Pharmacotherapy of Cough

Introduction

Cough is a protective reflex integral to clearing the airways of irritants, secretions, and foreign matter. Without a properly functioning cough mechanism, the risk of airway obstruction, infection, and subsequent respiratory complications increases significantly. Despite this physiological importance, persistent or unproductive cough can be disruptive, painful, and socially distressing. Chronic cough, typically defined as one lasting more than 8 weeks, can also be a hallmark sign of underlying pathologies such as asthma, gastroesophageal reflux disease (GERD), or chronic bronchitis (Goodman & Gilman, 2018).

The pharmacotherapy of cough aims to strike a balance between harnessing the cough’s protective role and suppressing excessive or harmful cough when it offers no physiological benefit. Understanding cough involves delving into its neurophysiology, the receptor triggers, the central processing within the brainstem’s cough center, and how medications either modulate these peripheral and central mechanisms or address the underlying causes. Current therapeutic options include opioid and non-opioid antitussives, expectorants, mucolytics, bronchodilators, and anti-inflammatory agents. This article offers a comprehensive, exploration of the modern pharmacological approaches to cough management, referencing key pharmacology texts such as “Goodman & Gilman’s The Pharmacological Basis of Therapeutics,” “Katzung’s Basic & Clinical Pharmacology,” and “Rang & Dale’s Pharmacology.”

Pathophysiology and Classification of Cough

The Cough Reflex

Cough begins with stimulation of afferent sensory nerve endings in the airway epithelium—particularly those in the larynx, trachea, and larger bronchi. These afferent signals, transmitted via vagus and glossopharyngeal nerves, converge on the cough center in the medulla. The medulla integrates these inputs and orchestrates the efferent signals distributed to the respiratory muscles (diaphragm, intercostals), pharyngeal and laryngeal muscles, and abdominal musculature, culminating in the characteristic forceful expiration (Rang & Dale, 2019).Coughing generally has three phases:

1. Inspiratory Phase: Rapid inhalation to generate a reservoir of air.
2. Compression Phase: Closure of the glottis and contraction of the expiratory muscles to elevate intrathoracic pressure.
3. Expiratory Phase: Sudden opening of the glottis and forceful expiration to expel irritants, mucus, or foreign particles.

Although the cough reflex is mostly protective, certain pathologies or stimuli can trigger excessive or nonproductive cough, necessitating pharmacological intervention.

Acute, Subacute, and Chronic Cough

Cough duration is commonly categorized:

• Acute Cough: Lasts up to 3 weeks; often caused by upper respiratory infections (common cold), acute bronchitis, pneumonia, or allergic rhinitis.
• Subacute Cough: Lasts between 3 and 8 weeks; may follow an acute infection (post-infectious cough).
• Chronic Cough: Persists longer than 8 weeks; etiologies include GERD, chronic bronchitis, bronchiectasis, asthma, postnasal drip, and even medication-induced (e.g., ACE inhibitors) (Katzung, 2020).

Rationale for Treating Cough

Cough serves a key defensive function, so treatment is generally reserved for:

1. Severe, Nonproductive Cough: Contributes to discomfort, sleep disruption, or negative impacts on quality of life.
2. Excessive, Harmful Cough: Risk of complications like rib fractures, urinary incontinence, or exacerbation of pre-existing conditions.
3. Underlying Etiology: For cough driven by infection or inflammatory disorders, addressing the cause also alleviates the symptom (Goodman & Gilman, 2018).

Therapeutic approaches often differentiate between symptomatic antitussives (which suppress cough reflex centrally or peripherally) and pro-tussive agents (expectorants, mucolytics) meant to facilitate airway clearance of secretions.

Pharmacological Strategies

1. Opioid Antitussives

Mechanism of Action

Certain opioids effectively suppress cough by acting on μ-opioid receptors in the central cough center—particularly the medulla—and possibly on peripheral afferent sensory nerve endings. While opioid analgesics share this property, their use in cough management typically involves milder opioids, at lower doses than for pain control, to limit adverse effects (Rang & Dale, 2019).

Commonly Used Opioid Antitussives

• Codeine: A weak opioid with moderate analgesic properties. In cough, codeine reduces the sensitivity of the cough center and can also dry up respiratory secretions. While historically common, concerns about respiratory depression, constipation, nausea, and dependence limit its usage.
• Hydrocodone: Similar to codeine but with a higher potential for abuse and respiratory depression. Generally reserved for severe cough refractory to other options.
• Pholcodine: Not available in all regions, but used in many countries as a central antitussive with comparatively mild sedation (Katzung, 2020).

Adverse Effects

• Respiratory Depression (especially in overdose or in compromised patients)
• Sedation, drowsiness
• Constipation
• Nausea, vomiting
• Potential for DependenceCaution is particularly necessary in pediatric populations and patients with chronic obstructive pulmonary disease (COPD) or compromised respiratory effort. Regulatory measures restrict over-the-counter availability of opioid antitussives in many jurisdictions (Goodman & Gilman, 2018).

2. Non-Opioid Antitussives

Dextromethorphan

One of the most widely used over-the-counter antitussives, dextromethorphan, is structurally related to opioid levorphanol but lacks significant analgesic or addictive properties at standard doses. Dextromethorphan suppresses the medullary cough center—possibly via sigma-1 or NMDA receptor modulation—and is considered safer than opioid antitussives in terms of respiratory depression (Rang & Dale, 2019).• Advantages: Minimal sedation, low risk of dependence, wide availability in combination cough and cold preparations.
• Adverse Effects: At high doses, dissociative or hallucinogenic effects (akin to phencyclidine or ketamine) can occur. Misuse among adolescents is a known concern (Katzung, 2020).

Benzonatate

Benzonatate is a peripherally acting antitussive that anesthetizes stretch receptors in the respiratory passages, reducing cough reflex initiation. It can also pass centrally. While it can be effective for persistent cough, potential adverse events include numbness of the oropharynx, especially if capsules are chewed, which can precipitate aspiration. Rare but serious allergic reactions or CNS effects (confusion, visual hallucinations) are documented (Goodman & Gilman, 2018).

3. Expectorants and Mucolytics

Mechanism and Rationale

In productive coughs, the aim is not to suppress the reflex but rather to enhance the clearance of secretions. Expectorants and mucolytics thin or loosen tracheobronchial secretions, making them easier to expel.

Guaifenesin (Glyceryl Guaacolate)

Guaifenesin is the most commonly used expectorant, purported to reduce the viscosity of mucus and facilitate its clearance. Although the evidence base for guaifenesin’s clinical efficacy in cough is mixed, it remains a staple in OTC cough and cold formulations. Generally, it is well tolerated, with minimal side effects like nausea or dizziness (Katzung, 2020).

N-Acetylcysteine (NAC) and Carbocisteine

N-Acetylcysteine (NAC) exerts a mucolytic effect by cleaving disulfide bonds in mucus glycoproteins, reducing sputum viscosity. NAC is routinely employed in conditions such as chronic bronchitis, cystic fibrosis, and acetaminophen overdose (though the latter is a distinct usage unrelated to cough). Carbocisteine is another mucolytic agent that alters mucus structure. Both can cause gastrointestinal upset or unpleasant smells/taste (Rang & Dale, 2019).

Dornase Alfa

A recombinant human deoxyribonuclease (DNase), dornase alfa specifically breaks down DNA in the sputum of cystic fibrosis patients, thereby reducing viscosity. Though not a treatment for common cough, it demonstrates how targeted mucolytic therapy can dramatically improve clearance (Goodman & Gilman, 2018).

4. Bronchodilators

Role in Cough

Bronchospasm or airway hyperreactivity can initiate or exacerbate cough. Therefore, bronchodilators may benefit patients with asthma, COPD, or other obstructive pathologies that present with cough. By reducing airway obstruction, bronchodilators can lessen cough frequency.

Classes of Bronchodilators

1. β2-Adrenergic Receptor Agonists: Albuterol (salbutamol), salmeterol, formoterol. These relax bronchial smooth muscle by increasing intracellular cAMP within the airway.
2. Anticholinergics: Ipratropium, tiotropium. By blocking muscarinic receptors, they reduce bronchoconstriction and mucus secretion.
3. Methylxanthines: Theophylline, though less commonly used due to narrow therapeutic index and side effect potential (Katzung, 2020).

Clinical Use

By targeting underlying airway disease, bronchodilators indirectly reduce cough. In asthmatic or COPD patients, optimum inhaled bronchodilator therapy is a mainstay for controlling cough that arises from airway hyperreactivity (Rang & Dale, 2019).

5. Anti-Inflammatory Therapies and Corticosteroids

A key driver of chronic cough can be airway inflammation, seen in conditions like allergic asthma, eosinophilic bronchitis, and beyond. Corticosteroids alleviate inflammation by modulating cytokine production, adhesion molecules, and inflammatory mediator release.• Inhaled Corticosteroids (ICS): Budesonide, fluticasone, beclomethasone. Highly effective in asthma-related cough; typically combined with bronchodilators.
• Oral Corticosteroids: Prednisone, methylprednisolone. Reserved for severe or refractory cases, given the systemic side effect profile.
• Leukotriene Receptor Antagonists: Montelukast can help if leukotriene-driven airway inflammation contributes to cough (Goodman & Gilman, 2018).For chronic cough where an eosinophilic or allergic component is suspected, a trial of inhaled steroids can help confirm steroid-responsive disease.

6. Combination Preparations

Most over-the-counter cough and cold products include combinations (e.g., dextromethorphan + guaifenesin, or antihistamine + nasal decongestant). While these can provide multimodal relief—reducing cough reflex sensitivity, facilitating mucus clearance, and addressing nasal congestion—clinical data on efficacy can be variable. Additionally, combination products carry greater risk of polypharmacy side effects, especially if patients simultaneously take other medications containing the same ingredients (Katzung, 2020).

Specific Etiology-Driven Treatment

Postnasal Drip (Upper Airway Cough Syndrome)

A prominent cause of chronic cough is postnasal drip, frequently associated with allergic rhinitis or chronic sinusitis. Treatment typically includes:

• Antihistamines (e.g., loratadine, cetirizine, fexofenadine) to reduce nasal discharge.
• Nasal Corticosteroids (e.g., fluticasone, mometasone, budesonide) to address inflammation in nasal passages.
• Decongestants (though caution in hypertensive patients due to systemic vasoconstrictive effects).

If cough improves when these interventions are used, postnasal drip is likely the culprit (Goodman & Gilman, 2018).

GERD-Related Cough

Gastroesophageal reflux disease can trigger cough via micro-aspiration or vagally mediated reflexes. According to guidelines, a proton pump inhibitor (e.g., omeprazole, lansoprazole, esomeprazole) trial for a few weeks clarifies if GERD is the underlying factor. H2 receptor antagonists such as ranitidine or famotidine may be used, albeit with typically less potency (Katzung, 2020).

Asthma and Eosinophilic Bronchitis

• Inhaled Corticosteroids plus bronchodilators are mainstays for asthma.
• For cough-variant asthma or eosinophilic bronchitis, ICS can greatly reduce cough by diminishing airway hyperresponsiveness.
• Leukotriene Modifiers (e.g., montelukast) help in some patients unresponsive to ICS alone (Rang & Dale, 2019).

ACE Inhibitor-Induced Cough

A well-known side effect of ACE inhibitors (e.g., enalapril, lisinopril) is a dry cough due to bradykinin and substance P accumulation. Switching to an angiotensin II receptor blocker (ARB) (e.g., losartan, valsartan) often resolves this cough (Goodman & Gilman, 2018).

Chronic Bronchitis and COPD

Patients with chronic bronchitis exhibit excessive mucus production and cough. Smoking cessation is vital. Pharmacologically, inhaled bronchodilators (β2 agonists or anticholinergics) and inhaled corticosteroids are used. Mucolytics (e.g., N-acetylcysteine) hold modest benefit in reducing sputum viscosity. Phosphodiesterase-4 inhibitors (e.g., roflumilast) can target inflammation (Katzung, 2020).

Pediatric and Special Populations

Pediatrics

• Cough remedies in children should be approached with caution, as young children are more vulnerable to respiratory depression from opioid antitussives and sedation from antihistamines.
• Over-the-counter cough and cold products are often contraindicated under a certain age (often <6 years) due to risk of serious adverse events and questionable efficacy.
• Honey is sometimes recommended for children over one year of age to soothe the throat and reduce cough frequency in mild infections (Rang & Dale, 2019).

Elderly

• The risk of sedation or confusion from certain agents (e.g., antihistamines, opioids) can be higher due to altered pharmacokinetics, polypharmacy, and comorbidities such as dementia.
• Non-sedating or low-sedating therapies are often preferred.
• Investigating underlying causes (e.g., heart failure, malignancy, aspiration) is essential given that persistent cough in older adults may reflect serious disease (Goodman & Gilman, 2018).

Pregnancy

• Most cough medications have not undergone robust trials in pregnant individuals. Dextromethorphan is generally considered low risk, but caution remains.
• Codeine, if necessary briefly, may be used, but concerns about fetal sedation or neonatal withdrawal highlight the need for strict risk-benefit evaluation.
• Non-pharmacological interventions (hydration, humidified air) are often preferred in pregnancy (Katzung, 2020).

Non-Pharmacological Approaches

Alongside medications, non-pharmacological strategies often help mitigate cough:

• Hydration and humidification: Keeping respiratory tract secretions less viscous.
• Honey, lozenges: Soothing the oropharynx, though direct evidence is modest.
• Smoking cessation: Essential for chronic bronchitis or COPD-driven cough.
• Airway Clearance Techniques: Postural drainage, chest physiotherapy—particularly in bronchiectasis or cystic fibrosis.
• Elimination of Environmental Triggers: Removing irritants like dust, pollution, or known allergens can reduce cough episodes (Rang & Dale, 2019).

Safety Considerations and Adverse Effects

Overuse and Misuse of OTC Cough Products

Over-the-counter cough remedies, including dextromethorphan-containing products, carry a risk of recreational misuse. High doses can cause neuropsychiatric effects, while combining them with alcohol or other CNS depressants can precipitate sedation or overdose (Katzung, 2020).

Drug Interactions

• MAO Inhibitors + dextromethorphan: Risk of serotonin syndrome.
• CNS Depressants + opioid antitussives: Summation of respiratory depression and sedation.
• Warfarin + certain cough medications (rarely) might alter INR, though clinically less common (Goodman & Gilman, 2018).

Dependence and Tolerance

Continuous use of opioid antitussives can produce physical dependence and lead to drug abuse. Furthermore, tolerance to the antitussive effect can necessitate higher doses for the same relief, potentially escalating adverse effects (Rang & Dale, 2019).

Rationale Use in Specific Populations

Due to variance in risk-benefit profiles—especially among pediatric and geriatric populations—guidelines typically recommend using lowest effective doses for the shortest durations necessary, or leaning on non-pharmacological measures when possible (Katzung, 2020).

Emerging and Future Therapies

Despite the prevalence of cough, historically there has been relatively limited pharmacological innovation. However, newer investigations explore:

• P2X3 Receptor Antagonists: These target ATP-gated ion channels implicated in chronic cough hypersensitivity. Early trials with gefapixant show promise in refractory chronic cough.
• TRPV1 (Vanilloid) Receptor Modulators: TRPV1 is linked to cough reflex sensitization triggered by capsaicin-like stimuli. Trials for selective antagonists aim to tame pathologic cough (Goodman & Gilman, 2018).
• Neurokinin Receptor Antagonists: Substance P involvement in airway hyperresponsiveness has spurred interest in neurokinin-1 receptor blockers.

Such specialized receptors highlight the complexity of cough as a multi-receptor, multi-pathway phenomenon. Enhanced understanding of peripheral sensory pathways, neuronal plasticity in cough reflex arcs, and inflammatory mediators drives these novel drug targets (Rang & Dale, 2019).

Clinical Approaches and Guidelines

Relatively few evidence-based guidelines exist specifically for cough, but broad consensus dictates:

1. Identify Underlying Etiology: Comprehensive evaluation for postnasal drip, asthma, GERD, infections, or medication-induced triggers.
2. Targeted Therapy: Use ICS for asthma-driven cough, or a PPI trial for suspected GERD, for instance.
3. Empiric Therapy: When cause is uncertain but suspicion is high (e.g., cough variant asthma), short trials help confirm or refute the diagnosis.
4. Limit Symptomatic Suppression: Reserve antitussive agents (especially opioids) for severe, nonproductive coughs or when cough is detrimental to patient well-being (Katzung, 2020).
5. Stepped Care: Titrate medication based on results and side effects. If cough persists despite thorough evaluation and therapy, specialized investigation (bronchoscopy, imaging) may be warranted (Goodman & Gilman, 2018).

Practical Recommendations

1. Acute Viral Cough: If mild, non-pharmacological measures (hydration, rest, honey in children >1 year) might suffice. If cough is severe, a short course of dextromethorphan could provide relief. Avoid antibiotic overuse without bacterial indication.
2. Chronic Unexplained Cough: Investigate common causes (postnasal drip, GERD, asthma), try appropriate therapy (e.g., inhaled steroids, PPI). Reassess in 2-4 weeks.
3. Productive or “Wet” Cough: Encourage airway clearance. An expectorant like guaifenesin for mild symptomatic relief, but emphasis on hydration and addressing the cause.
4. Severe Debilitating Cough: Opioid-based agents (e.g., codeine) might be considered under close supervision for short durations, especially in palliative or terminal care settings (Rang & Dale, 2019).

Conclusion

Cough is a complex, multifaceted reflex fundamental to airway protection yet often disruptive and distressing when excessive or nonproductive. Modern pharmacotherapy offers a range of tools from opioid and non-opioid antitussives, expectorants, mucolytics, and bronchodilators to anti-inflammatory agents like corticosteroids and leukotriene modifiers. Optimal management hinges on identifying and treating underlying etiologies, with symptomatic treatments reserved for cases where the cough confers more harm than benefit or significantly affects quality of life (Goodman & Gilman, 2018).

For acute self-limited coughs, supportive or minimal therapy often suffices. In persistent, chronic cough, a thorough diagnostic approach and etiology-specific therapies (e.g., PPIs for GERD, ICS for asthma, removing an ACE inhibitor) will often yield the best outcomes. Pediatric and elderly populations demand additional caution due to heightened susceptibility to adverse drug effects. Looking ahead, novel receptor antagonists targeting cough reflex hyperexcitability may provide new avenues for patients with refractory chronic cough. Still, time-honored fundamentals—examining the cause and exercising judicious medication use—remain at the core of safe and effective cough management (Katzung, 2020; Rang & Dale, 2019).

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition.
• Katzung BG, Basic & Clinical Pharmacology, 14th Edition.
• Rang HP, Dale MM, Rang & Dale’s Pharmacology, 8th Edition.