Respiratory Pharmacology

Two problems, two strategies

Bronchoconstriction vs inflammation. Drugs for obstructive airway disease target one of two processes. Bronchodilators (β2-agonists, muscarinic antagonists, theophylline) relax airway smooth muscle. Anti-inflammatory agents (inhaled corticosteroids, leukotriene modifiers, mast-cell stabilizers, biologics) quiet the inflammation that drives hyperreactivity and exacerbations.

Relievers vs controllers. Relievers (rescue) act within minutes and are used as needed: SABA (albuterol) and SAMA (ipratropium). Controllers (maintenance) are taken daily to reduce inflammation and exacerbations: ICS, LABA, LAMA, leukotriene modifiers, and biologics. Rising rescue-inhaler use signals poor control and a need to step up controller therapy.

Bronchodilators

β2-agonists. Receptor binding activates Gs and adenylyl cyclase; the rise in cAMP activates protein kinase A, which relaxes bronchial smooth muscle.

Albuterol, a short-acting agent (SABA), is the rescue drug. Salmeterol and formoterol are long-acting (LABA) maintenance drugs that are never used as monotherapy in asthma: the SMART trial showed that a LABA alone raises the risk of asthma death, so a LABA is always paired with an inhaled corticosteroid. Adverse effects reflect β stimulation: tremor, tachycardia, and hypokalemia (β2-stimulated Na⁺/K⁺-ATPase shifts K⁺ into cells).

Muscarinic antagonists. Vagal acetylcholine acts on M3 receptors (Gq) to constrict bronchi and stimulate mucus secretion; blocking M3 reverses both. Ipratropium is short-acting (SAMA); tiotropium is long-acting (LAMA) and a first-line maintenance bronchodilator in COPD. As quaternary amines they are poorly absorbed from the airway, so the main side effect is dry mouth.

Theophylline. A methylxanthine that inhibits phosphodiesterase (raising cAMP) and blocks adenosine receptors, producing bronchodilation. It has a narrow therapeutic index and is cleared by CYP450 (CYP1A2), so enzyme inhibitors such as cimetidine, ciprofloxacin, and erythromycin can precipitate toxicity: seizures and tachyarrhythmias. It is rarely used now.

Anti-inflammatory controllers

Inhaled corticosteroids (ICS). Fluticasone and budesonide are the first-line controllers for persistent asthma. They inhibit NF-κB, reducing transcription of inflammatory cytokines, and upregulate annexin A1 (lipocortin), which inhibits phospholipase A2 and limits the arachidonic acid supply for prostaglandins and leukotrienes. Local side effects are oral thrush and dysphonia; rinsing the mouth and using a spacer reduce them.

Leukotriene modifiers. 5-Lipoxygenase converts arachidonic acid into leukotrienes; the cysteinyl leukotrienes (C4, D4, E4) cause bronchoconstriction, mucus secretion, and edema through the CysLT1 receptor.

• Montelukast, zafirlukast: block the CysLT1 (LTD4) receptor; montelukast carries a warning for neuropsychiatric effects.
• Zileuton: inhibits 5-lipoxygenase, blocking leukotriene synthesis; hepatotoxic, so monitor LFTs.

These agents are especially useful in exercise-induced asthma and in aspirin-exacerbated respiratory disease (Samter triad: asthma, nasal polyps, aspirin sensitivity), where COX blockade shunts arachidonic acid toward leukotrienes.

Mast-cell stabilizers. Cromolyn and nedocromil prevent mast cell degranulation. They work only as prophylaxis, with no acute effect, and have largely been replaced by ICS, but their excellent safety keeps them occasionally in use for children.

Biologics and PDE-4 inhibition

Omalizumab. A monoclonal antibody that binds the Fc portion of free IgE, preventing it from binding FcεRI on mast cells and basophils; used for severe allergic asthma with elevated IgE.

Eosinophil-directed biologics. For severe eosinophilic asthma, mepolizumab neutralizes IL-5 (the eosinophil cytokine), benralizumab blocks the IL-5 receptor, and dupilumab blocks the IL-4 receptor α chain, inhibiting both IL-4 and IL-13 signaling.

Roflumilast. A selective PDE-4 inhibitor that raises cAMP in inflammatory cells. It is anti-inflammatory, not a bronchodilator, and reduces exacerbations in severe COPD with chronic bronchitis. Adverse effects: weight loss, nausea, and diarrhea.

Stepwise therapy: asthma and COPD

Asthma ladder. Therapy escalates until symptoms are controlled and steps down once the patient is stable.

Uncontrolled on low-dose ICS? Add a LABA to the ICS. Never add a LABA alone, and don't simply lean on more albuterol. Newer guidelines also use low-dose ICS-formoterol as the as-needed reliever, so every rescue dose delivers a steroid.

COPD maintenance. Start a LAMA and/or LABA with a SABA as needed. Add an ICS for frequent exacerbations or high blood eosinophils (ICS raise pneumonia risk in COPD), and add roflumilast or azithromycin for patients who keep exacerbating.

What lowers mortality. Smoking cessation and long-term home O₂ are the two classic interventions proven to improve survival in COPD; lung volume reduction surgery (selected upper-lobe emphysema) and triple LAMA/LABA/ICS therapy (frequent exacerbators) also show a survival benefit, while other inhaler regimens and roflumilast mainly relieve symptoms and prevent exacerbations. Home O₂ is indicated for a resting PaO₂ ≤55 mmHg or SaO₂ ≤88%, or for PaO₂ 56–59 mmHg with cor pulmonale or polycythemia.