Renal and Respiratory Pharmacology

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Renal and Respiratory Pharmacology — Key Facts for FMGE Core concept: Diuretics work at different nephron segments causing distinct electrolyte patterns; respiratory drugs include bronchodilators and anti-inflammatory agents High-yield point: Loop diuretics cause hypokalemia, metabolic alkalosis, hypocalcemia, ototoxicity; thiazides cause hypokalemia, hyperuricemia, hypercalcemia, hyperglycemia ⚡ Exam tip: Know which diuretics are most effective for each type of edema and the life-threatening complications of each drug class

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Renal and Respiratory Pharmacology — FMGE Study Guide

Diuretics

Site of Action in Nephron

Proximal tubule:

• Carbonic anhydrase inhibitors (acetazolamide)
• Osmotic diuretics (mannitol)

Thick ascending limb (TAL) of Loop of Henle:

• Loop diuretics (furosemide, bumetanide, torsemide)

Distal convoluted tubule (DCT):

• Thiazides (hydrochlorothiazide)
• Thiazide-like (chlorthalidone, indapamide)

Collecting duct:

• Potassium-sparing: Aldosterone antagonists (spironolactone, eplerenone), ENaC blockers (amiloride, triamterene)
• ADH antagonists (vaptans - conivaptan, tolvaptan)

Loop Diuretics

Examples: Furosemide, bumetanide, torsemide, ethacrynic acid

Mechanism: Block Na-K-2Cl cotransporter (NKCC2) in TAL → ↓reabsorption of Na, K, Cl, Mg, Ca

Effects:

• Potent diuresis (20-25% of filtered Na)
• Hypokalemia (↑distal Na delivery → ↑K secretion)
• Metabolic alkalosis (↓H+ secretion, volume contraction)
• Hypomagnesemia, hypocalcemia (unlike thiazides)
• Hyperuricemia (competitively inhibits uric acid secretion)
• Ototoxicity (Ethacrynic acid > Furosemide): Tinnitus, hearing loss (especially with aminoglycosides)
• Hypovolemia: Orthostatic hypotension, acute kidney injury

Uses:

• Acute pulmonary edema (IV furosemide - rapid relief)
• Severe volume overload (CHF, nephrotic syndrome)
• Resistant hypertension
• Hypercalcemia (loop diuretics + IV saline - “calciuresis”)
• Acute kidney injury (maintain urine output)

Pharmacokinetics:

• IV onset: 5 minutes; peak: 30 minutes
• Short duration (4-6 hours) - may need twice daily dosing
• Highly protein bound (secreted into proximal tubule via organic anion transporter - OAT)

Thiazide Diuretics

Examples: HCTZ, chlorthalidone, indapamide, metolazone

Mechanism: Block Na-Cl cotransporter (NCC) in DCT → ↓reabsorption of Na, Cl

Effects:

• Modest diuresis (5-10% of filtered Na)
• Hypokalemia (but less than loop diuretics)
• Hypercalcemia (↑proximal tubule Ca reabsorption)
• Hyperuricemia
• Hyperglycemia (↓insulin secretion, ↓peripheral glucose uptake)
• Hyponatremia, hypomagnesemia
• Metabolic alkalosis

Uses:

• First-line antihypertensive (low-dose thiazides)
• Edema (mild-moderate CHF, cirrhosis, nephrotic syndrome)
• Nephrogenic diabetes insipidus (paradoxical effect - mild hypovolemia → ↑ADH sensitivity)
• Osteoporosis (calcium-sparing effect)

Contraindications:

• Gout (precipitates attack)
• Severe renal impairment (ineffective if GFR <30 mL/min, except metolazone)

Potassium-Sparing Diuretics

Aldosterone antagonists:

Spironolactone:

• Competitively blocks aldosterone at mineralocorticoid receptor
• ↓ENaC expression → ↓Na reabsorption, ↓K secretion
• Proven mortality benefit in HFrEF (RALES trial)
• Side effects: Gynecomastia (anti-androgen effect), hyperkalemia, metabolic acidosis

Eplerenone: More selective (less anti-androgen effects); used for HF and post-MI LV dysfunction

ENaC blockers:

Amiloride/Triamterene:

• Directly block epithelial sodium channel (collecting duct)
• Weak diuretics (1-2% filtered Na)
• Used with thiazides/loop diuretics to prevent hypokalemia
• Side effects: Hyperkalemia (contraindicated in renal failure)

Carbonic Anhydrase Inhibitors

Acetazolamide:

• Inhibit CA in proximal tubule → ↓H+ secretion → ↓NaHCO3 reabsorption
• Weak diuretics; metabolic acidosis develops (bicarbonaturia)
• Uses: Glaucoma (↓aqueous humor production), altitude sickness (prevent respiratory alkalosis), metabolic alkalosis (correct), idiopathic intracranial hypertension
• Side effects: Paresthesias, hypokalemia, sulfa allergy (some cross-reactivity)

Osmotic Diuretics

Mannitol:

• Filtered but not reabsorbed → ↑tubular fluid osmolarity → ↓water reabsorption
• Uses: Acute glaucoma, cerebral edema, acute kidney injury (maintain urine flow)
• Side effects: Pulmonary edema, hyponatremia, headache, nausea

Respiratory Pharmacology

Bronchodilators

Beta-2 agonists:

• Short-acting (SABA): Albuterol (salbutamol) - rescue therapy for acute bronchospasm
• Long-acting (LABA): Salmeterol, formoterol - NOT for acute relief; for maintenance therapy
• Mechanism: β2 receptor → Gs → ↑cAMP → bronchial smooth muscle relaxation
• Side effects: Tremor, tachycardia (β1 cross-reactivity), hypokalemia, paradoxical bronchospasm

Methylxanthines:

• Theophylline: Bronchodilation by PDE inhibition, adenosine antagonism, ↑cAMP
• Narrow therapeutic index - requires drug level monitoring (10-20 μg/mL)
• Side effects: Nausea, vomiting, arrhythmias, seizures (toxicity)
• Interactions: CYP1A2 inhibitors (ciprofloxacin, erythromycin) → ↑theophylline levels
• Caffeine is related structure

Anticholinergics:

• Ipratropium: Short-acting inhaled anticholinergic (M3 blockade); COPD
• Tiotropium: Long-acting; COPD maintenance
• Side effects: Dry mouth, urinary retention, constipation

Anti-Inflammatory Agents

Inhaled Corticosteroids (ICS):

• Fluticasone, budesonide, beclomethasone, mometasone
• Most effective anti-inflammatory for asthma
• Mechanism: ↓inflammatory gene transcription (↓IL-4, IL-5, IL-13)
• Side effects (local): Oral candidiasis, dysphonia (hoarse voice) - use spacer/rinse mouth
• Systemic (high dose, long-term): Adrenal suppression, osteoporosis, cataracts, growth delay in children

Leukotriene receptor antagonists:

• Montelukast, zafirlukast: Block cysteinyl leukotriene receptors (CysLT1)
• Used for: Chronic asthma prophylaxis, exercise-induced bronchospasm
• Side effects: Churg-Strauss syndrome (eosinophilic vasculitis - associated with tapering of oral steroids)

Mast cell stabilizers:

• Cromolyn, nedocromil: Stabilize mast cells → prevent degranulation
• Uses: Exercise-induced bronchospasm, allergic asthma (prophylaxis, NOT acute)
• Very safe but modest efficacy

Other Respiratory Agents

Mucolytics:

• N-acetylcysteine (NAC): Disulfide bonds break in mucus → thinner secretions; also used as antidote for acetaminophen overdose
• Dornase alfa: Recombinant DNase for CF - breaks DNA in purulent sputum

Antitussives:

• Codeine, dextromethorphan: Suppress cough (central mechanism); used for dry, non-productive cough

Expectorants:

• Guaifenesin: Increases respiratory tract secretions (↑serum volume in airways) → thinner mucus
• Acetylcysteine: Mucolytic + expectorant

Pulmonary hypertension drugs:

• Prostacyclin analogs: Epoprostenol, iloprost, treprostinil (vasodilator, antiplatelet)
• Endothelin receptor antagonists: Bosentan, ambrisentan
• PDE5 inhibitors: Sildenafil, tadalafil (↑NO-cGMP pathway → vasodilation)

Antihistamines

H1 Blockers (Allergy Drugs)

First-generation (sedating):

• Diphenhydramine, chlorpheniramine, promethazine, hydroxyzine
• Cross BBB → sedation, cognitive impairment
• Also have anticholinergic effects (dry mouth, urinary retention, constipation)
• Used for: Allergic reactions, motion sickness, insomnia, cough/cold

Second-generation (non-sedating):

• Loratadine, desloratadine, cetirizine, levocetirizine, fexofenadine
• Less BBB penetration → minimal sedation
• Used for: Allergic rhinitis, chronic urticaria

Allergic Reactions Treatment

Anaphylaxis:

• Epinephrine IM (first-line) - α vasoconstriction (prevent hypotension), β bronchodilation, β stabilizes mast cells
• Antihistamines (diphenhydramine) - adjunct
• Corticosteroids - prevent late-phase reaction
• IV fluids, airway support as needed

Mild allergic reaction:

• Oral antihistamine (second-generation)
• Topical steroids for skin reactions

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