Alkaloids Rauwolfia

Rauwolfia serpentina (Apocynaceae) appears throughout India, Malaysia, and Thailand as small trees that grow wild in the humid forests. Now it is also cultivated in tropical countries. In India, its roots have been used as a folk medicine for snake bite and for dysentery, and as an antipyretic, among other things. The roots contain well known alkaloids reserpine, ajmaline, ajmalicine, and serpentine. 

Reserpine, which is an important antihypertensive medicine, has also been obtained from other Rauwolfia species such as R. heterophylla, R, canescens, R. Mr-suta, R, vomitoria, R, tetraphylla, and R. verticillata. 

Ajmaline has antiarrythmic activity on the heart muscle, conceivably due to its role in the sodium-carrying system, and is used clinically as a therapeutic agent in the treatment of cardiac arrythmia. Ajmaline is also used as an antihypertensive and a tranquilizer. 

Strictosidine is incorporated into both ajmaline and ajmalicine (114). Biogenetic aromatization of ring C of ajmalicine gives rise to serpentine. 

Yohimbine, which is described in Sect. 5.2.2.6.S on Yohimbe alkaloids, has also been isolated from the roots of Rauwolfia serpentina (67). 

Layer S = Silica gel G Ai = alumina G Ag = alumina C = cellulose powder. 

Ikram and Bakhsh [94] have separated five of the best known alkaloids from Rauwolfia serpentina on a loose alumina layer. Amongst older work, that of Waldi and co-workers [257], Teichert et al. [241] and ScHLEMMER and Link [203] are mentioned here. The last named authors have also worked out a method for quantitative determination of reserpine and other Rauwolfia alkaloids in this, the spot, detectable 

Ullmann and Kassalitzky [249] have established that solubilising agents such as, polyoxyethylene sorbitol monolaurate (Tween 20) have no deleterious effect on TLC on silica gel G layers, impregnated with formamide when developing with n-heptane-methyl ethyl ketone (70 + 35) in the dark. Following this preliminary work, they determined the reserpine and rescinamine contents in pharmaceutical preparations. 

TLC of Eauwolfia alkaloids, carried out under various conditions and with various techniques, is treated in the following articles also [12, 124, 138, 195-197]. 

The articles of Farnsworth et al. [51, 53, 54] and of Svoboda [235] may be named amongst the older work using TLC. MoKBri et al. [133 to 136] and TrojInek and co-workers [141, 142, 243] have also engaged in such work. Neuss et al. [40] have carried out a notable investigation on the TLC of these alkaloids they employed silica gel 6 and alumina layers, testing 11 solvents, of which five proved satisfactory. The colour reaction with cerium(IV)-sulphate (Rgt. No. 34) was quoted for all the alkaloids. In two-dimensional TLC on an alumina layer, pure chloroform (first dimension) and chloroform-ethyl acetate (50 + 50) (second dimension) were used for development. 

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Raymond-Hamet has given much attention to the action of the Rauwolfia alkaloids. Using Siddiqui s ajrhalinine, he found that it provokes hypotension accompanied by renal dilatation and exerts a true sympathi-colytic action. 1 Ajmaline and serpentine also induce hypotension and a decrease in intestinal action serpentinine diminishes the renal constrictive action of adrenaline, but does not alter its hypertensive effects. ... 

Radioisotopes, half-lives 49 Raffinose 158, 181 -184, 203, 204, 331 Rare earths cations 144 Ratanhia phenols 288 Rauwolfia alkaloids 314 Reaction chromatography 56 IT Reagents 144 IT... 

Most DA (up to 75%) is stored in vesicles like NA. This can be disrupted by the rauwolfia alkaloid, reserpine and by drugs like tetrabenazine. It should be emphasised that these drugs deplete the neurons of amines by stopping their incorporation into... 

Reserpine and Related Alkaloids. Rauwolfia alkaloid reserpine (109) and a... 

The Rauwolfia alkaloid reserpine, due to its strong central component of activity, is excluded from this review, even though it has the peripheral effect of releasing norepinephrine from storage sites where it can be metabolized by monoamine oxidase. This results in neurotransmitter depletion and it appears that good blood pressure control would be achieved by a drug which has this peripheral mechanism but lacks the central component. The Mead-Johnson compound MJ-10459-2 (LXI) shows activity in... 

Coincidental with the above developments, biomedical scientists in pharmaceutical companies were actively pursuing purified extracts and pure compounds derived from plants and animal sources (e.g., digitalis, rauwolfia alkaloids, and animal hormones) as human medicaments. Analogs and derivatives of these purified substances were also investigated... 

Rauwolfia derivatives became available in the 1950s in western medicine for the treatment of hypertension. The antihypertensive effects of rauwolfia alkaloids occur from their depletion of monoamines in adrenal chromaffin cells and sympathetic ganglia, and perhaps central neurons as well (Oates 1996). 

The primary limiting effect of reserpine is depression. Depletion of central monoamines is believed to be the mechanism for this effect (Heninger et al. 1996 Charney 1998). The depression may occur in a gradual and insidious manner, and the causal association between the drug and depression may be missed (Oates 1996). Rauwolfia alkaloids are contraindicated in anyone with a history of depression, and careful vigilance is required to ensure that they do not induce depression in otherwise normal individuals. Additional side effects are sedation and difficulty with concentration and performing complex mental tasks. 

Drugs that may affect nasal decongestants include beta blockers, furazolidone, guanethidine, methyidopa, MAO inhibitors, rauwolfia alkaloids, tricyclic antidepressants, urinary acidifiers, and urinary alkalinizers. 

Additive - the drugs have the same biochemical mechanism and will react with the target cells as long as receptor sites are available. Examples are the cyclooxygenase inhibitors (prostaglandin synthesis inhibitors) aspirin and acetaminophen (Tylenol ), antihypertensives propanolol and the rauwolfia alkaloids. 

Reports have recently been published of protonation at C-7 (a prerequisite for Mechanism 1) under strongly acidic conditions [16,17]. While investigating the protonation site of Rauwolfia alkaloids, Balon and co-workers [16] showed through l3C NMR studies that protonation takes place at C-7 in 18M H2S04. Experiments by Royer et al. [17] indicated that reserpine (1) and isoreserpine (2) are transformed into the corresponding 2,7-dihydro compounds (14) (55%) and (15) (87%) by NaBH3CN in TFA at room temperature, Scheme (6). This is only possible through protonation at C-7. Further evidence was provided by deuterium incorporation at C-7 when TFA-d was used. 

The rauwolfia alkaloids are now hardly ever prescribed in the UK, either as antihypertensives or as tranquillizers. Over a period of a few years, they have been rapidly superseded by synthetic alternatives. Reserpine has also been suggested to play a role in the promotion of breast cancers. Both ajmalicine (= raubasine) (Figure 6.76) and ajmaline (Figure 6.82) are used clinically in Europe, though not in the UK. Ajmalicine is employed as an antihypertensive, whilst ajmaline is of value in the treatment of cardiac arrhythmias. Ajmalicine is also extracted commercially from Catharanthus roseus (see page 357). 

Rauwolfia serpentina Benth, which derives its name from Leonhart Rauwolf, a 16th century botanist, and its serpentine root (Figure 56.1), has long been used in India for a variety of ailments. The discovery of its tranquilizing action, particularly in lowering the blood pressure, led to its introduction into Western medicine. The Rauwolfia alkaloids are derived from a family of tropical and semitropical plants related to oleander and periwinkle. They vary from small shrubs to tall trees. The important species from which the alkaloids are derived include Rauwolfia serpentina (Ophioxylon serpentinum or Indian snakeroot), R. micrantha, R. vomitoria, and R. hirsuta (Canescens heterophylla). 

Similar to serotonin, the Rauwolfia alkaloids potentiate the action of barbiturates and alcohol. This potentiating action is mediated through serotonin. The alkaloids also exert an antiveratrinic and antiarrhythmic action on the isolated heart. 

Although the Rauwolfia alkaloids show a low degree of acute toxicity, their continued use may be accompanied by serious side effects. One of the most troublesome symptoms observed in the therapeutic use of Rauwolfia alkaloids is nasal congestion and stuffiness, which may be so severe as to necessitate discontinuing of therapy. Increased motility of the bowel, diarrhea, and increased gastric secretion resulting from its action on the autonomic nervous system are frequently observed. Skin eruptions, epistaxis, and peptic ulceration are rare complications. 

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