Antihistamines, Decongestants, Antitussives & Asthma Biologics
Medicine-cabinet drugs whose mechanisms predict their dangers, plus cytokine-targeted biologics
H1 antihistamines
Mechanism. H1 receptors are Gq-coupled; histamine acting on them causes itching, sneezing, rhinorrhea, vasodilation, increased vascular permeability and some bronchoconstriction. H1 antihistamines are inverse agonists that stabilize the inactive receptor. They relieve itch, sneezing, rhinorrhea and urticaria but do little for congestion, have no role in treating asthma, and are only adjuncts to epinephrine in anaphylaxis.
| Feature | First generation | Second generation |
|---|---|---|
| Drugs | Diphenhydramine, chlorpheniramine, doxylamine, hydroxyzine, promethazine, meclizine, dimenhydrinate | Loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine |
| CNS entry | Lipophilic, cross the blood-brain barrier: sedation, slowed reactions | Polar P-glycoprotein substrates: little CNS entry (cetirizine mildly sedating) |
| Off-target blockade | Muscarinic (dry mouth, urinary retention, constipation, blurred vision, delirium), α1 (orthostasis) | Minimal |
| Main uses | Insomnia, motion sickness and vertigo, nausea, pruritus and anxiety | Allergic rhinitis, urticaria; once daily |
Turning side effects into uses. Diphenhydramine and doxylamine are sold as sleep aids; meclizine and dimenhydrinate suppress vestibular input for motion sickness and vertigo; promethazine treats nausea; hydroxyzine treats itching and anxiety; and doxylamine with pyridoxine treats nausea and vomiting of pregnancy. Promethazine carries boxed warnings for fatal respiratory depression in children younger than 2 and for severe tissue injury or gangrene after extravasation or intra-arterial injection.
Overdose. First-generation overdose produces an anticholinergic toxidrome: hyperthermia, dry flushed skin, mydriasis, urinary retention, tachycardia and delirium; young children may instead show paradoxical excitation. Large diphenhydramine ingestions also block cardiac sodium channels, widening the QRS and causing seizures; sodium bicarbonate treats the conduction toxicity.
Terfenadine's lesson. Early nonsedating antihistamines such as terfenadine were withdrawn because, when CYP3A4 inhibitors raised their levels, they blocked cardiac potassium channels, prolonged the QT interval and caused torsades. Fexofenadine, terfenadine's active metabolite, lacks this effect.
Other allergic rhinitis therapies
Intranasal glucocorticoids. Fluticasone, mometasone, budesonide and triamcinolone are the most effective single therapy for allergic rhinitis. By altering gene transcription they reduce cytokine production and the influx of eosinophils and mast cells into the mucosa, relieving congestion as well as sneezing, itching and rhinorrhea. Benefit builds over days. Local irritation and epistaxis are the main side effects, and systemic effects are minimal.
Cromolyn. This mast-cell stabilizer prevents degranulation, so it must be started before allergen exposure and does nothing for mediators already released. It is extremely safe but needs dosing several times daily; forms include nasal spray, eye drops for allergic conjunctivitis and an oral form for mastocytosis. Intranasal antihistamines (azelastine) and intranasal ipratropium for watery rhinorrhea are other options.
Decongestants
Mechanism. Nasal congestion reflects engorged venous sinusoids in the turbinates. α-Adrenergic agonists constrict these capacitance vessels and shrink the mucosa.
- Pseudoephedrine (oral) is mixed-acting: it releases norepinephrine and directly stimulates adrenergic receptors. It raises blood pressure and heart rate and causes insomnia, anxiety and urinary retention in men with prostatic enlargement. It can cause hypertensive crisis with MAOIs, is avoided in uncontrolled hypertension, and is sold from behind the counter because it is a methamphetamine precursor.
- Phenylephrine is a direct α1 agonist. Oral phenylephrine is largely inactivated by first-pass metabolism, and an FDA advisory panel judged it ineffective as a decongestant; the nasal spray does work.
- Oxymetazoline is a long-acting topical imidazoline α-agonist.
Topical decongestants used for more than about 3 days cause tachyphylaxis and rebound vasodilation (rhinitis medicamentosa). Stop the spray, often with an intranasal glucocorticoid. Swallowed imidazoline sprays or eye drops (oxymetazoline, tetrahydrozoline) stimulate central α2 receptors in toddlers, causing clonidine-like drowsiness, bradycardia and hypotension.
Cough and mucus agents
| Drug | Mechanism | Key hazards |
|---|---|---|
| Dextromethorphan | Morphinan that suppresses the medullary cough center; NMDA antagonist; inhibits serotonin reuptake; negligible μ-opioid activity | Serotonin syndrome with MAOIs, SSRIs or linezolid; PCP-like dissociation with high-dose misuse |
| Benzonatate | Ester local anesthetic (tetracaine-related) that blocks sodium channels in pulmonary stretch receptors | Capsules must be swallowed whole; one or two in a young child can cause seizures, arrhythmia and cardiac arrest |
| Codeine | μ-Opioid agonist after CYP2D6 conversion to morphine | Respiratory depression in ultrarapid metabolizers; constipation, sedation |
| Guaifenesin | Expectorant; thought to increase secretion volume and lower viscosity | Does not suppress cough; modest benefit |
| N-acetylcysteine | Free sulfhydryl cleaves disulfide bonds between mucins | Inhaled form can trigger bronchospasm |
Codeine pharmacogenetics. People with CYP2D6 gene duplications convert codeine to morphine rapidly. Deaths from respiratory depression led to contraindications in children younger than 12 and after tonsillectomy or adenoidectomy in those younger than 18; breastfed infants of ultrarapid-metabolizing mothers are also at risk.
Mucolytic contrasts. N-acetylcysteine is also the antidote for acetaminophen overdose, where it replenishes glutathione. Dornase alfa, used in cystic fibrosis, instead digests the extracellular DNA released by neutrophils in purulent sputum.
Type 2 asthma biologics
The type 2 cascade. Epithelial alarmins such as TSLP activate Th2 cells and type 2 innate lymphoid cells. These release IL-4, which drives IgE class switching; IL-5, which drives eosinophil production, activation and survival; and IL-13, which drives mucus, airway hyperresponsiveness and epithelial nitric oxide, raising FeNO. Biologics are added for severe asthma that stays uncontrolled on high-dose inhaled glucocorticoid plus LABA. They reduce exacerbations and oral steroid needs but are not rescue drugs.
| Drug | Target | Best fit | Notes |
|---|---|---|---|
| Omalizumab | IgE | Allergic asthma, elevated IgE, perennial aeroallergen sensitization | Anaphylaxis risk |
| Mepolizumab, reslizumab | IL-5 | High blood eosinophils | Mepolizumab subcutaneous; reslizumab IV, weight-based |
| Benralizumab | IL-5 receptor α | High blood eosinophils | Binds eosinophils and basophils and recruits NK cells for antibody-dependent cytotoxicity; near-complete eosinophil depletion |
| Dupilumab | IL-4 receptor α (blocks IL-4 and IL-13) | High FeNO and/or eosinophils | Also atopic dermatitis and nasal polyps; conjunctivitis, transient eosinophilia |
| Tezepelumab | TSLP | Severe asthma including low type 2 markers | Acts upstream of the whole cascade |
Treat helminth infections before starting type 2 biologics, because eosinophils and type 2 cytokines help defend against worms.