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QUINOLINE AND ISO QUINOLINE ALKALOIDS By Noor Hisham Al-Atraqchi MSc.pharmacognosy QUINOLINE ALKALOIDS QUINOLINE ALKALOIDS • • Alkaloids containing quinoline as their basic nucleous . Cinchona and its alkaloids are only members of this group that are therapeutically important at present. Consist of alkaloids and alkaloid salts obtained from the bark of certain Cinchona species : Quinine and Quinidine, Cinchonine and Cinchonidine. Cinchona alkaloids are present as salts with Quinic and Cinchotannic acids Cinchona bark: o Cinchona succirubra (Rubiaceae), and its varieties and hybrids containing not less than 6.5% of total alkaloids. 30-60% of which consists of quininetype alkaloids. The amount of alkaloids present depend on : the species, environment of the tree, age, method of bark collection. The former importance of cinchona bark and its alkaloids in the treatment of malaria has been lessened by the introduction of synthetic drugs, but it remains of great economic importance. CONSTITUENTS OF CINCHONA BARKS Cinchona bark contains quinoline alkaloids. The principal alkaloids are the stereoisomers quinine and quinidine and their respective demethoxy derivatives, cinchonidine and cinchonine. Both Quinine and Quinidine, Cinchonine and Cinchonidine are Diastereoisomers. Each pair differs in the stereochemistry at C-8 and C-9. HO H3CO HO 9 N N H H H3CO N Quinine 8 H H N Quinidine Uses: • Galenicals of cinchona have long been used as bitter tonics and stomachics. • Before World War II, quinine was the drug of choice for the treatment of malaria but became largely superseded by the advent of synthetic antimalarials developed during that period. • It has, however, remained of importance in Third World countries and has re-emerged as suitable for the treatment of Plasmodium falciparum infections (falciparum malaria) in the many areas where the organism is now resistant to chloroquine and other antimalarials. Quinine also has a use as a treatment for night cramps in the elderly . • Uses: • • Quinidine is employed for the prophylaxis of cardiac arrhythmias and for the treatment of atrial fibrillation: it also has antimalarial properties and like quinine is effective against chloroquine-resistant organisms. TOXICITY Over doses of cinchona products results in: 1. Temporary loss of hearing. 2. In impaired sight. 3. Ringing in the ear. This symptom of toxicity condition has been called cinchonism ISOQUINOLINE ALKALOIDS Isoquinoline alkaloids : • The isoquinoline structure occurs in a considerable member of alkaloids, widely distributed in plant families. • The important alkaloids in this group are: 1. Ipecac : emetine, cephaeline ,psychotrine 2. Curare: D. tubocurarine 3. Opium and its alkaloids. IPECAC ALKALOIDS dried root or rhizome of Cephaelis ipecacuanha of the Rubiaceae family. It should contain at least 2% alkaloids. Constituents: Ipecacuanha contains the alkaloids : emetine, cephaeline , psychotrine, psychotrine methylether • emetamine. These are isoquinoline derivatives. IPECACUANHA USES 1. 2. 3. Ipecac in the form of syrup is used in the treatment of drug over dose and in cases of poisonings. It produces emesis through a local irritant effect on the GI mucosa and a central medullary effect, by stimulation of the chemoreceptor trigger zone. Expectorant Treatment of Amoebic Dysentery Emetine (methyl cephaline) is antiamebic Emetine is more expectorant and less emetic in action than cephaeline , and is added to many cough medicines. Psychotrine and its O-methyl ether are selective inhibitors of human immunodeficiency virus and their study could lead to the development of therapeutically useful agents. Curare alkaloids Tubocurarine: • • Has a bisbenzylisoqinoline structure. It is obtained from the bark and stems of Chondrodendrum tomentosum ( family Menispermaceae) . • The term 'curare' is a generic one applied to various South American arrow poisons, because crude extract prepared from different species was used by certain natives of the Amazon regions of South America as arrow poison, which kills by paralysis of the muscles required to breathe . Tubocurarine chloride USES Tubocurarine chloride is employed as: 1. A skeletal mucosa relaxant (to secure muscle relaxation in surgical procedure without deep anesthesia). 2. Used to control convulsions of strychnine poisoning and of tetanus. 3. after shock treatment (in mental diseases) as it reduces convulsion 4. The compound was also a template for the development of other muscle relaxants ,e.g: atracurium. OPIUM Opium (Raw Opium) is the latex obtained by incision from the unripe capsules of Papaver somniferum (Papaveraceae) . Opium BP is required to contain not less than 10% of morphine and not Jess than 2.0% of codeine. The thebaine content is limited to 3%. PRODUCTION OF OPIUM The plant is an annual herb with large solitary flowers, either white or pink in color The incisions are made in the afternoon with an instrument bears narrow iron spikes which are drawn down the capsule to produce several longitudinal cuts. The incision must not penetrate into the interior of the capsule or latex will be lost. The latex, which is at first white, rapidly coagulates and turns brown. Early in the morning of the day following the making of the incisions the partly dried latex is scraped off. Each capsule is cut several times at intervals of 2 or 3 days. After collection the latex is placed in a tilted vessel so that the dark fluid which is not required may drain off. By exposure to air the opium acquires a suitable consistency for packing. OPIUM CONSTITUENTS Opium contain more than 40 alkaloids usually combined with a specific acid (Meconic acid) or with other acids e.g. sulfuric and acetic acids. Opium alkaloids can be sub classified into 3 main groups with different basic nuclei: 1. Phenanthrene alkaloids e.g. morphine , thebaine and codeine. 2. Benzylisoquinoline alkaloids e.g. papaverine and noscapine (narcotine). 3. Phenylethylamine alkaloids e.g. narceine Morphine Narceine USES OF OPIUM Opium and morphine are widely used to relieve pain and are particularly valuable as hypnotics, as, unlike many other hypnotics, they act mainly on the sensory nerve cells of the cerebrum. Both morphine and codeine decrease metabolism, and the latter, particularly before the introduction of insulin, was used for the treatment of diabetes. Opium, while closely resembling morphine, exerts its action more slowly and is therefore preferable in many cases (e.g. in the treatment of diarrhoea). Opium is also used as a diaphoretic. Alkaloids of opium: Morphine: • Is the most important of the opium alkaloids, morphine . • The molecule contains a phenolic and an alcoholic hydroxyl group. • Morphine was a used as a template for other analgesic agents including pethidine, which is one of the most widely used synthetic opiates. Uses • Morphine and its salts are classed as narcotic analgesics they are strongly hypnotic. • post operative analgesic for major operations, and for cancer patients (terminal pain). ADVERSE EFFECT: 1. 2. 3. 4. 5. 6. 7. 8. constipation sedation nausea and vomiting respiratory depression Miosis anticholinergic effect: dry mouth , urinary retension tolorance: increase doses required to maintane analgesia. dependence : addiction, if used for a long time Codeine: Is the most widely used opium alkaloid obtained from opium or prepared from morphine by methylation (of phenolic hydroxyl group) or from thebaine reduction and demethylation, it is methyl morphine (replace the phenolic hydroxyl group). Uses • Codeine and salt has narcotic analgesics • Codeine mainly used as antitussive, it suppress the coughing center in brain. • Codeine is less toxic and much weaker in action than morphine with less development of tolerance. The habitual use of codeine may, in some individuals, produce constipation PAPAVERINE -Benzyl isoquinoline type An opiate alkaloid isolated from the plant Papaver somniferum and produced synthetically. Action and uses: 1-papaverine decrease the tone of smooth muscles. It has spasmolytic and vasodilatation effect 2-it is neither narcotic nor addictive NOSCAPINE Noscapine or narcotine exists in opium as free base (3-10 %), it posses cough suppressant properties. Thebaine Thebaine is the starting point for the synthesis of many agents, including codeine and veterinary sedatives such as etorphine. SEMISYNTETIC PREARATION HEROIN Heroin: (diacetyl morphine). It is formed by acetylation of both hydroxyl groups using acetic anhydride . Heroin’s action is similar to morphine but more potent and dangerous of habit formation. This agent is highly useful in the management of pain, particularly in patients with terminal cancer.