Pharmacotherapy of Cough

Pharmacotherapy of Cough


Cough is a protective reflex that helps clear the airways of irritants and secretions. It can be classified as acute (<3 weeks duration) or chronic (>8 weeks).[1] While acute cough is usually self-limiting and resolves on its own, chronic cough can significantly impair quality of life. Pharmacological management is a key component of treating both acute and chronic cough. This article will review the major drug classes used to treat cough and their mechanisms of action.

Pathophysiology of Cough

The cough reflex is mediated by sensory nerves in the airways that are activated by mechanical and chemical stimuli. Afferent signals travel via the vagus nerve to the brainstem cough center, which then sends efferent signals to the respiratory muscles to produce the cough.[2]

The most important receptors involved in the cough reflex are:[3]

  • Rapidly adapting receptors (RARs): Activated by mechanical stimuli like bronchoconstriction
  • Slowly adapting stretch receptors (SARs): Activated by lung inflation
  • C-fiber receptors: Activated by chemical stimuli like capsaicin, bradykinin, acid

Peripheral and central sensitization of the cough reflex can occur in conditions like viral upper respiratory infections, asthma, GERD, and chronic bronchitis, leading to a heightened cough response.[4]

Antitussive Agents


Opioids like codeine, hydrocodone, and dextromethorphan are some of the most effective antitussives. They act centrally in the brainstem to suppress the cough reflex.[5] Codeine is a naturally occurring opiate that directly activates mu opioid receptors. Typical doses are 10-20 mg PO q4-6h.[6]

Dextromethorphan is a synthetic opioid derivative available OTC. It is the D-isomer of the codeine analog levorphanol. Unlike codeine, dextromethorphan has very weak mu receptor affinity and instead acts as an agonist at sigma-1 receptors and as an NMDA receptor antagonist.[7] Usual doses are 10-30 mg PO q4-8h.

The main side effects of opioid antitussives are sedation, nausea, constipation, and potential for abuse/dependence with long-term use. They should be used cautiously in children <18 years old due to risk of respiratory depression.[8]


Benzonatate is a non-narcotic oral antitussive chemically related to procaine. Its precise mechanism is unknown but may involve anesthetizing stretch receptors in the lungs and pleura.[9] Usual dose is 100-200 mg PO TID as needed. Benzonatate can cause choking if the capsules are chewed or dissolved. Seizures and cardiac arrest have rarely been reported.[10]


Doxylamine is a first-generation antihistamine with anticholinergic properties. It provides antitussive effects likely through both H1 receptor and muscarinic receptor antagonism. Typical doses are 7.5-12.5 mg PO q4-6h.[11] Doxylamine commonly causes drowsiness and anticholinergic side effects like dry mouth/nose, blurred vision, urinary retention.

Expectorants & Mucolytics


Guaifenesin is an expectorant that increases airway mucus production and decreases mucus viscosity to facilitate clearance.[12] Its mechanism may involve irritation of gastric vagal receptors.[13] Usual doses are 200-400 mg PO q4h. Side effects are typically mild GI upset. There is limited evidence for clinically significant benefit of guaifenesin in acute or chronic bronchitis.[14][15]

N-acetylcysteine (NAC)

NAC is a mucolytic that directly cleaves disulfide bonds in mucus glycoproteins, reducing mucus viscosity. Oral NAC is poorly absorbed; most studies have used nebulized NAC 300-1200 mg BID.[16] Inhaled NAC can cause bronchospasm in some patients. Oral NAC at high doses (>1200 mg/day) has caused nausea, vomiting and diarrhea.[17]


While bronchodilators do not directly suppress cough, they can be helpful adjuncts in patients with concomitant airway disease like asthma or COPD. By reducing bronchospasm and airway hyperresponsiveness, bronchodilators may indirectly reduce cough.

Beta-2 agonists

Short-acting inhaled beta-2 agonists like albuterol are first-line treatments for acute bronchospasm. They activate beta-2 receptors on airway smooth muscle, leading to relaxation and bronchodilation. Typical albuterol doses are 2 puffs of 90mcg inhaler q4-6h. Long-acting beta-2 agonists like salmeterol are used as controllers in persistent asthma/COPD.[18]


Inhaled anticholinergic agents like ipratropium and tiotropium provide bronchodilation by blocking acetylcholine binding to muscarinic receptors on airway smooth muscle. Ipratropium is short-acting with peak effect in 30-60 min; typical dose is 2 puffs of 17mcg inhaler q6h.[19] Tiotropium is long-acting and dosed once daily. Anticholinergics are less effective than beta-2 agonists for acute bronchospasm but have additive benefit when used in combination.


Theophylline is a nonselective phosphodiesterase inhibitor that has been used orally for chronic asthma and COPD. It increases intracellular cAMP, leading to airway smooth muscle relaxation. However, theophylline has a narrow therapeutic window with frequent adverse effects (nausea, vomiting, arrhythmias, seizures), and inhaled bronchodilators are now strongly preferred.[20]

Anti-Inflammatory Agents

Inflammation plays a key role in many chronic cough syndromes like asthma, nonasthmatic eosinophilic bronchitis, and post-viral cough hypersensitivity. Inhaled and oral anti-inflammatory agents can help reduce cough in these conditions.

Inhaled corticosteroids (ICS)

ICS are the mainstay of treatment for persistent asthma and eosinophilic bronchitis. They bind to intracellular glucocorticoid receptors and modulate gene transcription to reduce airway inflammation.[21] Fluticasone, budesonide, and mometasone are commonly used ICS. They are usually dosed 1-2 puffs BID depending on asthma severity. For refractory eosinophilic bronchitis, high-dose ICS (e.g. fluticasone 500-1000mcg/day) may be required.[22]

Leukotriene receptor antagonists (LTRA)

Montelukast is an oral LTRA used as an add-on controller medication in asthma. It blocks the effects of cysteinyl leukotrienes, reducing bronchoconstriction and inflammation. The usual dose is 10 mg PO nightly for adults, 5 mg for ages 6-14, 4 mg for ages 2-5.[23]

Oral corticosteroids

For acute asthma exacerbations not responding to inhaled therapy, a short course of oral prednisone (40-60 mg daily for 5-10 days) may be needed to gain control of symptoms including cough.[24] Oral steroids can also be an effective temporizing measure for difficult-to-control chronic cough due to asthma or other inflammatory conditions while initiating ICS.[25] However, the long-term use of oral steroids should be avoided due to their extensive side effect profile.

Neuromodulatory Agents

In some patients with refractory chronic cough, there is thought to be a neuropathic component involving central cough hypersensitivity. Several neuromodulatory medications have shown benefit in clinical trials for this subgroup.

Gabapentin and pregabalin

These anti-convulsant drugs bind to voltage-gated calcium channels, reducing release of excitatory neurotransmitters. A randomized trial found that gabapentin 300 mg daily significantly improved cough-specific quality of life compared to placebo.[26] Pregabalin 150-300 mg daily has also shown efficacy.[27]


Low-dose amitriptyline, a tricyclic antidepressant, has been used off-label for chronic refractory cough based on its effficacy for other neuropathic conditions. A small study reported cough improvement in the majority of patients treated with amitriptyline 10 mg nightly.[28] However, sedation and anticholinergic side effects can be limiting.

Novel Agents

P2X3 antagonists

The purinergic receptor P2X3 is expressed on airway sensory nerves and is involved in mediating the cough reflex. ATP released during airway inflammation and injury can activate P2X3, causing neuronal hypersensitivity. Drugs that block P2X3 represent a promising new class for refractory chronic cough.[29]

Gefapixant is a selective P2X3 antagonist that reduced cough frequency compared to placebo in phase 2 trials.[30][31] However, it caused taste disturbance in over 50% of subjects. Phase 3 trials at lower doses are ongoing. Other P2X3 antagonists like BLU-5937 are also in development and may have better tolerability.


A variety of pharmacologic options exist for managing acute and chronic cough. Antitussives like dextromethorphan are useful for symptom control in acute viral bronchitis. Treatment of chronic cough depends on the underlying etiology – bronchodilators and anti-inflammatory agents are helpful for cough due to asthma and COPD; neuromodulatory agents may benefit refractory cough with a neuropathic component. Continued research into the pathophysiology of cough will likely lead to novel targeted therapies in the near future. A systematic approach utilizing available pharmacology along with treatment of underlying triggers remains key to successful cough management.


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Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

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