Screening of Antitussive Drugs

Screening of Antitussive Drugs

1. Definition, rationale & the cough reflex arc to be probed

• An antitussive is a drug that suppresses cough; screening a candidate means demonstrating, in a validated animal model, that pre-treatment reduces an experimentally evoked cough compared with the animal's own control response (Vogel 4e V1 Part IV, "Antitussive Activity" pp.1001–2).
• Cough is a reflex. The reflex arc that every antitussive assay exploits: sensitive cough receptors in the bronchial tree — concentrated at the bifurcation of the trachea (carina) and larynx/large bronchi — are stimulated mechanically or chemically; afferents run mainly in branches of the vagus (superior laryngeal nerve, N. laryngicus superior); impulses reach a "cough centre" in the medulla oblongata; efferents close the glottis and drive the forced expiratory (expulsive) thrust (Vogel 4e V1 Part IV pp.1001, 1006).
• Screening therefore has two logical handles: (i) induce cough by a reproducible peripheral stimulus, then (ii) quantify how a test drug changes a defined endpoint (cough number / latency / expiratory force) versus a reference standard (Vogel 4e V1 Part IV pp.1001–7).
• A screen must distinguish site of action: irritant-inhalation and mechanical models detect both peripherally- and centrally-acting antitussives, whereas the superior-laryngeal-nerve model "by definition cannot detect compounds which act on cough receptors in the bronchial area" and so is selective for centrally active agents such as codeine (Vogel 4e V1 Part IV pp.1006–7).
• The pharmacology of cough as a target was reviewed by Reynolds et al. (2004) Trends Pharmacol Sci 25:569–576; experimental models were reviewed by Braga (1989) (Vogel 4e V1 Part IV pp.1002, 1007).