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Pharmacotherapy of Selected Diseases

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a. Bronchial Asthma

Classification (GINA Stepwise)

1. Bronchodilators

• Salbutamol (Albuterol) 100-200 mcg inhaled as needed - drug of choice for acute bronchospasm
• Terbutaline - available as inhaler and subcutaneous injection for severe attacks
• Mechanism: Activate beta-2 receptors on bronchial smooth muscle → increase cAMP → bronchodilation
• Onset within 5 minutes, duration 4-6 hours

• Salmeterol 50 mcg BD, Formoterol 12 mcg BD
• Duration 12 hours; NEVER used as monotherapy in asthma

• Ipratropium bromide - used adjunctively in acute severe asthma, especially useful in COPD-asthma overlap

• Tiotropium - add-on therapy at Step 4-5 for uncontrolled asthma

2. Inhaled Corticosteroids (ICS) - Cornerstone of controller therapy

• Beclomethasone 200-800 mcg/day, Budesonide 200-800 mcg/day, Fluticasone 100-500 mcg/day
• Mechanism: Reduce airway inflammation, decrease mucus secretion, reduce bronchial hyperreactivity
• Must rinse mouth after use to prevent oral candidiasis
• Most effective long-term controller; reduces exacerbations, hospitalizations

3. Systemic Corticosteroids

• Prednisolone 0.5-1 mg/kg/day orally for 5-7 days during acute exacerbations
• Hydrocortisone 100-200 mg IV in severe/life-threatening attacks
• Long-term use avoided due to Cushingoid effects; use minimum effective dose

4. Methylxanthines

• Theophylline / Aminophylline - narrow therapeutic index (10-20 mcg/mL)
• Mechanism: Phosphodiesterase inhibition → increased cAMP → bronchodilation; also has anti-inflammatory properties
• IV aminophylline used as add-on in severe acute asthma refractory to beta-agonists
• Oral theophylline: step 3-4 add-on; frequent drug interactions (ciprofloxacin, macrolides increase levels)

5. Leukotriene Receptor Antagonists (LTRA)

• Montelukast 10 mg OD orally (preferred), Zafirlukast
• Block cysteinyl leukotriene receptors; reduce bronchospasm, mucus secretion, and eosinophilic inflammation
• Particularly useful in aspirin-exacerbated asthma and allergic rhinitis-associated asthma
• Step 2 alternative to low-dose ICS; Step 3 add-on

6. Mast Cell Stabilizers

• Sodium cromoglycate, Nedocromil - inhibit mast cell degranulation
• Mainly prophylactic; useful in exercise-induced and allergen-induced asthma
• Less effective than ICS; largely replaced in adults but still used in children

7. Biologics (Severe Refractory Asthma - Step 5)

8. Acute Severe Asthma (Status Asthmaticus) Management

1. Oxygen - maintain SpO2 >94%
2. Nebulized salbutamol 5 mg + ipratropium 0.5 mg continuously or every 20 min × 3
3. Systemic corticosteroids - hydrocortisone 200 mg IV stat, then prednisolone 40-50 mg orally
4. Magnesium sulfate 1.2-2 g IV over 20 min - causes bronchial smooth muscle relaxation (blocks calcium entry)
5. IV aminophylline if no response to above
6. Heliox and mechanical ventilation in refractory cases

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b. Vertigo

1. Vestibular Suppressants (Acute Symptomatic Relief)

• Prochlorperazine 5-10 mg PO/IM or 25 mg PR - useful for nausea/vomiting accompanying vertigo
• Acts on D2 receptors in the chemoreceptor trigger zone (CTZ) and vestibular system

• Diazepam 2-5 mg TDS, Lorazepam 0.5-1 mg - reduce vestibular firing via GABA-A enhancement
• Short-term use only; risk of dependence and suppression of CNS compensation

• Scopolamine (hyoscine) transdermal patch - useful for motion sickness and short-term vertigo
• Blocks muscarinic receptors in the vestibular nucleus

2. Betahistine - Meniere's Disease

• Betahistine 8-16 mg TDS orally (up to 48 mg/day)
• H1 agonist and H3 antagonist - increases histamine in vestibular system; improves microcirculation of the labyrinth and reduces endolymphatic pressure
• Drug of first choice for Meniere's disease (endolymphatic hydrops)
• Reduces frequency and severity of vertigo attacks; needs weeks to show benefit

3. Drugs for Specific Causes

• Primary treatment is Epley's canalith repositioning maneuver - pharmacotherapy is NOT first-line
• Short course of meclizine if symptoms are disabling

• Acute phase: vestibular suppressants (meclizine, prochlorperazine) for 3-5 days
• Methylprednisolone 100 mg/day tapered over 3 weeks - accelerates vestibular recovery
• Valacyclovir was trialed (suspected herpes simplex) but evidence does not support routine use
• Vestibular rehabilitation exercises (Brandt-Daroff) to promote CNS compensation

• Betahistine (as above), low-sodium diet, diuretics (acetazolamide or hydrochlorothiazide + triamterene) to reduce endolymphatic pressure
• Intratympanic gentamicin (chemical ablation) for refractory cases - reduces vestibular hair cell activity
• Intratympanic dexamethasone - less ototoxic alternative

• Acute: triptans, NSAIDs, antiemetics
• Prophylaxis: propranolol, topiramate, amitriptyline, venlafaxine

4. Antiemetics (Associated Nausea/Vomiting)

• Ondansetron 4-8 mg - 5-HT3 antagonist; effective for nausea without sedation
• Metoclopramide 10 mg PO/IM/IV - dopamine antagonist, prokinetic

Key principle: Vestibular suppressants should NOT be used long-term as they impair CNS compensation (vestibular plasticity). They are for acute relief only (usually ≤3-5 days).

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c. Gout

Phase 1: Treatment of Acute Gouty Attack

• Indomethacin 50 mg TDS × 3-5 days (historically preferred NSAID for gout)
• Naproxen 500 mg BD, Diclofenac 50 mg TDS
• Mechanism: Inhibit COX-1 and COX-2 → reduce prostaglandin synthesis and neutrophil migration
• Contraindicated in renal impairment, peptic ulcer disease, anticoagulant use
• Add PPI (omeprazole) for GI protection

• 0.5-1 mg stat, then 0.5 mg every 6-8 hours until relief (max 6 mg per course)
• Low-dose regimen (1.2 mg then 0.6 mg after 1 hour) is as effective and better tolerated
• Mechanism: Binds tubulin → inhibits microtubule polymerization → impairs neutrophil migration, phagocytosis, and inflammasome activation (NLRP3) → blocks IL-1β release
• Side effects: diarrhea, nausea, vomiting (dose-limiting); myopathy/neuropathy with long-term use
• Drug interactions: cyclosporine, clarithromycin increase toxicity (P-gp and CYP3A4 inhibition)
• Can be used as prophylaxis: 0.5-0.6 mg OD-BD during urate-lowering therapy initiation

• Prednisolone 30-40 mg/day orally, tapered over 5-10 days
• Triamcinolone acetonide 10-40 mg intra-articular injection - for monoarticular gout
• Methylprednisolone IV in severe polyarticular attacks
• Particularly useful in renal failure, elderly, or post-operative patients

• Anakinra (IL-1Ra), Canakinumab (anti-IL-1β monoclonal Ab)
• Useful when NSAIDs, colchicine, and corticosteroids are all contraindicated

Phase 2: Urate-Lowering Therapy (ULT) - Initiated 2-4 Weeks After Acute Attack Resolves

• Start with low dose and titrate slowly to prevent mobilization flares
• Co-prescribe colchicine 0.5 mg BD for 3-6 months as flare prophylaxis during initiation

• Pegloticase (pegylated recombinant uricase) IV infusion every 2 weeks
• Converts uric acid to allantoin (highly soluble) → dramatic lowering
• Risk of infusion reactions, immunogenicity; very expensive

Dietary & Lifestyle Measures (Adjunctive)

• Avoid purines (red meat, organ meats, shellfish, beer)
• Increase fluid intake (>2 L/day) to prevent urate crystallization
• Avoid aspirin at low doses (raises urate), thiazides, cyclosporine, pyrazinamide
• Losartan (antihypertensive) has mild uricosuric effect - preferred in hypertensive gout patients

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d. Dyslipidemia

Classification (Fredrickson/WHO)

1. Statins (HMG-CoA Reductase Inhibitors) - First-Line for High LDL-C

• Mechanism: Inhibit HMG-CoA reductase → reduce intracellular cholesterol synthesis → upregulate hepatic LDL receptors → increase LDL clearance from blood
• Also modestly increase HDL-C (+5-10%) and lower TG (-20-30%)
• Side effects: myopathy/myalgia (check CK), hepatotoxicity (check LFTs), new-onset diabetes
• Statin myopathy risk increased with fibrate combination (especially gemfibrozil - avoid); preferred combination is fenofibrate + statin

2. Bile Acid Sequestrants (Resins)

• Cholestyramine 4-24 g/day, Colestipol, Colesevelam 3.75 g/day
• Mechanism: Bind bile acids in intestine → prevent enterohepatic circulation → liver uses cholesterol to make more bile acids → depletes hepatic cholesterol → upregulates LDL receptors
• Lower LDL by 15-30%; may raise TG slightly (avoid in hypertriglyceridemia)
• GI side effects: constipation, bloating; interfere with absorption of fat-soluble vitamins and drugs

3. Cholesterol Absorption Inhibitors

• Ezetimibe 10 mg OD
• Mechanism: Inhibits NPC1L1 transporter in small intestinal brush border → reduces intestinal cholesterol absorption by ~50% → lowers LDL by 15-20%
• Used as add-on to statins (additive LDL lowering); reduces MACE when added to statin (IMPROVE-IT trial)

4. PCSK9 Inhibitors - For Very High Cardiovascular Risk / Statin Intolerance

• Evolocumab 140 mg SC every 2 weeks or 420 mg monthly (FOURIER trial)
• Alirocumab 75-150 mg SC every 2 weeks (ODYSSEY trial)
• Mechanism: Monoclonal antibodies against PCSK9 → prevent degradation of LDL receptors → massive increase in LDL clearance (LDL reduction 50-65% on top of statins)
• Very expensive; indicated when LDL >100 mg/dL despite maximal statin + ezetimibe

5. Fibric Acid Derivatives (Fibrates) - Primary TG Lowering

• Fenofibrate 145-200 mg/day, Gemfibrozil 600 mg BD, Bezafibrate, Ciprofibrate
• Mechanism: PPAR-α agonists → increase lipoprotein lipase (LPL) activity → increased TG-rich lipoprotein clearance; also increase HDL-C by 10-25% and reduce LDL
• Primarily used when TG >500 mg/dL (pancreatitis risk) or combined dyslipidemia
• Preferred fibrate combined with statin is fenofibrate (lower myopathy risk vs gemfibrozil)

6. Niacin (Nicotinic Acid)

• Niacin 1-3 g/day (extended-release forms preferred: Niaspan)
• Most effective agent for raising HDL-C (+25-35%); also lowers TG (-30-50%) and LDL (-20-25%)
• Mechanism: Inhibits hepatic VLDL secretion; reduces free fatty acid release from adipose (via GPR109A)
• Side effects: flushing (prostaglandin-mediated; pretreat with aspirin 325 mg), hyperglycemia, hyperuricemia, hepatotoxicity
• Largely fallen out of favor due to failure to reduce CV events in trials (AIM-HIGH, HPS2-THRIVE) on top of statin therapy

7. Omega-3 Fatty Acids

• Icosapentaenoic acid (EPA) - Vascepa (4 g/day) - reduces CV events (REDUCE-IT trial) by 25% in patients with high TG
• EPA + DHA - Omacor/Lovaza 4 g/day - lowers TG by 20-50%
• Mechanism: Reduce hepatic VLDL-TG synthesis; increase TG clearance
• Well tolerated; mild GI side effects; fishy taste

8. Emerging/Other Agents

Treatment Goals (ACC/AHA 2019)

• Very high risk (ASCVD): LDL <70 mg/dL; consider adding ezetimibe or PCSK9i if not achieved
• High risk: LDL <100 mg/dL
• Moderate risk: LDL <130 mg/dL

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e. Open-Angle Glaucoma

Drug Classes and Agents

1. Prostaglandin Analogs - First-Line (Most Effective IOP Lowering)

• Mechanism: FP prostanoid receptor agonists → increase uveoscleral (unconventional) aqueous outflow → lower IOP
• Given once at bedtime (maximum effect during peak aqueous production at night)
• Side effects: prostaglandin-mediated - iris pigmentation (heterochromia), eyelash growth (hypertrichosis), periorbital fat atrophy, conjunctival hyperemia, uveitis
• Contraindicated in pregnancy; caution in aphakic/pseudophakic eyes (cystoid macular edema risk)

2. Beta-Blockers (Beta-Adrenergic Antagonists) - First or Second Line

• Mechanism: Block beta-2 receptors on ciliary epithelium → reduce aqueous humor production (20-30% IOP reduction)
• Timolol is the most widely used; often combined with prostaglandins
• Systemic absorption: bradycardia, bronchospasm, worsening heart failure, depression, masking hypoglycemia
• Contraindications: asthma/COPD (avoid non-selective), bradycardia, heart block, uncompensated heart failure
• Betaxolol is cardioselective - relatively safer in mild reactive airway disease
• Beware nocturnal dip phenomenon with timolol: reduces IOP during day but not at night

3. Alpha-2 Adrenergic Agonists

• Mechanism: Dual action - decrease aqueous production (via reduced cAMP in ciliary epithelium) AND increase uveoscleral outflow
• IOP reduction: 20-27%
• Side effects: ocular allergy/contact dermatitis (10-15% discontinue due to allergy), dry mouth, sedation
• Brimonidine is contraindicated in infants and young children (apnea, sedation, hypotension due to CNS penetration)
• Useful when beta-blockers are contraindicated; also provides some optic nerve neuroprotection (preclinical evidence)

4. Carbonic Anhydrase Inhibitors (CAIs)

• Acetazolamide 250 mg QDS orally or 500 mg SR BD; Methazolamide 25-50 mg BD-TDS
• Mechanism: Inhibit carbonic anhydrase (CA-II and CA-IV) in ciliary epithelium → reduce bicarbonate and water secretion → decrease aqueous humor production (IOP reduction 15-26%)
• Systemic CAIs (acetazolamide) used for acute IOP crises or when topical drugs fail
• Systemic side effects: paraesthesias, fatigue, sulfonamide hypersensitivity, hypokalemia, metabolic acidosis, nephrolithiasis (calcium oxalate stones); contraindicated in sulfa allergy

5. Miotics (Cholinergic Agents) - Rarely Used Now

• Pilocarpine 1-4% eye drops 4 times daily
• Mechanism: Muscarinic (M3) agonist → contracts ciliary muscle and iris sphincter → opens trabecular meshwork → increases conventional outflow
• IOP reduction: 20-30%
• Largely replaced by prostaglandins and beta-blockers due to poor tolerability
• Side effects: miosis (poor vision in dim light), brow ache, induced myopia, retinal detachment risk (avoid in high myopia)
• Still used in angle-closure glaucoma and as an alternative when other drugs fail

6. Fixed-Dose Combinations (to improve compliance)

7. Newer/Adjunctive Agents

• Netarsudil (Rho kinase / ROCK inhibitor) 0.02% OD - increases trabecular outflow and reduces episcleral venous pressure; IOP reduction ~20%
• Latanoprostene bunod (NO-releasing prostaglandin analog) - dual mechanism: FP agonist + NO → increases both uveoscleral and trabecular outflow
• Omidenepag isopropyl - selective EP2 prostanoid receptor agonist

Stepwise Approach in POAG

1. Start monotherapy with prostaglandin analog (first choice) or beta-blocker
2. If inadequate: Add second drug from different class (most commonly + timolol)
3. If inadequate: Add third agent (CAI or alpha-2 agonist) or switch to fixed combination
4. If maximum medical therapy fails: Laser trabeculoplasty (SLT/ALT) or surgical trabeculectomy

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Summary Table - Drug Classes at a Glance