Respiratory System

Bronchodilators — Classification

β2 agonists: SABA(salbutamol, terbutaline) · LABA(salmeterol, formoterol) · ultra-LABA(vilanterol, indacaterol). Anticholinergics: SAMA(ipratropium) · LAMA(tiotropium, glycopyrronium, umeclidinium). Methylxanthines: theophylline, aminophylline.

Bronchodilators — Mechanism

β2 agonists: β2→↑adenylyl cyclase→↑cAMP→PKA→↓MLCK activity→relaxation. +↓mast cell mediator release, +↑mucociliary clearance. Salbutamol=fast onset(rescue); salmeterol=slow onset(NOT for acute attacks, maintenance only); formoterol=fast+long(both roles, unusual for LABA).

Anticholinergics: competitive M3 block→↓ACh-mediated bronchoconstriction+secretion. Vagal tone contributes MORE in COPD than asthma → anticholinergics relatively more effective in COPD. Slow onset → not for acute rescue.

Methylxanthines: multifactorial — (1)non-selective PDE inhibition→↑cAMP/cGMP (though clinical levels may be too low for this alone) (2)adenosine receptor antagonism(adenosine itself provokes bronchoconstriction) (3)direct respiratory centre stimulation+↑diaphragm contractility(useful in neonatal apnoea/fatiguing COPD). NARROW therapeutic index, CYP1A2 metabolism → major interactions(inducers: rifampicin/phenytoin/smoking ↓levels; inhibitors: cimetidine/cipro/erythromycin ↑levels→toxic). 2nd-line behind SABA/anticholinergics.

Bronchodilators — Adverse Effects

β2 agonists: fine tremor(skeletal muscle β2) · tachycardia(some β1 cross-reactivity) · hypokalaemia(β2 intracellular K+ shift, esp high-dose nebulized) · tolerance with LABA MONOTHERAPY = NEVER use alone in asthma, always +ICS (mortality signal with LABA-only use).

Anticholinergics: dry mouth · (uncommon, inhaled poorly absorbed systemically due to quaternary ammonium structure) urinary retention/constipation/blurred vision.

Methylxanthines: dose-progressive — N/V+headache(lower toxic)→tremor/insomnia/tachyarrhythmia→seizures+fatal arrhythmias(severe). Narrow margin = common clinical scenario, not rare.

Corticosteroids (Respiratory)

Classification: Inhaled(ICS: beclomethasone, budesonide, fluticasone, mometasone) · Systemic(prednisolone, methylprednisolone, hydrocortisone — acute severe exacerbations).

Mechanism: cytoplasmic GR binding→nuclear translocation→gene transcription change: ↑anti-inflammatory proteins(lipocortin-1/annexin A1→inhibits phospholipase A2→cuts BOTH COX+LOX eicosanoid branches at the source) + ↓pro-inflammatory cytokines/adhesion molecules/cell recruitment. Anti-inflammatory NOT bronchodilator → NO acute rescue role, controls chronic inflammation only.

Adverse effects: Inhaled: oropharyngeal candidiasis+dysphonia(↓by rinsing mouth/spacer) · low but real systemic absorption→growth suppression in children(high-dose ICS, monitored). Systemic: full glucocorticoid profile(hyperglycaemia, osteoporosis, adrenal suppression, immunosuppression, peptic ulceration, mood change) — full detail under Corticosteroids (Hormones section).

Leukotriene Pathway Modifiers

Classification: LTRA(montelukast, zafirlukast) · 5-LOX inhibitor(zileuton). Mechanism: blocks CysLT1 receptor OR blocks leukotriene synthesis(zileuton). LTC4/D4/E4(“SRS-A”)=bronchoconstrictor+mucus+oedema, from LOX branch of arachidonic acid. Key link: NSAIDs blocking COX-only can shunt substrate→↑leukotrienes → LTRAs specifically useful in aspirin-exacerbated respiratory disease. Oral, maintenance only(exercise-induced, aspirin-sensitive asthma), NOT acute. Adverse effects: generally well tolerated, headache/GI upset. Zileuton=hepatotoxicity risk(LFT monitoring) → why LTRAs >> zileuton in practice.

Mast Cell Stabilizers

Sodium cromoglycate, nedocromil — stabilize mast cell membrane→↓degranulation/mediator release. PROPHYLACTIC ONLY(no effect once bronchospasm started). Superseded by ICS/LTRA but still used, esp. paediatric/exercise-induced asthma(safety profile).

Anti-IgE/Biologics

Omalizumab: anti-IgE monoclonal Ab, binds free IgE→prevents FcεRI engagement on mast cells/basophils. Reserved for SEVERE allergic asthma uncontrolled on max inhaled therapy — add-on, not first-line.

Mucolytics/Expectorants/Antitussives

Mucolytics: acetylcysteine(breaks disulfide bonds in mucus glycoproteins; ALSO paracetamol overdose antidote via glutathione repletion — separate unrelated use) · bromhexine, ambroxol. Expectorants: guaifenesin(↑secretion volume, modest evidence). Antitussives: codeine(opioid receptor, medullary cough centre, sub-analgesic dose) · dextromethorphan(similar central suppression, no significant opioid/dependence liability — preferred OTC agent). Appropriate for DRY non-productive cough only; suppressing productive cough impairs secretion clearance.

COPD vs Asthma — Practical Distinctions

Anticholinergics = proportionally bigger role in COPD (vagal tone contributes more to fixed obstruction). ICS used more SELECTIVELY in COPD (frequent exacerbators, eosinophilic phenotype) vs universal first-line in persistent asthma — COPD inflammation = neutrophil-driven, less steroid-responsive than asthma’s eosinophil/Th2-driven inflammation.

Clinical Relevance

Reliever vs controller = the organizing idea. SABA/anticholinergic = fast, acute attack. ICS/LTRA/mast cell stabilizer = slow, prevents attacks, does nothing during one. LABA-monotherapy = the clearest example of getting this wrong (bronchodilation without addressing inflammation → mortality signal) — why LABA+ICS combination is now fixed rule, never LABA alone.

Bronchodilators

Classification

1. β2 agonists
   • Short-acting (SABA): salbutamol (albuterol), terbutaline
   • Long-acting (LABA): salmeterol, formoterol
   • Ultra-long-acting: vilanterol, indacaterol
2. Anticholinergics (antimuscarinics)
   • Short-acting (SAMA): ipratropium bromide
   • Long-acting (LAMA): tiotropium, glycopyrronium, umeclidinium
3. Methylxanthines: theophylline, aminophylline (theophylline ethylenediamine salt, more water-soluble, used IV)

Mechanism of Action

β2 agonists: stimulate β2 receptors on bronchial smooth muscle → activate adenylyl cyclase → ↑cAMP → activates protein kinase A → phosphorylates myosin light-chain kinase, reducing its activity → smooth muscle relaxation. Also inhibit mast cell mediator release and enhance mucociliary clearance. Salbutamol’s fast onset (within minutes, inhaled) makes it the rescue drug of choice for acute bronchospasm; salmeterol/formoterol’s long duration (~12 hours) suits maintenance therapy but salmeterol’s slow onset makes it unsuitable for acute attacks (formoterol, unusually for a LABA, has a fast onset and can be used for both roles).

Anticholinergics: competitively block M3 muscarinic receptors on bronchial smooth muscle, preventing acetylcholine-mediated bronchoconstriction and mucus secretion. Because vagal tone contributes proportionally more to bronchoconstriction in COPD than in asthma, anticholinergics are relatively more effective in COPD; slower onset than SABAs makes ipratropium less suited to acute rescue use.

Methylxanthines: mechanism is genuinely multifactorial and incompletely settled, taught as: (1) non-selective phosphodiesterase inhibition → ↑cAMP/cGMP → bronchodilation (though the concentrations achieved clinically are lower than needed for significant PDE inhibition in vitro, so this alone likely doesn’t fully explain the effect); (2) adenosine receptor antagonism (adenosine itself can provoke bronchoconstriction in asthmatics — blocking its receptor is bronchodilator/anti-inflammatory); (3) direct stimulation of the respiratory centre and enhanced diaphragmatic contractility, useful in some neonatal apnoea and in fatiguing COPD patients. Narrow therapeutic index and extensive CYP1A2-mediated hepatic metabolism (subject to major interactions — enzyme inducers like rifampicin/phenytoin/smoking lower levels, enzyme inhibitors like cimetidine/ciprofloxacin/erythromycin raise them into the toxic range) have pushed methylxanthines to a distinctly second-line role behind inhaled β2 agonists/anticholinergics.

Adverse Effects

β2 agonists: fine tremor (skeletal muscle β2 receptors), tachycardia/palpitations (some β1 cross-reactivity, more with non-selective/older agents), hypokalaemia (β2-mediated intracellular K⁺ shift — clinically relevant with high-dose nebulized use, e.g. in severe acute asthma), and tolerance with regular LABA monotherapy — the specific reason LABAs are never used as monotherapy in asthma and are always combined with an inhaled corticosteroid (a black-box-level safety point, tied to a signal for increased asthma mortality with LABA-only use).

Anticholinergics: dry mouth, and (less commonly with inhaled use, due to poor systemic absorption) urinary retention/constipation/blurred vision from systemic antimuscarinic spillover — inhaled anticholinergics are far better tolerated systemically than atropine because quaternary ammonium structure (ipratropium, tiotropium) limits absorption across mucous membranes.

Methylxanthines: dose-related and progressive — nausea/vomiting and headache at lower toxic levels, then tremor/insomnia/tachyarrhythmias, and at severe toxicity, seizures and life-threatening arrhythmias; the therapeutic-to-toxic margin is narrow enough that this progression is a genuinely common clinical scenario, not a rare edge case.

Inhaled and Systemic Corticosteroids

Classification

• Inhaled (ICS): beclomethasone, budesonide, fluticasone, mometasone
• Systemic: prednisolone, methylprednisolone, hydrocortisone (for acute severe exacerbations)

Mechanism of Action

Corticosteroids bind cytoplasmic glucocorticoid receptors → translocate to the nucleus → modify gene transcription: upregulate anti-inflammatory proteins (e.g. lipocortin-1/annexin A1, which inhibits phospholipase A2, cutting off the entire eicosanoid cascade — prostaglandins and leukotrienes both — at its source, upstream of both the COX and LOX branches) and downregulate pro-inflammatory cytokines, adhesion molecules, and inflammatory cell recruitment. In asthma specifically, this reduces airway hyperresponsiveness, mucosal oedema, and mucus hypersecretion — corticosteroids are anti-inflammatory, not bronchodilator, so they do not relieve acute bronchospasm and are never rescue drugs; their role is controlling the underlying chronic inflammation that drives recurrent attacks. Inhaled delivery concentrates the effect at the airway while minimizing systemic exposure compared with oral/systemic therapy.

Adverse Effects

Inhaled: oropharyngeal candidiasis and dysphonia (hoarseness) — both reduced by rinsing the mouth after use and by spacer devices, which cut oropharyngeal deposition; systemic absorption is low but not zero, so growth suppression in children on high-dose ICS is a genuine, monitored concern.

Systemic (relevant mainly to short courses for exacerbations, or long-term use in severe disease): the full glucocorticoid adverse-effect profile — hyperglycaemia, osteoporosis, adrenal suppression (with abrupt-withdrawal risk after prolonged use), immunosuppression, peptic ulceration, mood/behavioural change — covered fully under Corticosteroids in the Hormones and Related Drugs section.

Leukotriene Pathway Modifiers

Classification

• Leukotriene receptor antagonists (LTRA): montelukast, zafirlukast
• 5-lipoxygenase inhibitor: zileuton (blocks leukotriene synthesis rather than its receptor)

Mechanism of Action

Block the cysteinyl leukotriene (CysLT1) receptor (montelukast/zafirlukast) or the synthesis of leukotrienes altogether via 5-lipoxygenase inhibition (zileuton) — leukotrienes (LTC4/D4/E4, the “slow-reacting substance of anaphylaxis”) are potent bronchoconstrictors and promote mucus secretion and airway oedema, produced via the lipoxygenase branch of arachidonic acid metabolism (see Autacoids — this is the same pathway where NSAIDs blocking only the cyclooxygenase branch can paradoxically shunt substrate toward increased leukotriene production, which is precisely why LTRAs are useful add-on therapy in aspirin-exacerbated respiratory disease). Oral, used for maintenance control (especially exercise-induced and aspirin-sensitive asthma), not for acute attacks.

Adverse Effects

Generally well tolerated; headache, GI upset. Zileuton carries a hepatotoxicity risk requiring liver function monitoring, one reason LTRAs (receptor antagonists) are far more widely used than the synthesis inhibitor.

Mast Cell Stabilizers

Sodium cromoglycate and nedocromil stabilize mast cell membranes, preventing degranulation and mediator release (histamine, leukotrienes) upon allergen exposure. Prophylactic only (no effect once bronchospasm has started), largely superseded by inhaled corticosteroids and LTRAs in current practice but still occasionally used, particularly in paediatric and exercise-induced asthma given a favourable safety profile.

Anti-IgE and Biologic Therapy

Omalizumab, a monoclonal antibody against IgE, binds free serum IgE and prevents it from engaging mast cell/basophil FcεRI receptors, reducing the allergic cascade at its earliest step. Reserved for severe allergic asthma poorly controlled on maximal inhaled therapy — an add-on for a specific, more difficult phenotype, not a first-line drug.

Mucolytics, Expectorants, and Antitussives

• Mucolytics (acetylcysteine, bromhexine, ambroxol): break disulfide bonds in mucus glycoproteins (acetylcysteine) or otherwise reduce mucus viscosity, easing expectoration — acetylcysteine is also the specific antidote for paracetamol overdose (an unrelated, separately examined use, via replenishing hepatic glutathione).
• Expectorants (guaifenesin): increase respiratory tract secretion volume, ostensibly easing productive cough, though evidence for efficacy is modest.
• Antitussives: codeine and dextromethorphan suppress the cough reflex centrally (codeine via opioid receptors in the medullary cough centre, at doses below its analgesic range; dextromethorphan acts similarly without significant opioid/analgesic or dependence liability, making it the more commonly used over-the-counter antitussive). Antitussives are appropriate for a dry, non-productive, distressing cough — suppressing a productive cough is generally undesirable, since it impairs clearance of secretions.

Drugs for COPD — Practical Distinctions from Asthma

Anticholinergics play a proportionally larger role in COPD than in asthma (vagal tone contributes more to COPD’s fixed airflow obstruction). Inhaled corticosteroids are used more selectively in COPD (reserved for frequent exacerbators, particularly with an eosinophilic phenotype) rather than as universal first-line controller therapy the way they are in persistent asthma — COPD’s underlying inflammation is neutrophil-driven and less corticosteroid-responsive than asthma’s eosinophil/Th2-driven inflammation, the mechanistic reason behind this differing role.

Clinical Relevance

The organizing distinction across this entire topic is reliever versus controller: β2 agonists (short-acting) and anticholinergics act fast on smooth muscle tone and are reached for during an acute attack; corticosteroids, LTRAs, and mast cell stabilizers act on the underlying inflammation over days to weeks and prevent attacks but do nothing during one. A LABA used alone, without an inhaled corticosteroid, is the clearest illustration of getting this distinction wrong in practice — bronchodilation without addressing inflammation, which trial evidence tied to increased mortality risk, which is exactly why the combination (never LABA monotherapy) is now the fixed rule.

• Sites of action of bronchodilator classes on the bronchial smooth muscle cell (β2 agonist/cAMP pathway vs anticholinergic/M3 blockade vs methylxanthine pathways).
• Arachidonic acid pathway link between NSAID-induced leukotriene shunting and leukotriene receptor antagonist action (cross-reference to the Autacoids eicosanoid pathway).
• Reliever vs controller drug classification across the whole topic, mapped to onset of action.

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