The Pharmacology of Cough.Pdf

Review TRENDS in Pharmacological Sciences Vol.25 No.11 November 2004 The pharmacology of cough Sandra M. Reynolds, Auralyn J. Mackenzie, Domenico Spina and Clive P. Page Sackler Institute of Pulmonary Pharmacology, Division of Pharmaceutical Sciences, Guy’s Campus, King’s College London, London SE1 1UL, UK Cough is an indispensable defensive reflex. Although Appropriate treatment of many diseases that have cough generally beneficial, cough is also a common symptom as a symptom often leads to improvement or abolition of of diseases such as asthma, chronic obstructive pul- cough. However, when the aetiology of cough is not monary disease (COPD) and lung cancer. Cough remains established or when cough persists despite treatment of a major unmet medical need and, although the centrally the disease, specific antitussive therapy is indicated [4]. acting opioids have remained the antitussive drug of Current antitussive drugs are divided broadly according choice for decades, such opioids possess many to their site of action as either central or peripheral, unwanted side-effects. However, new research into the although many antitussives act to some extent at both behaviour of airway sensory nerves has provided greater locations. Centrally acting antitussives act within the CNS insight into the mechanisms of cough and new avenues to suppress the central cough pathway and comprise the for the discovery of novel non-opioid antitussive drugs. majority of currently used antitussives. However, many of In this article, the pathophysiological mechanisms of these drugs, including the opioids, which have been the cough and the implications of this research for the antitussives of choice for decades, are limited by their many development of novel antitussive drugs will be dis- side-effects. Peripherally acting antitussives generally cussed. A poster depicting the pharmacology of cough is inhibit the responsiveness of airway nerve subtypes that available online and in print as supplementary material evoke cough, although these drugs are not used widely. to this article. However, as a better understanding of the cough pathway emerges, many new antitussives are being developed to act Cough is a normal protective reflex that is responsible for peripherally to avoid unwanted CNS effects. keeping the airways free of obstruction and harmful substances. However, cough is also the most common Sensory nerves and the cough reflex symptom for which medical advice is sought. Conse- The cough reflex is known to include a ‘hard wiring’ circuit quently, and despite a recent study suggesting that over- (Figure 1). The stimuli that initiate the cough reflex the-counter antitussive drugs possess little clinically stimulate sensory nerve fibres that have been divided relevant efficacy [1], such antitussives are among the broadly into three main groups: Ad-fibres, C-fibres and most widely used drugs in the world. Of course, this wide slowly adapting stretch receptors (SARs). These fibres usage probably reflects the many patients who self- have been differentiated based on their neurochemistry, medicate for acute cough associated with transient anatomical location, conduction velocity, physiochemical upper respiratory tract infections (‘colds’). However, the sensitivity and adaptation to lung inflation (Table 1). more serious medical problem is chronic cough, which can be a symptom of other more serious respiratory diseases, Ad-fibres such as asthma, chronic obstructive pulmonary disease Rapidly adapting receptors (RARs) are myelinated (COPD) and lung cancer. In addition, chronic cough can be Ad-fibres that are thought to terminate within or slightly a symptom of various extra-pulmonary conditions such as beneath the epithelium throughout the intrapulmonary post-nasal drip (PND), gastro-oesophageal reflux (GOR) or airways and respond to changes in airway mechanics to even ear and heart disorders [2]. Cough is also a side-effect regulate normal breathing [5]. These fibres fire in of certain medications (e.g. angiotensin-converting response to most tussive stimuli and it is likely that enzyme inhibitors). their stimulation is of primary importance in the elicita- The causes of cough are obviously diverse but the tion of the cough reflex [6]. In general, their activity is common link between them all is the activation of subsets increased by mechanical stimuli such as mucus secretion of airway sensory nerves. Diseases of the respiratory or oedema but they are insensitive to many chemical system can lead to activation of sensory nerves at the level stimuli that provoke cough, including bradykinin and of the airway lumen following the release of inflammatory capsaicin [7]. However, in the guinea-pig, at least, the mediators, increased mucus secretion or damage to the variability in mechanical and chemical sensitivities of airway epithelium. Disorders of other organs that have RARs is sufficient to believe there might be as many as neurons carried in the vagus (i.e. the oesophagus or the three subdivisions: RAR-like, nociceptive and polymodal heart) probably interact with airway neurons in higher Ad-fibres [3]. neuronal centres to elicit the cough reflex [3]. The RAR-like fibres are very responsive to mechanical Corresponding author: Clive P. Page ([email protected]). stimulation, unresponsive to direct chemical stimuli such Available online 2 October 2004 as bradykinin and capsaicin and have their cell bodies in www.sciencedirect.com 0165-6147/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2004.09.009 570 Review TRENDS in Pharmacological Sciences Vol.25 No.11 November 2004 Cortex NK receptor antagonists ?, 5-HT receptor antagonists, – 3 Placebo baclofen, – sigma receptor agonists NTS Cough and respiratory pattern generator CNS µ κ δ , , 2 opioids, nociceptin, – 5-HT1 receptor agonists Inspiratory and expiratory motoneurons Respiratory muscles Jugular Nodose ganglion ganglion Cough – Conduction blockade – (i.e. lidocaine, NSI619, Opioids ? Vagus nerve Vagus moguisteine, furosemide) – Nociceptin C-fibres Nociceptive RARs'Cough receptors' SARs Aδ-fibres TRPV1 + B2 receptor RSD931 antagonists – – Airway receptors Airway – + +++ Nociceptin + Epithelium Neurokinins Plasma extravasation, bronchospasm, mucus secretion NK receptor antagonists TRENDS in Pharmacological Sciences Figure 1. The cough reflex and sites of action of some antitussive agents. Airway sensory nerves [e.g. C-fibres, nociceptive Ad-fibres, rapidly adapting receptors (RARs), polymodal Ad-fibres (‘cough receptors’) and slowly adapting stretch receptors (SARs)] activated in response to a pro-tussive stimulus travel through the vagus nerve to the medulla, where they terminate in the nucleus tractus solitarius (NTS). Second-order neurons relay the message to the respiratory pattern generator, which modifies the activity of the inspiratory and expiratory motoneurons and leads to cough. Antitussives can act peripherally at the level of the airway receptors or on nerve conduction. They can also act centrally, both pre- and post-synaptically. www.sciencedirect.com Review TRENDS in Pharmacological Sciences Vol.25 No.11 November 2004 571 Table 1. Differentiation of the various sensory nerve receptors thought to be involved in cough, based on a selection of relevant physiological propertiesa,b Physiological property C-fibres Ad-fibres SARs Nociceptive ‘Cough’ receptors RARs Ganglia Jugular Nodose Conduction velocity Slow Fast Involved in the control of regular breathing No Yes Sensitivity to mechanical stimuli Low High Chemosensitivity: acid Yes Probably No Chemosensitivity: capsaicin, bradykinin Yes No Expresses sensory neurokinins Yes When sensitized? No aNot all of these receptors have been identified in species other than guinea-pigs. bAbbreviations: RARs, rapidly adapting receptors; SARs, slowly adapting receptors. thenodoseganglia[8,9]. By comparison, nociceptive antagonists [18,19] and neutral endopeptidase [20], sug- Ad-fibres are sensitive to capsaicin and bradykinin, are 15 gesting a role for neuropeptides, at least in guinea-pigs. times less responsive to mechanical stimulation and have However, there is also evidence suggesting that C-fibres their cell bodies in the jugular ganglia. do not evoke cough [10] and might even inhibit cough Polymodal Ad-fibres (‘cough receptors’) have been [21,22]. In several studies where C-fibre stimulants have identified only recently [10]. These fibres are similar to been administered systemically, mechanically induced RAR-like fibres because they originate in the nodose cough has been inhibited in various species [21–23].As ganglia, are activated by mechanical stimulation and acid described earlier, there is also now evidence that capsaicin but are unresponsive to capsaicin, bradykinin, smooth might exert its effects via mechanisms other than sensory muscle contraction or stretching of the airways. Severing neuropeptide release [15]. Indeed, TRPV1 receptors have these nerves abolishes the cough response to citric acid been identified on Ad nociceptive fibres [24], which under and mechanical stimulation in an anaesthetized model of normal physiological conditions do not synthesize neuro- cough in guinea-pigs. It has been proposed that the peptides, but can be activated by capsaicin. Such obser- primary function of these fibres is the elicitation of vations might explain the inability of tachykinin receptor cough and as such could be regarded as the ‘hard-wiring’ antagonists to modify cough clinically even though they of the cough reflex [10]. are antitussive in guinea-pigs [25].

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