Antitussive drugs dextromethorphan

Fig. 3.1 Morphine 1 has been the lead structure for the development of the major analgesic fentanyl 2, the antitussive drug dextromethorphan 3, the constipating drug loperamide 4, and the neuroleptic drug haloperidol 5.

Dextromethorphan hydrobromide is an antitussive drug with no analgesic or addictive action. Its antitussive effect is similar to codeine. The recommended oral dose for adults is 10-30mg three to six times a day, not to exceed 120mg daily. It is absorbed rapidly and completely when taken orally with a lag time of 15-30 min [72]. 

Figure 2.3 Dextromethorphan 6, the unnatural enantiomer of a narcotic morphine analog, is an antitussive drug. The antidiarrhea drug loperamide 7 and the neuroleptic drug haloperidol 8 also resulted from structural modification of morphine. The morphine antagonist nalorphine 9 differs from the opioid agonist morphine 3 (Figure 2.2) only by having an N-allyl group instead of the N-methyl group.

The alkaloid dextromethorphan is an antitussive drug manufactured by Lonza in enantiomerically pure form. While early synthesis involved the tedious resolution of an octahydroi-soquinoline intermediate with mandelic acid, a more recent process takes advantage of the catalytic reduction of a C-N double bond promoted by a chiral Ir/ferrocenylphosphine complex [70]. 

Cough suppression Useful antitussive drugs include codeine and dextromethorphan. They are given orally. 

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). 

Dextromethorphan is a morphinan derivative (Figure 8.6a). It is an antitussive drug comparable to codeine in terms of strength. At high doses it can cause depressive effects. It shows low toxicity and is added to antitussive syrups [61]. 

Most commonly, drugs which are administered as racemates have only one chiral centre. Levorphan and dextrorphan (based on the morphine structure) are unusual in that they have the opposite configurations at three chiral centres. Levorphan ([-] isomer 9 R, 13 R 14 R) is a narcotic analgesic which is potentially addictive whereas dextrorphan ([-L] isomer 9S, 13 S, 14S) is used as an antitussive drug in the form of its 0-methylether dextromethorphan. 

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 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). 

Dextromethorphan, the dextroisomer of the opioid levomethorphan is used as an antitussive, e.g. in Actifed the latter is sought as a drug of abuse by addicts. 

On two occasions, a fixed drug eruption occurred on the arm of a 45-year-old woman after using dextromethorphan as an antitussive (SEDA-16, 79). Worsening of urticaria pigmentosa has been attributed to dextromethorphan (SEDA-21, 87). 

Dextromethorphan is metabolized to dextrophan (Figure 34-40) by the cytochrome P4S0 isozyme 2D6 (GYP 2D6), which exhibits genetic polymorphism. Dextrophan also lacks analgesic activity, but it does retain antitussive action. Dextrophan may be responsible for the more pleasant psychotropic effects of high dose dextromethorphan, whereas the parent drug may cause dysphoria, sedation, and ataxia. Thus poor metabolizers (deficient in GYP 2D6 activity) may be less prone and extensive metabolizers more prone to continue the abuse of dextromethorphan. 

Both drugs are excellent antitussives. However, codeine promotes a much higher degree of constipation than does dextromethorphan. In addition, codeine has abuse potential, as it has the ability to cross into the CNS in high doses. 

---