Morphine antitussive

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

Codeine, mol wt 299.3, is a significantly less potent analgesic than morphine, requiring 60 mg (0.20 mmol) to equal the effectiveness of 10 mg (0.04 mmol) of morphine. However, codeine is orally effective, and it is less addictive and associated with less nausea than morphine. Codeine is used as an antitussive agent, although newer, nonaddictive agents are preferred (see Expectorants, antitussives, and related agents). 

Narcotic Antitussives. Since its isolation in 1832, codeine [76-57-3] (27) has been one of the most widely used and effective compounds for the treatment of cough. Though less potent than morphine [57-27-2] (28), it has become the reference against which most antitussives are measured. 

Molecular modifications of the morphine skeleton have produced numerous derivatives with antitussive properties, some of which have become commercially significant. Ethyknorphine [76-58-4] (29), a simple homologue of codeine, is prepared by ethylating morphine. It is pharmacologically similar to codeine but is seldom used clinically. Pholcodine [509-67-1] (30), the morpholinoethyl derivative of morphine, is used as an antitussive in a number of European countries. It is about one and a half times as potent as codeine, has Htde or no analgesic activity, and produces minimal physical dependence. The compound is prepared by the amino alkylation of morphine (48). 

Hydromorphone [466-99-9] (31) and hydrocodone [125-29-1] (32) are isomers of morphine and codeine, respectively. Hydromorphone can be prepared by catalytic rearrangement of morphine (49) or by oxidation of the aliphatic hydroxyl group of dihydromorphine (50). Hydrocodone can be similarly prepared. As an antitussive, hydromorphone is several times more active than morphine and hydrocodone is slightly more active than codeine. Hydromorphone has a much higher addiction potential than hydrocodone. 

Modifications of the morphine skeleton have produced butorphanol [42408-82-2] (35) and drotebanol [3176-03-2] (36), which in animal models have demonstrated antitussive activity much greater than that of codeine (51,52). Butorphanol is also a potent analgetic of the narcotic antagonist type (51). Both compounds possess a unique 14-hydroxyl group. 

The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

Included in the noimarcotic class of antitussives are many compounds that do not possess a morphine skeleton and which vary widely from each other with respect to stmctural features and pharmacologic profiles. 

Noscapine [128-62-1] (45) is the second most abundant alkaloid found in opium. Unlike most opium alkaloids, however, it has an isoquinoline rather than a phenanthrene ting system. Noscapine was first isolated in 1817 but its antitussive activity was not demonstrated pharmacologically until 1952 (63). Clinical studies have confirmed its effectiveness. It is not a narcotic and has a wide margin of safety when given orally. Death could be produced in rats only with doses > 800 mg/kg (64). Noscapine is isolated from the water-insoluble residue remaining after processing opium for the manufacture of morphine. 

Morphine and related opiates are known to suppress the cough reflex these compounds have thus been used extensively in antitussive preparations. Since this activity is not directly related to the analgesic potency, the ideal agent is one that has much reduced analgesic activity and thus, presumably, lower addiction potential. The weak analgesic codeine (4) is... 

Alkaloids Glycoside Morphine Codeine Digitalis glycosides Sennosides Analgesic, Antitussive Cardiovascular diseases, Laxatives... 

Hydromorphone (I) and hydrocodone (II) belong to the morphine group of drugs and are used invariably in combination with other ingredients in a number of proprietory antitussive and analgesic antipyretic mixtures. However, interest in the pharmacokinetics of hydromorphone and hydrocodone in human subjects required an adequate assay for drug levels in plasma. 

Opium alkaloids [Codeine (12), Morphine (13)] Papaver somniferum L. (opium poppy) Antitussive Narcotic analgesic... 

Hydrocodone is an opium analgesic (pain reliever) and antitussive (cough suppressant). It is related in structure to other alkaloids used as drugs, such as morphine and codeine (see Section 8). It increased 20% in number of prescriptions for one year. Its synthesis from codeine is by simple reactions. 

Codeine occurs naturally in opium but the amount is too small to be useful. It is prepared from morphine by methylating the phenolic hydroxyl group with diazomethane, dimethyl sulfate, or methyl iodide. Codeine does not possess the same degree of analgesic potency as morphine but is used as an antitussive, a cough suppressant. Hydrocodone was discussed in Section 3.4. It is made from codeine. 

Codeine is similar to morphine in terms of properties, but its pain-relieving ability is significantly less and it causes addiction to some degree. This drug is very effective in oral use and is used for average to moderate pain. It is often used as an antitussive drug. Synonyms for codeine are codyl, acutus, and others. 

Oxymorphone is approximately 10 times more active than morphine. Euphoric effects as well as vomiting are expressed significantly stronger than in morphine. Oxymorphone also displays poor antitussive activity. 

Opium Street Names Auntie Emma, big O. black stuff, block, gum, hop, ope, tar (brand generic called tincture of opium, laudanum, paregoric (CIII), B O suppositories [CIII]) Use Some medical uses (antidiarrheal, antitussive, antispas-modic) illegally used to produce morphine and h oin can be swallowed or smoked Actions Narcotic contains morphine Effects Pain relief, euphoria, drowsiness/N, constipation, confusion, sedation, resp dqjression and arrest, tol -ance, addiction, unconsciousness, coma, death... 

Like morphine, codeine is a naturally occurring opioid found in the poppy plant. Codeine is indicated for the treatment of mild to moderate pain and for its antitussive effects. It is widely used as an opioid antitussive because at antitussive doses it has few side effects and has excellent oral bioavailability. Codeine is metabolized in part to morphine, which is believed to account for its analgesic effect It is one of the most commonly used opioids in combination with nonopioids for the relief of pain. The administration of 30 mg of codeine in combination with aspirin is equivalent in analgesic effect to the administration of 65 mg of codeine. The combination of the drugs has the advantage of reducing the... 

Oxymorphone is 10 times as potent as morphine, with actions similar to those of hydromorphone. Oxymorphone, however, has httle antitussive activity, and as such is a useful analgesic in patients with pulmonary disease who need to retain the ability to cough. 

Meperidine differs from morphine in that it has far less antitussive effect and little constipative effect. The drug is particularly useful in cancer patients and in pulmonary patients, in whom the cough reflex must remain intact. However, it does have more seizure-inducing activity than morphine. Although meperidine produces spasms of the biliary tract and colon, such spasms are of shorter duration than those produced by morphine. 

Levorphanol (Levo-Dromoran) is an L-isomer morphi-nan derivative of morphine that is five to seven times more potent than morphine. It produces all of the side effects associated with morphine but less nausea. It is indicated for moderate to severe pain as a preoperative anxiolytic. It is often used in combination with thiopental to reduce the latter drug s anesthetic dose and to decrease postoperative recovery time. The o-isomer of levorphanol, dextrorphan, does not possess opioid analgesic activity but is a useful antitussive. 

Certain opioids are used mainly for their antitussive effects. Such drugs generally are those with substituents on the phenolic hydroxyl group of the morphine structure. The larger the substituent, the greater the antitussive versus analgesic selectively of the drugs. 

Codeine is a natural alkaloid found in the opium plant. As a pharmaceutical, codeine is used as an analgesic, antitussive, and antidiar-rheal. Codeine is also commonly combined with other cough suppressants as well as with aspirin and ibuprofen. In the United States, codeine is a Schedule III controlled substance, which means that its distribution is more tightly regulated than unscheduled drugs. Codeine has pain-relieving qualities principally because, once in the body, about 10 percent of codeine turns into morphine. This conversion occurs in the liver, where an enzyme changes codeine s... 

It is a methyl ester of morphine and less potent analgesic than morphine. It is widely used as antitussive agent. Pholcodeine is also used as antitussive agent and causes less constipation (Details are given in chapter Drugs acting on respiratory system ). 

Codeine, which is an opium alkaloid is most commonly opiate used as antitussive and more selective for cough centre. Like morphine, it depresses cough centre but is less constipating and abuse liability is low. It is relatively safe drug used in cough along with analgesic property and it s only important adverse effect is constipation. 

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