So far, a total of 91 alkaloids were separated from Rauwolfia, and identification of the chemical structures was obtained. Among them, reserpine, ajmaline, and yohimbine have been researched plentifully and thoroughly. Ajmaline, mainly as the class Ia anti-arrhythmic drug, could cause severe hypotension or worsen arrhythmia, so currently ajmaline is almost not applicable in clinic. Many compounds derived from Rauwolfia plants have significant and distinct pharmacological effects, just like reserpine as an antihypertensive drug, ajmaline as an anti-arrhythmic drug, and yohimbine as an adrenergic α2 receptor antagonist. In the foreseeable future, a systematic research on the Rauwolfia and its active ingredients will take on an important significance.
KeywordsAjmaline Anti-arrhythmic Rauwolfia
Molecular formula, C20H26N2O2; MW, 326.43; CAS, 4360-12-7
Appearance: white or yellowish crystal powder. Melting point: its anhydride is 205–207 °C. Optical rotation: +144° (chloroform). Solubility: well soluble in organic solvents, such as methanol, ethanol, etc., and slightly soluble in water. Storage temperature: 2–8 °C.
Dosage Form and Indications
Ajmaline is recorded in the Japanese Pharmacopoeia (17th ed.).
Dosage form: tablet (50 mg), injection (50 mg).
Ajmaline has anti-arrhythmic effect for treating atrial premature contraction (APC) or ventricular premature contraction (VPC), paroxysmal supraventricular or ventricular tachycardia, and paroxysmal atrial fibrillation.
Rauwolfia (Luo Fu Mu) is derived from the plants Rauvolfia verticillata (Lour.) Baill. and R. yunnanensis Tsiang, and the root is usually used as its medicinal part. R. verticillata (Lour.) Baill. var. hainanensis Tsiang and R. vomitoria Afzel. ex Spreng have been also used as traditional Chinese herb.
Rauwolfia is one of the important traditional herbs in southern China. Its scope of treatment includes cold, fever, sore throat, headache, and dizziness caused by hypertension, abdominal pain and diarrhea, scabies, and so on. Rauwolfia is also used to treat insomniac dizziness, bruises, sprains, and venomous snake bites in folk.
In the “Flora of China,” 135 species of Rauwolfia were recorded, mostly distributed in the tropics and subtropics, a few in the temperate regions. There are nine species, four varieties, and three cultivated species in China.
History of R&D
Since 1930s, abundant studies have been focused on the Rauwolfia plants. So far, a total of 91 alkaloids were separated from Rauwolfia, and the identification of the chemical structures was obtained, including 2 non-indole alkaloids (thebaine and papaverine) and 89 indole alkaloids . In accordance with the basic framework, indole alkaloids can be divided into seven classes, such as the ajmaline class, the reserpine class, the yohimbine class, the dehydro-rauwolfine class, the serpentine class, the tetrahydroalstonine class, etc. Among them, reserpine (see No. 95 Reserpine), ajmaline, and yohimbine have been researched plentifully and thoroughly, while studies on other alkaloids are still in progress.
In the early studies of indole alkaloids, three key compounds have been researched and developed for treating cardiovascular diseases.
One of the three key compounds is reserpine. The studies show that reserpine can decrease sympathetic function, blood pressure, and heart rate by reducing the storage of catecholamine and 5-hydroxytryptamine in brain and other tissues, inhibiting the uptake and the synthesis of norepinephrine, a neurotransmitter of sympathetic nerve endings, and promoting the release of norepinephrine. Therefore, reserpine has been developed into a classic drug for hypertension treatment . Although reserpine can be independently used as antihypertensive drug, it is commonly used in combination with diuretics for the treatment of mild to moderate hypertension, because of its weak hypotensive effect and its side effects such as sedation.
The second key compound is ajmaline. Mainly as the class Ia anti-arrhythmic drug, ajmaline also has other pharmacological effects including antivirus, antihypertension, and anti-vasodilation on the coronary artery. The dosage form of ajmaline has been developed into injections, tablets, and other formulations. In the early clinical application, cardiopulmonary resuscitation, temporary pacing, and ajmaline were used together to restore the stability of hemodynamics and terminate arrhythmia. The certain studies have found that ajmaline could cause severe hypotension or worsen arrhythmia, further causing serious ventricular fibrillation or fatal sudden cardiac arrest in patients with the organic heart disease, so currently ajmaline is almost not applicable in clinic.
The last but not the least compound is yohimbine. It is not only a plant-origin drug for treating erectile dysfunction but also a good agent for selective antagonism of epinephrine α2 receptor .
Rauwolfia as the major natural sources of anti-arrhythmic drug (ajmaline) and antihypertensive drug (reserpine) has been a research focus worldwide. Furthermore, the pharmacological studies on Rauwolfia are no longer limited to the anti-arrhythmia and antihypertensive effects. A large number of reports on the anti-inflammatory, antibacterial, antiviral, and antitumor effects, inhibition of central nervous system, and reduction in blood glucose and blood lipid have emerged in recent years.
R. serpentina (She Geng Mu) is the first anti-arrhythmic herbal medicine in the psychiatry history. Ajmaline has a potent anti-arrhythmic effect for treating atrial and ventricular arrhythmias and also has a good effect on the treatment of Wolff-Parkinson-White syndrome. Ajmaline plays a main role in decreasing the permeability of sodium ion on the myocardial cell membrane by moderately inhibiting the sodium channel. The electrophysiological effect of ajmaline is similar to that of quinidine, but it is stronger than quinidine.
In addition, ajmaline has a mild anti-sympathetic effect. It affects sympathetic nerve endings to release more sodium, dilate the coronary artery, relax vascular smooth muscle, and then decrease blood pressure. Therefore, it is suitable for clinical treatment of atrial and ventricular premature beats, pre-excitation syndrome with supraventricular tachycardia, but not suitable for the treatment of paroxysmal atrial fibrillation and sinus tachycardia.
Ajmaline and papaverine from Rauvolfia plants have a certain degree of inhibition on proliferation of human nasopharyngeal carcinoma KB cells in a concentration-dependent manner. Meanwhile, ajmaline, rescinnamine, and papaverine also have a certain degree of inhibition on the proliferation of human leukemia HL-60 cells in a concentration-dependent manner. It indicates ajmaline maybe has the potential effects on prevention and treatment of leukemia .
Oral absorption of ajmaline is rapid, but with a low bioavailability. It usually takes about 20 min to show efficacy after oral administration and 40–60 min to reach the maximum efficacy. Ajmaline is metabolized mainly in the liver, which is mostly excreted through feces, and a small amount is excreted in the urine.
Ajmaline would be increased in blood concentration and prolonged T1/2 when administration is combined with quinidine.
Ajmaline could slow down the ventricular rate obviously which could cooperate with digitalis to control atrial fibrillation. So both of them have a synergistic effect on atrioventricular conduction .
Ajmaline has the anti-arrhythmic effects for the treatment of atrial or ventricular extrasystoles, paroxysmal supraventricular or ventricular tachycardia, and paroxysmal atrial fibrillation. The lethal dose for human ranged from 100 to 500 mg/kg.
For the treatment of paroxysmal atrial fibrillation, the patient should be under ECG monitoring. When ajmaline is administrated at 50 mg/10 mL at the speed of 1 mL/min by intravenous injection, the patient’s blood pressure should be monitored before and during the drug administration and then continually measured every 15 min after administration. If there is no effect, it can be repeated after 1 h. Furthermore, the patient should stay in hospital for at least 6 h. Once the atrial fibrillation disappears, the treatment should be discontinued.
For safety reasons, patients should be hospitalized for medication and given ECG monitoring.
Ajmaline should be stored at room temperature away from moisture, heat, and light.
Ajmaline could inhibit cardiac conduction, further causing heart block and decreasing myocardial contractility at high doses. It might also cause arrhythmias, coma, and even death. Arrhythmia could accidentally occur even at the normal venous dose.
The common side effect events were reported, including vomiting, diarrhea, headache, blurred vision, nystagmus, fatigue, tinnitus, confusion, fall of blood pressure, respiratory depression, lack of granulocytes, hepatotoxicity, etc.
Rauwolfia, the traditional Chinese medicine for treating hypertension, have been brought into systematic research of chemistry and pharmacology, finding a number of bioactive compounds and developing different drugs for clinical applications. Researches show that the same plant may contain a variety of compounds with different effects and mechanisms, which may be developed into different drugs, and achieve treatment by the combined pharmacological effects.
Rauwolfia is one of the important folk medicines in the Li national for the treatment of fever, headache, hypertension, traumatic injury, etc. In Hainan province of China, there are five Rauwolfia species and one cultivated Rauwolfia species, namely, R. verticillata (Lour.) Baill.; R. verticillata (Lour.) Baill. var. hainanensis Tsiang; R. tiaolushanensis Tsiang; R. serpentina (Linn.) Benth. ex; R. teiraphylla Linn.; and R. vomitoria Afzel. ex Spreng. The two Rauwolfia species, R. verticillata (Lour.) Baill. var. hainanensis Tsiang and R. tiaolushanensis Tsiang, are endemically and particularly distributed in Hainan island. Only a few studies on them have been reported. Many medicinal plants in the unusual Hainan’s climate and environment have unique pharmacological activities. It is expected that these unique medicinal plants will be a huge and abundant treasure for the research and development of the new drugs.
Many compounds derived from Rauwolfia plants have significant and distinct pharmacological effects, just like reserpine as an antihypertensive drug, ajmaline as an anti-arrhythmic drug, and yohimbine as an adrenergic α2 receptor antagonist. In the foreseeable future, a systematic research on the Rauwolfia and its active ingredients will take on an important significance for the further development and reasonable application of these new drugs.
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