Airway drugs

Allergic asthma vs allergic rhinitis

• Allergic asthma affects the lower airways

• Allergic rhinitis affects the upper airways

Both allergic rhinitis and allergic asthma run on the same Type I hypersensitivity pathway.

What are the steps of the Type I hypersensitivity pathway?

1. APCs recognise the allergen and presents it to Th0

2. Th0 differentiates to Th2, which releases IL-4, IL-5, IL-13

3. The cytokine signalling drives B cells to become plasma cells, which produce IgE

4. IgE coats mast cells/eosinophils, which are abundant in the mucosa of the airways

5. Upon re-exposure, the allergen cross-links IgE, triggering mast cell degranulation (histamine. leukotrienes, prostaglandin, cytokine release), leading to inflammation and symptoms, such as sneezing, itchy nose/eyes, runny nose

Drugs can target different points in this pathway to prevent the symptoms of obstructed airflow.

Why does asthma need two drug classes to be countered?

Because allergen exposure impacts lung function twice:

• Early phase (0–3h): mast cell degranulation → histamine/leukotrienes → immediate bronchospasm

• Late phase (3–8h): eosinophil/cell infiltration → deeper, more prolonged inflammatory drop in lung function

This is why two drugs are needed, one drug per phase, not one drug doing both jobs. For example: a bronchodilator (β2-agonist) only treats the early, spasm-driven phase. It does nothing for the late inflammatory phase.

Differences in 1st gen and 2nd gen antihistamines?

• First generation - causes sedation as it easily crosses the blood-brain barrier; also used to treat motion sickness, as it blocks histamine in the CNS, reducing nausea and dizziness

• Second generation - non-sedating as it doesn’t cross the BBB, more selective for peripheral H1 receptors, avoiding CNS effects

Loratadine

• First-line treatment of allergic rhinitis

• H1 receptor antagonist

• Only blocks histamine from binding to receptor in target tissue, not the release of histamine

• 2nd generation antihistamine: doesn't cross the BBB → non-sedating

Salbutamol

• most commonly used bronchodilator

• β2-adrenergic agonist

• Mechanism: Binds β2 receptor (Gs-coupled GPCR) on airway smooth muscle → activates adenylate cyclase → increased cAMP → activates PKA → smooth muscle relaxation → bronchodilation

• Salbutamol is a SABA (short-acting β2-adrenergic agonist), often combined with LABA (long-acting) such as salmeterol (paired with Inhaled Corticosteroid (ICS), as it’s dangerous to take the LABA alone)

• Administration: inhaled, but only 10–20% actually reaches the lungs, the rest is swallowed, absorbed via GI, undergoes first-pass metabolism, and the bit that reaches systemic circulation causes side effects, including:

  • tremor (skeletal muscle β2)

  • tachycardia (cardiac β)

  • possible receptor downregulation with chronic use

Budesonide

• Inhaled glucocorticoid (ICS)

• Used for allergy and allergic rhinitis

• Mechanism: (i) binds to intracellular glucocorticoid receptor, displacing HSP70/90 chaperones, (ii) receptor-ligand complex translocates to nucleus and binds DNA, (iii) alters gene transcription (up or down), (iv) altered protein synthesis → altered cell function

  • This drug is slow and genomic → not useful for acute relief, only for long-term control, which is why do you need both a bronchodilator and a corticosteroid

• Cellular effects: ↓eosinophils (↑apoptosis), ↓cytokines from T-cells/macrophages/epithelium, ↓mast cell numbers, ↓vascular leak, ↓mucus secretion, and importantly ↑β2-receptor expression on smooth muscle (this is why ICS + LABA combos work synergistically)

• Side effects: hoarseness; oral candidiasis (thrush) due to local immunosuppression in the mouth/throat as inhaled steroid deposits there; nosebleeds if taken as a nose spray

Omalizumab

• Anti-IgE monoclonal antibody

• Mechanism: binds free circulating IgE (not IgE already bound to mast cells) → decreases free/cell-bound IgE → decreases expression of the high-affinity IgE receptor (FcεRI) on mast cells/basophils → decreases mediator release → decreases allergic inflammation

• Used as add-on therapy for severe allergic asthma (passive immunisation), not first-line

Give an example of an "add-on medication" with a different mechanism than the standard β2-agonist

Cholinergic (muscarinic) antagonists — e.g. ipratropium, tiotropium

• ACh normally acts on M1/M3 receptors on airway smooth muscle/mucus glands, resulting in contraction + mucus secretion

• Antagonist blocks this, causing bronchodilation + less mucus.

• Low systemic bioavailability when inhaled (limiting side effects, which is good).

  • Main side effect: dry mouth

Give an example of an add-on drug that act as Leukotriene antagonists.

• oral drug (not inhaled)

• Stimulated CysLT1 receptors result in bronchoconstriction, mucus secretion, vascular permeability, eosinophil recruitment

• Drug blocks the CysLT1 receptor → blocks all of the above

Summary

Asthma	Allergic rhinitis
β2-agonists Glucocorticoids	Antihistamines Glucocorticoids
Add on/alternative: Anticholinergic Leukotriene antagonists	Add on/alternative: Anticholinergic Leukotriene antagonists