The Rauwolfia Alkaloids

FIGURE 56.1 A flowering Rauwolfia serpentina plant. Note the serpentine root from which the plant obtains 

In the unanesthetized dog, reserpine selectively depresses the sympathetic centers and induces facilitation of the parasympathetic centers in the diencephalon. The latter effect accounts for the bradycardia, miosis, aggravation of bronchial asthma, renal and biliary colic, and ulcerative colitis observed in some patients receiving the drug. 

Large single doses of reserpine (1 to 5 mg/kg) in animals cause a progressive decline in the serotonin content in the intestine. After 16 h, about 90% of it disappears and the level remains low for about 48 h, after which it gradually rises to its normal level again in the course of about 7 d. Similar changes occur in the platelets. The brain is more sensitive to the effects of reserpine so that 80% of the serotonin originally present disappears within 1 hr, and the liberation of serotonin may be observed in doses as low as 0.05 mg/kg. 

It therefore appears that the main action of reserpine is to produce a biochemical change so that the cells no longer retain a high concentration of serotonin. In other words, the binding of serotonin is prevented. Thus, after the administration of 5-hydroxytryptophan (a precursor of serotonin) to rabbits pretreated with reserpine, serotonin is rapidly formed but remains in a free form. Presumably, free serotonin, before it is metabolized to 5-hydroxyindole acetic acid by amine 

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. 

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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. ... 

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... 

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... 

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. 

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). 

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. 

For the most recent review of chemistry and pharmacology of the Rauwolfia alkaloids see R. A. Lucas in Progress in Medicinal Chemistry (G. P. Ellis and G. B. West, eds.), p. 146. Butterworths, Washington and London, 1963. 

Extensive use of column chromatography has been necessary to separate the Rauwolfia alkaloids, and in this connection attention is drawn to a publication which concerned itself with the more refined technique of gradient elution chromatography (123). Paper chromatography has been used extensively for analytical, fractionation, and identification purposes (124, 15). This tool is not particularly useful for the assay of crude extracts, since certain alkaloids show up clearly whereas others cannot be resolved. More information as to specific alkaloidal composition is better obtained from more highly purified fractions. 

The arbitrary classification of Rauwolfia alkaloids (91) is simplified here, and it is slightly different from a recent arrangement (92). The Rauwolfia alkaloids can all be regarded as yohimbinoid derivatives as shown in Chart I, viz. the yohimbines (all yohimbine isomers) 18-hydroxyyohimbines (reserpine-type alkaloids) ring E heterocycles and their anhydronium analogs (ajmalicine, serpentine) ajmaline-type (which includes sarpagine) and compounds of unknown constitution. 

Reserpine. As mentioned earlier, the Rauwolfia alkaloid reserpine is noted for its ability to deplete aromatic biogenic amines in nervous tissue of mammals and insects. One of the more remarkable effects of reserpine in humans is to render individuals indifferent to environmental stimuli. Reserpine appears to have a similar effect on insects, although information is still relatively scanty. In the cockroach, Periplaneta americana, reserpine at 50 vg/g causes strong and long-lasting depletion of the aromatic biogenic amines dopamine, octopamine, and 5-hydroxytryptamine (24). Numerous authors have noted that reserpine has tranquilizing effects on insects, e.g., the ant Formica rufa (30) and . americana (24,31). 

Another useful collection of data on alkaloids is contained in the 1979 report of Fanso-Free and colleagues, who described a study of the Rauwolfia alkaloids and related model compounds [66]. Their results are summarized in Figure 14.9. 

The Rauwolfia alkaloids, including reserpine, are now little used. They act by depleting neurotransmitter stores of catecholamines and reducing sympathetic nervous activity, but their effects are non-specific, and nervous system adverse effects (depression, drowsiness, tiredness, confusion) are prominent. There is also a troublesome incidence of diarrhea, hjrperprolactinemia, gynecomastia, and a possible withdrawal syndrome. 

Furthermore, the rauwolfia alkaloids (reserpine and others), which also began to be used at that time in psychiatry (and as antihypertensives see Chapter 10), were found to be potent depletors of brain NE and 5-HT in animals. These and additional findings over the next decade led to the (mono)amine hypothesis of mental disorders. The DA hypothesis of schizophrenia is currently the one with the most supportive evidence. 

Quinidine is the current drug of choice in the treatment of auricular arrhythmias. The other Cinchona alkaloids, the cryptopine-like compounds, sparteine and related substances, and the Rauwolfia alkaloids are primarily of interest in these arrhythmias. Quinidine or digitalis occasionally prove of therapeutic merit in preventing the ventricular arrhythmias. 

It is, however, interesting to observe that a good number of sympathomimetics in fact do not really mimic the actions of noradrenaline or adrenaline at the effector receptor. They merely induce the release of noradrenaline from the sympathetic postganglionic adrenergic nerves. Such sympathomimetics which exert their action indirectly are comparatively less effective in patients treated with noradrenaline depleting drugs, for instance, the rauwolfia alkaloids, or other adrenergic neuron blockers. 

Reserpine and other rauwolfia alkaloids deplete the brain of monoamines, including dopamine, thereby reducing their effects. This can lead to parkinsonian-like symptoms, and may oppose the actions of administered levodopa. There are not only sound pharmacological reasons for believing this to be an interaetion of elinieal importance, but a reduction in the antiparkinsonian activity of levodopa has been observed in patients given reserpine. The rauwolfia alkaloids should be avoided in patients with Parkinson s disease, whether or not they are taking levodopa. 

Not understood. A possible explanation is that because the rauwolfia alkaloids deplete the neurotransmitter from the sympathetic nerve supply to the heart, the parasympathetic vagal supply (i.e. heart slowing) has full rein. Digitalis also causes bradycardia which in the presence of the rauwolfia becomes excessive. In this situation the rate could become so slow that ectopic foci, which would normally be swamped by a faster, more normal beat, begin to fire, leading to the development of arrhythmias. Syncope could also result from the combination of bradycardia and the hypotensive effects of reserpine. 

Central excitation and possibly hypertension can occur if rauwolfia alkaloids are given to patients already taking an MAOI, but is less likely if the rauwolfia alkaloid is given first. Theoretically additive blood-pressure lowering effects are also a possibility. The use of drugs that have the potential to cause depression, such as the rauwolfia alkaloids or tetrabenazine, is generally contraindicated in patients needing treatment for depression. 

In the class of the butyrophenones, which has yielded a number of interesting psycho-active agents [119] - chiefly as a result of research done in the Janssen laboratories-two hypotensive compounds are also worth mentioning. They are the co-piperidino-butyrophenone (XII)-which, combined with the Rauwolfia alkaloid rescinnamine and the benzyl-piperazine trimetazidine, is marketed... 

May enhance hypertensive effects of buspirone, levodopa, methylphenidate, and the rauwolfia alkaloids. 

Members of the yohimbine alkaloid family possess a characteristic penta-cyclic indole skeleton 1. Representative compounds in this family include the Rauwolfia alkaloids, such as reserpine (2) and deserpidine (3), and the yohimbines (4-9). These compounds exhibit a wide range of medicinal properties (1,2). Reserpine, for example, has been used extensively in the treatment... 

A number of other interesting syntheses which do not employ the synthetic designs discussed above have been developed. A major challenge in all of these syntheses and, in particular those targeted at the Rauwolfia alkaloids, is the generation of the proper stereochemistry at C(3). Several studies (75-80) have been conducted to understand and control this critical issue. 

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