Antitussive drugs--past, present, and future

Abstract

Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.

Fig. 1.

Total sales and market share percentage of the over-the-counter and prescription dextromethorphan products, years 2005–2009 in United States. It shows 19% increase in OTC combination products since 2005 to 2009. Eaches, the number of packets, bottles, and vials of a product shipped in a unit. Figure modified from www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/drugsafetyandriskmanagementadvisorycommittee/ucm226621.pdf

Fig. 2.

Multiple vagal afferent nerve subtypes innervate the airways and lungs.

Fig. 3.

Chemical structure of anhydrous dextromethorphan hydrobromide.

Fig. 4.

Metabolism of dextromethorphan.

Fig. 5.

Chemical structure of codeine.

Fig. 6.

Chemical structure of lidocaine or lignocaine.

Fig. 7.

Chemical structure of benzonatate.

Fig. 8.

Chemical structure of caramiphen.

Fig. 9.

Chemical structure of carbetapentane.

Fig. 10.

Chemical structure of chlophedianol.

Fig. 11.

Chemical structure of levodropropizine.

Fig. 12.

Chemical structure of menthol.

Fig. 13.

Chemical structure of erdosteine.

Fig. 14.

(A) Chemical structure of erythromycin. (B) Chemical structure of amoxicillin. (C) Chemical structure of doxycycline.

Fig. 15.

Chemical structure of beclamethasone dipropionate.

Fig. 16.

Chemical structure of salbutamol (albuterol).

Fig. 17.

Chemical structure of ipratropium bromide.

Fig. 18.

Chemical structure of guaifenesin.

Fig. 19.

Chemical structure of carbocisteine.

Fig. 20.

Chemical structure of theobromine.

Fig. 21.

Chemical structure of disodium cromoglycate.

Fig. 22.

Chemical structure of levocloperastine.

Fig. 23.

Chemical structure of amitriptyline.

Fig. 24.

Chemical structure of memantine.

Fig. 25.

Chemical structure of glaucine.

Fig. 26.

Chemical structure of moguisteine.

Fig. 27.

Chemical structure of cilomilast.

Fig. 28.

Chemical structure of NS1619.

Fig. 29.

Chemical structure of furosemide.

Fig. 30.

Chemical structure of ouabain.

Fig. 31.

Chemical structure of montelukast.

Fig. 32.

Chemical structure of tropan.

Fig. 33.

Chemical structure of anandamide.

Fig. 34.

Chemical structure of SB-705498.

Fig. 35.

Chemical structure of HC-030031.

Fig. 36.

Chemical structure of baclofen.

Fig. 37.

Chemical structure of E121.

Fig. 38.

Chemical structure of gabapentin.

Fig. 39.

Chemical structure of thalidomide.