CINCHONA ALKALOIDS

                        

Cinchona consists of various species and is found in Colombia, Ecuador, Peru and Bolivia. Pelletier and Caventon (182O) isolated the alkaloids quinine and cinchonine from Cinchona bark. Woodward and Doering (1945) syhthesized quinine in the laboratory. The crude drug contains about 35 alkaloids, of which quinine, quinidine, cinchonine and cinchonidine are the most abundant and the most important compounds. The average commercial yields of alkaloids from Cinchona bark are: quinine (5%), quinidine (0.1%), cinchonine (0.3%) and cinchonidine (0.4%), Some of Cinchona alkaloids (e.g. quinicine and cinchonicine) are amorphous. The amount of alkaloids present vary considerably in different species and hybrids. The cultivated bark contains 7-10% total alkaloids of which about 70% is quinine.

Cinchona alkaloids possess four asymmetric centres, carbons 3, 4, 8 and 9. All the cinchona alkaloids are identical in configuration at C-3 and C-4. Four different isomers may exist as a result of different configurations at C-8 and C-9. The differences in orientation give rise difference in the optical rotation of the alkaloids.

Stereochemical changes at C-8 have little effect on antimalarial activity. Quinine, quinidine, cinchonine and cinchonidine are active against P. vivax. Inversion at C-3 does not have important effect on activity. When the configuration at C-9 is changed to form ept isomers, the compounds become inactive. If the secondary alcohol group is modified by any way, the activity decreases markedly. The entire quinuclidine nucleus has been shown to be unnecessary for activity. However, C-arylB-tertiary amino alcohol system about the central C-9 is essential for activity.

After oral administration, the Cinchona alkaloids are absorbed readily and almost completely with peak blood-level concentrations occurring in l to 4 hours. When administration is stopped, blood levels fall off very quickly. A single dose of quinine is disposed of in about 24 hours. Therefore, repeated doses are to be administered. Soluble quinine salts produce higher initial blood levels than are obtained with the free base. In animals, quinine is concentrated mainly in pancreas, liver. spleen, lung and kidney. Small amounts of the drug are present in the blood, muscle or connective and nervous tissues. In liver oxidation of quinine forms a hydroxy group at 2'-position of the quinoline ring. The resulting degradation products, called carbostyrils, are not toxic, eliminated readily and possess lower antimalarial activity than the parent compound. The carbostyrils may be oxidized to dihydroxy compounds.

The long-term administration of quinine in normal therapeutic doses may give rise to a train of symptoms known as cinchonism, characterized by tinnitus, headache, nausea, and disturbed vision in its mild form. Other side effects are vomiting, abdominal pain, diarrhoea, vertigo, fever, pruritus, and rashes. Some patients are hypersensitive to quinine and even small doses may give rise to cinchonism together with other hypersensitivity reactions including angio-oedema and asthma. Thrombocytopenia, hypoprothrombinaemia, and haemolysis may occur and organulocytosis has been reported. The symptoms ofoverdosage include gastro-intestinal, central nervous system, and cardiovascular disturbances. Visual disturbances are normally reversible but may be permanent, and may rarely include sudden blindness. Severe poisoning can produce convulsions, coma, respiratory depression and death. Large doses of quinine can induce abortion, and congenital oalformations. However, quinine should not be withheld from regnant women with life-threatening malaria.

In addition to antimalarial action, Cinchona alkaloids are antipyretic. It has been used for the treatment of night cramps or "restless legs". The antimalarial action of Cinchona alkaloids may be obtained by oral, intravenous or intramuscular aministration. Intravenous injections may cause severe cardiovascular depression leading to generalized collapse.