Antitussives dextromethorphan

To test the scope of the reaction, the over-the-counter antitussive Dextromethorphan was N-demethylated to the morphinan in 87 % yield as depicted in scheme 133. 

Dextromethorphan, an effective antitussive drug, is the dextrorotatory stereoisomer of a derivative of levorphanol. The drug is available without a prescription and is the active component in many over-the-counter cough suppressants. Dextromethorphan has no appreciable analgesic activity and minimal abuse liability. In comparison with codeine—also an effective antitussive—dextromethorphan causes less constipation. The answer is (D). 

Uses. In many cases cyanoacetic acid, cyanoacetates, or cyanoacetamide can be used alternatively. The traded cyanoacetic acid is mainly iatended for the synthesis of the cough remedy dextromethorphan [125-71-3] (31) (61) (see Expectorants, antitussives, and related agents) and of the fungicide cymoxanil [57966-95-7] (32) (62) (see Fungicides,agricultural). 

Nonnarcotic Antitussives. The most centrally active, noimarcotic antitussive is dextromethorphan [125-71-3] (39). It is similar to codeine in terms of potency and mechanism of action, ie, it is a direct depressant of the cough center. It is unique in that even though it is stmcturaHy related to codeine, it is not addictive. 

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. 

The synthesis (60) and potent antitussive activity (61) of dimemorfan [36309-01-0] (41), D-3-methyl-/V-methylmorphinan, have been reported. This compound, prepared by a modification of the Grewe process, differs from dextromethorphan only by having a methyl group, rather than a methoxy group, in the 3 position. 

Other applications include bioequivalent measurements of bromazepam, an anticonvulsant, in human plasma. The lower limit of quantitation (LLOQ) was 1 ng/mL (Gongalves et al. 2005). Kuhlenbeck et al. (2005) studied antitussive agents (dextromethorphan, dextrophan, and guaifenesin) in human plasma LLOQ values were 0.05, 0.05, and 5 ng/mL, respectively. Other compounds studied were nucleoside reverse transcriptase inhibitors, zidovudine (AZT) and lamivudine (3TC) (de Cassia et al. 2004) and stavudine (Raices et al. 2003) in human plasma, and paclitaxel, an anticancer agent, in human serum (Schellen et al. 2000). 

Codeine, dextromethorphan and pholcodine are opioid cough suppressants indicated for dry cough. Sedating antihistamines, such as diphenhydramine, tend to have an antitussive action as well. Vitamin C is not used in the management of cough but may be used as a prophylaxis against colds. 

Dextromethorphan is an opioid antitussive similar in action to codeine and pholcodine. Codeine and pholcodine are considered to be more potent than dextromethorphan. Dextromethorphan tends to cause less constipation and dependence than codeine. Cough suppressants are not usually recommended in children under 2 years. 

Pharmacology Dextromethorphan is the d-isomer of the codeine analog of levorphanol. Its cough suppressant action is due to a central action on the cough center in the medulla. Dextromethorphan 15 to 30 mg equals 8 to 15 mg codeine as an antitussive. 

Dextromethorphan (Mediquell, Benylin DM, PediaCare 1, Delsym, Others) [OTC] [Antitussive] Uses Control nonproductive cough Action Suppresses medullary cough center Dose Adults. 10-30 mg PO q4h PRN (max 120 mg/24 h) Peds. 2-6 y 2.5-7.5 mg q4-8h (max 30 mg/24 h) 7-12 y 5-10 mg q4-8h (max 60 mg/24/h) Caution [C, /-] Not for persistent or chronic cough Contra < 2 y. Disp Caps, lozenges, syrup, Liq SE GI disturbances Interactions T Effects W/ amiodarone, fluoxetine, quinidine, terbinafme T risk of serotonin synd Wf sibutramine, MAOIs T CNS depression Wf antihistamines, antidepressants, sedative, opioids, EtOH EMS Will not affect cough caused by asthma,... 

Dextromethorphan hydrobromide is the D-isomer of levorphanol. It lacks CNS activity but acts at the cough center in the medulla to produce an antitussive effect. It is half as potent as codeine as an antitussive. Anecdotal reports of abuse exist, but studies of abuse potential are lacking. It has few side effects but does potentiate the activity of monoamine oxidase inhibitors, leading to hypotension and infrequently coma. Dextromethorphan is often combined in lozenges with the local anesthetic benzocaine, which blocks pain from throat irritation due to coughing. 

An antitussive agent, then, is a drug that suppresses or prevents cough. Codeine and dextromethorphan are the most commoniy used antitussives. Other opioids are also effective antitussive agents, but are not used as medicines to suppress cough. 

Dextromethorphan is a synthetic compound and its dextroisomer is used as antitussive and is as effective as codeine without any addiction liability. 

The opioid derivatives most commonly used as antitussives are dextromethorphan, codeine, levopropoxyphene, and noscapine (levopropoxyphene and noscapine are not available in the USA). They should be used with caution in patients taking monoamine oxidase inhibitors (see Table 31-5). Antitussive preparations usually also contain expectorants to thin and liquefy respiratory secretions. Importantly, due to increasing reports of death in young children taking dextromethorphan in formulations of over-the-counter "cold/cough" medications, its use in children less than 6 years of age has been banned by the FDA. Moreover, due to variations in the metabolism of codeine, its use for any purpose in young children is being reconsidered. 

Dextromethorphan is the dextrorotatory stereoisomer of a methylated derivative of levorphanol. It is purported to be free of addictive properties and produces less constipation than codeine. The usual antitussive dose is 15-30 mg three or four times daily. It is available in many over-the-counter products. Dextromethorphan has also been found to enhance the analgesic action of morphine and presumably other -receptor agonists. However, abuse of its purified (powdered) form has been reported to lead to serious adverse events including death. 

Dextromethorphan and its O-demethylated metabolite dextrorphan (morphinans), are also low to medium affinity NMDA channel blockers. The former has been in clinical use as an antitussive for about 40 years and could therefore be considered as a very safe drug (Bern et al., 1992). 

Dematteis, M., Lallement, G., and Mallaret, M., Dextromethorphan and dextrorphan in rats common antitussives — different behavioui al profiles, Fund. Clin. Pharmacol., 12, 526, 1998. 

The calcium ion antagonists nifedipine 21829-25A] (62), verapamil [52-55-9] (63), and flunarizine [52468-60-7] (64) exhibit antitussive effects in a dose-dependent manner in guinea pigs (91). Pretreatment with a subthreshold dose of nifedipine also markedly increased the antitussive effects of morphine, dihydrocodeine, and dextromethorphan. However, none of the calcium ion antagonists are used clinically as antitussive agents. They are used in the treatment of angina and hypertension (see Cardiovascularagents). 

Konrad D, Sobetzko D, Schmitt B, Schoenle EJ. Insulin-dependent diabetes mellitus induced by the antitussive agent dextromethorphan. Diabetologia 2000 43(2) 261-2. 

The narcotic antagonists are naltrexone and naloxone (Narcan). Dextromethorphan (Romilar) is used as an antitussive preparation. Apomorphine is used as an emetic agent. 

Dextromethorphan (Romilar) is the dextroisomer of the methyl ether of levorphanol. Unlike its levorotatory congener, it possesses no significant analgesic property, exerts no depressant effects on respiration, and lacks addiction liability. It is an antitussive agent with a potency approximately one half that of codeine. 

---