Morphine antitussive preparations

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... 

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. 

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. 

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 the methylic ether of morphine (3-methylmorphine) and can be isolated from opium during the extraction of morphine, but is usually prepared by the methylation of morphine. Codeine is used in medicine as an antitussive drug and furthermore it has analgesic properties. It may cause addiction, but less than morphine. 

N-oxides of morphine and several morphine derivatives have been prepared by the action of isopropanol/H202 on the appropriate tertiary base.(156) At best, the N-oxides were weak analgesics, but dihydromorphinone N-oxide and codeine N-oxide did exhibit good antitussive properties/157 ... 

A a X o (X PO/SC/IM. Rapid absorption, half-life = 3h. 10% demethylated to form morphine, the rest is conjugated in liver and excreted in urine. Low risk of abuse. Similar to morphine. Included in a number of cough medicine preparations because of antitussive effects. 

Opiates, narcotic compounds extracted or derived from opium, are a remarkable source of lead compounds for their potent pharmaceutical effects such as analgesics, antitussives and ataractics, and of which many synthetic derivatives have been prepared [8, 72], Apomorphine (28), a dopamine agonist derivative from morphine (5) but without analgesic properties like morphine, was recently approved as a therapy for Parkinson s disease [73], Hydrocodone (30) is a narcotic agent derived from thebaine (29) and is commonly combined with other analgesics such as acetaminophen and ibuprofen as drugs to relieve pain. [74]. Naloxone (31) and naltrexone (32) are both opioid receptor antagonists. Naloxone is used as a treatment for opioid... 

---