(1999; 295 pages)
Radix Rauwolfiae is the dried root of Rauvolfia serpentina (L.) Benth. ex Kurz (Apocynaceae) (1–4).
Ophioxylon obversum Miq., O. sautiferum Salisb., O. serpentinum L., Rauvolfia obversa (Miq.) Baill., R. trifoliata (Gaertn.) Baill. (3–5).
Selected vernacular names
Most commonly called "rauwolfia". Acawerya, aika-wairey, akar-tikos, arsol, bhudra, bongmaiza, chandmaruwa, chandra, chandrika, chotachand, chotachard, chundrika, chundrooshoora, churmuhuntree, chuvannayilpuri, covanamilpori, covannamipori, dhanbarua, dhannerna, dogrikme, eiya-kunda, ekaweriya, garudpathal, hadki, harkai, harkaya, ichneumon plant, Indian snakeroot, indojaboku, karai, karavi, karuvee, makeshwar chadrika, makeshwar churna, matavi-aloos, nogliever, nundunee, pagla-ka-dawa, palalganni, patalaagandhi, poelé pandak, poeleh pandak, pushoomehnunkarika, ra-yom, radix mungo, radix mustelae, raiz de mongo alba, rametul, ratekaweriya, rayom noi, rauvolfia, rauwalfia, rauwolfia, Rauwolfiawurzel, sanochado, sapasan, sarpagandha, sarpgandha, serpentina, sjouanna-amelpodi, snakeroot, sung, suvapaval-amepodi, talona, vasoopooshpa, vasura (5–8).
Small, erect, glabrous shrub, 30–60 cm high. Leaves whorled, 7.5–17.5 cm long, lanceolate or oblanceolate, acute or acuminate, tapering gradually into the petiole, thin. Flowers white or pinkish; peduncles 5.0–7.5 cm long; pedicels and calyx red. Calyx lobes 2.5 mm long, lanceolate. Corolla about 1–1.3cm long; tube slender; inflated slightly above middle; lobes much shorter than tube, obtuse. Drupes about 6 mm (diameter), single or didymous and more or less connate, purplish black when ripe (1).
Plant material of interest: root
The root occurs as segments 5–15cm in length and 3–20mm in diameter, subcylindrical to tapering, tortuous or curved, rarely branched, occasionally bearing twisted rootlets, which are larger, more abundant, and more rigid and woody on the thicker parts of the roots. Externally light brown to greyish yellow to greyish brown, dull, rough or slightly wrinkled longitudinally, yet smooth to the touch, occasionally showing rootlet scars on the larger pieces, with some exfoliation of the bark in small areas that reveals the paler wood beneath. Bark separates easily from the wood on scraping. Fracture short but irregular, the longer pieces readily breaking with a snap, slightly fibrous marginally. The freshly fractured surfaces show a rather thin layer of greyish yellow bark, and the pale yellowish white wood constitutes about 80% of the radius. The smooth transverse surface of larger pieces shows a finely radiate stele with three or more clearly marked growth rings; a small knob-like protuberance is frequently noticeable in the centre. The wood is hard and of relatively low density (1).
Root odour is indistinct, earthy, reminiscent of stored white potatoes, and the taste is bitter (1).
A transverse section of the root shows externally 2–8 alternating strata of cork cells, the strata with larger cells alternating with strata made up of markedly smaller cells. Each stratum composed of smaller cells includes 3–5 tangentially arranged cell layers. In cross-sectional view, the largest cells of the larger cell group measure 40–90µm radially and up to 75µm tangentially, while the cells of the smaller group measure 5–20µm radially and up to 75µm tangentially. The walls are thin and suberized. The secondary cortex consists of several rows of tangentially elongated to isodiametric parenchyma cells, most densely filled with starch grains; others (short latex cells) occur singly or in short series and contain brown resin masses. The secondary phloem is relatively narrow and is made up of phloem parenchyma (bearing starch grains and less commonly tabular to angular calcium oxalate crystals up to 20µm in length; also, occasionally, with some brown resin masses in outer cells and phloem rays) interlaid with scattered sieve tissue and traversed by phloem rays 2–4 cells in width. Sclerenchyma cells are absent in root (a distinction from other Rauvolfia species). Cambium is indistinct, narrow, dark, and wavering. The secondary xylem represents the large bulk of the root and shows one or more prominent annual rings with a dense core of wood about 500µm across at the centre. The xylem is composed of many wood wedges separated by xylem rays, and on closer examination reveals vessels in interrupted radial rows, much xylem paren- chyma, many large-celled xylem rays, few wood fibres, and tracheids, all with lignified walls. The xylem fibres occur in both tangential and radial rows. The xylem rays are 1–12, occasionally up to 16 cells in width (1, 3).
Powdered plant material
Powdered Radix Rauwolfiae is brownish to reddish grey. Numerous starch grains (simple, 2- to 3-compound, occasionally 4-compound) present; simple grains spheroid, ovate, plano- to angular-convex, or irregular; hilum simple, Yshaped, stellate, or irregularly cleft; unaltered grains 6–34µm in diameter; altered grains up to about 50µm; large unaltered grains clearly show polarization cross; calcium oxalate prisms and cluster crystals scattered, about 10–15µm in size; brown resin masses and yellowish granular secretion masses occur occasionally; isolated cork cells elongated, up to 90µm in length; phelloderm and phloem parenchyma cells similar in appearance; vessels subcylindrical, up to 360µm in length and about 20–57µm in diameter, the vessel end walls oblique to transverse, generally with openings in the end walls, some vessels showing tyloses; tracheids pitted, with moderately thick, tapering, beaded walls, with relatively broad lumina, polygonal in cross-section; xylem parenchyma cells with moderately thick walls with simple circular pits, cells polygonal in crosssection, bearing much starch, sometimes with brown resin masses; xylem fibres with thick heavily lignified walls showing small transverse and oblique linear pits and pointed simple to bifurcate ends, measuring about 200–750µm in length. No phloem fibres or sclereids are present in root (colourless non-lignified pericycle or primary phloem fibres, single or in small groups, may be present from rhizome or stem tissues) (1).
The plant is found growing wild in the sub-Himalayan tracts in India and is also found in Indonesia, Myanmar, and Thailand (3).
Overcollection of Radix Rauwolfiae in India has significantly diminished supply and since 1997 there has been an embargo on export of this drug from India. Reserpine is currently either extracted from the roots of Rauvolfia vomitoria of African origin or produced by total synthesis.
General identity tests
Macroscopic and microscopic examinations (1–3) and thin-layer chromatographic analysis for the presence of characteristic indole alkaloids (2, 3).
The test for Salmonella spp. in Radix Rauwolfiae products should be negative. The maximum acceptable limits of other microorganisms are as follows (9–11). For preparation of decoction: aerobic bacteria-not more than 107/g; moulds and yeast-not more than 104/g; Escherichia coli-not more than 102/g; other enterobacteria -not more than 104/g. Preparations for internal use: aerobic bacteria- not more than 105/g; moulds and yeast-not more than 103/g; Escherichia coli-not more than 101/g; other enterobacteria-not more than 103/g.
Foreign organic matter
Not more than 2.0% of stems, and not more than 3.0% of other foreign organic matter (1).
Not more than 10% (2).
Not more than 2.0% (1, 2).
Not more than 12% (2).
To be established in accordance with national requirements. Normally, the maximum residue limit of aldrin and dieldrin in Radix Rauwolfiae is not more than 0.05 mg/kg (11). For other pesticides, see WHO guidelines on quality control methods for medicinal plants (9) and guidelines for predicting dietary intake of pesticide residues (12).
Recommended lead and cadmium levels are no more than 10 and 0.3mg/kg, respectively, in the final dosage form of the plant material (9).
For analysis of strontium-90, iodine-131, caesium-134, caesium-137, and plutonium-239, see WHO guidelines on quality control methods for medicinal plants (9).
Other purity tests
Chemical, alcohol-soluble extractive and water-soluble extractive tests to be established in accordance with national requirements.
Contains not less than 1% total alkaloids (2, 3); and a minimum of 0.1% alkaloids of the reserpine–rescinnamine group (3).
Thin-layer chromatography to detect the presence of the reserpine– rescinnamine group of alkaloids (2, 3, 13). Quantitative analysis of total and reserpine–rescinnamine group of alkaloids can be performed by spectrophotometric analysis (2, 3) or by high-performance liquid chromatography (14, 15).
Major chemical constituents
Radix Rauwolfiae contains more than 60 indole alkaloids; the principal hypotensive alkaloids are identified as reserpine and rescinnamine (1, 6).
Crude drug and powder. Package in well-closed containers and store at 15– 25°C (9) in a dry place, secure against insect attack (1).
Uses supported by clinical data
The principal use today is in the treatment of mild essential hypertension (16– 22). Treatment is usually administered in combination with a diuretic agent to support the drug's antihypertensive activity, and to prevent fluid retention which may develop if Radix Rauwolfiae is given alone (18).
Uses described in pharmacopoeias and in traditional systems of medicine
As a tranquillizer for nervous and mental disorders (4, 5).
Uses described in folk medicine, not supported by experimental or clinical data
As a tonic in states of asthenia, a cardiotonic and antipyretic; against snake and insect bites; and for constipation, liver diseases, flatulence, insomnia, and rheumatism (8).
It is well accepted that the pharmacological effects of Radix Rauwolfiae are due to its alkaloids, especially the reserpine–rescinnamine group. The experimental pharmacology of reserpine and related compounds has been well documented (5, 16–18, 23). Powdered Radix Rauwolfiae, as well as various forms of extracts (ethanolic, dried), has been reported to lower the blood pressure of experimental animals (dogs or cats) by various routes of administration (5).
Radix Rauwolfiae and its major alkaloids probably lower high blood pressure by depleting tissue stores of catecholamines (epinephrine and norepinephrine) from peripheral sites. By contrast, their sedative and tranquillizing properties are thought to be related to depletion of catecholamines and serotonin (5- hydroxytryptamine) from the brain. Following absorption from the gastrointestinal tract the active alkaloids concentrate in tissues with high lipid content. They pass the blood–brain barrier and the placenta. Radix Rauwolfiae products are characterized by slow onset of action and sustained effect. Both the cardiovascular and central nervous system effects may persist following withdrawal of the drug. The active alkaloids are metabolized in the liver to inactive compounds that are excreted primarily in the urine. Unchanged alkaloids are excreted primarily in the faeces (16).
Radix Rauwolfiae products are contraindicated in patients who have previously demonstrated hypersensitivity to the plant or its alkaloids. They are also contraindicated in patients with a history of mental depression (especially those with suicidal tendencies) during or shortly after therapy with monoamine oxidase inhibitors; active peptic ulcer, sinus node disorders, ulcerative colitis; epilepsy; or decreased renal function; and in patients receiving electroconvulsive therapy (16, 18).
Radix Rauwolfiae products may cause mental depression (24). Recognition of depression may be difficult because this condition may often be disguised by somatic complaints (masked depression). The products should be discontinued at first signs of depression such as despondency, early morning insomnia, loss of appetite, impotence, or self-deprecation. Drug-induced depression may persist for several months after drug withdrawal and may be severe enough to result in suicide. Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma. The use of Radix Rauwolfiae products may impair alertness and make it inadvisable to drive or operate heavy machinery (16, 18).
Because Radix Rauwolfiae preparations increase gastrointestinal motility and secretion, they should be used cautiously in persons with a history of peptic ulcer, ulcerative colitis, or gallstones where biliary colic may be precipitated. Persons on high doses should be observed carefully at regular intervals to detect possible reactivation of peptic ulcer (16).
Caution should be exercised when treating hypertensive patients with renal insufficiency since they adjust poorly to lowered blood-pressure levels (16).
When administered concurrently, the following drugs may interact with or potentiate Radix Rauwolfiae and its alkaloids (16, 18): alcohol or other central nervous system depressants, other antihypertensives or diuretics, digitalis glycosides or quinidine, levodopa, levomepromazine, monoamine oxidase inhibitors, sympathomimetics (direct-acting) and tricyclic antidepressants.
Concomitant use of Radix Rauwolfiae products and anaesthetics may provoke a fall in blood pressure (4, 17, 25) and add to the β-adrenoceptor–blocking activity of propranolol (25).
Drug and laboratory test interactions
Chronic administration of Radix Rauwolfiae preparations may increase serum prolactin levels and decrease excretion of urinary catecholamines and vanilmandelic acid. Therefore, any diagnostic tests performed for these determinations should be interpreted with caution (16).
Radix Rauwolfiae preparations slightly decrease absorbance readings obtained on urinary steroid colorimetric determinations (e.g. modified Glenn– Nelson technique or Holtorff Koch modification of Zimmermann reaction), and thus false low results may be reported (16).
Preoperative withdrawal of Radix Rauwolfiae products does not necessarily ensure circulatory stability during the procedure, and the anaesthetist must be informed of the patient's drug history (4, 17, 25).
Caution is indicated in elderly patients and also in those suffering from coronary and cerebral arteriosclerosis. Administration of products including Radix Rauwolfiae preparations at doses that might precipitate a sharp decrease in blood pressure should be avoided (17).
Carcinogenesis, mutagenesis, impairment of fertility
Animal carcinogenicity studies using reserpine at doses 50 times as high as the average human dose have been conducted with rats and mice. Carcinogenic effects associated with the administration of reserpine include an increased incidence of adrenal medullary phaeochromocytomas in male rats, unidentified carcinomas of the seminal vesicles in male mice, and mammary cancer in female mice; carcinogenic effects were not seen in female rats (14, 23, 26). Bacteriological studies to determine mutagenicity using reserpine showed negative results (16). The extent of risk to humans is uncertain (16, 26–28).
Pregnancy: teratogenic effects
Reserpine, the major active alkaloid in Radix Rauwolfiae, administered parenterally has been shown to be teratogenic in rats at doses up to 2mg/kg and to have an embryocidal effect in guinea-pigs at 0.5 mg daily (27). There are no adequate and well-controlled studies in pregnant women.
Pregnancy: non-teratogenic effects
Increased respiratory secretions, nasal congestion, cyanosis, hypothermia, and anorexia have occurred in neonates of mothers treated with Radix Rauwolfiae (16, 28, 29). Therefore, the use of Radix Rauwolfiae is not recommended during pregnancy.
Rauwolfia alkaloids are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, use of Radix Rauwolfiae during lactation is not recommended.
Safety and effectiveness in children have not been established (16).
The following adverse reactions have been observed, but there are insufficient data to support an estimate of their frequency. The reactions are usually reversible and disappear when the Radix Rauwolfiae preparations are discontinued (16, 18).
Cardiovascular system: bradycardia, arrhythmias, particularly when used concurrently with digitalis or quinidine, angina-like symptoms. Water retention with oedema in persons with hypertensive vascular disease may occur rarely, but the condition generally clears with cessation of therapy, or the administration of a diuretic agent. Vasodilation produced by rauwolfia alkaloids may result in nasal congestion, flushing, a feeling of warmth, and conjunctival congestion.
Central nervous system: sensitization of the central nervous system manifested by optic atrophy, glaucoma, uveitis, deafness, and dull sensorium. Other reactions include depression, paradoxical anxiety, nightmares, nervousness, headache, dizziness, drowsiness. Large doses have produced parkinsonian syndrome, other extrapyramidal reactions, and convulsions.
Gastrointestinal system: hypersecretion and increased intestinal motility, diarrhoea, vomiting, nausea, anorexia, and dryness of mouth. Gastrointestinal bleeding has occurred in isolated cases.
Respiratory system: dyspnoea, epistaxis, nasal congestion.
Hypersensitivity: purpura, pruritus, rash.
Other: dysuria, muscular aches, weight gain, breast engorgement, pseudolactation, impotence or decreased libido, gynaecomastia.
Powder, 200 mg daily in divided doses for 1–3 weeks; maintenance 50–300mg daily (1). Doses of other preparations should be calculated accordingly. Doses of Radix Rauwolfiae should be based on the recommended dosage of rauwolfia alkaloids, which must be adjusted according to the patient's requirements and tolerance in small increments at intervals of at least 10 days. Debilitated and geriatric patients may require lower dosages of rauwolfia alkaloids than do other adults (18). Rauwolfia alkaloids may be administered orally in a single daily dose or divided into two daily doses (18).
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