There are currently no effective treatments for controlling the cough response with an acceptable therapeutic ratio. However, several new mechanisms have been identified which may lead to the development of new drugs.
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Chronic cough is associated with many inflammatory airways diseases such as asthma, chronic obstructive pulmonary disease (COPD), post viral infections, pulmonary fibrosis, and bronchiectasis. Indeed, it is the first and most persistent symptom of diseases such as asthma and COPD.1,2 Furthermore, it is the most common respiratory complaint for which medical attention is sought and, although UK annual sales of over the counter (OTC) cough remedies are over £0.5 billion, effective treatments for cough are very limited. In fact, a recent study has suggested that OTC medicines for acute cough cannot be recommended because there is no good evidence for their effectiveness given that, even in studies where OTC compounds showed minimal benefits, these were of doubtful clinical relevance.3 The identification of new therapeutic targets for the treatment of chronic cough will therefore be of immense therapeutic benefit and will greatly enhance the quality of life of patients.
The most effective antitussive agents are opioids such as morphine, diamorphine, and codeine which, in all probability, act both centrally on brainstem opioid receptors and on receptors located peripherally on sensory nerve endings in the airways.4 However, at their effective doses they also cause physical dependence, respiratory depression, and gastrointestinal symptoms. Morphine and diamorphine are very addictive but are useful in treating severe distressing cough in patients with terminal illness such as bronchial carcinoma. Several opiate-containing proprietary cough mixtures contain low doses of weaker opioids such as codeine, but there is no strong evidence that these are more effective than the demulsant vehicle.
Non-narcotic antitussive agents
Dextromethorphan is the dextro isomer of the opiate levomethorphan and it has no analgesic or sedative properties. Dextromethorphan is the most commonly used antitussive in the USA. Orally administered dextromethorphan is as effective as codeine in suppressing cough and has been used as a constituent of many OTC preparations. Furthermore, recent reports suggest that patients with an opioid resistant cough achieved symptomatic relief with the peripherally acting non-opioid drug benzonatate.5 Levodropropizine, oxalamine, and prenoxdiazine are available as cough treatments in Europe. Clinical studies have shown favourable data with levodropropizine in cancer related cough.6
Local anaesthetics such as lignocaine are delivered locally to the airways and have been shown to attenuate capsaicin induced cough in humans.7 However, the effect is transient and the antitussive effect is accompanied by oropharyngeal anaesthesia leading to an increased risk of aspiration of airway secretions and food. This treatment should be avoided in patients with asthma because it may induce severe bronchoconstriction. Interestingly, lozenges containing local anaesthetics are often used as OTC treatment for acute cough such as that following an upper respiratory tract infection.
Menthol has been proposed as an antitussive treatment and has been shown to inhibit citric acid induced cough in normal volunteers, but to a lesser extent than lignocaine.8 However, it has advantages over lignocaine as menthol does not result in oropharyngeal anaesthesia and may therefore be a more selective antitussive treatment.9
New drugs for the treatment of cough may be directed at an extremely heterogeneous group of targets. A major distinction in this regard is the ability of certain drugs to inhibit the underlying inflammatory process that under certain conditions cause cough—for example, anti-inflammatory drugs for the treatment of asthma or COPD or novel proton pump inhibitors as treatment for gastro-oesophageal reflux—or compounds that are targeted to inhibit sensory nerve activity directly which should, in theory, inhibit cough of any aetiology. However, here we would like to focus on compounds that can be classified as symptomatic antitussive agents which recognise as their main targets ion channels, receptors, or other molecules expressed peripherally in primary sensory neurons or by inhibition of central mechanisms.
Ligands acting at G protein coupled receptors
In addition to the classical opioids such as enkephalins, β-endorphins, and dynorphins, new opioid peptides have been described which have functional effects in the airways—for example, the endogenous opioid peptide nociceptin/orphanin FQ and endomorphins 1 and 2 have recently been isolated.10 Nociceptin and the endomorphins are structurally different from one another and from the classical opioids.
Three classical opioid receptors have been identified pharmacologically: OP1 (formerly the δ-opioid receptor), OP2 (formerly the κ-opioid receptor), and OP3 (formerly the µ-opioid receptor). The opioids currently used as antitussive treatment predominantly bind the OP3 receptor and are therefore associated with characteristic side effects. New opioid peptides such as the endomorphins also activate the OP3 receptor. However, the endogenous opioid peptide nociceptin/orphanin FQ has some homology to the dynorphin family but lacks the N-terminal tyrosine residue which is essential for binding classical opioid receptors. Interestingly, nociceptin binds to the opioid receptor-like 1 receptor (ORL1). Furthermore, ORL1 has already been shown to inhibit sensory nerve function in guinea pig airways in vitro and may be an excellent target for new antitussive treatments.11,12
Neurokinin receptor antagonists
Tachykinins such as substance P and neurokinin A have been shown to elicit cough, and neurokinin receptor antagonists have been shown to be effective antitussive agents in animal models. Data have implicated a role for the NK2 receptor and possibly the NK1 receptor in this antitussive action. In fact, the NK2 receptor antagonist SR 48968 has been shown to inhibit citric acid induced cough in conscious guinea pigs,13,14 but an antitussive effect of NK1 receptor antagonists is still debated. Recent data have suggested a role for NK3 receptor activation in evoking a tussive response.15,16 SB 235375, a high affinity selective, reversible, and competitive antagonist, is also effective against citric acid induced cough in guinea pigs.16 It is a low CNS penetrant compound and, as such, it has been suggested that this compound has a peripheral mechanism of action even though there have been no reports of the presence of functional NK3 receptor antagonists in the human lung.
Bradykinin receptor antagonists
Bradykinin has been shown to elicit cough in man,17 and exposure of guinea pigs to aerosols of citric acid (low pH solution) or capsaicin produces reproducible cough presumably initiated by the activation of C fibres.18 Prior exposure of guinea pigs to bradykinin or the angiotensin converting enzyme (ACE) inhibitor captopril enhanced citric acid induced cough. In both cases this enhancement was prevented by treatment with the bradykinin B2 receptor antagonist.18 Bradykinin induced sensitisation of C fibres may be the mechanism operative in ACE inhibitor induced cough where a proportion of patients receiving this treatment for hypertension or cardiac failure exhibit a chronic cough and increased cough sensitivity to citric acid or capsaicin. ACE is an enzyme which is involved in the breakdown of bradykinin and therefore it has been hypothesised that the increased levels of bradykinin in the airways of patients on ACE inhibitor therapy could cause sensitisation of airway C fibres leading to the enhanced sensitivity of the cough reflex which could theoretically be treated with B2 receptor antagonists. Consistent with these pharmacological data describing a role for bradykinin in ACE inhibitor cough are studies which show that bradykinin B2 receptor gene polymorphism is associated with ACE inhibitor related cough.19
Inhibition of prostanoid synthesis/action
The high tussive potency of the prostaglandins in humans suggests that their local release in various respiratory pathophysiological conditions may be responsible for the accompanying cough/irritancy.17,20 In patients with asthma cough thresholds with indomethacin and OKY-046 (thromboxane synthase inhibitor) treatment were significantly greater than with placebo, which supports the hypothesis that thromboxane A2 may be one of the cyclooxygenase products augmenting airway cough sensitivity in asthma.21 Furthermore, it has been suggested that prostaglandins may have a role in the genesis of cough induced by ACE inhibitors, and inhibition of prostaglandin synthesis with indomethacin22 or a thromboxane antagonist23 can reduce or abolish the incidence of this side effect. However, although prostaglandins may be involved in cough associated with ACE inhibitor therapy, evidenced by the ability of the non-steroidal anti-inflammatory sulindac to inhibit cough in patients on this treatment, the same compound was ineffective in patients not on ACE inhibitor therapy but with idiopathic dry unproductive cough.24
Ion channel modulators
Transient receptor potential (TRP) channels
Recently, receptors have been cloned on sensory nerves that are activated by thermal stimuli. The cold and menthol sensitive receptor (CMR1) has recently been characterised and cloned and is a member of the TRP family of excitatory ion channels.25 Interestingly, menthol has been proposed as an antitussive treatment and has been shown to inhibit citric acid induced cough in normal volunteers.8 Activators of this particular channel may therefore prove to be useful therapeutic agents. The heat sensitive channels VR1 and VRL-1 are TRP channels that detect temperatures over a wide range. The VR1 channel is activated by capsaicin, the main pungent ingredient in hot chilli peppers; however, the related channel VRL-1 does not respond to capsaicin but is activated by temperatures exceeding 50°C.26,27 Since the actions of the sensory nerve stimulant capsaicin on sensory nerves may be mediated by activation of the VR1 receptor, blocking these channels may be a good target for an antitussive treatment.
Potassium channel openers
In single fibre recording studies, NS1619, an opener of large conductance calcium activated potassium (BKCa) channels, has been shown to inhibit the firing of Aδ and C fibres innervating the guinea pig airway. In the same study the guinea pig tussive response elicited to citric acid was also inhibited by NS1619 which underlines the usefulness of this class of compounds for cough treatment in the future.28
Other workers have suggested that ATP sensitive potassium channels may be a good target following studies in which openers of these channels (pinacidil and cromakalim) reduced citric acid induced cough in guinea pigs.29
It has been shown that frusemide can reduce the potentiation of capsaicin induced cough by prostaglandin F2α (PGF2α). Frusemide had no effect on capsaicin induced cough alone. In view of these findings it has been suggested that changes in local ionic concentrations by frusemide, particularly chloride ions within the vicinity of epithelial cough receptors, may be responsible for this inhibitory effect.30
Treatment of the underlying cause of cough can often be effective—for example, inhaled corticosteroids for asthma related cough. However, at the moment there are no effective treatments controlling the cough response per se with an acceptable therapeutic ratio. There is therefore a need for more selective drugs with a favourable side effect profile. The future looks promising with identification of several new mechanisms which may lead to new drugs that target the increased sensitivity of sensory fibres resulting in exaggerated cough.
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