Respiratory & Gastrointestinal Pharmacology

• Definition
  • Chronic inflammatory disorder of the airways
  • Key features: bronchial hyperreactivity, reversible airflow obstruction, airway edema, mucus hypersecretion
• Early asthmatic response (EAR)
  • Occurs within 30–60 minutes of allergen exposure
  • Mediated by mast cell degranulation
  • Primary mediators: histamine, leukotrienes (LTC₄, LTD₄, LTE₄), prostaglandin D₂
  • Result: acute bronchospasm, increased vascular permeability
• Late asthmatic response (LAR)
  • Develops 4–8 hours after exposure
  • Driven by eosinophil and lymphocyte infiltration
  • Release of inflammatory cytokines (IL-4, IL-5, IL-13)
  • Result: airway wall edema, mucus plugging, sustained bronchoconstriction
• Key inflammatory mediators
  • Histamine: from mast cells; causes bronchospasm, vasodilation
  • Leukotrienes: potent bronchoconstrictors, increase mucus production
  • Prostaglandins: PGD₂ promotes bronchoconstriction
  • Platelet-activating factor (PAF): induces eosinophil chemotaxis

• Mechanism
  • Selective agonism at β₂-adrenergic receptors on airway smooth muscle
  • Activation → G₅ protein → adenylyl cyclase ↑ → cAMP ↑
  • cAMP → protein kinase A activation → myosin light-chain kinase inhibition → smooth muscle relaxation
  • Also inhibit mast cell mediator release and enhance mucociliary clearance
• Short-acting β₂ agonists (SABA)
  • Albuterol (salbutamol), metaproterenol, terbutaline
  • Onset: 5–15 minutes; duration: 4–6 hours
  • Use: acute bronchospasm relief, exercise-induced bronchospasm prophylaxis
  • Preferred inhaled route for rapid onset and minimal systemic effects
• Long-acting β₂ agonists (LABA)
  • Salmeterol, formoterol
  • Onset: 20–30 minutes (salmeterol) or faster (formoterol)
  • Duration: 12 hours or more
  • Use: nocturnal asthma prophylaxis, adjunct to inhaled corticosteroids
  • Never use as monotherapy — increased risk of asthma-related death
• Adverse effects
  • Systemic (with overuse): tachycardia, palpitations, tremor, anxiety
  • Hypokalemia (shift of K⁺ into cells)
  • Hyperglycemia (glycogenolysis)
  • Tolerance with regular use (β-receptor desensitization)

• Mechanism
  • Block M₃ muscarinic receptors on airway smooth muscle
  • Prevent acetylcholine-induced bronchoconstriction
  • Reduce vagal tone → bronchodilation
  • Also decrease mucus secretion from submucosal glands
• Agents
  • Ipratropium: short-acting; onset 15–30 min, duration 4–6 h
  • Tiotropium: long-acting; once-daily dosing, duration >24 h
  • Both administered via inhalation
• Clinical use
  • Acute asthma (especially in combination with SABA)
  • COPD — first-line maintenance therapy
  • Preferred over β-agonists in patients with cardiovascular disease
  • Drug of choice for β-blocker-induced bronchospasm
• Adverse effects
  • Minor atropine-like effects: dry mouth, cough, throat irritation
  • Minimal systemic absorption via inhaled route
  • Paradoxical bronchospasm (rare)

• Mechanism
  • Non-selective phosphodiesterase (PDE) inhibition → cAMP ↑ → smooth muscle relaxation
  • Adenosine receptor antagonism (A₁, A₂) → prevents adenosine-induced bronchoconstriction
  • Also: histone deacetylase activation → anti-inflammatory effects
• Clinical use
  • Adjunctive therapy for asthma and COPD
  • Regular use reduces symptom frequency
  • Aminophylline (IV) for status asthmaticus or severe bronchospasm
• Narrow therapeutic window
  • Target serum concentration: 5–15 mcg/mL
  • Monitoring essential for safe use
• Adverse effects (dose-related)
  • GI: nausea, vomiting, diarrhea
  • Cardiovascular: tachycardia, arrhythmias
  • CNS: insomnia, tremor, seizures (at high levels)
• Drug interactions
  • Increased toxicity with: erythromycin, cimetidine, fluoroquinolones, allopurinol
  • Decreased levels with: phenytoin, rifampin, phenobarbital, smoking

• Agents
  • Cromolyn sodium (cromoglicate)
  • Nedocromil sodium
• Mechanism
  • Inhibit degranulation of pulmonary mast cells
  • Reduce release of histamine, leukotrienes, and PAF
  • May also inhibit sensory nerve activation (nedocromil)
  • Mechanism not fully understood — thought to involve chloride channel blockade
• Clinical use
  • Prophylactic treatment of asthma
  • Effective for allergen-induced and exercise-induced asthma
  • Reduce bronchial hyperreactivity over weeks of use
  • Not effective for acute bronchospasm
• Administration
  • Inhaled via nebulizer or metered-dose inhaler
  • Onset: weeks (prophylactic benefit)
• Adverse effects
  • Throat irritation, cough, unpleasant taste (nedocromil)
  • Minimal systemic toxicity
  • Bronchospasm can occur — pre-treat with β₂ agonist if needed

• Mechanism
  • Bind to glucocorticoid receptor → translocate to nucleus
  • Modulate gene transcription (transactivation and transrepression)
  • Suppress pro-inflammatory cytokines (IL-1, IL-4, IL-5, TNF-α)
  • Inhibit phospholipase A₂ → ↓ arachidonic acid → ↓ prostaglandins, leukotrienes
  • Reduce eosinophil survival and recruitment
• Inhaled corticosteroids (ICS)
  • Budesonide, flunisolide, fluticasone, beclomethasone
  • First-line prophylactic therapy for persistent asthma
  • Reduce BHR, symptom frequency, and exacerbation risk
  • Prevent β-receptor desensitization from excessive SABA use
• Systemic corticosteroids
  • Prednisone (oral), methylprednisolone (IV)
  • Reserved for severe acute exacerbations or status asthmaticus
  • Short courses (5–10 days) with taper
• Adverse effects (inhaled)
  • Oropharyngeal candidiasis (thrush)
  • Dysphonia (hoarseness)
  • Prevention: use spacer, rinse mouth after use
• Adverse effects (systemic)
  • Adrenal suppression, osteoporosis, hyperglycemia, weight gain
  • Immunosuppression, Cushingoid features
  • Growth suppression in children (with prolonged use)

• Leukotriene receptor antagonists (LTRAs)
  • Montelukast, zafirlukast
  • Selective antagonists at cysteinyl leukotriene (LTD₄) receptors
  • Block leukotriene-mediated bronchoconstriction, mucus secretion, and eosinophil recruitment
  • Slow onset (days to weeks) — prophylactic use only
  • Indications: exercise-induced bronchospasm, aspirin-exacerbated respiratory disease, mild persistent asthma
• Lipoxygenase inhibitor
  • Zileuton
  • Inhibits 5-lipoxygenase (5-LOX) → prevents formation of all leukotrienes (LTA₄, LTB₄, LTC₄, LTD₄, LTE₄)
  • More rapid onset (1–3 hours) than LTRAs
  • Adjunctive therapy to corticosteroids
• Adverse effects (LTRAs)
  • Generally well-tolerated
  • Headache, GI upset, elevated liver enzymes (rare)
  • Neuropsychiatric effects (montelukast): agitation, depression, suicidality — FDA boxed warning
• Adverse effects (zileuton)
  • Hepatotoxicity — monitor liver function tests
  • Elevated transaminases, drug-induced hepatitis

• Mechanism
  • Selective inhibition of phosphodiesterase-4 (PDE-4)
  • Prevents breakdown of cAMP in inflammatory and immune cells
  • cAMP ↑ → protein kinase A activation → ↓ pro-inflammatory cytokine release
  • Reduces neutrophil and eosinophil activity
• Clinical use
  • Indicated for severe COPD with chronic bronchitis and frequent exacerbations
  • Adjunct to bronchodilators and inhaled corticosteroids
  • Not a bronchodilator — anti-inflammatory effects only
• Adverse effects
  • GI: nausea, diarrhea, weight loss (dose-dependent)
  • Neuropsychiatric: insomnia, depression, anxiety
  • Headache, dizziness

• Histamine physiology
  • Synthesized from histidine via histidine decarboxylase
  • Stored in mast cells, basophils, enterochromaffin-like cells
  • Released by IgE-mediated degranulation, drugs, or physical stimuli
• H₁ receptors
  • Distribution: vascular endothelium, bronchial smooth muscle, CNS
  • Effects: vasodilation, increased vascular permeability, bronchoconstriction, itch
• H₁ antagonists (first-generation)
  • Diphenhydramine, promethazine, hydroxyzine, meclizine
  • Lipophilic → cross BBB → sedation, anticholinergic effects
  • Uses: allergic rhinitis, urticaria, motion sickness, insomnia
• H₁ antagonists (second-generation)
  • Loratadine, cetirizine, fexofenadine
  • Less lipophilic → minimal CNS effects
  • Non-sedating, longer duration, preferred for allergic rhinitis
• H₂ receptors
  • Distribution: gastric parietal cells, cardiac muscle, mast cells
  • Effects: ↑ gastric acid secretion, ↑ heart rate, vasodilation
• H₂ antagonists
  • Cimetidine, ranitidine, famotidine
  • Competitive blockade of histamine at parietal cell H₂ receptors
  • Reduce gastric acid secretion (used in GERD, peptic ulcer)
  • Cimetidine: CYP450 inhibitor → drug interactions; anti-androgenic effects

• Proton pump inhibitors (PPIs)
  • Omeprazole, esomeprazole, pantoprazole, lansoprazole
  • Irreversible inhibition of H⁺/K⁺-ATPase (proton pump) in gastric parietal cells
  • Most potent acid-suppressing agents
  • Used for GERD, peptic ulcer, Zollinger–Ellison syndrome
  • Long-term use: B₁₂ deficiency, osteoporosis risk, C. difficile infection
• PGE₁ analog
  • Misoprostol
  • Synthetic prostaglandin E₁ analog
  • Stimulates mucus and bicarbonate secretion, reduces gastric acid
  • Protects gastric mucosa (cytoprotective)
  • Used to prevent NSAID-induced gastric ulcers
  • Adverse effects: diarrhea, abdominal cramps; contraindicated in pregnancy (abortifacient)
• Sucralfate
  • Polymer of sucrose octasulfate and aluminum hydroxide
  • Forms a viscous, adherent barrier over ulcer craters
  • Protects from acid, pepsin, and bile
  • Used for duodenal ulcer, stress ulcer prophylaxis
  • Adverse effects: constipation, aluminum accumulation (renal impairment)
• NSAID-induced ulcer prevention
  • Misoprostol is the only agent specifically approved for NSAID ulcer prophylaxis
  • Alternative: co-therapy with PPI or H₂ blocker

• 5-HT₁ₐ partial agonist
  • Buspirone
  • Partial agonism at presynaptic and postsynaptic 5-HT₁ₐ receptors
  • Anxiolytic with no benzodiazepine-like sedation or dependence
  • Slow onset (weeks), no acute panic relief
• 5-HT₁ᵦ/₁ᵈ agonists (triptans)
  • Sumatriptan, rizatriptan, zolmitriptan
  • Agonists at 5-HT₁ᵦ/₁ᵈ receptors on cranial vessels and trigeminal nerve terminals
  • Cause vasoconstriction of intracranial vessels, inhibit neuropeptide release
  • Used for acute migraine (not prophylaxis)
  • Contraindicated: coronary artery disease, uncontrolled hypertension, hemiplegic migraine
• 5-HT₂ antagonists
  • Cyproheptadine: H₁ + 5-HT₂ antagonist; used for serotonin syndrome, appetite stimulation
  • Atypical antipsychotics (e.g., risperidone, olanzapine) have 5-HT₂ antagonism
• 5-HT₃ antagonists
  • Ondansetron, granisetron, palonosetron
  • Block 5-HT₃ receptors in the chemoreceptor trigger zone and gut
  • Highly effective antiemetics (especially chemotherapy-induced nausea)
  • Adverse effects: headache, constipation, QT prolongation (ondansetron)

• Dopamine (D₂) antagonists
  • Metoclopramide: D₂ antagonist + 5-HT₄ agonist; prokinetic, used for gastroparesis, chemotherapy nausea
  • Prochlorperazine: D₂ antagonist; used for nausea, vertigo
  • Adverse: extrapyramidal symptoms, tardive dyskinesia, hyperprolactinemia
• H₁ antagonists
  • Meclizine, promethazine, dimenhydrinate
  • Use: motion sickness, vertigo, nausea
  • Promethazine has significant sedative and anticholinergic effects
• Muscarinic antagonist
  • Scopolamine (transdermal patch)
  • Use: motion sickness prophylaxis
  • Adverse: dry mouth, drowsiness, blurred vision
• Cannabinoid
  • Dronabinol (synthetic THC)
  • Use: chemotherapy-induced nausea, appetite stimulation in AIDS
  • Adverse: euphoria, dizziness, cognitive impairment
• 5-HT₃ antagonists
  • Ondansetron (see serotonergic section)
• NK₁ antagonists
  • Aprepitant
  • Blocks substance P at neurokinin-1 (NK₁) receptors in the brainstem
  • Use: highly emetogenic chemotherapy (in combination with 5-HT₃ antagonist + steroid)
  • Adverse: fatigue, hiccups, constipation, CYP3A4 inducer

• Mechanism
  • Inhibit cyclooxygenase (COX) → ↓ prostaglandin synthesis from arachidonic acid
  • COX-1: constitutive — gastric protection, platelet aggregation, renal perfusion
  • COX-2: inducible — inflammation, pain, fever
• Non-selective NSAIDs
  • Aspirin, indomethacin, ibuprofen, naproxen, sulindac
  • Inhibit both COX-1 and COX-2
  • Uses: analgesia, antipyresis, anti-inflammatory, cardiovascular prophylaxis (aspirin)
  • Adverse: GI ulcers, bleeding, renal impairment, hypersensitivity (aspirin → bronchospasm in asthma)
• COX-2 selective inhibitors (coxibs)
  • Celecoxib
  • Selective COX-2 inhibition → preserved COX-1 (less GI toxicity)
  • Uses: osteoarthritis, rheumatoid arthritis, acute pain
  • Adverse: increased cardiovascular risk (MI, stroke), renal toxicity, edema
• Aspirin unique properties
  • Irreversible COX-1 inhibition (platelets → antiplatelet effect for 7–10 days)
  • Used for: CVD prevention, acute MI, stroke prophylaxis
  • Reye's syndrome risk in children with viral illness
• Acetaminophen
  • COX inhibition central (not peripheral); weak anti-inflammatory
  • Analgesic, antipyretic — safe for patients with GI or bleeding risk
  • Toxic metabolite (NAPQI) — hepatic necrosis in overdose
  • Antidote: N-acetylcysteine (provides sulfhydryl groups for detoxification)

• Common agents
  • Hydrocortisone (short-acting, high mineralocorticoid activity)
  • Prednisone (intermediate-acting, moderate mineralocorticoid activity)
  • Triamcinolone (intermediate, low mineralocorticoid activity)
  • Dexamethasone (long-acting, very low mineralocorticoid activity)
  • Betamethasone (long-acting, very low mineralocorticoid activity)
• Relative potencies
  • Anti-inflammatory: dexamethasone > prednisone > hydrocortisone
  • Mineralocorticoid (Na⁺ retention): hydrocortisone >> prednisone >> dexamethasone
  • Dexamethasone and betamethasone have negligible mineralocorticoid effects
• Clinical uses
  • Asthma, COPD exacerbations (see above)
  • Allergic conditions, autoimmune diseases, organ transplantation
  • Cerebral edema (dexamethasone)
  • Antenatal fetal lung maturation (betamethasone)
• Adverse effects (chronic use)
  • Cushing's syndrome: moon face, buffalo hump, central obesity
  • Osteoporosis, avascular necrosis, growth suppression (children)
  • Hyperglycemia, diabetes, hypertension
  • Immunosuppression, infections, delayed wound healing
  • Adrenal suppression (HPA axis) — need gradual taper