23 March 2010

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.

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