The regressiоn equаtiоn belоw is predicting а person’s hourly eаrnings (wage) using years of education (educ), years of experience (exper), and two dummy variables. The dummy variable married equals 1 if the person is married and 0 if otherwise. The dummy variable metro equals 1 if the person lives in a metro area and 0 if otherwise. ANOVA Table Source Degrees of Freedom Sum of Squares Regression 4 3370.1 Error 60 7611.1 Total 64 10981.2 Coefficients Table Source Coefficients Standard Error Intercept -20.57 8.16 educ 2.16 0.48 exper 0.19 0.13 married 5.92 3.17 metro 3.89 3.26 What would you predict the wage to be for a person with 14 years of education, 4 years of experience, who is married, and does not live in a metro area? Round your answer to the second decimal place.
DRUG THERAPY OF HEART FAILURE (HF) 1) RAAS Inhibitоrs A. ACE Inhibitоrs (ACEIs): Enаlаpril, Lisinоpril, Cаptopril Effects: ↓ mortality (proven survival benefit) ↓ preload & afterload ↓ remodeling Use: First-line in HFrEF (if no fluid overload → ACEI alone; if overload → + diuretic) AEs: Cough (↑ bradykinin) Angioedema Hyperkalemia Renal impairment B. ARBs: Valsartan, Losartan Use: ACEI intolerance (cough/angioedema) Alternative RAAS blockade AEs: Hyperkalemia Hypotension Renal dysfunction(No cough—no bradykinin effect) C. ARNI (Angiotensin Receptor–Neprilysin Inhibitor): Sacubitril/Valsartan (Entresto) Mechanism Sacubitril → inhibits neprilysin → ↑ natriuretic peptides ↑ ANP/BNP → natriuresis, vasodilation, ↓ remodeling Valsartan → blocks AT1 receptor → prevents Ang II effects Important Concept Neprilysin breakdowns: Natriuretic peptides (beneficial) Ang II + bradykinin (problem if not blocked) Therefore MUST combine with ARB AEs: Hypotension Hyperkalemia Renal failure Angioedema (esp. if combined with ACEI) Contraindication: ACEI use within 36 hours → risk of severe angioedema D. Aldosterone Antagonists (ARAs): Spironolactone (± Eplerenone) Effects: ↓ Na⁺ retention, ↑ K⁺ retention ↓ fibrosis & remodeling ↓ mortality in severe HFrEF AEs: Hyperkalemia Gynecomastia (spironolactone) 2) Diuretics Mechanism ↓ Na⁺/H₂O → ↓ plasma volume ↓ preload → ↓ pulmonary edema, peripheral edema ↓ congestion symptoms A. Thiazides Mild–moderate HF Works only if renal function adequate B. Loop Diuretics: Furosemide Uses: Acute pulmonary edema Severe CHF Renal impairment cases C. Potassium-Sparing: Spironolactone Also in RAAS class Used in combination therapy Mortality benefit in severe HF 3) Direct Vasodilators Mechanism ↓ preload (venodilation) ↓ afterload (arteriolar dilation) A. Nitrates (Venodilation → ↓ preload) Nitroglycerin (IV in acute HF) Isosorbide dinitrate B. Hydralazine (Arteriolar dilation → ↓ afterload) Useful in: Acute HF with hypertension Pulmonary edema C. Combination Therapy: Hydralazine + Isosorbide Dinitrate (BiDil) ↓ preload + afterload ↓ remodeling ↓ mortality in African American patients Used when: ACEI/ARB not tolerated or insufficient D. Nitroprusside (IV) Balanced venous + arterial dilation Used in hypertensive emergencies with HF 4) β-Blockers (Disease-Modifying Therapy) Rationale Chronic sympathetic activation causes: Tachycardia Remodeling Increased O₂ demand RAAS activation β-blockers reverse these effects Effects: ↓ mortality ↓ remodeling ↓ HR → ↓ myocardial oxygen demand ↓ renin → ↓ RAAS activation Drugs: β1-selective: Metoprolol, Bisoprolol Mixed α1/β: Carvedilol Clinical Use: Stable mild–moderate HFrEF Always start LOW and go SLOW Contraindication: Acute decompensated HF Use with other cardiac depressants (e.g., non-DHP CCBs) 5) Positive Inotropic Drugs (Acute or Refractory HF) A. β1-Agonist: Dobutamine ↑ cAMP → ↑ Ca²⁺ → ↑ contractility IV only Uses: Acute decompensated HF Cardiogenic shock AEs: Tachycardia Angina B. PDE-3 Inhibitor: Milrinone ↑ cAMP (cardiac + vascular) Effects: ↑ contractility Vasodilation → ↓ preload & afterload Uses: Acute HF Post–heart transplant support Refractory cardiogenic shock AEs: Hypotension Arrhythmias N/V C. Digoxin (Na⁺/K⁺ ATPase inhibitor) ↑ intracellular Ca²⁺ → ↑ contractility Also ↑ vagal tone → ↓ HR Use: Refractory systolic HF (rare now) Limitations: Narrow therapeutic window Not first-line 6) Ivabradine (HCN Channel Blocker) Blocks SA node “funny current” (If) Effect: ↓ HR without affecting contractility Uses: Chronic HFrEF with HR ≥ 70 bpm Stable angina AEs: Bradycardia 7) Cardiac Myosin Inhibitors: Aficamten Mechanism: ↓ actin-myosin interaction → ↓ contractility Use: Hypertrophic cardiomyopathy (NOT standard HF therapy) Question: A 67-year-old man with HFrEF (EF 30%) has been taking lisinopril for several months. His cardiologist plans to switch him to sacubitril/valsartan to further reduce mortality and hospitalizations. He took his last dose of lisinopril this morning and is eager to start the new medication today. Which of the following is the most appropriate next step?
DRUG THERAPY OF HYPERTENSION 1) RAAS INHIBITORS (MOST IMPORTANT HTN SYSTEM TARGET) Blоcking RAAS → ↓ Angiоtensin II → ↓ vаsоconstriction + ↓ аldosterone ↓ Nа⁺/H₂O retention → ↓ volume ↓ sympathetic activity ↓ cardiac remodeling (HF benefit) A. ACE Inhibitors (ACEIs): Lisinopril, Enalapril, Captopril, Fosinopril, Benazepril MOA ACE inhibition → ↓ Angiotensin II ↑ Bradykinin → ↑ NO + PGI₂ → vasodilation Major physiologic effects ↓ SVR (vasodilation) ↓ aldosterone → ↓ Na⁺/H₂O retention Efferent arteriole dilation → ↓ intraglomerular pressure → ↓ proteinuria Uses (very high yield) First-line HTN (esp. DM, CKD) HFrEF (mortality benefit) Post-MI Proteinuric CKD Hypertensive urgency Adverse Effects (classic exam set) Dry cough (↑ bradykinin) Angioedema (dangerous) Hyperkalemia Hypotension (first dose) ↓ GFR in bilateral renal artery stenosis Teratogenic (fetal renal failure, oligohydramnios) Key interactions NSAIDs ↓ effect (↓ prostaglandins → afferent constriction) K⁺ supplements / K-sparing diuretics → severe hyperkalemia B. Angiotensin II Receptor Blockers (ARBs): Losartan, Valsartan, Candesartan, Telmisartan MOA Block AT1 receptor → inhibit Ang II actions directly Key differences vs ACEIs ❌ No bradykinin effect → NO cough ❌ No angioedema Uses ACEI intolerance (cough/angioedema) HTN, CKD, HFrEF AEs Hyperkalemia Hypotension Teratogenic Same renal risk in bilateral renal artery stenosis C. Renin Inhibitors: Aliskiren MOA Directly inhibits renin → ↓ Ang I → ↓ Ang II Uses Resistant HTN (limited clinical use) AEs Hyperkalemia Hypotension Renal dysfunction Avoid with ACEI/ARB (↑ renal + K⁺ toxicity) D. Aldosterone Receptor Antagonists (ARAs): Spironolactone, Eplerenone MOA Block aldosterone in collecting duct → ↓ Na⁺/H₂O retention + ↑ K⁺ retention Uses (VERY HIGH YIELD) Resistant HTN (key drug!) HFrEF (mortality benefit) Primary hyperaldosteronism Post-MI HF Hypokalemia Spironolactone: hirsutism, PCOS AEs Hyperkalemia (major) Metabolic acidosis Gynecomastia (spironolactone) Impotence, menstrual irregularities Contraindicated in pregnancy (spironolactone) 2) DIURETICS (↓ Na⁺ → ↓ volume + long-term ↓ SVR) A. Thiazides / Thiazide-like: Hydrochlorothiazide, Chlorthalidone, Indapamide MOA Block Na⁺/Cl⁻ cotransporter in DCT Uses (first-line HTN) Mild–moderate HTN Elderly Stroke prevention (very high yield) Calcium stone prevention (↓ urinary Ca²⁺) Nephrogenic DI AEs (“hyper” mnemonic) HyperGLUC: Hyperglycemia Hyperlipidemia Hyperuricemia (gout) Hypercalcemia Hypokalemia Hyponatremia Metabolic alkalosis B. Loop Diuretics: Furosemide, Bumetanide, Torsemide, Ethacrynic acid MOA Block Na⁺/K⁺/2Cl⁻ in thick ascending limb Uses HTN with CKD Pulmonary edema (HF) Edema (HF, liver, renal failure) Hypercalcemia (treatment) AEs (important distinctions) Ototoxicity Hypokalemia Hypocalcemia Hypomagnesemia Dehydration Interstitial nephritis Ethacrynic acid = safe in sulfa allergy C. K⁺-sparing diuretics 1. Aldosterone antagonist: Spironolactone, Eplerenone MOA Block aldosterone in collecting duct → ↓ Na⁺/H₂O retention + ↑ K⁺ retention Uses (VERY HIGH YIELD) Resistant HTN (key drug!) HFrEF (mortality benefit) Primary hyperaldosteronism Post-MI HF Hypokalemia Spironolactone: hirsutism, PCOS AEs Hyperkalemia (major) Metabolic acidosis Gynecomastia (spironolactone) Impotence, menstrual irregularities Contraindicated in pregnancy (spironolactone) 2. ENaC blockers: Amiloride, Triamterene MOA Block epithelial Na⁺ channels in collecting duct Uses Same as ARAs (adjunct HTN, hypokalemia prevention) AEs Hyperkalemia Amiloride: ↑ BUN Triamterene: Kidney stones Crystalluria AKI Megaloblastic anemia Question: A 68-year-old woman is started on a first-line antihypertensive medication. Two weeks later, she reports polyuria, weakness, and a gout flare. Laboratory findings include: Serum sodium: 131 mEq/L (ref: 135–145 mEq/L) Serum uric acid: elevated Which medication is most likely responsible?