Rauwolfia alkaloids Antihypertensives

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). 

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 Over a period of a few years, they have been rapidly superseded by synthetic alternatives.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). 

Within the last 10 years, Rauwolfia products have become important therapeutic agents, both as sedatives and antihypertensives. Although their production and use have fallen off since the peak years of 1955 and 1956, it is estimated that their total sales at the consumers level in 1961 still amounted to 100 million in the United States alone. Since 1952, the year reserpine was first isolated, several thousand articles have been published on the isolation, chemistry, pharmacology, and clinical aspects of reserpine and other Rauwolfia alkaloids, and today these investigations are still being pursued. Botanists estimate the number of identified Rauwolfia species to be about 50, of which R. serpentina,... 

Although natural and synthetic Rauwolfia alkaloids are available in high purity today, ground root in tablet form and partially separated Rauwolfia fractions are still used therapeutically. In this connection, the alseroxylon fraction should be mentioned, since it is defined as a selected Rauwolfia fraction from which the sympathicolytic and hypertensive alkaloids have been removed and which retains only the total antihypertensive, bradycardie, and sedative activity (119). 

The asymmetric total synthesis of rauwolfia alkaloids (-)-yohimbane and (-)-alloyohimbane was carried out by S.C. Bergmeier et al. by utilizing a novei aziridine-allylsilane cyclization and the Bischler-Napieralski isoquinoline synthesis as key steps.These alkaloids have a characteristic pentacyclic ring framework and exhibit a wide range of interesting biological activities such as antihypertensive and antipsychotic properties. 

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. 

It is a potent antihypertensive agent which exerts its action mainly by causing direct peripheral vasodilation. It has been observed that its effect on diastolic pressure is more marked and pronounced than on systolic pressure. It is employed in the treatment of essential and early malignant hypertension usually in conjunction with thiazide diuretics or rauwolfia alkaloids. 

Rauwolfia alkaloids such as reserpine cause adrenergic neurones to become depleted of their normal stores of noradrenaline (norepinephrine). In this way they prevent or reduce the normal transmission of impulses at the adrenergic nerve endings of the sympathetic nervous system and thereby act as antihypertensives. Since the brain also possesses adrenergic neu-... 

Neuronal Norepinephrine Depleting Agents. Reserpine (Table 6) is the most active alkaloid derived from Rauwolfia serpentina. The principal antihypertensive mechanism of action primarily results from depletion of norepinephrine from peripheral sympathetic nerves and the brain adrenergic neurons. The result is a drastic decrease in the amount of norepinephrine released from these neurons, leading to decrease in vascular tone and lowering of blood pressure. Reserpine also depletes other transmitters including epinephrine, serotonin [50-67-9] dopamine [51-61-6] ... 

Many alkaloids have pronounced biological properties, and a substantial number of the pharmaceutical agents used today are derived from naturally occurring amines. As a few examples, morphine, an analgesic agent, is obtained from the opium poppy Papaver somnifemm. Cocaine, both an anesthetic and a central nervous system stimulant, is obtained front the coca bush Erythroxylon coca, endemic to upland rain forest areas of Colombia, Ecuador, Peru, Bolivia, and western Brazil. Reserpine, a tranquilizer and antihypertensive, comes from powdered roots of the semitropical plant Rauwolfia serpentina. Ephedrine, a bronchodilator and decongestant, is obtained front the Chinese plant Ephedra sinica. 

Antihypertensive agents, substances that lower high blood pressure, are an important subclass of cardiovascular agents. Reserpine, an indole alkaloid obtained from the Rauwolfia plant, was the first successful drug to... 

Another fruitful means of identifying pharmacologically active natural products has been that of folk law remedies, many of which are plant products. Typical examples include alkaloids, such as atropine (from plants of the Solanaceae family, known to the ancient Greeks) and reserpine (from Rauwolfia serpentina, the snakeroot), which is popular in India as a herbal remedy for use as a tranquilizer or antihypertensive. Other chapters in the book relate to stigmines (based on phy-sostigmine, an anticholinesterase alkaloid from the Calabar bean in West Africa) that are used to treat Alzheimer s disease (Chapter 11-12), and opioid receptor ligands (based on morphine, the most important alkaloid of the opium poppy) for pain relief and as antitussives (Chapter 11-11). 

Reserpine is an alkaloid from plants of the genus Rauwolfia, used in medicine since ancient times in southern Asia, particularly for insanity more recently, reserpine was extensively used in psychiatry but is now obsolete. Reserpine depletes adrenergic nerves of noradrenaline primarily by blocking amine storage within vesicles present in the nerve ending, so reducing stores of releasable transmitter. Its antihypertensive action is due chiefly to peripheral action, but it enters the CNS and depletes catecholamine stores there too this explains the sedation, depression and parkinsonian (extrapyramidal) side effects that can accompany its use. The effects on catecholamine storage persist for days to weeks after it is withdrawn. 

No studies were found on the hypnotic activity of the phenolic acids however, the hypnotic activity of alkaloids is known. Dl-Tetrahydropalmatine (dl-THP), a naturally occurring alkaloid, has been intensively studied for its sedative and hypnotic effects. A putative explanation for its mechanism and target of action involves the dopaminergic neurotransmission system [371]. Reserpine, an alkaloid from Rauwolfia serpentina Benth. ex Kurz, was widely used for its antihypertensive action. Flowever, its use has been reduced because of its... 

One of the most fascinating products containing multiple components is a combination of the natural product reserpine, hydralazine hydrochloride, and hydrochlorothiazide. This drug product is available in tablet form and contains 0.1 mg of reserpine USP, 25 mg of hydralazine hydrochloride, and 15 mg of hydrochlorothiazide (Fig. 6). Reserpine is an indole alkaloid derived from the dried root of Rauwolfia serpentina and is well known for its complex molecular architecture, the challenges faced during its total synthesis, and its profound effect on the central nervous system as an antihypertensive. Hydralazine is also an antihypertensive and hydrochlorothiazide has diuretic properties. The combination of these three very different molecular structures brings diversity to the analytical testing required. 

Much more complex are the thousands of alkaloids that include an indole (or 2,3-dihydroindole) sub-unit and in each of these one can discern the tryptamine nnit of the biosynthetic precursor tryptophan strychnine (33.3.2) (Strychnos nux vomica), vincristine (33.7) (Catharanthus roseus), and the antipsychotic and antihypertensive reserpine (Rauwolfia serpentina) are examples. A group of amides of lysergic acid, for example, ergotamine, occur in ergot fnngi (e.g. Claviceps purpurea), the remainder of the molecule comprising proline, phenylalanine and alanine nnits. Lysergic acid diethylamide is the notorious LSD. 

The dried roots of the plant Rauwolfia serpentina3 and other species have been used in India for many centuries to treat various maladies. Its real value to Western medicine (tranquilizer and antihypertensive) was not appreciated until the 1950s following the identification of its alkaloidal contents (Table 10-3). Today the alkaloids are used in their pure state or as the product alseroxylon (Rauwiloid), a fat-soluble alkaloidal fraction from R. serpentina containing reserpine rescinnamide. Standardized powdered whole root (Raudixin) is also still in use. Combinations of these alkaloids with diuretics may be more effective antihypertensive products. 

An old and historically important drug that affects the storage and release of norepinephrine is reserpine. Reserpine is one of several indole alkaloids isolated from the roots of Rauwolfia serpentina] these roots were used in India for centuries both as a remedy for snake bites and as a sedative. The antihypertensive effects of the root extracts were first reported in India in 1918 and in the West in 1949. Shortly thereafter, reserpine was isolated and identified as the principal active agent. Reserpine was the first effective antihypertensive drug introduced into Western medicine, but it has largely been replaced in clinical use by agents with fewer side effects. 

An active alkaloid that is extracted from the root of shrubs of the genus Rauwolfia, and used tis a tranquilizer or sedative. It is also used as an antihypertensive dmg, in the treatment of high blood pressure, various mental diseases, and tension. 

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