Comprehensive Drug Pharmacology Reference

Based on Katzung's Basic and Clinical Pharmacology, 16th Edition

1. HMG-CoA Reductase Inhibitors (Statins)

• Stabilization of atherosclerotic plaques
• Improved endothelial function via increased nitric oxide production
• Anti-inflammatory effects (reduced CRP)
• Inhibition of platelet aggregation
• Reduced oxidative stress

• Most are prodrugs (lovastatin, simvastatin are lactone prodrugs activated hepatically)
• Extensive first-pass hepatic metabolism (hepatoselectivity)
• Lovastatin and simvastatin: metabolized by CYP3A4
• Fluvastatin, rosuvastatin: CYP2C9 substrates
• Pravastatin: not CYP metabolized (safest for drug interactions)
• Rosuvastatin: longest half-life (~19 h), highest potency

• Primary and secondary prevention of cardiovascular events
• Familial hypercholesterolemia
• Reduce risk of MI, stroke, and cardiovascular death regardless of baseline LDL

• Myopathy (most important): myalgia, myositis, rhabdomyolysis (rare). Risk increased by CYP3A4 inhibitors (azole antifungals, macrolides, cyclosporine), high doses
• Hepatotoxicity: elevated transaminases (usually mild, reversible)
• New-onset diabetes (slightly increased risk)
• Contraindicated in pregnancy (teratogenic)

• CYP3A4 inhibitors increase plasma levels of lovastatin/simvastatin/atorvastatin
• Fibrates + statins = increased myopathy risk
• Niacin + statins = increased myopathy risk

2. Warfarin

• Oral, essentially complete absorption
• Metabolized by CYP2C9 (S-warfarin) and CYP3A4 (R-warfarin)
• Eliminated primarily as inactive metabolites in urine
• Therapeutic INR: 2-3 for most indications; 2.5-3.5 for mechanical heart valves

• DVT/PE treatment and prevention
• Atrial fibrillation (stroke prevention)
• Mechanical heart valve prostheses
• Hypercoagulable states

• Bleeding (principal toxicity) - any site
• Skin necrosis (from protein C depletion in early therapy, especially with protein C deficiency)
• Teratogenicity (warfarin embryopathy in first trimester - "fetal warfarin syndrome")
• Purple toe syndrome (cholesterol microembolism)

• Increased anticoagulation (bleeding risk): amiodarone, fluconazole, metronidazole, trimethoprim-sulfamethoxazole, cimetidine (CYP2C9 inhibitors)
• Decreased anticoagulation (thrombosis risk): rifampin, carbamazepine, barbiturates (CYP inducers); vitamin K
• Aspirin/NSAIDs: increased GI bleeding risk
• S-warfarin is 4x more potent - drugs affecting its metabolism have greater impact

• Vitamin K1 (phytonadione) - takes 6-24 hours for effect
• Fresh frozen plasma or prothrombin complex concentrate for immediate reversal

3. Nitroglycerin (Organic Nitrates)

• Sublingual: onset 1-3 min, duration 30 min (first-pass avoided)
• Oral: extensive first-pass hepatic metabolism (organic nitrate reductase)
• Transdermal patches: continuous delivery; tolerance develops
• IV infusion: for acute situations (ACS, heart failure)

• Acute relief of angina pectoris (sublingual)
• Prophylaxis of angina (long-acting oral or transdermal)
• Acute coronary syndromes (IV)
• Acute decompensated heart failure (reduces preload)
• Hypertensive emergencies (IV nitroprusside - related agent)

• Headache (very common, due to meningeal vessel dilation)
• Orthostatic hypotension and reflex tachycardia
• Contraindicated with PDE-5 inhibitors (sildenafil, tadalafil) - severe hypotension risk
• Contraindicated if elevated intracranial pressure
• Methemoglobinemia with very high doses or amyl nitrite

4. Calcium Channel Blockers (CCBs)

1. Vascular smooth muscle relaxation → vasodilation
2. Reduced cardiac contractility (negative inotropy)
3. Slowed sinoatrial node automaticity and atrioventricular node conduction (Katzung, Block 3, lines 30-38)

• All orally active with high first-pass effect (low oral bioavailability)
• High plasma protein binding
• Extensive hepatic metabolism (primarily CYP3A4)
• Verapamil and diltiazem: also available IV for arrhythmia management
• Amlodipine: very long half-life (~35-50 h), once-daily dosing (Katzung, Block 3, lines 24-34)

• Hypertension (all CCBs)
• Angina pectoris - stable, vasospastic (Prinzmetal), and unstable
• Supraventricular arrhythmias (verapamil, diltiazem)
• Rate control in atrial fibrillation/flutter (verapamil, diltiazem)
• Raynaud phenomenon (dihydropyridines)
• Migraine prophylaxis (verapamil)

• Dihydropyridines: peripheral edema, flushing, headache, reflex tachycardia
• Verapamil: constipation (most common), bradycardia, AV block, heart failure
• Diltiazem: bradycardia, AV block (less than verapamil)
• Contraindicated: verapamil/diltiazem in WPW + AF or in combination with beta-blockers (risk of complete heart block); in systolic heart failure

5. Digoxin

• SA node: Decreased automaticity (vagal effect)
• AV node: Increased refractory period, slowed conduction (vagal + direct)
• Atrial/ventricular muscle: Shortened action potential duration
• Purkinje fibers: Increased automaticity at toxic doses (DADs - delayed afterdepolarizations)

• Oral bioavailability: ~70-80% (tablets), ~100% (elixir)
• Half-life: ~36-40 hours (longer in renal impairment)
• Primarily eliminated by the kidney unchanged
• Large volume of distribution (binds to skeletal muscle)
• Narrow therapeutic index (therapeutic: 0.5-2.0 ng/mL)
• Hypokalemia, hypomagnesemia, and hypercalcemia increase toxicity

• Rate control in atrial fibrillation/flutter (slows ventricular rate)
• Systolic heart failure with reduced ejection fraction (improves symptoms but does not reduce mortality per DIG trial)
• Paroxysmal supraventricular tachycardia (now rarely first-line)

• GI: Nausea, vomiting, anorexia, diarrhea (earliest signs of toxicity)
• Cardiac: Bradycardia, heart block, ventricular ectopy (bigeminy, VT/VF in severe toxicity)
• CNS: Confusion, visual disturbances (xanthopsia - yellow-green halos), headache
• Toxicity precipitants: Hypokalemia (loop diuretics), hypomagnesemia, renal failure, hypothyroidism, quinidine, amiodarone (increase digoxin levels)

• Correct electrolytes (potassium, magnesium)
• Atropine for bradyarrhythmias
• Digoxin-specific antibody fragments (Digibind/DigiFab) for life-threatening toxicity

6. Angiotensin Receptor Blockers (ARBs)

• No vasoconstriction
• No aldosterone secretion (prevents sodium/water retention)
• No sympathetic stimulation
• No cellular growth/proliferation

• All oral; generally good bioavailability
• Most are highly protein-bound
• Losartan is a prodrug converted to the active metabolite EXP-3174 by CYP2C9 (5-10x more potent)
• Telmisartan has the longest half-life (~24 h) - true once-daily
• Primarily hepatic elimination (biliary excretion), making them preferable over ACE inhibitors in patients with renal artery stenosis

• Hypertension
• Heart failure with reduced EF (valsartan, candesartan)
• Post-MI with LV dysfunction (valsartan, captopril trial data; valsartan in VALIANT)
• Diabetic nephropathy (losartan, irbesartan - FDA approved)
• Alternative to ACE inhibitors when ACE inhibitor cough is intolerable

• Hyperkalemia (especially with CKD, K⁺-sparing diuretics, NSAIDs)
• Hypotension (first-dose effect, especially volume-depleted patients)
• Deterioration of renal function (bilateral RAS)
• Teratogenicity (fetotoxic in 2nd/3rd trimester - Category D/X; contraindicated in pregnancy)
• No cough (key advantage over ACE inhibitors)
• Rare angioedema (less than ACE inhibitors but cross-reactivity exists)

7. ACE Inhibitors

1. ↓ AII → vasodilation, ↓ aldosterone → natriuresis, ↓ sympathetic tone
2. ↑ Bradykinin → vasodilation (via NO and prostaglandin release) + cough/angioedema

• Captopril: active drug (contains SH group); oral, short half-life, 3x daily dosing
• Most others (enalapril, lisinopril, etc.): prodrugs (ester prodrugs) requiring hepatic conversion to active diacid form (enalaprilat, lisinoprilat)
• Primarily renal excretion; dose adjustment required in CKD
• Fosinopril: dual hepatic/renal elimination - safest in severe renal failure

• Hypertension
• Heart failure with reduced EF (reduces mortality - CONSENSUS, SOLVD trials)
• Post-MI (reduces LV remodeling and mortality - SAVE trial with captopril)
• Diabetic nephropathy (reduces proteinuria, slows progression)
• CKD with proteinuria
• Left ventricular dysfunction

• Dry cough (10-15% of patients; due to bradykinin/substance P accumulation) - most common reason for discontinuation
• Angioedema (rare but serious; bradykinin-mediated; can be life-threatening if laryngeal; most common in African Americans)
• Hyperkalemia
• First-dose hypotension (especially in sodium/volume-depleted patients)
• Acute renal failure in bilateral renal artery stenosis (efferent arteriole dilation → ↓ GFR)
• Teratogenicity (fetotoxic; contraindicated in pregnancy - all trimesters)
• Dysgeusia (taste disturbance) with captopril (due to SH group)

8. Isoproterenol

• β₁ (cardiac): ↑ heart rate (positive chronotropy), ↑ contractility (positive inotropy), ↑ AV conduction velocity, ↑ automaticity of all pacemaker tissue
• β₂ (smooth muscle): Bronchodilation, vasodilation (skeletal muscle and splanchnic), uterine relaxation, glycogenolysis, glucagon release

• ↑↑ Heart rate and cardiac output
• ↓ Peripheral vascular resistance (β₂ vasodilation in muscle)
• ↓↓ Diastolic blood pressure (no α-mediated vasoconstriction)
• Systolic BP: may increase slightly (↑ CO) or remain unchanged
• Pulse pressure widens

• Poor oral bioavailability (extensive first-pass metabolism)
• IV, sublingual, inhalation routes used
• Metabolized by COMT (not MAO to any significant extent)
• Short duration of action

• Complete heart block and hemodynamically significant bradycardia (now largely replaced by pacing)
• Torsades de pointes (increases heart rate to suppress EADs)
• Bronchospasm (now replaced by selective β₂ agonists)
• During electrophysiology studies to assess arrhythmia inducibility

• Tachycardia, palpitations, arrhythmias (ventricular ectopy, VT/VF)
• Angina (increases myocardial O₂ demand)
• Tremor, headache, flushing
• Hypokalemia (β₂ stimulation drives K⁺ into cells)
• Paradoxical worsening of bronchoconstriction at high doses

9. Tetracyclines

• Oral absorption: variable; food, dairy, antacids (Ca²⁺, Mg²⁺, Al³⁺), iron significantly reduce absorption by chelation
• Doxycycline: best oral bioavailability, longer half-life (~18 h), once or twice daily, excreted in feces (safe in renal failure)
• Minocycline: highest lipophilicity, penetrates CNS/saliva well
• Tetracycline: short half-life, 4x daily dosing
• Distributed to many tissues; chelates calcium → deposits in bone and teeth

• Atypical pneumonia (Mycoplasma, Chlamydia pneumoniae, Legionella - though fluoroquinolones often preferred)
• STIs: Chlamydia trachomatis, lymphogranuloma venereum, syphilis (penicillin allergy)
• Rocky Mountain spotted fever, Q fever, ehrlichiosis (doxycycline - drug of choice)
• Lyme disease (doxycycline - first line)
• Brucellosis (doxycycline + rifampin)
• Cholera (doxycycline)
• Acne vulgaris (doxycycline, minocycline)
• MRSA skin infections (doxycycline, minocycline)

• GI: Nausea, vomiting, esophagitis (take with plenty of water, upright position)
• Dental: Permanent yellow-brown discoloration of deciduous teeth; contraindicated in children < 8 years and pregnancy
• Bone: Inhibits bone growth in children
• Photosensitivity (especially doxycycline) - avoid sun exposure
• Hepatotoxicity with high doses (especially IV)
• Fanconi syndrome with outdated tetracycline (degradation product)
• Minocycline: vestibular toxicity (dizziness, vertigo), lupus-like syndrome, pigmentation
• Superinfection (Candida, C. diff)

10. Isoniazid (INH)

• Excellent oral bioavailability (~100%)
• Diffuses well into all tissues including CSF, caseous lesions, macrophages
• Metabolized primarily by N-acetyltransferase 2 (NAT2): acetylation
• Slow acetylators (genetic polymorphism): 50% of Caucasians and African Americans - higher plasma levels, greater drug effect and toxicity
• Fast acetylators: 80-90% of Asians - lower levels, possible lower efficacy, higher risk of hepatotoxicity (toxic acetyl-hydrazine metabolite)
• Eliminated in urine (primarily as acetylated metabolites)
• Half-life: 1-4 hours (fast acetylators) vs 2-5 hours (slow acetylators)

• First-line treatment of active tuberculosis (always in combination to prevent resistance)
• Latent TB infection (LTBI) prophylaxis: 9-month INH monotherapy (standard)
• Shorter regimens: 3-4 months INH + rifampin; 12-week INH + rifapentine

• Peripheral neuropathy (most common) - caused by INH-induced pyridoxine (B6) deficiency. Prevented by pyridoxine supplementation (25-50 mg/day)
• Hepatotoxicity (most serious): INH-induced hepatitis; risk increases with age (>35 years: 1-2%), alcohol use, other hepatotoxic drugs. Monitor LFTs. Discontinue if ALT >3-5x ULN with symptoms
• Drug-induced lupus-like syndrome
• CNS effects: seizures (especially in pyridoxine deficiency), euphoria
• Drug interactions: Inhibits CYP2C9, CYP2C19, CYP3A4 - increases phenytoin, carbamazepine, warfarin levels

11. Macrolides

• Erythromycin: acid-labile, enteric-coated forms used; metabolized by CYP3A4; narrow therapeutic index
• Clarithromycin: better bioavailability, active metabolite (14-OH-clarithromycin), twice-daily dosing; strong CYP3A4 inhibitor
• Azithromycin: excellent oral bioavailability, very large volume of distribution (accumulates in tissues at 10-100x serum levels), long intracellular half-life (>68 h in tissues, serum ~40 h), once-daily or Z-pack (5 days), NO significant CYP interactions, renal excretion minimal

• Community-acquired pneumonia (atypical coverage)
• Pertussis (whooping cough) - azithromycin or erythromycin (drug of choice)
• H. pylori eradication (clarithromycin + amoxicillin + PPI)
• STIs: Chlamydia (azithromycin 1g single dose)
• MAC prophylaxis/treatment in HIV patients
• Group A strep pharyngitis (penicillin allergy)
• Skin/soft tissue infections (gram-positive coverage)

• GI effects: Nausea, vomiting, diarrhea, abdominal cramping (most common; due to motilin receptor agonism - erythromycin is actually used as a prokinetic)
• Hepatotoxicity: Cholestatic hepatitis (erythromycin estolate > other formulations)
• QT prolongation (risk of torsades de pointes; all macrolides, especially azithromycin and clarithromycin)
• Drug interactions: Erythromycin and clarithromycin are potent CYP3A4 inhibitors - increase levels of statins (rhabdomyolysis risk), warfarin, cyclosporine, colchicine; azithromycin has minimal CYP3A4 effect
• Ototoxicity with high doses (erythromycin)
• Telithromycin: severe hepatotoxicity (largely withdrawn from use in US)

12. Metformin

• Oral, bioavailability ~50-60%
• Not protein-bound, not metabolized by liver
• Excreted unchanged by kidney (tubular secretion)
• Half-life: ~6 hours (plasma), but accumulates in intestinal wall and liver
• Hold before contrast (risk of contrast-induced AKI leading to metformin accumulation and lactic acidosis); restart 48h after if renal function normal

• First-line agent for type 2 diabetes (ADA guidelines)
• Prediabetes / prevention of T2DM
• Polycystic ovary syndrome (PCOS) - off-label, improves insulin resistance and ovulation
• Weight management (mild weight loss effect or weight-neutral)
• Cardiovascular benefit: UKPDS showed reduced cardiovascular events in obese T2DM

• GI: Nausea, diarrhea, abdominal discomfort (most common; reduced by taking with food, slow titration)
• Lactic acidosis (rare but serious; risk increased in renal failure, liver failure, heart failure with hypoperfusion, alcohol use, IV contrast administration)
• Vitamin B12 deficiency with long-term use (impairs ileal B12 absorption)
• No hypoglycemia when used as monotherapy

• eGFR < 30 mL/min/1.73m² (hold if eGFR 30-45)
• Active hepatic disease
• Chronic alcohol use
• IV contrast administration (hold prior)

13. Glyburide (Glibenclamide)

• Oral, well absorbed
• Highly protein-bound (albumin)
• Hepatically metabolized to active metabolites (unlike glipizide which is metabolized to inactive products)
• Active metabolites accumulate in renal failure → prolonged hypoglycemia
• Half-life: ~10 hours, but duration of action up to 24 hours
• Avoid in elderly and renal impairment (glipizide preferred)

• Type 2 diabetes mellitus
• Lower doses require combination with other agents in advanced T2DM

• Hypoglycemia (most common and serious - can be prolonged and severe, especially in elderly, fasting, renal/hepatic impairment)
• Weight gain (stimulates insulin release → anabolic effects)
• Disulfiram-like reaction with alcohol (some sulfonylureas)
• Hyponatremia (SIADH-like effect)
• Rarely: hepatotoxicity, blood dyscrasias, skin reactions

14. Glipizide

• Hepatically metabolized to inactive metabolites - no accumulation in renal failure
• Short half-life: ~2-4 hours (vs glyburide's ~10 h); extended-release form (GITS) available
• Lower risk of hypoglycemia compared to glyburide
• Preferred in elderly patients and those with CKD (vs glyburide)
• Take 30 minutes before meals for best effect

• Less risk of prolonged hypoglycemia
• Still causes weight gain
• Preferred in renal impairment

15. GLP-1 Receptor Agonists

• Pancreatic beta cells: Glucose-dependent insulin secretion (only when glucose is elevated - low hypoglycemia risk)
• Pancreatic alpha cells: Suppress glucagon secretion
• Gastric: Slow gastric emptying (reduces postprandial glucose spikes, promotes satiety)
• Hypothalamus: Reduce appetite and food intake (central effect)
• Cardiovascular: Direct cardioprotective effects (reduced inflammation, anti-atherogenic)

• All require subcutaneous injection (except oral semaglutide - first oral GLP-1RA)
• Exenatide twice-daily; extended-release exenatide once-weekly
• Liraglutide: once daily SC
• Semaglutide: once-weekly SC (Ozempic) or once-daily oral (Rybelsus)
• Dulaglutide: once-weekly SC

• Type 2 diabetes (combination therapy)
• Weight management (liraglutide 3mg/Saxenda; semaglutide 2.4mg/Wegovy - FDA approved for obesity)
• Cardiovascular risk reduction in T2DM patients with established CVD (liraglutide, semaglutide - LEADER and SUSTAIN-6 trials)
• Non-alcoholic fatty liver disease (emerging evidence)

• GI: Nausea, vomiting, diarrhea (most common, dose-dependent, improve with time) - most pronounced on initiation
• Pancreatitis (rare; black-box warning; hold if acute abdominal pain)
• Thyroid C-cell tumors (rodent studies; black-box warning for liraglutide; contraindicated in MEN-2, medullary thyroid cancer history)
• Injection site reactions
• Low hypoglycemia risk (glucose-dependent mechanism) - but risk increases with sulfonylurea or insulin combination
• Gallstones (weight loss-related)

16. SGLT2 Inhibitors (Gliflozins)

• Lowers blood glucose (A1C reduction: ~0.5-1%)
• Causes osmotic diuresis (reduces intravascular volume, lowers BP)
• Reduces sodium reabsorption (natriuresis)
• Leads to weight loss (~2-3 kg)
• Shifts metabolism toward fat oxidation and ketone body utilization

• Reduced preload and afterload (volume/pressure reduction)
• Direct anti-inflammatory effects on myocardium
• Improved cardiac energy metabolism (ketone bodies as fuel)
• Reduced tubulo-glomerular feedback → reduced intraglomerular pressure → nephroprotection

• All oral, once daily
• Hepatic glucuronidation (mainly UGT enzymes)
• Efficacy diminishes as GFR falls (less glucose filtered → less effect on glycemia)
• Dapagliflozin approved down to eGFR ≥25 for HF/CKD indications

• Type 2 diabetes
• Heart failure with reduced ejection fraction (DAPA-HF, EMPEROR-Reduced - reduced hospitalization and CV death regardless of diabetes status)
• HFpEF (EMPEROR-Preserved - dapagliflozin and empagliflozin)
• Chronic kidney disease (dapagliflozin DAPA-CKD; empagliflozin EMPA-KIDNEY - slows CKD progression)
• Cardiovascular risk reduction in T2DM with established CVD (empagliflozin EMPA-REG OUTCOME; canagliflozin CANVAS)

• Genital mycotic infections (most common - vulvovaginal candidiasis, balanitis; due to glycosuria creating a favorable environment)
• UTIs (more frequent, though some agents show mixed data)
• Euglycemic diabetic ketoacidosis (rare but serious; more common with type 1 DM off-label use, fasting, surgery)
• Volume depletion, hypotension (especially with loop diuretics or in elderly)
• Lower limb amputations (canagliflozin - CANVAS trial; monitor foot care)
• Fournier gangrene (necrotizing fasciitis of genitalia - rare but black-box warning)
• Bone fractures (canagliflozin)

17. Levothyroxine (T4)

• Basal metabolic rate (upregulates Na⁺/K⁺-ATPase)
• Protein synthesis, carbohydrate and lipid metabolism
• Cardiac function (↑ heart rate, contractility, cardiac output)
• Normal growth and development (essential for CNS maturation in infants)

• Oral absorption: 70-80% fasting; significantly reduced by calcium, iron, antacids, PPIs, cholestyramine (take on empty stomach, 30-60 min before food)
• Half-life: ~7 days (T4); this provides stable levels with once-daily dosing
• Converted to T3 peripherally (80% of circulating T3 comes from T4 deiodination)
• Eliminated via hepatic conjugation → biliary excretion; enterohepatic circulation

• Hypothyroidism (first-line replacement)
• TSH suppression in differentiated thyroid carcinoma (high doses)
• Myxedema coma (IV T4 ± IV T3)
• Congenital hypothyroidism (critical to start early to prevent cretinism)

• At correct doses: none
• Overdose/supraphysiologic: palpitations, tachycardia, atrial fibrillation (in elderly), weight loss, heat intolerance, tremor, insomnia, osteoporosis (with chronic TSH suppression)
• Adrenal crisis if given to patients with undiagnosed adrenal insufficiency (T4 accelerates cortisol metabolism)

18. Triiodothyronine (T3, Liothyronine)

• Half-life: ~1 day (much shorter than T4's 7 days) → rapid onset, more fluctuating levels
• Higher oral bioavailability (~95%)
• Given 2-3x daily or as timed-release formulation
• More rapid onset of action (useful in myxedema coma)

• Myxedema coma (IV T3 or oral T3 for rapid thyroid hormone replacement)
• Short-term thyroid hormone withdrawal preparation for radioiodine scanning in thyroid cancer
• Some patients with hypothyroidism not responding to T4 alone (combined T4/T3 therapy - controversial)
• Radioactive iodine scan preparation (T3 is stopped closer to scanning than T4)

• Higher risk of cardiac adverse effects than T4 due to rapid peaks in T3 levels
• Angina, arrhythmias, palpitations
• Monitoring: T3 levels, not TSH (TSH remains suppressed)

19. Propylthiouracil (PTU)

1. Inhibits thyroid peroxidase (TPO): Blocks the oxidation of iodide to iodine and blocks iodine organification (incorporation into tyrosine residues on thyroglobulin) and coupling of iodotyrosines (MIT and DIT → T3, T4)
2. Inhibits peripheral conversion of T4 to T3 (blocks type 1 deiodinase in liver/kidney) - unique to PTU (methimazole does NOT have this second mechanism)

• Oral; well absorbed; half-life ~1-2 hours but thyroid stores are depleted gradually (clinical effect takes 2-4 weeks for full effect)
• Must be dosed 3 times daily (vs methimazole once daily)
• High protein binding (does not cross placenta as readily as methimazole in first trimester)
• Drug of choice in first trimester pregnancy (methimazole causes aplasia cutis; reversed in 2nd/3rd trimester)
• Drug of choice in thyroid storm (due to peripheral T4→T3 block)

• Hyperthyroidism (Graves disease, toxic nodular goiter)
• Thyroid storm (IV high-dose with PTU)
• First-trimester pregnancy with hyperthyroidism

• Agranulocytosis (most serious; 0.1-0.5%; immune-mediated; sudden onset; fever + sore throat → stop drug immediately, check WBC)
• Hepatotoxicity (serious - fulminant hepatic necrosis; black-box warning; more common with PTU vs methimazole)
• Skin rashes, pruritus
• Arthralgias, vasculitis
• Hypothyroidism with over-treatment
• ANCA-associated vasculitis (rare)

20. Glucocorticoids

• Transactivation: Binds GRE (glucocorticoid response elements) → ↑ anti-inflammatory genes (annexin-1/lipocortin-1, IL-10, IκBα)
• Transrepression (most anti-inflammatory): Binds NF-κB and AP-1 transcription factors → ↓ pro-inflammatory mediators (IL-1, IL-2, IL-6, TNF-α, COX-2, iNOS, phospholipase A2)

• ↑ Gluconeogenesis (hyperglycemia)
• ↑ Protein catabolism (muscle wasting)
• ↑ Lipolysis + fat redistribution (central obesity, moon face, buffalo hump)
• Inhibit insulin signaling (steroid-induced diabetes)
• Mineralocorticoid effects (varying degrees): sodium retention, potassium excretion

• Well absorbed orally; variable potency and half-lives
• Prednisone is a prodrug → prednisolone (active; hepatic conversion)
• Dexamethasone: negligible mineralocorticoid activity, long half-life - used for cerebral edema, meningitis, fetal lung maturity
• Budesonide: high first-pass → low systemic bioavailability (inhaled/topical preferred)

• Asthma and COPD (inhaled and systemic)
• Allergic and anaphylactic reactions
• Rheumatoid arthritis, SLE, vasculitis, IBD
• Adrenal insufficiency (replacement)
• Organ transplant rejection prophylaxis
• Cerebral edema (dexamethasone)
• Nausea/vomiting (dexamethasone - antiemetic)
• Fetal lung maturity (betamethasone IM at 24-34 weeks)
• COVID-19 (dexamethasone - RECOVERY trial: reduced mortality in severe disease)
• Nephrotic syndrome, multiple sclerosis exacerbations

• Metabolic: Hyperglycemia, hyperlipidemia, central obesity
• Musculoskeletal: Osteoporosis, avascular necrosis (femoral head most common), myopathy
• Endocrine: HPA axis suppression (Cushing syndrome), adrenal insufficiency on withdrawal
• GI: Peptic ulcer disease (especially with NSAIDs)
• Immunosuppression: Opportunistic infections (PCP, fungal, TB reactivation)
• Ophthalmologic: Cataracts (posterior subcapsular), glaucoma
• CNS: Euphoria, psychosis, insomnia
• Skin: Thin skin, striae, impaired wound healing
• Growth suppression in children

21. Spironolactone

• Anti-androgenic effects (blocks androgen receptors): important for clinical uses and side effects
• In heart failure: blocks the harmful cardiac fibrosis and remodeling effects of aldosterone

• Oral; extensive first-pass; active metabolite canrenone (long half-life ~16 h) responsible for most diuretic effect
• Slow onset: 2-3 days to full effect
• Hepatically metabolized; caution in liver disease (altered metabolism)
• Half-life of spironolactone itself: ~1.5 h; canrenone: ~16 h

• Heart failure with reduced EF (RALES trial: 30% mortality reduction; EMPHASIS-HF for eplerenone)
• Primary hyperaldosteronism (diagnosis and treatment)
• Edema (cirrhotic ascites - first-line; nephrotic syndrome)
• Hypertension (especially resistant HTN - added as 4th agent)
• Hypokalemia prevention with other diuretics
• Polycystic ovary syndrome (anti-androgenic effects)
• Hirsutism (anti-androgen)
• Transgender hormone therapy (female-affirming, in higher doses)

• Hyperkalemia (serious - can be fatal; monitor K⁺; avoid with ACE inhibitors/ARBs in high-risk patients or monitor closely)
• Gynecomastia and breast tenderness in men (anti-androgenic and weak estrogenic effects)
• Menstrual irregularities in women
• Hyperchloremic metabolic acidosis
• Eplerenone: less gynecomastia, more selective

22. Loop Diuretics

• Massive NaCl reabsorption is prevented (25% of filtered NaCl can be excreted - most powerful diuretics)
• The medullary concentration gradient is dissipated → impaired urinary concentrating ability
• Increased delivery of Na⁺ to distal tubule → increased K⁺ and H⁺ secretion (hypokalemia, metabolic alkalosis)
• Calcium and magnesium excretion also increase (calciuria, magnesiuria)

• Furosemide: oral bioavailability variable (10-100%); IV for rapid diuresis; excreted by kidney
• Torsemide: more consistent oral bioavailability; longer acting
• Bumetanide: 40x more potent than furosemide by weight; short-acting
• Ethacrynic acid: the only non-sulfonamide loop diuretic - used in sulfonamide allergy; more ototoxic

• Acute pulmonary edema (furosemide IV - first-line emergency treatment)
• Chronic heart failure
• Cirrhotic ascites (with spironolactone)
• Hypercalcemia (forced diuresis with saline + furosemide - increases Ca²⁺ excretion)
• Hypertensive urgency
• Nephrotic syndrome edema
• Acute kidney injury oliguria (debated)

• Hypokalemia (can precipitate digoxin toxicity - monitor K⁺)
• Hypomagnesemia (often coexists with hypokalemia)
• Metabolic alkalosis (loss of H⁺ and Cl⁻)
• Hyponatremia
• Volume depletion, hypotension
• Hyperuricemia (competes with uric acid secretion → gout)
• Ototoxicity (dose-dependent; furosemide < ethacrynic acid; increased risk with aminoglycosides)
• Hypocalcemia (chronic use - calciuria)
• Hyperglycemia (blunts insulin release at high doses)
• Sulfonamide cross-reactivity (furosemide, torsemide, bumetanide; ethacrynic acid is safe in sulfonamide allergy)

23. Thiazide Diuretics

• Reduced NaCl reabsorption (5-8% of filtered Na⁺)
• Increased Na⁺ delivery to the collecting duct → increased K⁺ and H⁺ secretion (hypokalemia)
• Decreased calcium excretion (thiazides increase Ca²⁺ reabsorption in DCT via Na-Ca exchange) - opposite to loop diuretics

• All oral; variable bioavailability
• Chlorthalidone: longest half-life (~45-60 h), once daily, superior cardiovascular outcomes vs HCTZ
• Metolazone: works even with reduced GFR (can be used in CKD) - synergistic with loop diuretics
• HCTZ: shorter half-life; widely used
• Indapamide: has additional Ca²⁺ channel blocking vasodilatory properties

• Hypertension (first-line; JNC guidelines favor chlorthalidone)
• Edema (mild CHF, liver disease, corticosteroid-induced)
• Hypercalciuria/nephrolithiasis (reduces urinary calcium - prevents calcium stones)
• Nephrogenic diabetes insipidus (paradoxically reduces urine volume by causing mild volume depletion → increased proximal tubular reabsorption)
• Osteoporosis prevention (reduces urinary calcium loss)

• Hypokalemia (risk of arrhythmias, especially with digoxin or hypomagnesemia)
• Hyperuricemia (gout precipitation; competes with uric acid secretion)
• Hyperglycemia / new-onset diabetes (impairs insulin secretion - avoid in diabetes if possible)
• Hyperlipidemia (increases LDL and TG slightly)
• Hyponatremia (especially SIADH-prone elderly women - can be severe)
• Hypercalcemia (with thiazide use + hyperparathyroidism or excess calcium intake)
• Hypomagnesemia
• Photosensitivity (sulfonamide-related)
• Sulfonamide cross-reactivity (like loop diuretics; metolazone may be safer)

24. Carbonic Anhydrase Inhibitors (CAIs)

• Urine: alkaline (rich in HCO₃⁻, Na⁺, K⁺)
• Blood: hyperchloremic metabolic acidosis (HCO₃⁻ depleted from serum)
• Reduced aqueous humor production (CA inhibition in ciliary body)
• Reduced CSF production

• Oral; good absorption
• Not metabolized; excreted unchanged in urine
• Self-limiting: as metabolic acidosis develops and plasma HCO₃⁻ falls, less substrate is available → diuresis wanes

• Glaucoma (reduces aqueous humor formation and intraocular pressure) - dorzolamide used topically; acetazolamide orally
• Altitude sickness prophylaxis and treatment (accelerates ventilatory acclimatization - by inducing metabolic acidosis, which stimulates breathing and compensates for respiratory alkalosis at altitude)
• Epilepsy (adjunctive; absence seizures)
• Metabolic alkalosis treatment (e.g., after mechanical ventilation)
• Idiopathic intracranial hypertension (pseudotumor cerebri)
• Urine alkalinization (to increase excretion of weak acids like aspirin in overdose)
• Periodic hypokalemic paralysis

• Hypokalemia (K⁺ wasted with HCO₃⁻)
• Hyperchloremic metabolic acidosis (self-limiting; desired in altitude sickness)
• Nephrolithiasis (calcium phosphate stones - alkaline urine increases calcium-phosphate precipitation)
• Paresthesias (tingling of extremities and face - very common)
• Drowsiness, confusion
• Sulfonamide-based drug (contraindicated in sulfonamide allergy; can cause blood dyscrasias)
• Teratogenic (avoid in first trimester)
• Contraindicated in hepatic cirrhosis (increased NH₃ absorption from alkaline urine → hepatic encephalopathy)

25. Osmotic Diuretics

1. Retains water in the tubule - osmotic force opposes the normal passive water reabsorption driven by solute transport in the PCT and descending loop of Henle
2. Increases tubular flow → increased Na⁺ and water excretion
3. Creates an osmotic gradient in plasma - draws water from intracellular compartment into the extravascular space and then into plasma → useful for acute reduction of intracranial pressure (ICP) and intraocular pressure (IOP)
4. Not a natriuretic diuretic - predominantly a water diuretic

• IV only (not absorbed orally); poor GI absorption
• Not metabolized; excreted entirely by glomerular filtration
• Half-life: ~100 minutes
• Does not cross blood-brain barrier (only works peripherally, drawing water from CNS into plasma)

• Elevated intracranial pressure (cerebral edema, head trauma, neurosurgery) - first-line osmotic agent; reduces ICP by drawing water from brain parenchyma
• Acute angle-closure glaucoma (reduces IOP acutely before surgery)
• Prevention of acute tubular necrosis during surgery or hemolytic transfusion reactions (maintains tubular flow)
• Forced diuresis in poisoning (increases urine flow to speed excretion of nephrotoxins)
• Neurosurgery (reduction of intracranial and intraocular pressure)

• Pulmonary edema (if mannitol is not excreted quickly - initial plasma volume expansion can precipitate pulmonary edema, especially in heart failure or renal failure patients)
• Hypernatremia (water diuresis without proportional Na⁺ loss → plasma Na⁺ rises)
• Hyponatremia (early, transient - osmotic shift of water from cells dilutes plasma Na⁺)
• Volume overload (initial expansion of intravascular volume before diuresis)
• Hypokalemia, hypomagnesemia (secondary to diuresis)
• Rebound ICP rise (if blood-brain barrier is disrupted, mannitol can enter brain tissue and draw water in)
• Contraindicated in anuria/renal failure (accumulates; causes volume overload), active intracranial bleeding, severe heart failure, severe dehydration

Quick Reference Summary Table

1. Mechanism of Action - molecular target and downstream effects
2. Pharmacokinetics - absorption, distribution, metabolism, elimination, half-life, notable PK features
3. Clinical Uses - approved and major off-label indications
4. Adverse Effects - ranked by clinical importance
5. Drug Interactions - where significant (warfarin, macrolides, statins especially)

• Warfarin: S-enantiomer is 4x more potent (CYP2C9 substrate); VKORC1 mutation causes resistance; protein C/S depletion explains early hypercoagulability
• Nitroglycerin: ALDH2 bioactivation; tolerance via sulfhydryl depletion; nitrate-free interval required
• CCBs: State-dependent channel blockade; α1 subunit binding; dihydropyridines vs verapamil/diltiazem selectivity differences
• Isoniazid: NAT2 acetylator status determines pharmacokinetics and toxicity profile
• Metformin: AMPK activation via complex I inhibition - mechanism Katzung emphasizes
• PTU: Dual mechanism (TPO inhibition + peripheral deiodinase inhibition) distinguishing it from methimazole
• SGLT2 inhibitors: Major outcomes trials cited (EMPA-REG, DAPA-HF, DAPA-CKD)
• Thiazides vs loop diuretics: Opposite effects on calcium excretion - a classic Katzung teaching point