Anti tubercular drugs

Reading File

Finding Sources

Reading File

I now have rich content from both Goodman & Gilman and Katzung. Let me compile the comprehensive answer.

Anti-Tubercular Drugs

Mycobacteria are intrinsically resistant to most antibiotics due to three main barriers: a lipid-rich cell wall (>60% lipid, mainly mycolic acids), abundant efflux pumps, and intracellular location within macrophages and necrotic tissue. Combination therapy is mandatory to prevent resistance emergence during prolonged treatment.

Classification

Category	Drugs
First-line	Isoniazid (INH), Rifampin (RIF), Pyrazinamide (PZA), Ethambutol (EMB)
Rifamycin analogs	Rifapentine (RPT), Rifabutin
Second-line injectable	Streptomycin, Amikacin, Kanamycin, Capreomycin
Fluoroquinolones	Moxifloxacin, Levofloxacin
Group A (MDR-TB)	Bedaquiline, Linezolid, Clofazimine
Newer (XDR-TB)	Pretomanid, Delamanid
Older second-line	Cycloserine, Ethionamide, Para-aminosalicylic acid (PAS)

First-Line Drugs

1. Isoniazid (INH)

Mechanism: A prodrug activated by mycobacterial catalase-peroxidase (KatG). The activated metabolite inhibits InhA (enoyl-ACP reductase), blocking mycolic acid synthesis - essential for the mycobacterial cell wall. Also inhibits DHFR.

Activity: Bactericidal for actively dividing M. tuberculosis; bacteriostatic for dormant organisms.

Pharmacokinetics:

Well absorbed orally; penetrates all tissues and CSF
Metabolized by acetylation (NAT2) - fast and slow acetylators exist
Slow acetylators have higher plasma levels and more peripheral neuropathy risk
Half-life: ~1 hour (fast acetylators) vs. ~3 hours (slow acetylators)

Dose: 5 mg/kg/day (max 300 mg/day)

Adverse effects:

Peripheral neuropathy (most common) - due to pyridoxine (B6) depletion; prevented with pyridoxine 25-50 mg/day (mandatory in pregnancy, alcoholism, malnutrition, diabetes)
Hepatotoxicity - most serious; incidence increases with age and alcohol use
Drug-induced lupus (antinuclear antibodies)
INH overdose triad: Seizures refractory to phenytoin/barbiturates + anion gap metabolic acidosis + coma. Antidote: IV pyridoxine gram-for-gram with ingested INH (INH depletes pyridoxal-5'-phosphate → decreased GABA → seizures)

Drug interactions: Potent inhibitor of CYP2C19 and CYP3A; weak inducer of CYP2E1

2. Rifampin (Rifampicin)

Mechanism: Binds the β-subunit of DNA-dependent RNA polymerase (rpoB), blocking chain formation in RNA synthesis. Bactericidal.

Activity: Broad-spectrum; active against M. tuberculosis (MIC 0.06-0.25 mg/L), M. leprae, many gram-positive and gram-negative organisms.

Pharmacokinetics:

Oral absorption good; enterohepatic recirculation; excreted mainly in feces
Widely distributed including CSF (with inflamed meninges)
Dose: 10 mg/kg/day (max 600 mg/day)

Adverse effects:

Orange discoloration of urine, sweat, tears (harmless; stains soft contact lenses)
Hepatotoxicity and cholestatic jaundice
Thrombocytopenia, rash, nephritis
Flu-like syndrome (fever, chills, myalgias, anemia) if given less frequently than twice weekly

Drug interactions: Potent inducer of CYP1A2, 2C9, 2C19, 2D6, 3A4 - significantly lowers levels of methadone, anticoagulants, cyclosporine, anticonvulsants, HIV protease inhibitors, NNRTIs, integrase inhibitors, oral contraceptives.

Resistance: Point mutations in rpoB gene.

3. Rifapentine

An analog of rifampin with lower MICs. Cross-resistance with rifampin is complete. Long half-life (~13 hours for drug + active metabolite 25-desacetylrifapentine), allowing once-daily or weekly dosing.

Used in the newer 4-month regimen (RPT + MOX + INH + PZA, daily for 8 weeks, then RPT + MOX + INH for 9 weeks). Also used as single-drug weekly therapy for latent TB (3HP regimen: once-weekly RPT + INH x 12 weeks).

4. Rifabutin

Preferred over rifampin in HIV patients on antiretroviral therapy because it is a weaker CYP inducer. Active against many strains of M. tuberculosis and M. avium complex (MAC). MIC ~0.125 mg/L.

5. Pyrazinamide (PZA)

Mechanism: Prodrug converted to pyrazinoic acid by mycobacterial pyrazinamidase (PncA). Active mainly in acidic environments (e.g., within macrophage phagolysosomes). Inhibits fatty acid synthase I (FAS I).

Activity: Only active against M. tuberculosis (not NTM). Sterilizing activity against dormant bacilli in acidic milieu - key reason it allows treatment shortening from 9 to 6 months.

Dose: 15-30 mg/kg/day (max 2 g/day)

Adverse effects:

Hyperuricemia (most common) - by inhibiting renal urate excretion; gout can occur
Hepatotoxicity (dose-related)
Arthralgia, myalgia, flushing
Non-gouty polyarthralgia (very common, not true gout)

6. Ethambutol (EMB)

Mechanism: Inhibits arabinosyl transferase III (encoded by embB gene), disrupting arabinogalactan biosynthesis → mycobacterial cell wall disruption.

Activity: Bacteriostatic; primarily used to protect companion drugs against resistance. Active against M. tuberculosis (MIC 0.5-2 mg/L), M. kansasii, M. avium.

Dose: 15-25 mg/kg/day

Adverse effects:

Retrobulbar (optic) neuritis - dose-related; presents as decreased visual acuity and red-green color blindness. Baseline visual acuity and color vision should be tested; contraindicated in young children (cannot report visual changes)
Hyperuricemia
Peripheral neuropathy (less common)

Treatment Regimens for Drug-Susceptible TB

Standard 6-Month Regimen (HRZE/HR)

Phase	Duration	Drugs
Intensive	8 weeks	INH + RIF + PZA + EMB (daily)
Continuation	18 weeks	INH + RIF (daily or 3x/week)

INH + RIF for 9 months cures 95-98% of drug-susceptible TB.

Newer 4-Month Regimen (RPTHZ/RPTH)

Phase	Duration	Drugs
Intensive	8 weeks	RPT + MOX + INH + PZA (daily)
Continuation	9 weeks	RPT + MOX + INH (daily)

Non-inferior to the 6-month regimen for drug-susceptible pulmonary TB in persons ≥12 years weighing ≥40 kg.

Second-Line Drugs

Fluoroquinolones (Moxifloxacin, Levofloxacin)

Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV. Key role in MDR-TB regimens. Moxifloxacin is used in the 4-month regimen. Risk of QT prolongation.

Streptomycin / Aminoglycosides

Inhibit 30S ribosomal subunit. Largely phased out of TB treatment due to irreversible ototoxicity (hearing loss) and vestibular damage. Still used for NTM and drug-resistant MAC.

Ethionamide / Prothionamide

Structural analog of INH. Inhibits InhA (same target as INH). Used in MDR-TB. Significant GI intolerance and hepatotoxicity; thyroid dysfunction.

Cycloserine

Inhibits D-alanine racemase and D-alanine:D-alanine ligase, blocking cell wall peptidoglycan synthesis. Major CNS toxicity: psychosis, seizures, depression; requires pyridoxine supplementation.

Para-aminosalicylic acid (PAS)

Inhibits folate synthesis (similar to sulfonamides). Bacteriostatic. GI intolerance is the main limitation.

Capreomycin

Cyclic peptide with aminoglycoside-like activity. Nephrotoxicity and ototoxicity (CN VIII damage) - do not combine with aminoglycosides.

Newer Drugs for MDR-TB / XDR-TB

Bedaquiline

Mechanism: Inhibits ATP synthase (subunit c of mycobacterial F1F0-ATP synthase) - completely novel target. Bactericidal against both replicating and dormant M. tuberculosis.

Dose: 400 mg OD x 2 weeks, then 200 mg three times/week x 22 weeks (with food).

Adverse effects: Nausea, arthralgia, headache, hepatotoxicity. Black-box warning: QT prolongation - can be fatal; use with caution with other QT-prolonging drugs.

Drug interactions: Metabolized by CYP3A4; avoid potent CYP3A4 inducers (including rifampin - use rifabutin instead).

Pretomanid

A nitroimidazoloazine, FDA-approved 2019. Requires reductive activation. Under aerobic conditions: inhibits mycolic acid synthesis. Under anaerobic conditions: releases nitric oxide (toxic to intracellular mycobacteria). Active against both replicating and latent M. tuberculosis.

Dose: 200 mg OD with food.

Used in the BPaL regimen (Bedaquiline + Pretomanid + Linezolid x 6 months) for XDR-TB, pre-XDR-TB, or treatment-nonresponsive MDR-TB.

Clofazimine

A fat-soluble riminophenazine dye. WHO Group A drug for RR/MDR-TB. Multifactorial mechanism: membrane disruption, inhibition of K+ transport, generation of H₂O₂, interference with electron transport chain, efflux pump inhibition, anti-inflammatory effects on macrophages.

Adverse effects: Skin discoloration (reddish-brown to black), GI intolerance. Long half-life (~70 days) due to accumulation in fatty tissues.

MDR-TB and XDR-TB

Term	Definition
MDR-TB	Resistant to at least INH + RIF
Pre-XDR-TB	MDR-TB + resistance to any fluoroquinolone
XDR-TB	MDR-TB + fluoroquinolone resistance + bedaquiline/pretomanid resistance

WHO Group A drugs for MDR-TB (always include when possible): Levofloxacin/moxifloxacin, bedaquiline, linezolid.

Latent TB Treatment

Regimen	Duration	Notes
INH daily	6-9 months	Standard
RIF daily	4 months	Preferred single-drug option
INH + RPT (3HP)	Once weekly x 12 weeks	Short, effective, high adherence
INH + RIF	3 months	Alternative

Drug-Specific Toxicity Summary

Drug	Key Toxicity	Mnemonic/Note
INH	Peripheral neuropathy, hepatitis	Prevented with B6; overdose → seizures
Rifampin	Orange secretions, hepatitis, CYP inducer	Rifampin = Red/Orange
PZA	Hyperuricemia, hepatitis, arthralgia	PZA = "PuZy Acid" (uric acid)
Ethambutol	Optic neuritis (color blindness)	EMB = "Eyes"
Streptomycin	Ototoxicity, nephrotoxicity	CN VIII damage
Cycloserine	Psychosis, seizures	CNS toxicity
Bedaquiline	QT prolongation, hepatotoxicity	Black-box warning
Clofazimine	Skin discoloration, GI	Reddish-brown pigmentation

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics; Katzung's Basic and Clinical Pharmacology, 16th Edition

Anti hypertensive drugs

Reading File

Finding Sources

Reading File

Finding Sources

Reading File

I now have comprehensive content from Goodman & Gilman covering all major antihypertensive drug classes. Let me compile the full answer.

Anti-Hypertensive Drugs

Blood pressure = Cardiac Output × Peripheral Vascular Resistance. Drugs lower BP by reducing one or both of these. Hypertension is defined as ≥130/80 mmHg (AHA/ACC) or ≥140/90 mmHg (ESC guidelines).

Classification

Class	Examples
Diuretics	Thiazides, loop diuretics, K+-sparing, aldosterone antagonists
ACE Inhibitors (ACEi)	Enalapril, lisinopril, ramipril, captopril
ARBs	Losartan, valsartan, telmisartan, candesartan
Calcium Channel Blockers (CCBs)	Amlodipine, nifedipine, verapamil, diltiazem
Beta Blockers (BBs)	Atenolol, metoprolol, bisoprolol, propranolol, nebivolol
Alpha Blockers	Prazosin, doxazosin, terazosin
Mixed α/β Blockers	Labetalol, carvedilol
Central sympatholytics	Clonidine, methyldopa, moxonidine, guanfacine
Direct vasodilators	Hydralazine, minoxidil, sodium nitroprusside, diazoxide
Renin inhibitors	Aliskiren
Aldosterone antagonists (MRA)	Spironolactone, eplerenone

1. Diuretics

Thiazides (Hydrochlorothiazide, Chlorthalidone, Indapamide)

Mechanism: Inhibit Na+/Cl- cotransporter in the distal convoluted tubule → natriuresis → reduced blood volume and cardiac output initially; with long-term use, peripheral vascular resistance falls (likely via reduced intracellular Na+/Ca2+ in vascular smooth muscle and reduced T-cell-mediated inflammation).

Preferred in: Most patients as first-line; isolated systolic hypertension in elderly; Black patients (especially when used with CCBs).

Adverse effects:

Hypokalemia (most common) - can precipitate arrhythmias
Hyperuricemia - can precipitate gout
Hyperglycemia - worsen diabetes
Hyperlipidemia (minor)
Hyponatremia, hypercalcemia (can be useful in osteoporosis)
Sexual dysfunction, weakness

Drug interactions: Potentiated by NSAIDs (reduce efficacy); hypokalemia worsens digoxin toxicity; reduce lithium clearance → toxicity.

Loop Diuretics (Furosemide, Bumetanide, Torsemide)

Mechanism: Inhibit Na+/K+/2Cl- cotransporter in thick ascending limb of Henle.

Use in hypertension: Less preferred for chronic HTN; used when heart failure, renal insufficiency, or fluid overload is present. Also used in hypertensive emergencies IV.

Adverse effects: Hypokalemia, hyponatremia, hypomagnesemia, ototoxicity (at high doses), hyperuricemia, metabolic alkalosis.

K+-Sparing Diuretics (Amiloride, Triamterene)

Block Na+ channels in collecting duct. Weak antihypertensives; mainly used to counteract hypokalemia from thiazides. Risk: hyperkalemia - avoid with ACEi/ARBs in renal failure.

Aldosterone Antagonists / MRA (Spironolactone, Eplerenone)

Mechanism: Competitively block mineralocorticoid receptors → prevent aldosterone-driven Na+ retention.

Key uses:

Resistant hypertension (4th-line) - spironolactone has ~2x larger BP-lowering effect than beta blockers or α blockers in resistant HTN
Heart failure (reduces mortality)
Primary hyperaldosteronism

Adverse effects of Spironolactone:

Gynecomastia, erectile dysfunction (anti-androgenic effect - not seen with eplerenone)
Hyperkalemia
Menstrual irregularities

Eplerenone is more selective (no anti-androgenic effects) but less potent.

2. ACE Inhibitors (ACEi)

Examples: Captopril, Enalapril, Lisinopril, Ramipril, Quinapril, Perindopril, Fosinopril, Trandolapril

Mechanism: Inhibit angiotensin-converting enzyme → prevents conversion of Angiotensin I → Angiotensin II → less vasoconstriction + less aldosterone secretion → reduced Na+ retention + reduced peripheral resistance. Also prevent breakdown of bradykinin → vasodilation (and cough).

Pharmacokinetics: Most are prodrugs (e.g., enalapril → enalaprilat). Lisinopril is active directly. Most excreted renally.

Therapeutic advantages:

Reduce proteinuria and slow progression of diabetic nephropathy (preferred in DM + HTN)
Reduce mortality post-MI (especially with reduced EF)
Improve outcomes in heart failure
Reduce left ventricular hypertrophy

Adverse effects:

Dry cough (most common, 10-15%) - due to accumulation of bradykinin and substance P in airways. Switch to ARB if intolerable.
Angioedema (rare but life-threatening) - bradykinin-mediated; more common in Black patients and smokers. Contraindication to rechallenge.
Hyperkalemia - avoid with K+-sparing diuretics and ARBs
Renal failure in bilateral renal artery stenosis (reduce efferent arteriolar tone → drop GFR)
Teratogenic (Category D in 2nd/3rd trimester) - cause fetal renal tubular dysplasia

Absolute contraindications: Bilateral renal artery stenosis, pregnancy, history of angioedema.

3. Angiotensin Receptor Blockers (ARBs)

Examples: Losartan, Valsartan, Telmisartan, Candesartan, Irbesartan, Olmesartan

Mechanism: Block AT1 receptors directly → prevent AngII-mediated vasoconstriction and aldosterone release. Unlike ACEi, they do NOT increase bradykinin levels.

Advantages over ACEi:

No cough (no bradykinin accumulation)
Equivalent renal and cardiac protection
Better tolerated

Adverse effects:

Hyperkalemia
Angioedema (rarer than with ACEi, but cross-reactivity ~10%)
Teratogenic - same contraindications as ACEi
Fetotoxic

Note: Combination of ACEi + ARB (dual RAAS blockade) is contraindicated - increases risk of hypotension, hyperkalemia, and renal failure without additional benefit.

4. Calcium Channel Blockers (CCBs)

Mechanism: Block voltage-gated L-type Ca2+ channels in vascular smooth muscle and cardiac cells → reduced intracellular Ca2+ → vasodilation (all CCBs) and/or reduced cardiac rate/contractility (non-dihydropyridines).

Subclasses

Subclass	Drugs	Main Action
Dihydropyridines (DHPs)	Amlodipine, Nifedipine, Felodipine, Nicardipine	Vascular > cardiac; arteriolar dilation
Non-DHPs - Phenylalkylamines	Verapamil	Cardiac > vascular; ↓ HR, ↓ AV conduction
Non-DHPs - Benzothiazepines	Diltiazem	Intermediate; ↓ HR and vasodilation

Amlodipine: Long-acting; no reflex tachycardia; preferred CCB for HTN. First-line in elderly, Black patients, isolated systolic HTN, angina.

Therapeutic uses:

First-line HTN (all CCBs)
Angina (all, but especially verapamil/diltiazem for vasospastic; amlodipine for stable)
Atrial fibrillation rate control (verapamil, diltiazem)
Raynaud's phenomenon (DHPs)

Adverse effects:

DHPs: Peripheral edema (ankle swelling, dose-dependent), flushing, headache, reflex tachycardia (less with amlodipine)
Verapamil/Diltiazem: Bradycardia, AV block, constipation (verapamil), negative inotropic effects
Contraindication: Verapamil/diltiazem + beta blockers → severe bradycardia/heart block

5. Beta Blockers (BBs)

Examples: Propranolol (non-selective), Atenolol, Metoprolol, Bisoprolol (β1-selective), Nebivolol (β1 + NO release), Carvedilol (α1/β), Labetalol (α1/β)

Mechanism of antihypertensive action:

Reduce cardiac output (↓ HR and contractility)
Inhibit renin secretion from JG cells (β1 effect)
Reduce CNS sympathetic outflow
Peripheral presynaptic β2 blockade reduces NE release

Cardioselectivity: β1-selective agents (atenolol, metoprolol, bisoprolol) preferred to avoid bronchospasm, but selectivity is dose-dependent.

Preferred in:

HTN + coronary artery disease/post-MI
HTN + heart failure (carvedilol, bisoprolol, metoprolol succinate)
HTN + aortic aneurysm
HTN + atrial fibrillation (rate control)
Pheochromocytoma (only after α-blockade to prevent hypertensive crisis)

Adverse effects:

Bradycardia, AV block
Bronchospasm (non-selective; avoid in asthma/COPD)
Peripheral vasoconstriction (cold extremities, worsens Raynaud's)
Mask hypoglycemic symptoms in diabetics (except sweating)
Dyslipidemia (↑ TG, ↓ HDL)
Fatigue, depression, sexual dysfunction
Rebound hypertension on abrupt withdrawal - taper slowly

Contraindications: Decompensated heart failure (acutely), severe asthma, 2nd/3rd degree AV block, severe peripheral artery disease.

6. Alpha Blockers (α1 Antagonists)

Examples: Prazosin (short-acting), Doxazosin, Terazosin (long-acting)

Mechanism: Block postsynaptic α1 receptors on arterioles and veins → vasodilation → reduced peripheral resistance.

Special use: Beneficial in hypertensive men with benign prostatic hyperplasia (BPH) - relax both vascular and prostatic smooth muscle.

Adverse effects:

First-dose phenomenon: Severe orthostatic hypotension and syncope (give first dose at bedtime)
Nasal congestion, palpitations
Fluid retention (use with diuretic)

7. Mixed α/β Blockers

Labetalol

Blocks α1, β1, and β2 receptors (α:β ratio ~1:3 oral, 1:7 IV). Used in hypertensive emergencies, particularly in pregnancy (pre-eclampsia), aortic dissection, and pheochromocytoma crisis (not first choice for pheo). IV infusion or bolus. Safe in pregnancy.

Carvedilol

Blocks α1 + non-selective β blockade. Also antioxidant. Preferred in heart failure with HTN.

8. Central Sympatholytics

Methyldopa

Mechanism: Prodrug → α-methylnorepinephrine → stimulates central α2 receptors → reduces sympathetic outflow. Peak effect delayed 6-8h despite short t½.

Preferred use: Hypertension in pregnancy (safest, most evidence). Dose: 250 mg twice daily to max 2g/day.

Adverse effects:

Sedation, fatigue, reduced psychic energy
Positive Coombs test (20% after 1 year) → hemolytic anemia in 1-5% (requires discontinuation)
Hepatotoxicity (with fever)
Hyperprolactinemia → gynecomastia, galactorrhea
Drug-induced lupus, depression

Clonidine

Mechanism: Stimulates central α2A receptors in brainstem → reduced sympathetic outflow (↓ plasma NE). Also used for opioid withdrawal, ADHD, and menopausal flushing.

Key adverse effects:

Sedation, dry mouth (most common)
Rebound hypertension on abrupt withdrawal (taper slowly)
Bradycardia
Constipation

9. Direct Vasodilators

Hydralazine

Arteriolar vasodilator (mechanism: opens K+ channels → hyperpolarization; may involve NO release). Reduces peripheral resistance without affecting veins.

Uses: Severe hypertension; hypertension in pregnancy (IV); heart failure (with nitrates, the "BiDiL" combination).

Adverse effects:

Reflex tachycardia and fluid retention (combine with BB + diuretic)
Drug-induced lupus (dose-dependent; especially slow acetylators, HLA-DR4 positive; anti-histone antibodies)
Headache, flushing, palpitations

Minoxidil

Opens ATP-sensitive K+ channels → profound arteriolar vasodilation. Reserved for severe resistant hypertension (requires BB + diuretic to offset reflex tachycardia and fluid retention).

Adverse effects:

Hypertrichosis (hirsutism - used topically for alopecia)
Fluid retention, edema, pericardial effusion
Reflex tachycardia

Sodium Nitroprusside

Rapidly releases NO → dilates both arteries and veins. Used IV for hypertensive emergencies and acute heart failure. Duration of action: minutes. Risk: cyanide toxicity (metabolized to cyanide; use sodium thiosulfate as antidote). Protect from light.

Fenoldopam

Selective D1 dopamine receptor agonist → renal arteriolar and peripheral vasodilation. IV use in hypertensive emergencies. Advantage: Improves renal perfusion (useful in renal impairment).

Diazoxide

Opens K+ channels. IV bolus for hypertensive emergencies. Causes marked sodium retention; also used in hypoglycemia (inhibits insulin secretion).

10. Renin Inhibitor

Aliskiren

Direct renin inhibitor → blocks the first step of the RAAS → reduces AngI, AngII, and aldosterone.

Pharmacokinetics: Poor oral bioavailability (<3%); high-fat food reduces absorption; t½ ≥24h; hepatobiliary excretion.

Limitations: Combination with ACEi/ARBs is contraindicated (↑ hyperkalemia, hypotension, renal failure risk). Use in hypertension remains limited.

Adverse effects: Diarrhea, rare cough, angioedema, teratogenic.

Drug Selection Based on Compelling Indications

Condition	Preferred Drug(s)
Diabetes + HTN	ACEi or ARB (+ CCB or thiazide)
Diabetic nephropathy / proteinuria	ACEi or ARB (first-line)
Post-MI	ACEi/ARB + BB
Heart failure (reduced EF)	ACEi/ARB + BB + spironolactone + diuretics
Stable angina	BB + CCB (amlodipine)
Coronary artery disease	ACEi + BB
Atrial fibrillation (rate control)	BB or non-DHP CCB (verapamil/diltiazem)
Isolated systolic HTN (elderly)	Thiazide, ACEi, ARB, or CCB
HTN in pregnancy	Methyldopa, Labetalol, Nifedipine (extended release)
BPH + HTN	Alpha blocker (doxazosin)
Pheochromocytoma	Alpha blocker first (phenoxybenzamine), then BB
Resistant HTN (4th agent)	Spironolactone
Hyperaldosteronism	MRA (spironolactone/eplerenone)
Left ventricular hypertrophy	ACEi, ARB, or CCB
Metabolic syndrome	ACEi, ARB, or CCB (avoid BB + thiazide)

Treatment Algorithm (AHA/ACC)

BP 130-139/80-89 mmHg: Lifestyle modification; start drug if 10-year ASCVD risk ≥10% or existing CVD/DM/CKD
BP ≥140/90: Lifestyle + single drug (ACEi/ARB, CCB, or thiazide)
Not controlled: Add second agent (2-drug combination)
Still not controlled: Triple therapy (ACEi/ARB + CCB + thiazide)
Resistant HTN (>3 drugs): Add spironolactone; refer to specialist

First-line preferred classes: ACEi/ARBs, CCBs, thiazides, and (for select indications) beta blockers.

Key Drug Interactions & Contraindications Summary

Combination	Problem
ACEi + ARB	Contraindicated (hyperkalemia, renal failure)
BB + Verapamil/Diltiazem	Severe bradycardia / heart block
BB + Non-selective + Asthma	Bronchospasm
Thiazide + Digoxin	Hypokalemia → digoxin toxicity
ACEi + K+-sparing diuretic	Severe hyperkalemia
Aliskiren + ACEi/ARB	Contraindicated
RAAS inhibitors	Contraindicated in pregnancy

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics; Katzung's Basic and Clinical Pharmacology, 16th Edition; Brenner and Rector's The Kidney

This is a shared conversation. Sign in to Orris to start your own chat.