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From the Townsend Letter
May 2015

Rauwolfia in the Treatment of Hypertension
by Douglas Lobay, Bsc, ND
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Rauwolfia serpentina is a very safe and effective natural treatment for hypertension. This article first reviews the botany, history, and folk use of this plant. It talks about cardiologist Rustom Jal Vakil and the introduction of rauwolfia in modern medicine. It then discusses the chemical composition, pharmacology, and mechanism of action of reserpine and rauwolfia. It looks at the medical use of this plant with emphasis on its role in treating hypertension. It then critically looks at adverse side effects, toxicology, and carcinogenicity. It dispels the association between this plant and breast cancer. It further discusses the importance and screening of patients that minimizes the occurrence of depression. It concludes with a discussion of my personal experience of prescribing rauwolfia in the treatment of hypertension and recommendations for dosage.

Rauwolfia serpentina is perennial shrub from the Apocynaceae, or dogbane, family. It is native to tropical and subtropical regions of Asia, including India, Burma, Bangladesh, Sri Lanka, and Malaysia. It grows in moist, warm forests to a height between 60 and 90 centimeters. It has dark green leaves that grow up to 10 centimeters long and up to 5 centimeters wide in whorls of 3 to 5 leaves. It has numerous shiny purple or black fruit that are about 0.5 centimeters in diameter. The plant has a strong, snakelike taproot that grows up to 50 centimeters in length and 2.5 centimeters in diameter.1,2

History and Folk Use
Rauwolfia serpentina has been used in Indian folk medicine for thousands of years to treat a wide variety of maladies, including snake and insect bites, febrile conditions, malaria, abdominal pain, and dysentery. It was also used as a uterine stimulant, febrifuge, and cure for insanity. The plant is named after the 16th-century German physician Leonard Rauwolf, who studied it while he was traveling in India. It is reported that Indian political leader Mahatma Gandhi drank a tea made from this plant to help him relax and sleep after a long, busy day.

Rustom Jal Vakil
Rustom Jal Vakil is the British-trained medical physician who first popularized the use of rauwolfia for the treatment of hypertension.3-5 He published a watershed paper about the antihypertensive properties of Rauwolfia serpentina in the British Medical Journal in 1949. He presented detailed results of treating high blood pressure with the root of Rauwolfia serpentina in 50 patients. At this time, there was no effective pharmacological treatment of hypertension available anywhere in the world. This seminal paper stimulated widespread scientific research and pharmacologic interest in rauwolfia. By the end of 1949, 60,000 (90%) of Indian physicians were using rauwolfia in the treatment of hypertension. At its peak, India used 650 tonnes of the dried root per year, and worldwide usage was 20,000 tonnes per year to over 17 countries. One manufacturer claimed to have sold 94 million tablets of the dried root in 1954 alone.6

Chemical Composition
The most important group of phytochemicals found in this plant are indole alkaloids. Over 50 different indole and indoline alkaloids have been isolated in this plant. The alkaloids are derived from amino acid tryptophan into a variety of heterocyclic ring structures. The most pharmacologically active indole alkaloids are ajmaline, deserpidine, rescinnamine, reserpine, serpentine, and yohimbine. All parts of the plant contain alkaloids, but the root has the highest amount. The exact concentration of alkaloids in the root varies from 0.7% to 3.3% of the dried weight of the root. Another more conservative estimate suggests that the total alkaloids varies from 0.8% to 1.3% of the dried weight of the plant. Other species in the same genus, including R. caffra, R. canescens, R. heterophylla, and R. vomitoria, have been found to be adulterants to Rauwolfia serpentina. They do contain variable amounts of indole alkaloids and may be used as a suitable alternative.7-9

Reserpine is the most widely studied indole alkaloid found in this plant. In an effort by the scientific community to isolate a single constituent of rauwolfia, reserpine was believed to be the most pharmacologically active ingredient. The exact concentration of reserpine varies from 0.03 to 0.14% of the dry weight of the root of Rauwolfia serpentina. Other alkaloids believed to have medicinal action include canescine, deserpidine, recanescine, and rescinnamine. In 1952 CIBA Labs from Switzerland published the first complete report on the chemistry and pharmacology of reserpine. Also in 1952, they introduced the first isolated drug of reserpine, called Serpasil. Reserpine has a chemical formula of C33H40N209 and a molecular mass of 609 grams, and is odorless, insoluble in water, slightly soluble in alcohol, and freely soluble in acetic acid.9-11
Reserpine has an average absorption rate of 50% after oral ingestion. Absorption occurs usually 1 to 2 hours after oral consumption, although a slower rate between 2 to 4 hours has also been reported. Reserpine is widely distributed throughout the body to the brain, liver, spleen, kidneys, and adipose tissue. It is widely distributed to red blood cells and central and peripheral neurons. It has been found in breast milk and crosses the placenta. Its initial half-life has been observed to be 4 to 5 hours. Its elimination half-life has been determined to be between 45 to 168 hours in plasma. Hepatic metabolism accounts for about 62% of the degradation of reserpine, while kidney elimination accounts for less than 8%. Up to 60% of eliminated metabolites are reserpine itself.12,13

Mechanism of Action
The mechanism of action of reserpine is well researched. Reserpine binds to protein receptors on the membrane of specialized secretory vesicles found in the intracellular cytosol of presynaptic neurons. The membrane receptors are called vesicular monamine transporters, or VMAT for short. The VMATs normally bind intracellular neurotransmitters, including adrenaline, noradrenaline, dopamine, histamine, and serotonin. They facilitate the transfer of these chemicals into the vesicle. The vesicle then binds to the terminal end of the presynaptic neuron and releases these chemicals into the synapse. These chemicals pass over and bind to receptors on the postsynaptic neuron and ultimately facilitate the propagation of the nervous impulse. Reserpine binds strongly to the VMAT receptor and prevents the neurotransmitters from being incorporated into the presynaptic vesicle. It thus prevents and dampens the promulgation of the nervous signal in primarily sympathetic neurons of the brain and peripheral nervous system.14,15

Rauwolfia and Hypertension
In a clinical trial of Rauwolfia serpentina in essential hypertension, Vakil treated 50 patients with initial blood pressures greater than 160/95 millimeters. After 4 weeks of taking the medicine, systolic blood pressure dropped between 2 and 54 millimeters in the group of patients. 22 out 47 patients showed a moderate drop in systolic blood pressure from 10 to 24 millimeters. 13 out of 47 patients showed a marked drop in systolic blood pressure greater than 25 millimeters. 38 out of 47 patients showed a drop in diastolic blood pressure between 4 and 34 millimeters with an average drop of 11 millimeters. 27 patients showed a moderate drop of diastolic blood pressure between 5 and 14 millimeters, and 7 patients showed a drop greater than 15 millimeters. The hypotensive action of the drug was perceptible 2 weeks after stopping the drug in 91% of patients and in 75% of patients after 4 weeks of discontinuing the drug. No serious adverse side effects were noted.16,17
In 1952, a purified standardized isolated alkaloid extract called alseroxylon was introduced to the US. The active ingredients of the purified extract were a mixture of reserpine and rescinnamine. In this study 346 patients with hypertension were treated on an outpatient basis in public and private hospitals. Original blood pressure was greater than 150/100 millimeters on admission. During the control period patients received placebo. A consistent decrease in blood pressure readings of greater than 20 millimeters was observed in patients treated with the alseroxylon extract.18
A rauwolfia product called Serpina was given to over 100 patients for periods of 1 month to 1 year. 1 to 3 Serpina tablets per daily dose were well tolerated. Its action is slow to appear from 3 to 6 days and disappears from 7 to 21 days after stopping the drug. It did not produce any serious side effects. It appears to be more effective in young, neurotic hypertensive patients with tachycardia than in those with long-established, fixed hypertension with organic, vascular disease. 39 patients with an average blood pressure reading of 192/122 millimeters and pulse of 82 were treated with Serpina alone. The average blood pressure dropped to an average of 165/95 millimeters and a pulse of 70. In 13 out of 39 patients blood pressure was controlled to normal at less than 150/90 millimeters.19
A Cochrane Database Review was undertaken to investigate the dose-related effect of reserpine on blood pressure, heart rate, and withdrawals due to adverse effects. Medical databases included Central, Embase, and Medline. Selection criteria included only truly randomized, controlled trials comparing reserpine monotherapy with placebo or no treatment in patients with primary hypertension. Four randomized controlled trials were found to meet inclusion criteria. None of the trials reported any withdrawals due to adverse effects. The authors concluded that reserpine is effective in reducing systolic blood pressure to the same degree as other first-line antihypertensive drugs. They suggested that more randomized controlled trials are needed to assess the effects of reserpine on blood pressure and determine the dose-related safety profile before this drug could be widely recommended as a primary antihypertensive drug.20 Reserpine is also one of the few antihypertensive drugs that have been shown to produce a reduction in mortality in randomized controlled trials.21

Adverse Side Effects and Toxicology
The most common adverse side effect of reserpine is nasal congestion that occurred in 5% to 15% of patients taking rauwolfia products. Other side effects include lethargy, sedation, psychiatric depression, hypotension, nausea, vomiting, abdominal cramping, gastric ulceration, nightmares, bradycardia, anginalike symptoms, bronchospasm, skin rash, itching and withdrawal psychosis in one case, galactorrhea, breast enlargement, and sexual dysfunction.12,22 There does not appear to be an association between reserpine and cancer. Earlier studies in the late 1960s and early 1970s suggested an association between reserpine and breast cancer. A reevaluation of three original studies showed that exclusion bias played an important role in the erroneous conclusions reached.23 The incidence of depression in patients taking rauwolfia and reserpine products was studied between 1954 and 1956 in an outpatient clinic. Rauwolfia and reserpine can cause depression in susceptible patients. The authors concluded that dosage is an important factor but not the sole factor involved. They advised that before starting rauwolfia therapy, a complete medical history of mental illness and depression is recommended. They further recommended that the daily dose of reserpine is limited to less than 0.75 milligrams per day.24 No increased risk of birth defects has been shown in female humans who consumed reserpine at any time during their pregnancy. No mutagenic or genotoxic effects of reserpine have been demonstrated.12

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