Therapy of Cough - A Complete Guide for MBBS Students

First, Understand the Cough Reflex (Why we need these drugs)

• Productive cough (with sputum) - helpful, should NOT always be suppressed
• Dry/non-productive cough - irritating, no benefit, should be suppressed

Golden rule: Always treat the underlying cause first (infection? GERD? ACE inhibitor use?). Suppression is only symptomatic.

Classification of Drugs Used in Cough

DRUGS FOR COUGH
├── 1. ANTITUSSIVES (Cough suppressants - suppress the cough)
│       ├── A. Opioid antitussives (Central acting)
│       └── B. Non-opioid antitussives
│               ├── Central: Dextromethorphan
│               └── Peripheral: Benzonatate
└── 2. EXPECTORANTS & MUCOLYTICS (Help clear mucus)
        ├── Expectorants: Guaifenesin, Ammonium salts, Iodide salts
        └── Mucolytics: Acetylcysteine (NAC), Dornase alfa, Bromhexine, Ambroxol

PART 1: ANTITUSSIVES (Cough Suppressants)

A. Opioid Antitussives (Central Acting)

1. Codeine

• Class: Opioid (natural opium alkaloid)
• Mechanism: Decreases sensitivity of the cough center in the CNS to peripheral stimuli
• Dose: 15 mg is usually enough to suppress cough (much lower than analgesic dose - 30-60 mg)
• Key point: Antitussive effect occurs at sub-analgesic doses - the cough center appears more sensitive than pain pathways
• Side effects: Constipation, dysphoria, fatigue, sedation, addiction potential
• Caution: Avoid in children (risk of respiratory depression due to CYP2D6 variability); use caution with MAO inhibitors

2. Noscapine (Narcotine)

• A natural opium alkaloid
• Comparable antitussive efficacy to codeine
• Less addiction potential than codeine
• Not available in the USA but used in India and Europe

B. Non-Opioid Antitussives

1. Dextromethorphan (DXM) - Central Acting

• Structure: Dextrorotatory stereoisomer of a methylated derivative of levorphanol (morphine derivative but mirror image)
• Mechanism:
  • Blocks the medullary cough center
  • Also blocks NMDA receptors in the CNS
• Why important: No analgesic effect, no addiction at therapeutic doses - making it safe for OTC use
• Dose: 15-30 mg three to four times daily
• Side effects: Dysphoria at high doses; potential drug of abuse in powdered form
• Warning: Banned by FDA in children under 6 years due to deaths reported in OTC cold/cough products
• Caution: Can cause serotonin syndrome if combined with SSRIs or MAO inhibitors
• Enhancement effect: Also enhances the analgesic action of morphine

Think of it this way: Dextromethorphan is like codeine's "safer twin" - same cough-suppressing action but without the opioid analgesic and addictive properties.

2. Benzonatate - Peripheral Acting

• Mechanism: Chemically similar to local anesthetics (like tetracaine and benzocaine) - it anesthetizes the stretch receptors in the lungs, respiratory passages, and pleura, blocking the afferent signal before it even reaches the brain
• Key distinction: Unlike all opioids, this works peripherally, not centrally
• Dose: Capsule form; must be swallowed whole with plenty of water
• Side effects: Dizziness, numbness of tongue/mouth/throat (if capsule is chewed or broken - drug contacts oral mucosa directly)

3. Levopropoxyphene

• Stereoisomer of the weak opioid dextropropoxyphene
• Devoid of opioid effects
• Usual dose: 50-100 mg every 4 hours
• Sedation is a notable side effect
• Not available in the USA

PART 2: EXPECTORANTS and MUCOLYTICS

Expectorants

1. Guaifenesin (Guaiphenesin)

• Most widely used expectorant; found in countless OTC cough syrups
• Mechanism: Reduces mucus viscosity and loosens mucus in the airways, enhancing mucociliary clearance
• Effect: Converts a dry irritating cough to a productive cough - patient can now cough out the secretions
• Side effects: GI disturbances (nausea), dizziness, headache, skin rash; kidney stones with excessive use
• Often combined with codeine or dextromethorphan in combination products

2. Ammonium salts and Iodide salts

• Older expectorants; mechanism poorly understood
• Iodides (potassium iodide) can cause thyroid problems with prolonged use

Mucolytics

1. Acetylcysteine (N-Acetylcysteine / NAC)

• Mechanism: Splits the disulfide bonds of viscous mucoproteins (the bonds that make mucus thick and sticky)
• Routes: Oral (for COPD), IV (for acetaminophen/paracetamol overdose as antidote), inhaled (now NOT recommended)
• Why inhaled is stopped: Inhaled acetylcysteine can cause reflex bronchospasm - the irritant effect of the sulfhydryl groups triggers bronchoconstriction, worsening the patient
• Smell problem: Has a strong sulfur/rotten egg smell - so it is mixed with cola or fruit juice for oral use
• Side effects (oral): Nausea, vomiting, stomatitis
• Side effects (IV): Rash, drug fever, itch, rarely anaphylaxis
• Memory trick: NAC's sulfhydryl group (-SH) = Snaps disulfide bonds in mucus

2. Dornase Alfa (DNase)

• Special use: Specifically for Cystic Fibrosis (CF)
• Mechanism: A recombinant human DNase enzyme that hydrolyzes extracellular DNA in purulent secretions
• In CF, neutrophils accumulate in the airways and release DNA when they die - this DNA makes sputum extremely viscous. Dornase alfa cleaves this DNA.
• Route: Nebulizer, once daily
• Side effects: Voice changes, pharyngitis, laryngitis, rhinitis, chest pain

3. Bromhexine and Ambroxol

• Commonly used in India and Europe (Katzung mentions these in context of non-US drugs)
• Bromhexine: Depolymerizes mucopolysaccharides; also stimulates surfactant production
• Ambroxol: Active metabolite of bromhexine; has local anesthetic properties in addition to mucolytic action; commonly used in pediatric syrups
• Well tolerated; mild GI side effects

Quick Summary Table

Exam Must-Knows

1. Antitussive dose of codeine (15 mg) < Analgesic dose (30-60 mg) - the cough center is more sensitive
2. Dextromethorphan has NO opioid/analgesic activity - it's a stereoisomer (mirror image) of an opioid
3. Benzonatate is the only PERIPHERAL antitussive - all others act centrally
4. Acetylcysteine breaks disulfide (-S-S-) bonds - this is its mucolytic mechanism
5. Dornase alfa = CF only - it cleaves DNA, not protein bonds
6. Do NOT inhale acetylcysteine - causes bronchospasm
7. Serotonin syndrome can occur with dextromethorphan + SSRIs/MAOIs
8. Productive cough = don't suppress - use expectorants/mucolytics instead