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Calcium Channel Blockers (CCBs) - USMLE Step 1 High-Yield Guide

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QUICK ORIENTATION: Three Chemical Classes

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MECHANISM OF ACTION

• Vascular smooth muscle: Calcium influx drives contraction. Block it → arteriolar vasodilation → decreased SVR (afterload reduction). CCBs dilate arterioles, NOT veins.
• Cardiac muscle: Calcium drives both contractility (inotropy) and the slow depolarization of SA/AV nodal tissue (chronotropy/dromotropy).

Lippincott Illustrated Reviews: Pharmacology - Note: Diltiazem is the strongest coronary vasodilator, nifedipine has the most adverse effects (18%), and verapamil has the most AV conduction slowing.

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DRUG-BY-DRUG HIGH-YIELD BREAKDOWN

1. Nifedipine / Amlodipine (DHPs)

• Potent arteriolar vasodilation → decreased SVR
• Minimal cardiac conduction effect (no chronotropy/dromotropy)
• Reflex tachycardia with short-acting nifedipine (baroreceptor response to rapid BP drop)
• Amlodipine has an extremely long half-life (30-50 hours) - no sustained-release formulation needed

• Hypertension (first-line in Black patients, diabetics, asthmatics, peripheral vascular disease)
• Stable and vasospastic (Prinzmetal) angina
• Nimodipine: subarachnoid hemorrhage (crosses BBB, prevents cerebral vasospasm)
• Nicardipine/Clevidipine: IV use for hypertensive urgency/emergency

• Peripheral edema (capillary dilation, not heart failure)
• Reflex tachycardia (especially short-acting nifedipine)
• Gingival hyperplasia (nifedipine - classic USMLE finding)
• Headache, flushing, dizziness

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2. Verapamil (Phenylalkylamine)

• Most negative inotropic CCB
• Negative chronotropy (slows HR), negative dromotropy (slows AV conduction)
• Weaker vasodilator than DHPs

• Hypertension
• Angina (stable, vasospastic)
• Rate control in atrial fibrillation/flutter and SVT (especially AVNRT)
• Migraine and cluster headache prophylaxis
• Hypertrophic obstructive cardiomyopathy (HOCM) - when beta-blockers fail

• Constipation (most common SE - classic USMLE answer)
• First-degree AV block (dose-dependent)
• Hypotension
• Bradycardia

• AV block (2nd or 3rd degree)
• Sick sinus syndrome (without pacemaker)
• HFrEF (worsens due to negative inotropy)
• WPW + atrial fibrillation - NEVER use verapamil (blocks AV node, forces conduction through accessory pathway → VF)
• Concurrent beta-blocker use IV (severe bradycardia/AV block)

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3. Diltiazem (Benzothiazepine)

• Intermediate between verapamil and nifedipine
• Affects both cardiac and vascular smooth muscle
• Less negative inotropy than verapamil
• Best side-effect profile among CCBs (only 2% adverse effect frequency)

• Same as verapamil for rate control in AFib/flutter, SVT
• Angina (excellent for vasospastic angina - coronary vasodilator)
• Hypertension

• Bradycardia, AV block (less than verapamil)
• Hypotension

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CLINICAL INDICATIONS MATRIX

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ADVERSE EFFECT SUMMARY TABLE

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USMLE TRAPS - HIGH YIELD

• Lippincott Illustrated Reviews: Pharmacology

• Katzung's Basic and Clinical Pharmacology, 16th Ed.

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RANKING COMPARISONS (Tested Directly on NBME)

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PHARMACOKINETICS TO REMEMBER

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HIGH-YIELD CLINICAL PEARL: CCB vs Beta-Blocker Comparison

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TAKE-HOME POINTS (USMLE Speed Review)

1. "pines" = DHPs = vascular selective = no rate slowing = peripheral edema + reflex tachycardia + gingival hyperplasia
2. Verapamil = strongest cardiac effect = constipation = best for SVT/AFib rate control; AVOID in HFrEF, AV block, WPW+AFib
3. Diltiazem = intermediate; best side-effect profile (2%); great for vasospastic angina
4. Nimodipine = SAH only (cerebral vasospasm prevention)
5. Non-DHPs CONTRAINDICATED in HFrEF - only amlodipine is safe in HF
6. Short-acting nifedipine contraindicated post-MI - reflex tachycardia increases cardiac demand
7. CCB OD = hyperglycemia + bradycardia/hypotension; treat with high-dose insulin + calcium
8. WPW + AFib + Verapamil = VFib - most dangerous CCB drug-condition combination
9. CCBs preferred over beta-blockers in: asthma, DM, PVD, Black patients (for HTN)
10. Amlodipine half-life = 30-50h - slowest onset and longest duration

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• Mechanism & Physiology (what you need to know cold)
• Drug-by-drug or concept-by-concept breakdown (NBME loves specifics)
• Clinical Indications Matrix (when to use / when to avoid)
• Adverse Effects Table
• USMLE TRAPS (the exact wrong answers NBME plants)
• Ranking Comparisons (directly tested)
• Take-Home Points (speed review bullets)

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HYDRALAZINE - USMLE Step 1 | NBME-Style Guide

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MECHANISM & PHYSIOLOGY

1. Reduces intracellular calcium in arteriolar smooth muscle → vasodilation
2. Inhibits oxidases → prevents breakdown of endogenous nitric oxide (NO) → enhances NO signaling → additional vasodilation
3. Acts on arterioles only - NOT veins (critical USMLE distinction)

• Decreased SVR (afterload ↓)
• Increased cardiac output (compensatory)
• Reflex tachycardia (baroreceptor response to BP drop)
• NO effect on preload (veins are spared)

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PHARMACOKINETICS (TESTED HEAVILY)

The Acetylator Phenotype - HIGH YIELD

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THERAPEUTIC USES

1. Hypertension (3rd or 4th line)

• Not a first-line agent due to reflex tachycardia and tachyphylaxis
• Used when first- and second-line agents are insufficient
• Must always be used with a beta-blocker (to blunt reflex tachycardia) and a diuretic (to prevent edema)

2. Heart Failure with Reduced EF (HFrEF) - HIGHEST YIELD USE

• Hydralazine + Isosorbide dinitrate (BiDil) = the fixed-dose combination
• Specifically shown to improve survival in self-identified African American patients with HFrEF who are already on guideline-directed therapy (beta-blocker + ACEi or ARB) - from the A-HeFT trial
• Rationale: Black patients tend to have lower NO bioavailability and less RAAS activation - hydralazine/nitrate combo restores NO signaling
• Also used when patients are intolerant of ACEi/ARBs (e.g., bilateral renal artery stenosis, angioedema from ACEi, pregnancy)

3. Hypertensive Emergencies in Pregnancy (Eclampsia/Pre-eclampsia)

• IV hydralazine is a classic first-line agent for severe hypertension in pregnancy
• Safe for fetus; does not affect uteroplacental blood flow significantly
• Given alongside magnesium sulfate (for seizure prophylaxis in eclampsia)

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ADVERSE EFFECTS TABLE

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DRUG-INDUCED LUPUS (DIL) - DEDICATED SECTION

• Sulfasalazine
• Hydralazine ← most classic
• Isoniazid (INH)
• Procainamide ← most common cause overall
• Penicillamine

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CLINICAL INDICATIONS & CONTRAINDICATIONS

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COMPARISON: HYDRALAZINE vs. MINOXIDIL

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USMLE TRAPS

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RANKINGS & COMPARISONS

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TAKE-HOME POINTS

1. Mechanism: Direct arteriolar vasodilator (NOT venous) → decreases afterload, increases CO, triggers reflex tachycardia
2. Must combine with beta-blocker (anti-tachycardia) + diuretic (anti-edema) when used for HTN
3. HFrEF use: Hydralazine + isosorbide dinitrate = proven survival benefit in Black patients (A-HeFT trial) and as alternative when ACEi/ARB is not tolerated
4. Pregnancy: IV hydralazine = first-line for hypertensive emergency in eclampsia (with MgSO4 for seizures)
5. Drug-induced lupus: ANA+, anti-histone+, anti-dsDNA negative, no renal involvement, reverses on stopping drug
6. Slow acetylators = higher drug levels = more DIL risk
7. Peripheral neuropathy = B6 deficiency (same as INH) → treat with pyridoxine
8. Dose >200 mg/day = 10-20% incidence of lupus syndrome
9. Hydralazine vs Minoxidil: both arteriolar dilators, but minoxidil opens K+ channels, is more potent, and causes hypertrichosis
10. Never give alone in CAD - reflex tachycardia increases ischemia risk

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HYPERTENSIVE EMERGENCY - USMLE Step 1 | NBME-Style Guide

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DEFINITIONS - THE FIRST THING TESTED

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PHYSIOLOGY: WHY THE ORGANS GET DAMAGED

• Brain: Loss of autoregulation → forced hyperperfusion → vasogenic cerebral edema → hypertensive encephalopathy; or alternatively, thrombotic/hemorrhagic stroke
• Heart: Increased afterload → LV strain → acute decompensated heart failure, pulmonary edema; or plaque rupture → ACS
• Kidney: Fibrinoid necrosis of renal afferent arterioles → microangiopathic hemolytic anemia (MAHA) + acute kidney injury
• Aorta: Shear stress on aortic wall → dissection
• Eye: Retinal arteriolar damage → flame hemorrhages, papilledema, cotton-wool spots

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TARGET ORGAN DAMAGE - INCIDENCE TABLE (HIGH YIELD)

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TREATMENT FRAMEWORK - THE GOLDEN RULE

Reduce mean arterial pressure (MAP) by no more than 25% within the first hour.

• Exception - Aortic dissection: Target SBP <120 mmHg within minutes (fastest reduction needed)
• Exception - Ischemic stroke (no tPA): Do NOT aggressively lower BP - relative hypertension maintains penumbra perfusion; only treat if SBP >220 or DBP >120
• Exception - Ischemic stroke (+ tPA given): Keep SBP <180 mmHg to prevent hemorrhagic transformation

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DRUG SELECTION BY CLINICAL SCENARIO

1. Aortic Dissection

• Why: Must reduce both BP AND heart rate (HR)/force of contraction simultaneously - decreased dP/dt (rate of pressure rise) is the goal
• Critical rule: Give beta-blocker BEFORE vasodilator - a pure vasodilator causes reflex tachycardia → increases shear stress → worsens dissection
• Target: SBP <120 mmHg as fast as safely possible

2. Hypertensive Encephalopathy

• Gradual MAP reduction of 25% in first hour
• Avoid nitroprusside (can increase ICP via cerebral vasodilation)

3. Acute Ischemic Stroke

• If tPA given: Keep SBP <180/DBP <105
• If no tPA: Only treat if BP >220/120; otherwise permissive hypertension

4. Intracerebral Hemorrhage (ICH)

• Target SBP <140 within first hour (to limit hematoma expansion)

5. Acute HF + Pulmonary Edema

• Nitrates primarily reduce preload (venodilation) → decongest lungs fast
• Avoid beta-blockers (negative inotropes in acute decompensation)

6. Acute Coronary Syndrome (ACS)

• Reduces preload/afterload, relieves coronary spasm
• Avoid direct vasodilators (reflex tachycardia increases O2 demand)

7. Pheochromocytoma Crisis / MAOI + Tyramine / Cocaine

• Pure catecholamine excess state → alpha-receptor blockade is critical
• NEVER give beta-blocker first (unopposed alpha activity → paradoxical severe HTN)
• For cocaine: benzodiazepines + phentolamine; avoid beta-blockers

8. Eclampsia / Severe Preeclampsia

• Add Magnesium sulfate for seizure prophylaxis (NOT an antihypertensive)
• Avoid: ACEi, ARBs, nitroprusside (all teratogenic/fetal harm)

9. Hypertensive Emergency with Renal Impairment

• Uniquely increases renal blood flow, diuresis, and natriuresis while lowering BP
• Renoprotective - preferred when renal perfusion is a concern

10. Perioperative / Post-op Hypertension

• Clevidipine: onset <2 min, half-life <1 min; ideal for OR/ICU titration

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DRUG PROFILES - IV AGENTS

Sodium Nitroprusside

• Class: Balanced arterial + venous vasodilator (NO donor)
• Mechanism: Spontaneously releases NO → activates sGC → ↑cGMP → smooth muscle relaxation (both arteries and veins)
• Onset: Seconds; Duration: 1-2 min (easiest to titrate)
• Use: Severe HTN emergencies (most conditions except pheochromocytoma); aortic dissection (with beta-blocker)
• Major SE: Cyanide toxicity (high dose >5 mcg/kg/min, prolonged use, renal failure); thiocyanate toxicity
  • Mechanism: Nitroprusside → releases CN⁻ → metabolized by rhodanese (needs thiosulfate) → thiocyanate (renally excreted)
  • Treat cyanide toxicity with: sodium thiosulfate (provides sulfur donor) or hydroxocobalamin
• Other SEs: Rebound hypertension on discontinuation, raised ICP, methemoglobinemia

IV Labetalol

• Class: Combined alpha-1 and beta (nonselective) blocker (ratio alpha:beta = 1:7)
• Mechanism: Blocks both alpha-1 (vasodilation) and beta (decreased CO, HR)
• Onset: 5-10 min; Duration: 3-6 hours
• Best for: Aortic dissection, stroke, eclampsia, most general HTN emergencies
• Avoid in: Acute decompensated HF, asthma/COPD (beta-blockade), high-degree AV block
• Advantage: Lowers BP WITHOUT reflex tachycardia (because of beta-blockade)

IV Nicardipine

• Class: Dihydropyridine CCB (IV form)
• Mechanism: Arteriolar vasodilation (no cardiac conduction effect)
• Onset: 5-15 min; Duration: 4-6 hours
• Best for: Stroke (ischemic or hemorrhagic), post-op HTN, eclampsia, general HTN emergency
• SE: Reflex tachycardia, headache, flushing

Clevidipine

• Class: Ultrashort DHP CCB (IV only)
• Half-life: <1 minute (metabolized by blood esterases)
• Best for: Perioperative/OR/ICU use where precise, rapid BP titration needed
• SE: Reflex tachycardia; lipid emulsion vehicle (caution in hypertriglyceridemia)

IV Nitroglycerin

• Class: Nitrate (primarily venodilator)
• Mechanism: Converts to NO → venodilation >> arterial dilation → decreased preload primarily
• Best for: ACS, acute decompensated HF with pulmonary edema
• SE: Headache, tachycardia, methemoglobinemia (rare), tolerance with prolonged use

Phentolamine

• Class: Non-selective alpha-blocker (competitive)
• Best for: Pheochromocytoma crisis, MAOI + tyramine reaction, cocaine-induced HTN emergency
• SE: Reflex tachycardia (no beta-blockade), hypotension

Fenoldopam

• Class: Selective dopamine D1 receptor agonist
• Mechanism: Vasodilation via D1 activation; also increases renal perfusion + natriuresis
• Best for: HTN emergency with renal impairment (preferred over nitroprusside in renal failure)
• Advantage over nitroprusside: No cyanide toxicity risk; increases (not decreases) renal blood flow
• SE: Tachycardia, hypokalemia, elevated intraocular pressure (avoid in glaucoma)

Esmolol

• Class: Ultra-short acting, cardioselective beta-1 blocker (IV)
• Half-life: ~9 minutes
• Best for: Aortic dissection (with nitroprusside), perioperative tachycardia + HTN
• Avoid: Asthma, acute decompensated HF

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DRUG SELECTION MATRIX (NBME SPEED REFERENCE)

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USMLE TRAPS

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TAKE-HOME POINTS

1. Emergency = TOD present; Urgency = no TOD - numbers alone don't define emergency
2. Max 25% MAP reduction in first hour - faster reduction causes ischemia in adapted vasculature
3. Aortic dissection: Beta-blocker FIRST (labetalol/esmolol), THEN nitroprusside if needed; target SBP <120 fast
4. Stroke (no tPA): Permissive HTN - only treat if SBP >220; do not rush
5. Stroke + tPA: Keep SBP <180 to prevent hemorrhagic conversion
6. ACS / Pulmonary edema: IV nitroglycerin (preload reduction)
7. Pheo/cocaine/MAOI: Phentolamine FIRST - never beta-blocker first (unopposed alpha = disaster)
8. Eclampsia: Hydralazine/labetalol + MgSO4 (for seizures); avoid ACEi/ARBs
9. Renal failure: Fenoldopam > Nitroprusside (fenoldopam increases renal flow; nitroprusside accumulates thiocyanate)
10. Nitroprusside toxicity: Cyanide → lactic acidosis → treat with sodium thiosulfate or hydroxocobalamin

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RANOLAZINE - USMLE Step 1 | NBME-Style Guide

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MECHANISM & PHYSIOLOGY - THE CORE CONCEPT

Step-by-step mechanism:

1. Blocks the late inward sodium current (late I-Na) - the primary antianginal mechanism
   • During ischemia, the late Na⁺ current becomes abnormally prolonged and increased
   • This excess Na⁺ entry activates the Na⁺/Ca²⁺ exchanger (NCX), which then imports Ca²⁺ into the cell
   • The resulting calcium overload → increases diastolic tension → reduces coronary perfusion → worsens ischemia
2. Blocking late I-Na → less Na⁺ enters → NCX imports less Ca²⁺ → decreased intracellular Ca²⁺ → decreased diastolic wall tension → improved myocardial relaxation and coronary perfusion
3. Net effect: Reduced myocardial oxygen consumption and improved perfusion WITHOUT altering heart rate or blood pressure

Also blocks:

• IKr (rapid delayed rectifier K⁺ current) - at therapeutic doses, this prolongs QT slightly
• At higher concentrations: early I-Na (like class I antiarrhythmic), mild IKr and ICa blockade

The key distinction:

Ranolazine does NOT reduce HR, does NOT lower BP, does NOT reduce contractility meaningfully. It works purely through metabolic/ionic channel modulation.

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COMPARISON OF ANTIANGINAL MECHANISMS

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THERAPEUTIC USES

1. Chronic Stable Angina (FDA-Approved Indication)

• Used when first-line agents (beta-blockers, nitrates, CCBs) are insufficient or not tolerated
• Add-on therapy to any combination of: beta-blockers, nitrates, CCBs
• Increases exercise duration, delays onset of anginal symptoms, and delays ST depression on treadmill testing
• Reduces frequency of anginal episodes and sublingual nitroglycerin use

2. Refractory Angina (Most High-Yield Use)

• "A patient with stable angina is already on a maximized beta-blocker and long-acting nitrate but continues to have angina. HR is 52, BP is 108/70. What do you add?" → Ranolazine
• Perfect when you cannot add more HR-lowering or BP-lowering drugs

3. Antiarrhythmic Use (Off-Label, Not FDA-Approved as Antiarrhythmic)

• Shown to reduce AF, SVT, and ventricular arrhythmias in CAD trials
• Shortens action potential duration in long QT syndrome type 3 (LQT3) specifically - because LQT3 is caused by excessive late I-Na (gain-of-function SCN5A mutation), which ranolazine directly blocks
• Under investigation in combination with dronedarone for AF suppression
• NOT FDA-approved as an antiarrhythmic - this is a classic USMLE trap

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PHARMACOKINETICS

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ADVERSE EFFECTS

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DRUG INTERACTIONS - CRITICAL FOR USMLE

Hepatic cirrhosis → CONTRAINDICATED

• Severe hepatic impairment markedly increases QT prolongation risk

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CLINICAL INDICATIONS & CONTRAINDICATIONS

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USMLE TRAPS

• Strong CYP3A inhibitors (ketoconazole, ritonavir, clarithromycin) = Contraindicated entirely
• Moderate CYP3A inhibitors (diltiazem, verapamil, grapefruit juice) = Reduce dose to 500 mg BID (do not stop)
• NBME will present a patient on ranolazine who starts diltiazem or verapamil for rate control - the correct answer is to reduce the ranolazine dose, NOT stop it.

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RANKINGS & COMPARISONS

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TAKE-HOME POINTS

1. Mechanism: Blocks late I-Na → prevents Ca²⁺ overload via NCX → reduces diastolic tension and O2 demand
2. No hemodynamic effects - HR unchanged, BP unchanged, contractility unchanged
3. Use: Chronic stable angina as add-on or when beta-blockers/CCBs cannot be used/maximized
4. NOT for acute attacks - sublingual NTG is for acute; ranolazine is prophylactic
5. Metabolized by CYP3A - contraindicated with strong CYP3A inhibitors/inducers; dose-limit with moderate inhibitors (diltiazem, verapamil, grapefruit)
6. QTc prolongs (blocks IKr) BUT no torsades - because late I-Na block suppresses EADs
7. LQT3 - ranolazine shortens QT (because LQT3 = excess late I-Na)
8. NOT FDA-approved as antiarrhythmic despite antiarrhythmic properties
9. Mild creatinine elevation = pharmacologic artifact, not true AKI
10. Contraindicated in hepatic cirrhosis (severe QTc prolongation risk) and with strong CYP3A inhibitors

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SACUBITRIL/VALSARTAN (ENTRESTO) - USMLE Step 1 | NBME-Style Guide

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MECHANISM - TWO ACTIONS IN ONE MOLECULE

Component 1: Valsartan (ARB)

• Blocks AT1 receptors (angiotensin II type 1)
• Prevents: vasoconstriction, aldosterone release, sympathetic activation, myocardial fibrosis, ventricular hypertrophy
• Same mechanism as any ARB (losartan, valsartan, etc.)

Component 2: Sacubitril (Neprilysin Inhibitor - prodrug)

• Sacubitril (prodrug) → converted by plasma esterases → LBQ657 (active metabolite)
• LBQ657 inhibits neprilysin (neutral endopeptidase)
• Neprilysin normally degrades: ANP, BNP, CNP (natriuretic peptides), adrenomedullin, bradykinin, substance P, and angiotensin II
• Blocking neprilysin → these peptides accumulate → vasodilation, natriuresis, diuresis, anti-fibrosis, anti-hypertrophy, reduced sympathetic tone

Why ARB + neprilysin inhibitor (not ACEi + neprilysin inhibitor)?

• Both ACE AND neprilysin degrade bradykinin
• Combining ACEi + sacubitril = double bradykinin accumulation → unacceptably high angioedema risk
• ARB does NOT degrade bradykinin → combining ARB + neprilysin inhibitor is safe (only one bradykinin pathway blocked)

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NET HEMODYNAMIC EFFECTS

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CLINICAL INDICATION - THE PARADIGM-HF TRIAL

• Trial stopped early due to clear benefit
• 20% reduction in composite of CV death or HF hospitalization
• 22% reduction in sudden cardiac death
• Reduction in all-cause mortality
• Less renal dysfunction and hyperkalemia than enalapril
• More hypotension than enalapril

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WHEN TO USE - INDICATIONS

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PHARMACOKINETICS

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ADVERSE EFFECTS

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THE BNP vs. NT-proBNP TRAP - Most Tested Lab Fact

Rule: A patient on sacubitril/valsartan with elevated BNP does NOT necessarily have worsening HF - the drug itself raises BNP by blocking its degradation. Use NT-proBNP instead.

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USMLE TRAPS

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COMPARISON: SACUBITRIL/VALSARTAN vs. ACEi vs. ARB

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GDMT FRAMEWORK: WHERE SACUBITRIL/VALSARTAN FITS

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TAKE-HOME POINTS

1. ARNI = Sacubitril (neprilysin inhibitor) + Valsartan (ARB) = Entresto; LCZ696 is the drug code
2. Mechanism: Sacubitril → (plasma esterases) → LBQ657 → blocks neprilysin → ↑ ANP/BNP/CNP → vasodilation, natriuresis, anti-remodeling; Valsartan → blocks AT1 receptor
3. Why ARB not ACEi: Both ACE and neprilysin degrade bradykinin - combining ACEi + sacubitril = angioedema risk
4. Use: HFrEF (EF ≤40%) symptomatic on optimized therapy - replace ACEi/ARB with ARNI
5. 36-hour washout from ACEi before starting - no exceptions
6. BNP is unreliable on this drug (neprilysin degrades BNP → sacubitril raises BNP artifactually) - use NT-proBNP
7. PARADIGM-HF: 20% reduction in CV death/hospitalization vs. enalapril
8. Contraindications: ACEi-induced angioedema, hereditary angioedema, pregnancy, SBP <95 mmHg, bilateral RAS
9. Adverse effects: Hypotension (most common) > angioedema > hyperkalemia > renal impairment (less renal toxicity than ACEi)
10. No cough (no ACEi component) - safe switch for ACEi-induced cough patients

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LIPID-LOWERING DRUGS - USMLE Step 1 | NBME-Style Guide

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ORIENTATION: THE BIG PICTURE

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1. STATINS (HMG-CoA Reductase Inhibitors)

Mechanism

• Statins are structural analogs of HMG-CoA (the substrate of HMG-CoA reductase)
• They competitively inhibit HMG-CoA reductase - the rate-limiting enzyme in hepatic cholesterol synthesis (HMG-CoA → mevalonate)
• Decreased intrahepatic cholesterol → hepatocytes upregulate LDL receptors on their surface → increased LDL clearance from plasma
• Key: They don't just block synthesis - the main effect is LDL receptor upregulation

Pleiotropic (Non-lipid) Effects - USMLE loves these

• Decreased oxidative stress and vascular inflammation
• Increased atherosclerotic plaque stability
• Start immediately after ACS regardless of lipid levels (plaque stabilization, not just LDL lowering)

Pharmacokinetics - High Yield

Adverse Effects

Drug Interactions

• Gemfibrozil + statin = highest myopathy/rhabdomyolysis risk (gemfibrozil inhibits glucuronidation of statins + CYP2C9)
• CYP3A4 inhibitors (clarithromycin, azole antifungals, cyclosporine, grapefruit juice) + CYP3A4-metabolized statins = ↑ statin levels → myopathy
• Solution for transplant patients: Use pravastatin or rosuvastatin (minimal CYP3A4) when on cyclosporine

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2. BILE ACID SEQUESTRANTS (Resins)

Mechanism

• Cholestyramine, Colestipol, Colesevelam are anion exchange resins
• They bind bile acids in the intestinal lumen → prevent enterohepatic recirculation of bile acids → bile acids are excreted in feces
• Liver must synthesize more bile acids from cholesterol → intrahepatic cholesterol falls → LDL receptor upregulation (same downstream effect as statins but different upstream trigger)
• Effect: ↓ LDL

Key Properties

• Not absorbed - act entirely in the GI lumen (no systemic absorption)
• Safe in pregnancy (not absorbed)
• Safe in children with familial hypercholesterolemia (FH)
• Colesevelam also approved for Type 2 diabetes (lowers blood glucose - mechanism unclear)

Adverse Effects

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3. NIACIN (Nicotinic Acid / Vitamin B3)

Mechanism

• Inhibits VLDL secretion from liver (inhibits adipose tissue intracellular lipase via Gi receptor → ↓ free fatty acid flux to liver → ↓ VLDL production)
• Decreases LDL (secondary, because less VLDL → less LDL conversion)
• Decreases HDL catabolism → ↑↑↑ HDL (most potent HDL-raising drug available)
• Decreases triglycerides (↓ VLDL)
• Decreases Lp(a) - unique property

Lipid Effects Summary

Adverse Effects - Most Tested

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4. FIBRATES

Mechanism

• Gemfibrozil, Fenofibrate are peroxisome proliferator-activated receptor alpha (PPAR-α) agonists
• PPAR-α activation in liver → ↑ lipoprotein lipase (LPL) expression → ↑ TG clearance from VLDL/chylomicrons
• Also: ↓ VLDL synthesis, ↑ HDL (via ↑ Apo A-I and A-II synthesis)
• Primary effect: ↓↓↓ Triglycerides (up to 50%)

Best Use

• Hypertriglyceridemia (TG >500 mg/dL - pancreatitis prevention)
• Mixed dyslipidemia (high TG + low HDL)
• Type III hyperlipoproteinemia (dysbetalipoproteinemia) - fibrates are first-line

Adverse Effects

• Gemfibrozil = much higher rhabdomyolysis risk (inhibits statin glucuronidation via UGT pathway + CYP2C8/2C9)
• Fenofibrate = preferred fibrate when statin co-administration is needed

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5. EZETIMIBE

Mechanism

• Inhibits NPC1L1 (Niemann-Pick C1-Like 1) transporter in small intestinal brush border
• Blocks absorption of dietary and biliary cholesterol from the gut lumen
• Liver cholesterol falls → ↑ LDL receptors (same downstream effect as statins)
• Effect: ↓ LDL ~15-20% (modest alone; additive with statins)

Key Properties

• Works at intestinal brush border (not systemically absorbed to site of action)
• Additive with statins (complementary mechanisms: statins block synthesis, ezetimibe blocks absorption)
• IMPROVE-IT trial: Adding ezetimibe to simvastatin after ACS reduced CV events further
• Safe in combination with statins (low myopathy risk unlike fibrates)

Adverse Effects

• Generally very well tolerated
• Mild GI symptoms
• Rarely: hepatitis, myopathy (when combined with statins, additive risk)
• May increase risk of gallstones (similar to bile acid changes)

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6. PCSK9 INHIBITORS

Mechanism

• Evolocumab (Repatha) and Alirocumab (Praluent) are monoclonal antibodies (mAbs) against PCSK9
• PCSK9 (proprotein convertase subtilisin/kexin type 9) is a hepatic enzyme that normally binds to LDL receptors → directs them to lysosomes for degradation → fewer LDL receptors on hepatocytes
• Blocking PCSK9 → LDL receptors are recycled back to cell surface instead of degraded → ↑↑↑ LDL receptor density → massive LDL clearance
• Can reduce LDL by 50-65% on top of statins

Clinical Use

• Familial hypercholesterolemia (heterozygous and homozygous)
• High CV risk patients inadequately controlled on max-dose statin + ezetimibe
• Statin-intolerant patients (with or without ezetimibe)
• FOURIER trial (evolocumab): 15% ↓ in CV events; median LDL reduced to 30 mg/dL
• ODYSSEY trial (alirocumab): Reduced CV death/major events in post-ACS patients

Route and Dosing

• Subcutaneous injection (every 2 weeks or monthly)
• NOT oral

Adverse Effects

• Injection site reactions (most common)
• Nasopharyngitis, flu-like symptoms
• Evolocumab: modest increase in new-onset diabetes risk
• Generally very well tolerated

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LIPID EFFECTS COMPARISON TABLE (Most Tested)

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DRUG FOR EACH LIPID DISORDER

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USMLE TRAPS

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RANKINGS

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TAKE-HOME POINTS

1. Statins = HMG-CoA reductase inhibitor → ↑ LDL receptors → #1 LDL lowering; pleiotropic benefits; start after ACS regardless of LDL
2. Bile acid resins = not absorbed; ↓ LDL; raise TG; only safe class in pregnancy; bind other drugs (give separately)
3. Niacin = best HDL raiser; flushing prevented by aspirin (not antihistamines); causes hyperglycemia + hyperuricemia
4. Fibrates = PPAR-α agonist → LPL activation → best TG lowering; cause gallstones; avoid gemfibrozil + statin
5. Ezetimibe = blocks NPC1L1 → ↓ intestinal cholesterol absorption; additive with statins
6. PCSK9 inhibitors = mAbs; prevent LDL receptor degradation → massive LDL ↓; SC injection; best for FH and statin-intolerant
7. Statin myopathy: CK monitoring; highest risk when combined with gemfibrozil or CYP3A4 inhibitors
8. Lovastatin/simvastatin = evening dosing; atorvastatin/rosuvastatin = any time
9. Pravastatin = safest statin with CYP3A4-based drug interactions (cyclosporine, macrolides, azoles)
10. Statins + pregnancy = absolutely contraindicated; resins are the only option

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LIPID PHYSIOLOGY: FROM GUT LUMEN TO LIVER

Cholesterol | Triglycerides | Fatty Acids - Complete USMLE Step 1 Guide

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STEP 0 - WHAT ARE WE STARTING WITH?

• Triglycerides (TG) = glycerol + 3 fatty acids (most abundant dietary fat)
• Cholesterol = free or esterified (as cholesterol esters)
• Fatty acids (FA) = already free, or released during TG digestion

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STEP 1 - DIGESTION IN THE GI LUMEN

DIETARY TG
    ↓
Lingual lipase (minor, mouth) → Gastric lipase (minor, stomach)
    ↓
SMALL INTESTINE LUMEN:
  Pancreatic lipase + Colipase
    ↓
TG → 2-Monoacylglycerol (2-MG) + 2 Free Fatty Acids (FFA)
  (NOTE: cholesterol esters are hydrolyzed by cholesterol esterase → free cholesterol)
    ↓
Bile salts (from liver/gallbladder) emulsify products into MICELLES
  (micelle = tiny sphere: hydrophilic outside, hydrophobic inside)
  [Contents of micelle: 2-MG, FFA, free cholesterol, fat-soluble vitamins A, D, E, K]

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STEP 2 - ABSORPTION INTO THE ENTEROCYTE

Fatty Acids: TWO different routes depending on chain length

SHORT-CHAIN FA (<6 carbons) & MEDIUM-CHAIN FA (6-12 carbons)
    ↓
Diffuse DIRECTLY through enterocyte → enter PORTAL VEIN → go STRAIGHT TO LIVER
(They bypass the lymph system entirely)

LONG-CHAIN FA (>12 carbons) [the majority of dietary fat]
    ↓
Absorbed into enterocyte via FATP (fatty acid transport protein) / FABP-pm
    ↓
Inside enterocyte: re-esterified back into TG
(2-MG + FFA → TG, via smooth ER)

Cholesterol: NPC1L1 is the gatekeeper

FREE CHOLESTEROL (from micelle)
    ↓
Absorbed via NPC1L1 transporter on brush border membrane
(This is EXACTLY what ezetimibe blocks - highest-yield pharm connection)
    ↓
Inside enterocyte: cholesterol + fatty acid → CHOLESTERYL ESTER
(enzyme: ACAT - acyl CoA:cholesterol acyltransferase)

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STEP 3 - PACKAGING INTO CHYLOMICRONS (Inside the Enterocyte)

INSIDE ENTEROCYTE (smooth ER + Golgi):

Long-chain TG
+ Cholesteryl esters
+ Phospholipids
+ Fat-soluble vitamins (A, D, E, K)
+ ApoB-48 (structural backbone, synthesized here)
+ MTP (microsomal TG transfer protein) assists assembly
    ↓
= NASCENT CHYLOMICRON
    ↓
Secreted via exocytosis into INTESTINAL LYMPHATICS (lacteals)

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STEP 4 - THE LYMPH JOURNEY (Thoracic Duct → Blood)

Lacteal (villus lymph capillary)
    ↓
Mesenteric lymphatics
    ↓
Cisterna chyli
    ↓
THORACIC DUCT
    ↓
Empties into SUBCLAVIAN VEIN (left side)
    ↓
Systemic BLOODSTREAM

• ApoC-II transferred from HDL → essential cofactor for LPL (without it, TGs cannot be hydrolyzed)
• ApoE transferred from HDL → needed for eventual liver uptake

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STEP 5 - CHYLOMICRON PROCESSING IN THE BLOOD (EXOGENOUS PATHWAY)

CHYLOMICRON in blood (large, TG-rich, ApoB-48, ApoC-II, ApoE)
    ↓
Reaches capillaries of ADIPOSE, MUSCLE, HEART
    ↓
LIPOPROTEIN LIPASE (LPL) - anchored on capillary endothelium
(activated by ApoC-II on the chylomicron surface)
    ↓
LPL hydrolyzes TG → FFA + glycerol (released into tissues)
  ├─ Muscle: FFA oxidized → CO₂ + H₂O (energy)
  └─ Adipose: FFA re-esterified → stored TG
    ↓
CHYLOMICRON SHRINKS as TG is removed:
  - Excess phospholipids, ApoCs, ApoA transferred BACK to HDL
  - ApoB-48 and ApoE remain on the particle
    ↓
= CHYLOMICRON REMNANT (TG-poor, cholesterol-rich)
    ↓
LIVER: ApoE on remnant binds hepatic remnant receptors (LRP1 / apoE receptor)
    ↓
Taken up by ENDOCYTOSIS → digested by lysosomes
    ↓
Cholesterol released inside hepatocyte:
  → used for bile acid synthesis
  → used for new lipoprotein synthesis (VLDL)
  → suppresses HMG-CoA reductase (feedback)
  → downregulates LDL receptors if excess

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STEP 6 - THE LIVER PROCESSES & REDISTRIBUTES LIPIDS (ENDOGENOUS PATHWAY)

LIVER makes VLDL (Very Low Density Lipoprotein):
  Contents: TG (mostly from de novo lipogenesis) + cholesteryl esters
           + ApoB-100 (liver-specific, full-length)
           + phospholipids + vitamin E
  Assembly requires: MTP (same enzyme as chylomicron assembly)
    ↓
VLDL secreted into BLOOD
(VLDL = "hepatic chylomicron" - carries endogenous TG to periphery)
    ↓
SAME PROCESS AS CHYLOMICRON:
LPL (activated by ApoC-II, donated by HDL) hydrolyzes VLDL TG
FFA → muscle (oxidation) or adipose (storage)
    ↓
VLDL REMNANT = IDL (Intermediate Density Lipoprotein)
  [Equal parts cholesterol and TG by this stage]
    ↓
TWO FATES OF IDL:
  ├─ 40-60%: Taken up by LIVER directly via ApoE → LDL receptor
  └─ 40-60%: Further processed by HEPATIC LIPASE (HL)
                ↓
              More TG removed, phospholipids removed, apolipoproteins shed
                ↓
             = LDL (Low Density Lipoprotein)
             [Almost pure cholesterol core, only ApoB-100 remains]

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STEP 7 - LDL DELIVERY TO TISSUES

LDL (ApoB-100 only, cholesterol-rich)
    ↓
ApoB-100 binds LDL RECEPTOR (LDLR) on:
  - Liver (~70% of LDL clearance)
  - Peripheral tissues (adrenal, gonads, muscle, etc.)
    ↓
RECEPTOR-MEDIATED ENDOCYTOSIS (clathrin-coated pit)
    ↓
LYSOSOME: LDL degraded
  - ApoB-100 → amino acids
  - Cholesteryl esters → hydrolyzed → FREE CHOLESTEROL
    ↓
Free cholesterol inside cell:
  ├─ Incorporated into CELL MEMBRANES
  ├─ Used for STEROID HORMONE synthesis (adrenal, gonads)
  ├─ Suppresses HMG-CoA REDUCTASE (↓ endogenous synthesis)
  ├─ Activates ACAT (re-esterified and stored)
  └─ Downregulates LDLR expression (↓ further uptake)

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STEP 8 - HDL: THE REVERSE CHOLESTEROL TRANSPORT PATHWAY

LIVER + INTESTINE → Synthesize NASCENT (DISCOIDAL) HDL
  [Contains: ApoA-I + phospholipids + minimal cholesterol]
    ↓
In PERIPHERAL TISSUES (especially macrophages):
ABCA1 transporter exports FREE CHOLESTEROL from cell → donated to ApoA-I/HDL
    ↓
LCAT (Lecithin-Cholesterol AcylTransferase) - enzyme on HDL surface
  Esterifies free cholesterol → CHOLESTERYL ESTER (CE)
  CE moves to hydrophobic CORE of HDL
  HDL expands: disc → sphere (HDL3 → HDL2)
    ↓
MATURE SPHERICAL HDL (CE-rich)
    ↓
TWO ROUTES TO RETURN CHOLESTEROL TO LIVER:

Route 1 - DIRECT:
  HDL binds SR-B1 (Scavenger Receptor B1) on hepatocytes
  Selective CE transfer to liver (HDL particle is recycled/released)
    ↓
  Liver: CE hydrolyzed → cholesterol → bile acids → excreted in bile

Route 2 - INDIRECT (via CETP):
  CETP (Cholesteryl Ester Transfer Protein) transfers CE from HDL → ApoB particles (VLDL/LDL)
  In exchange for TG
  These ApoB particles (now cholesterol-enriched) taken up by liver via LDLR

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THE MASTER FLOW CHART

DIET → GI LUMEN
        ↓
   [Bile salts + lipases]
        ↓
    MICELLES
        ↓
   ENTEROCYTE (small intestine)
   ├── Short/medium FA → portal vein → LIVER (directly)
   └── Long FA + cholesterol + fat-soluble vitamins
            ↓ (packaged with ApoB-48 via MTP)
       CHYLOMICRON → LYMPH → THORACIC DUCT → BLOOD
            ↓ (acquires ApoC-II + ApoE from HDL)
       LPL at capillaries (ApoC-II activates)
            ↓
       FFA → Muscle (oxidation) / Adipose (storage)
       CHYLOMICRON REMNANT (ApoB-48 + ApoE)
            ↓ (ApoE → hepatic receptor LRP1)
          LIVER
   ┌──────────────────────────────────────────┐
   │  LIVER processes lipids:                  │
   │  Makes VLDL (ApoB-100, TG-rich)           │
   └──────────────────────────────────────────┘
            ↓
       VLDL → BLOOD
            ↓ (LPL again, ApoC-II from HDL)
       FFA → Muscle (oxidation) / Adipose (storage)
       IDL (VLDL remnant)
            ↓
       40-60% → LIVER directly (ApoE → LDLR)
       40-60% → Hepatic Lipase (HL) action
            ↓
          LDL (ApoB-100 only, cholesterol-rich)
            ↓
       LDLR on liver + peripheral tissues
            ↓
       Endocytosis → cholesterol for membranes/
       steroid hormones/bile acids

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APOLIPOPROTEIN CHEAT SHEET (USMLE Direct)

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KEY ENZYMES & PROTEINS - TESTED DIRECTLY

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USMLE TRAPS FROM THIS PHYSIOLOGY

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TAKE-HOME SUMMARY (One-Liners)

1. TG digestion → lipase → 2-MG + FFA → micelles → enterocyte → re-esterified to TG → packed into chylomicron
2. Cholesterol → absorbed via NPC1L1 → esterified (ACAT) inside enterocyte → chylomicron
3. Short/medium FA → portal vein → liver directly (no chylomicron)
4. Chylomicron (ApoB-48) → lymph → blood → LPL (activated by ApoC-II) → TG released to tissues → chylomicron REMNANT → liver via ApoE
5. VLDL (ApoB-100) = liver's version; same LPL processing → IDL → either liver or → LDL
6. LDL = end product of VLDL, cholesterol-rich, ApoB-100 only → LDLR uptake by liver/peripheral tissues
7. HDL = reverse cholesterol transport; ApoA-I activates LCAT; cholesterol esterified → SR-B1 delivers CE to liver
8. CETP transfers CE from HDL → VLDL/LDL; statins, fibrates, niacin and PCSK9 inhibitors all ultimately work by ↑ LDLR expression
9. LPL deficiency / ApoC-II deficiency = TG >1000, milky plasma, pancreatitis, Type I hyperlipoproteinemia
10. ABCA1 deficiency = Tangier disease; NPC1L1 block = ezetimibe; PCSK9 block = evolocumab/alirocumab

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