Pharmacology of Antitussives and Expectorants

Introduction/Overview

Cough is a complex, protective reflex mediated by the vagus nerve, serving to clear the airways of secretions, irritants, and foreign particles. While essential for pulmonary defense, cough can become excessive, non-productive, and debilitating, significantly impairing quality of life, sleep, and recovery. The pharmacological management of cough involves two principal strategies: suppression of the cough reflex itself and facilitation of productive expectoration. Antitussives are agents that suppress the cough center in the medulla or act peripherally on sensory receptors, thereby diminishing the urge to cough. Expectorants and mucolytics, conversely, aim to increase the volume or decrease the viscosity of respiratory tract secretions, promoting their clearance and transforming a dry, irritating cough into a more productive one.

The clinical relevance of these agents is substantial, given the high prevalence of acute and chronic cough associated with upper respiratory tract infections, bronchitis, chronic obstructive pulmonary disease (COPD), and other pulmonary conditions. However, their use requires careful consideration, as cough is often a symptom of underlying pathology, and inappropriate suppression may be detrimental. A thorough understanding of the pharmacology, appropriate indications, and limitations of these drugs is therefore fundamental for rational therapeutic decision-making.

Learning Objectives

• Classify major antitussive and expectorant agents based on their site and mechanism of action.
• Explain the molecular and neurophysiological mechanisms by which opioid and non-opioid antitussives suppress the cough reflex.
• Describe the pharmacokinetic profiles of prototype agents, including key considerations for dosing and administration.
• Evaluate the therapeutic applications, adverse effect profiles, and major drug interactions for commonly used antitussives and expectorants.
• Apply knowledge of special population considerations, including pediatric use, pregnancy, and renal or hepatic impairment, to clinical prescribing decisions.

Classification

Antitussives and expectorants are categorized based on their primary pharmacological action. A clear classification framework aids in understanding their therapeutic roles and selecting appropriate agents.

Antitussives (Cough Suppressants)

Antitussives are broadly divided into central and peripheral acting agents.

• Centrally Acting Antitussives
  • Opioid Antitussives: Codeine, Hydrocodone, Pholcodine. These are agonists at mu-opioid receptors within the central nervous system.
  • Non-Opioid Antitussives: Dextromethorphan (a dextro-isomer of the opioid levorphanol but lacking classical opioid agonism), Benzonatate (a peripherally-acting agent with some central effects).
• Peripherally Acting Antitussives
  • Local Anesthetics: Benzonatate (also classified here due to its anesthetic action on pulmonary stretch receptors).
  • Demulcents: Honey, glycerin, lozenges. These soothe irritated pharyngeal mucosa, providing a barrier against irritants.

Expectorants and Mucolytics

These agents facilitate the removal of secretions from the respiratory tract.

• Expectorants (Secretagogues): Guaifenesin, Potassium Iodide, Ipecacuanha (emetine). They are believed to increase the volume and/or decrease the tenacity of respiratory tract fluid.
• Mucolytics: N-Acetylcysteine (NAC), Carbocisteine, Erdosteine, Dornase alfa (recombinant human deoxyribonuclease). These drugs act chemically to break down the molecular structure of mucus.
• Mucokinetic Agents: Beta₂-adrenergic agonists (e.g., salbutamol), Methylxanthines (e.g., theophylline). While primarily bronchodilators, they may enhance mucociliary clearance.
• Saline Expectorants: Hypertonic saline (3-7%), administered via nebulization.

Mechanism of Action

The mechanisms underlying cough suppression and expectoration are distinct, involving modulation of neural pathways and the physical properties of respiratory secretions.

Mechanism of Antitussive Action

The cough reflex arc consists of afferent sensory fibers (predominantly vagal), a central cough center in the medulla oblongata, and efferent motor pathways. Antitussives act at various points along this arc.

Central Antitussives

Opioid Antitussives (Codeine, Hydrocodone): These agents exert their primary effect by agonism at mu-opioid receptors (MOR) located within the nucleus tractus solitarius (NTS) and other brainstem regions integral to the cough center. Activation of these G_i/o-protein-coupled receptors leads to inhibition of adenylate cyclase, reduced cyclic AMP (cAMP) production, hyperpolarization of neurons via increased potassium conductance, and inhibition of voltage-gated calcium channels. The net effect is a depression of neuronal excitability within the cough center, raising the threshold for triggering the cough reflex. It is noteworthy that the antitussive effect of these opioids occurs at doses lower than those required for analgesia, suggesting a degree of receptor subtype or pathway selectivity.

Dextromethorphan: This agent is the d-isomer of the codeine analogue levorphanol but lacks significant affinity for classical opioid receptors at therapeutic doses. Its antitussive action is primarily mediated through non-competitive antagonism of the N-methyl-D-aspartate (NMDA) receptor and agonism at sigma-1 receptors. Furthermore, dextromethorphan is metabolized to dextrorphan, a more potent NMDA antagonist. The precise link between NMDA receptor modulation in the brainstem and cough suppression is an area of ongoing research but is believed to involve inhibition of glutamatergic neurotransmission within the central cough pathway.

Peripheral Antitussives

Benzonatate: This drug is a long-chain polyglycol derivative structurally related to tetracaine. It acts as a local anesthetic on the vagal sensory fibers in the bronchi, alveoli, and pleura. By inhibiting voltage-gated sodium channels, benzonatate dampens the transduction of sensory signals from pulmonary stretch receptors (particularly rapidly adapting receptors, or RARs) to the cough center. This peripheral “numbing” effect interrupts the afferent limb of the cough reflex.

Demulcents: Agents like honey or glycerin-based syrups form a protective coating over irritated oropharyngeal and laryngeal mucosa. This physical barrier reduces direct stimulation of mucosal cough receptors by air flow, particulate matter, or inflammatory mediators, thereby decreasing afferent input.

Mechanism of Expectorant and Mucolytic Action

These agents target the physical and chemical properties of respiratory mucus, a complex gel consisting of water, glycoproteins (mucins), lipids, ions, and cellular debris.

Expectorants

Guaifenesin (Glyceryl Guaiacolate): The exact mechanism remains incompletely elucidated. The prevailing hypothesis is that guaifenesin acts as a gastric irritant, triggering a vagally-mediated reflex that increases the output of respiratory tract fluid from the submucosal glands of the bronchi. Alternatively, a direct action on the secretory cells may occur. The result is an increase in the volume of less viscous, more easily cleared respiratory secretions, which lubricates irritated airways and may indirectly dampen cough by reducing the stimulation of cough receptors.

Mucolytics

N-Acetylcysteine (NAC): This agent is a derivative of the amino acid L-cysteine. Its mucolytic action is based on the free sulfhydryl (-SH) group, which cleaves disulfide (S-S) bonds linking glycoprotein polymers within the mucus gel. This chemical disruption breaks down the cross-linked network of mucins, significantly reducing sputum viscosity and elasticity. NAC also possesses antioxidant properties, scavenging reactive oxygen species, which may be beneficial in inflammatory lung conditions.

Carbocisteine and Erdosteine: These thiol derivatives also break disulfide bonds but may have additional effects on mucin synthesis, favoring the production of less viscous mucin subtypes.

Dornase Alfa (Recombinant Human Deoxyribonuclease): This enzyme selectively cleaves extracellular DNA released from degenerating neutrophils, which is a major contributor to the thick, purulent sputum characteristic of cystic fibrosis. By hydrolyzing long DNA chains, it reduces the viscosity of sputum without affecting mucin structure.

Hypertonic Saline: When inhaled, hypertonic saline (3-7% NaCl) creates an osmotic gradient that draws water into the airway lumen, hydrating the mucus layer and improving its clearance. It may also directly stimulate coughing and ciliary activity.

Pharmacokinetics

The pharmacokinetic properties of these agents influence their onset, duration of action, dosing regimens, and potential for interactions.

Antitussives

Codeine

• Absorption: Well absorbed from the gastrointestinal tract, with oral bioavailability approximately 50% due to moderate first-pass metabolism.
• Distribution: Widely distributed; crosses the blood-brain barrier and placenta. Volume of distribution is approximately 3-6 L/kg.
• Metabolism: Undergoes extensive hepatic metabolism primarily via cytochrome P450 2D6 (CYP2D6) to morphine (active), and to a lesser extent via CYP3A4 to norcodeine. Its activity is highly dependent on CYP2D6 phenotype; poor metabolizers experience reduced efficacy, while ultra-rapid metabolizers are at risk for opioid toxicity.
• Excretion: Renal excretion of metabolites, with a small portion as unchanged drug. Elimination half-life (t_1/2) is 3-4 hours.
• Dosing: Typical adult antitussive dose is 10-20 mg every 4-6 hours as needed, not to exceed 120 mg in 24 hours.

Dextromethorphan

• Absorption: Rapidly absorbed from the GI tract.
• Distribution: Distributes into the CNS.
• Metabolism: Extensively metabolized in the liver by CYP2D6 to dextrorphan (active) and by CYP3A4 to 3-methoxymorphinan. CYP2D6 phenotype significantly influences its effects; poor metabolizers may experience reduced efficacy, while extensive metabolizers convert it rapidly to dextrorphan.
• Excretion: Primarily renal excretion of metabolites. Plasma t_1/2 is 2-4 hours but can be prolonged in CYP2D6 poor metabolizers.
• Dosing: Adult dose is 10-30 mg every 4-8 hours, with a maximum of 120 mg/day. Sustained-release formulations are available.

Benzonatate

• Absorption: Absorbed from the gastrointestinal tract.
• Distribution: Distributed systemically.
• Metabolism: Hydrolyzed by esterases to metabolites including para-aminobenzoic acid (PABA).
• Excretion: Renal excretion. t_1/2 is 3-8 hours.
• Dosing: 100-200 mg three times daily. Capsules must be swallowed whole, as chewing or sucking can release the local anesthetic, causing oropharyngeal numbness and a risk of aspiration.

Expectorants and Mucolytics

Guaifenesin

• Absorption: Rapidly absorbed from the GI tract.
• Metabolism: Undergoes extensive hepatic metabolism, primarily via oxidative O-dealkylation.
• Excretion: Renal excretion of metabolites, with a small amount unchanged. t_1/2 is approximately 1 hour.
• Dosing: 200-400 mg every 4 hours, with a maximum of 2.4 g/day. Sustained-release formulations allow for 12-hour dosing.

N-Acetylcysteine (Oral/Inhaled)

• Absorption (Oral): Well absorbed but undergoes significant first-pass metabolism, with systemic bioavailability of approximately 10%.
• Distribution (Oral/IV): Distributed to extracellular fluid; crosses the placenta. When inhaled, action is primarily topical on the airway surface liquid.
• Metabolism: Deacetylated in the liver and other tissues to cysteine, which is incorporated into glutathione.
• Excretion: Primarily renal as inactive metabolites. t_1/2 for the acetylated form is about 2 hours.
• Dosing: As a mucolytic, typical nebulized dose is 3-5 mL of a 20% solution (600-1000 mg) 3-4 times daily. Oral doses for mucolysis are 600-1200 mg daily in divided doses.

Therapeutic Uses/Clinical Applications

The selection of an antitussive or expectorant must be guided by the nature of the cough (productive vs. non-productive) and the underlying etiology.

Antitussives

Centrally acting antitussives are generally reserved for dry, hacking, non-productive coughs that serve no useful purpose and cause significant distress, sleep disruption, or complications (e.g., rib fracture, urinary incontinence).

• Acute Upper Respiratory Tract Infections (URTIs): Short-term use of dextromethorphan or low-dose codeine may be considered for severe, disruptive cough.
• Chronic Cough: In conditions like chronic bronchitis or lung cancer, where cough is refractory and debilitating, opioids like codeine or hydrocodone may be used palliatively.
• Post-operative and Post-procedural Cough: Suppression is sometimes necessary to prevent strain on surgical sites (e.g., after thoracic or abdominal surgery).
• Benzonatate is often used as an alternative to opioids, particularly when sedation or constipation is a concern, or in cases of cough triggered by specific maneuvers or deep inspiration.

It is crucial to emphasize that antitussives are contraindicated in productive cough associated with conditions like bronchiectasis or cystic fibrosis, where suppression could lead to retention of secretions and worsening of infection.

Expectorants and Mucolytics

These agents are indicated for productive coughs with thick, tenacious mucus that is difficult to expectorate.

• Guaifenesin: Used empirically in acute bronchitis, URTIs, and chronic conditions like COPD to facilitate clearance of respiratory secretions. Evidence for its efficacy is mixed, but it is widely used and generally well-tolerated.
• N-Acetylcysteine (NAC):
  • Mucolytic: A cornerstone in the management of cystic fibrosis and bronchiectasis to reduce sputum viscosity. Also used in COPD exacerbations and atelectasis.
  • Antidote: For acetaminophen (paracetamol) overdose (IV or oral).
  • Off-label: Investigated for its antioxidant effects in idiopathic pulmonary fibrosis and other interstitial lung diseases.
• Dornase Alfa: Standard therapy for cystic fibrosis patients with moderate to severe disease to improve pulmonary function and reduce exacerbation frequency.
• Hypertonic Saline: Used in cystic fibrosis and non-CF bronchiectasis as a chronic therapy to improve mucociliary clearance and hydration of airway surface liquid.
• Carbocisteine/Erdosteine: Used in COPD and chronic bronchitis to reduce sputum viscosity and frequency of exacerbations.

Adverse Effects

The adverse effect profiles vary significantly between classes, ranging from mild nuisance effects to serious, life-threatening reactions.

Antitussives

Opioid Antitussives (Codeine, Hydrocodone)

• Common: Sedation, dizziness, constipation, nausea, dry mouth.
• Serious: Respiratory depression (dose-dependent, risk increased with concomitant CNS depressants), dependence and tolerance with prolonged use. In children, particularly those who are CYP2D6 ultra-rapid metabolizers, codeine has been associated with fatal respiratory depression, leading to contraindications in pediatric tonsillectomy/adenoidectomy patients and strong warnings in all children under 12.
• Black Box Warnings: Codeine and hydrocodone carry black box warnings for risk of addiction, abuse, misuse, life-threatening respiratory depression, and accidental ingestion. Codeine specifically warns against use in children for post-operative pain management following tonsillectomy/adenoidectomy.

Dextromethorphan

• Common: Drowsiness, dizziness, gastrointestinal upset.
• Serious: At high doses or in susceptible individuals (e.g., CYP2D6 poor metabolizers taking high doses), serotonin syndrome may occur, particularly when combined with other serotonergic drugs (SSRIs, MAOIs). Abuse for dissociative/hallucinogenic effects can lead to agitation, hyperexcitability, and nystagmus.

Benzonatate

• Common: Sedation, headache, dizziness, gastrointestinal discomfort, nasal congestion.
• Serious: Hypersensitivity reactions. Severe effects include CNS stimulation (tremors, restlessness, seizures) followed by profound CNS depression. If the capsule is chewed or dissolved in the mouth, local anesthesia of the oropharynx can cause choking and aspiration. Overdose can mimic local anesthetic systemic toxicity, with perioral numbness, cardiac arrhythmias, and cardiovascular collapse.

Expectorants and Mucolytics

Guaifenesin

• Common: Generally well-tolerated. Nausea, vomiting, and drowsiness are occasionally reported. Kidney stone formation is a theoretical risk due to its metabolism to compounds that may crystallize, but this is rare.

N-Acetylcysteine

• Inhaled: Bronchospasm (can be severe, often pretreated with a bronchodilator), stomatitis, rhinorrhea, unpleasant odor (rotten eggs due to sulfur).
• Oral: Nausea, vomiting, diarrhea, rash.
• Intravenous (for overdose): Anaphylactoid reactions (flushing, rash, hypotension, bronchospasm) are relatively common but usually manageable with antihistamines and slowing the infusion.

Dornase Alfa

• Common: Voice alteration, pharyngitis, rash, conjunctivitis.
• Serious: Hypersensitivity reactions are rare.

Drug Interactions

Significant interactions arise primarily from pharmacodynamic synergism or alterations in metabolic pathways.

Major Drug-Drug Interactions

• Opioid Antitussives + Other CNS Depressants: Concomitant use with alcohol, benzodiazepines, barbiturates, sedating antihistamines, or other opioids produces additive CNS and respiratory depression, increasing the risk of profound sedation, coma, and fatal respiratory arrest.
• Dextromethorphan + Serotonergic Agents: Concurrent use with monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants can precipitate serotonin syndrome, characterized by hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes.
• Dextromethorphan + CYP2D6 or CYP3A4 Inhibitors: Drugs like quinidine (potent CYP2D6 inhibitor), fluoxetine, paroxetine, or ketoconazole (CYP3A4 inhibitor) can increase dextromethorphan plasma levels, potentiating both its therapeutic and adverse effects, including serotonin syndrome.
• Codeine + CYP2D6 Inhibitors: Agents such as fluoxetine or bupropion may reduce the conversion of codeine to its active metabolite, morphine, diminishing its antitussive efficacy.
• N-Acetylcysteine + Activated Charcoal: When used for acetaminophen overdose, oral NAC may be adsorbed by activated charcoal if administered simultaneously, reducing its efficacy. Dosing should be staggered.
• Potassium Iodide + Other Sources of Iodine/Potassium: Risk of hyperkalemia or iodine-induced thyroid dysfunction.

Contraindications

• All Antitussives in Productive Cough: Contraindicated when cough is necessary to clear secretions (e.g., bronchiectasis, cystic fibrosis).
• Opioid Antitussives: Contraindicated in acute asthma, respiratory depression, paralytic ileus, and known hypersensitivity. Codeine is contraindicated in children under 12 for cough and cold, and in all children undergoing tonsillectomy/adenoidectomy for obstructive sleep apnea.
• Dextromethorphan: Contraindicated in patients taking MAOIs or within 14 days of discontinuing them.
• Benzonatate: Contraindicated in patients with known hypersensitivity to the drug or related compounds (e.g., tetracaine).
• Iodide-containing expectorants: Contraindicated in pregnancy (risk of fetal goiter), hyperthyroidism, and iodine hypersensitivity.

Special Considerations

The use of cough medications requires careful adjustment in specific patient populations due to altered pharmacokinetics, pharmacodynamics, or unique risks.

Pregnancy and Lactation

• Pregnancy (Category C for most agents): Generally, non-pharmacological measures are preferred. If medication is necessary, dextromethorphan or guaifenesin are often considered among the safer options for short-term use, though data are limited. Opioid antitussives (Category C) should be avoided, especially near term, due to risks of neonatal respiratory depression and withdrawal. Iodide expectorants are contraindicated (Category D) due to risk of fetal hypothyroidism and goiter.
• Lactation: Codeine and its active metabolite morphine are excreted in breast milk and can cause sedation and respiratory depression in the infant, particularly if the mother is a CYP2D6 ultra-rapid metabolizer. Dextromethorphan is considered compatible with breastfeeding in usual doses. Guaifenesin is also generally considered compatible.

Pediatric Considerations

The use of cough and cold medications in children, particularly those under 6 years of age, is highly controversial and restricted.

• General Restriction: Major health authorities advise against the use of over-the-counter cough and cold preparations in children under 6 due to lack of proven efficacy and significant risks of serious adverse effects, including overdose.
• Codeine: Contraindicated for cough in children under 12. Its use in adolescents (12-18) who are obese or have conditions like sleep apnea is also not recommended.
• Dextromethorphan: Not recommended under 6 years; use in older children should be weight-based and cautious.
• Honey: For children over 1 year, a small dose of honey (e.g., 2.5 mL) before bedtime may be as effective as dextromethorphan and is a recommended non-pharmacological intervention. Honey is contraindicated in infants under 1 year due to risk of infant botulism.
• Mucolytics (e.g., NAC, Dornase Alfa): Used in specific pediatric conditions like cystic fibrosis under specialist supervision.

Geriatric Considerations

• Increased sensitivity to CNS effects of opioids and dextromethorphan due to age-related changes in pharmacokinetics (reduced clearance) and pharmacodynamics (increased brain sensitivity).
• Greater risk of constipation, dizziness, falls, and confusion with opioid antitussives.
• Reduced renal and hepatic function may prolong the elimination of drugs and their metabolites, necessitating lower doses or extended dosing intervals.
• Non-opioid agents like benzonatate or guaifenesin may be preferred first-line due to a more favorable safety profile.

Renal and Hepatic Impairment

• Renal Impairment: Drugs and active metabolites excreted renally (e.g., morphine from codeine, guaifenesin metabolites) may accumulate. Dose reduction is often necessary in moderate to severe renal impairment. Monitoring for signs of toxicity (CNS depression, nausea) is advised.
• Hepatic Impairment: For drugs with extensive hepatic metabolism (codeine, dextromethorphan, guaifenesin, NAC), clearance may be significantly reduced in cirrhosis or severe hepatitis. This can lead to exaggerated and prolonged effects. Opioids should be used with extreme caution, if at all, due to the heightened risk of precipitating hepatic encephalopathy and respiratory depression. Dose adjustment is mandatory.

Summary/Key Points

• Cough pharmacology is divided into antitussives (suppress the reflex) and expectorants/mucolytics (aid secretion clearance). Selection depends on whether the cough is non-productive and disruptive or productive with thick secretions.
• Centrally acting antitussives include opioid agonists (codeine, hydrocodone) acting on brainstem mu receptors and non-opioids like dextromethorphan (NMDA antagonist). Peripherally acting agents include benzonatate (local anesthetic on pulmonary stretch receptors).
• Expectorants like guaifenesin may increase respiratory tract fluid volume via a gastric reflex. Mucolytics like N-acetylcysteine chemically break disulfide bonds in mucus, while dornase alfa cleaves extracellular DNA in purulent sputum.
• Pharmacokinetics are crucial: Codeine’s activation is CYP2D6-dependent; dextromethorphan is metabolized by CYP2D6 and CYP3A4. Most agents have short half-lives, requiring multiple daily doses.
• Opioid antitussives carry significant risks of respiratory depression, sedation, constipation, and dependence, with strict contraindications in young children. Dextromethorphan poses a risk of serotonin syndrome with other serotonergic drugs.
• Antitussives are generally contraindicated in productive cough. Over-the-counter cough medications are not recommended for children under 6 years of age. Honey may be an effective alternative for children over 1 year.
• Special caution is required in geriatric patients, those with renal/hepatic impairment, and during pregnancy/lactation, often favoring non-opioid agents and lower doses.

Clinical Pearls

• Always assess the need for antitussive therapy; suppressing a productive cough can be harmful.
• In children, prioritize non-pharmacological management (hydration, humidified air, honey for those >1 year) over medication.
• When prescribing an opioid antitussive, start with the lowest effective dose for the shortest duration and explicitly warn patients about additive CNS depression with alcohol.
• Consider benzonatate as an alternative to opioids for patients at risk of sedation or constipation, but instruct them to swallow capsules whole to prevent local anesthetic toxicity.
• For patients with cystic fibrosis or bronchiectasis, mucolytic therapy (e.g., dornase alfa, hypertonic saline, NAC) is a mainstay of chronic management to improve clearance and reduce exacerbations.
• Be vigilant for the potential of dextromethorphan to interact with common antidepressants, and inquire about all medications, including over-the-counter products, to avoid serotonin syndrome.

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