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Monday, August 11, 2025

Antitussives


Introduction

  • Antitussives are pharmacological agents that suppress coughing.

  • Used primarily for dry, non-productive coughs that interfere with rest, cause discomfort, or contribute to complications (e.g., post-surgical wound strain).

  • They act by targeting the cough reflex pathway at various levels:

    • Centrally in the medullary cough center.

    • Peripherally in respiratory tract receptors or afferent nerve endings.

  • Classified broadly into opioid and non-opioid agents, and sometimes combined with other drugs in cough preparations.

Cough Reflex Overview

  • Initiated by irritation or stimulation of receptors in the respiratory tract (larynx, trachea, bronchi).

  • Sensory signals transmitted via the vagus nerve to the medullary cough center in the brainstem.

  • Efferent signals cause coordinated contraction of respiratory muscles, producing cough.

  • Antitussives work by dampening afferent input, modulating central cough center activity, or reducing efferent responsiveness.

Classification

1. Centrally Acting Opioid Antitussives

  • Mechanism: Suppress cough center activity in the medulla by binding to opioid receptors.

  • Examples:

    • Codeine – gold standard; moderate efficacy; some analgesic and sedative effects; potential for dependence.

    • Hydrocodone – stronger cough suppression; higher abuse potential.

  • Limitations: Respiratory depression risk, constipation, potential for abuse, contraindicated in children in some regions.

2. Centrally Acting Non-Opioid Antitussives

  • Mechanism: Suppress cough reflex centrally without significant opioid receptor binding.

  • Examples:

    • Dextromethorphan – widely used; similar efficacy to codeine for mild cough; no analgesia; abuse potential at high doses (dissociative effects).

    • Butamirate – non-opioid, antitussive with bronchodilatory activity; not available in all markets.

3. Peripherally Acting Antitussives

  • Mechanism: Reduce sensitivity of cough receptors or soothe respiratory mucosa.

  • Examples:

    • Benzonatate – anesthetizes stretch receptors in the lungs and pleura; chemically related to local anesthetics.

    • Lozenges or syrups with demulcents (e.g., glycerol, honey) – coat and soothe irritated mucosa.

4. Mixed-Mechanism and Combination Preparations

  • Often combine antitussives with expectorants, decongestants, or antihistamines for broader symptom relief.

  • Example: Dextromethorphan + guaifenesin.

Pharmacokinetics

Codeine

  • Oral absorption: Good bioavailability.

  • Metabolism: Hepatic via CYP2D6 to morphine (active metabolite).

  • Half-life: 3–4 hours.

  • Excretion: Renal.

Dextromethorphan

  • Oral absorption: Rapid.

  • Metabolism: Hepatic via CYP2D6 to dextrorphan (active metabolite).

  • Half-life: 3–6 hours.

  • Excretion: Renal.

Benzonatate

  • Oral absorption: Variable; must be swallowed whole to avoid local anesthesia of mouth/throat.

  • Metabolism: Hydrolysis to para-aminobenzoic acid (PABA).

  • Duration: 3–8 hours.

Clinical Indications

  • Suppression of dry, hacking coughs interfering with sleep or daily activities.

  • Post-surgical or post-injury situations where cough may impair healing (e.g., hernia repair).

  • Cough associated with minor throat and bronchial irritation.

  • Certain chronic cough conditions (only after ruling out treatable causes).

Advantages

  • Improve comfort and rest in patients with persistent dry cough.

  • Reduce coughing fits that cause muscle strain, sleep disruption, or discomfort.

  • Some agents available OTC for easy access.

Limitations

  • Should not be used in productive coughs unless clinically justified (risk of mucus retention).

  • Symptomatic relief only – do not treat underlying cause.

  • Potential for abuse (especially opioids and dextromethorphan).

  • Adverse effect profiles vary, with CNS depression and sedation risks for some agents.

Adverse Effects

Opioid Antitussives (Codeine, Hydrocodone)

  • Sedation, dizziness.

  • Respiratory depression (especially in children or with overdose).

  • Constipation.

  • Nausea, vomiting.

  • Risk of dependence and abuse.

Non-Opioid Central Agents (Dextromethorphan)

  • Drowsiness, dizziness.

  • GI upset.

  • High doses: dissociative hallucinations, psychosis (NMDA receptor antagonism).

Peripherally Acting Agents (Benzonatate)

  • GI upset.

  • Numbness of oral mucosa if capsule is chewed or dissolved.

  • Hypersensitivity reactions.

Contraindications

  • Hypersensitivity to the drug.

  • Use of MAO inhibitors within the past 14 days (for dextromethorphan – risk of serotonin syndrome).

  • Respiratory depression, acute asthma attack (opioids).

  • Children under specific age cut-offs for codeine and hydrocodone in many countries.

Precautions

  • Elderly: increased risk of sedation and falls.

  • Patients with chronic respiratory disease: risk of mucus plugging.

  • Pregnancy and lactation: weigh benefits and risks; codeine passes into breast milk.

  • CYP2D6 ultra-rapid metabolizers: risk of opioid toxicity from codeine.

Drug Interactions

Codeine / Hydrocodone

  • Additive CNS depression with alcohol, benzodiazepines, sedative-hypnotics.

  • CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) may reduce efficacy of codeine.

Dextromethorphan

  • Serotonergic drugs (SSRIs, MAOIs, linezolid) – risk of serotonin syndrome.

  • CYP2D6 inhibitors increase plasma levels.

Benzonatate

  • No significant CYP-mediated interactions, but caution with other CNS depressants.

Special Populations

Pediatrics

  • Avoid codeine in children due to risk of rapid conversion to morphine and respiratory depression.

  • Dextromethorphan used with caution; avoid in very young children per local guidelines.

Elderly

  • More sensitive to sedative and hypotensive effects.

  • Dose adjustments may be necessary.

Pregnancy

  • Dextromethorphan generally considered low risk; opioids used only when benefits outweigh risks.

Future Directions

  • Development of selective P2X3 receptor antagonists for chronic cough.

  • Novel non-opioid central agents with minimal CNS side effects.

  • Combination formulations targeting both cough reflex suppression and airway inflammation.




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