. Controlling diet and life-style help tremendously

in treating hypertension, but if the nervous system could not be partially

controlled, many cases of hypertension would continue to be

problematic. Reserpine has made that control possible.