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Antihypertensives & Heart Failure Drugs

Name: Antihypertensives & Heart Failure Drugs
Creator: Veli Bakalov, MD

Which drugs lower pressure, which prolong life, and the side effects that give them away

Cardiovascular·Pharmacology·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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ACE inhibitors lower angiotensin II and raise bradykinin (cough, angioedema); side effects CATCHH; avoid in pregnancy and bilateral renal artery stenosis.
ARBs block the AT1 receptor without raising bradykinin, so they avoid the cough but keep teratogenicity and hyperkalemia.
ACE inhibitors protect the diabetic kidney by dilating the efferent arteriole and lowering intraglomerular pressure.
Thiazides block the DCT Na-Cl cotransporter: hypokalemic alkalosis, hyponatremia, and hyperGLUC (hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia); loops instead waste calcium.
Dihydropyridines (amlodipine, nifedipine) dilate vessels (edema, reflex tachycardia); verapamil and diltiazem slow the heart and should not be combined with β-blockers.
Hydralazine: arteriolar dilator for pregnancy and (with nitrates) HF in Black patients; reflex tachycardia and drug-induced lupus; minoxidil causes hypertrichosis.
HFrEF mortality benefit: ACE inhibitor/ARB/ARNI, carvedilol/metoprolol succinate/bisoprolol, aldosterone antagonist, SGLT2 inhibitor, hydralazine + nitrate; loops and digoxin are symptomatic only.
Spironolactone blocks androgen receptors (gynecomastia) while eplerenone is selective; both cause hyperkalemia.
Digoxin inhibits the Na+/K+-ATPase (↑ intracellular Ca2+, ↑ vagal tone); toxicity (nausea, yellow vision, arrhythmias) is worsened by hypokalemia; antidote is digoxin Fab.

Blocking the renin–angiotensin–aldosterone system

Angiotensinogen → angiotensin IRenin from the kidney.
Angiotensin I → angiotensin IIACE, blocked by -prils; ACE also degrades bradykinin.
Angiotensin II at the AT1 receptorBlocked by -sartans.
AldosteroneIts receptor is blocked by spironolactone and eplerenone.

ACE inhibitors. The -prils (lisinopril, enalapril, captopril) lower angiotensin II and aldosterone and raise bradykinin; renin rises as feedback is lost. Uses: hypertension, heart failure (mortality benefit), diabetic nephropathy, and post-MI.

Kidney effects. Removing angiotensin II constriction of the efferent arteriole lowers intraglomerular pressure and proteinuria, slowing diabetic nephropathy; the modest early fall in GFR is expected. In bilateral renal artery stenosis, filtration depends on efferent tone, so these drugs can precipitate acute kidney injury.

Adverse effects (CATCHH). Cough, Angioedema, Teratogenicity, raised Creatinine, Hyperkalemia, and Hypotension. Accumulated bradykinin causes the dry cough and angioedema. Avoid in pregnancy, bilateral renal artery stenosis, and hereditary angioedema (C1 esterase inhibitor deficiency).

ARBs. The -sartans (losartan, valsartan) block the AT1 receptor directly without affecting bradykinin, so cough and angioedema are much less common; swapping to an ARB is the usual fix for ACE-inhibitor cough. They share the teratogenicity, hyperkalemia, and renal cautions.

Diuretics

Thiazides. Hydrochlorothiazide and chlorthalidone block the Na-Cl cotransporter in the distal convoluted tubule and are first-line for hypertension. They enhance distal calcium reabsorption, lowering urinary calcium, which helps prevent calcium stones.

Loop diuretics. Furosemide, bumetanide, and torsemide block the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb. As the most potent diuretics they treat edema and congestion, relieving heart failure symptoms without reducing mortality.

Thiazides vs loop diuretics

Feature	Thiazides	Loop diuretics
Target	Na-Cl cotransporter, distal convoluted tubule	NKCC2, thick ascending limb
Main use	Hypertension; calcium stones	Edema, pulmonary congestion, HF symptoms
Calcium	↓ Urinary calcium → hypercalcemia	↑ Urinary calcium → hypocalcemia
Electrolytes	Hypokalemic metabolic alkalosis, hyponatremia	Hypokalemic metabolic alkalosis, hypomagnesemia
Signature effects	hyperGLUC: hyperglycemia, hyperlipidemia, hyperuricemia, hypercalcemia	Ototoxicity, gout, interstitial nephritis

Both classes are sulfa drugs except ethacrynic acid, the non-sulfa loop diuretic.

Calcium channel blockers and sympatholytics

Two families of calcium channel blockers

Feature	Dihydropyridines	Non-dihydropyridines
Examples	Amlodipine, nifedipine	Verapamil, diltiazem
Main site	Vascular smooth muscle	Heart: SA and AV nodes, myocardium
Uses	Hypertension, angina	Rate control, angina
Adverse effects	Peripheral edema, reflex tachycardia, flushing, gingival hyperplasia	Bradycardia, AV block, worsened heart failure; constipation with verapamil

Do not combine verapamil or diltiazem with a β-blocker: additive AV block, bradycardia, and negative inotropy. Avoid them in HFrEF.

β-blockers. The -olols lower heart rate, contractility, and renin release. Uses: hypertension, angina, post-MI and heart failure (mortality benefit), and arrhythmias. Adverse effects: bradycardia, AV block, bronchospasm, masked hypoglycemia, fatigue, and erectile dysfunction. Only three reduce mortality in HFrEF: carvedilol, metoprolol succinate, and bisoprolol.

α1-blockers. Prazosin, terazosin, and doxazosin dilate arterioles and relax the prostate and bladder neck, a good fit when hypertension coexists with BPH. The signature adverse effect is first-dose orthostatic hypotension.

Central α2-agonists. Clonidine and methyldopa reduce sympathetic outflow from the brainstem. Abrupt clonidine withdrawal causes rebound hypertension; methyldopa is safe in pregnancy but can cause a Coombs-positive hemolytic anemia.

Direct vasodilators and hypertensive emergency

Hydralazine. Raises cGMP and dilates arterioles more than veins, lowering afterload. It is used in pregnancy and, with a nitrate, for heart failure in Black patients. Reflex tachycardia and fluid retention are common, so it is paired with a β-blocker and diuretic; it can also cause drug-induced lupus with anti-histone antibodies.

Minoxidil. Opens potassium channels, hyperpolarizing and relaxing arteriolar smooth muscle; hypertrichosis is its signature effect.

Hypertensive emergency. Severe hypertension with end-organ damage is treated with IV nitroprusside, which releases nitric oxide, raising cGMP to dilate both arteries and veins. Prolonged use risks cyanide toxicity. Labetalol, nicardipine, and fenoldopam (a dopamine D1 agonist that also promotes renal perfusion and natriuresis) are alternatives.

In pregnancy, labetalol, nifedipine, methyldopa, and hydralazine are the usual choices; ACE inhibitors and ARBs are contraindicated because they injure the fetal kidney.

Heart failure pharmacology

HFrEF drugs: survival vs symptoms

Drug	Action	Effect	Watch for
ACE inhibitor, ARB, or ARNI	RAAS blockade; sacubitril inhibits neprilysin, raising natriuretic peptides	↓ Mortality	Hyperkalemia; never give an ARNI with an ACE inhibitor (angioedema)
β-blocker	Carvedilol, metoprolol succinate, bisoprolol	↓ Mortality	Bradycardia, hypotension
Aldosterone antagonist	Spironolactone, eplerenone (K+-sparing)	↓ Mortality (RALES)	Hyperkalemia; gynecomastia with spironolactone
SGLT2 inhibitor	Blocks proximal-tubule glucose reabsorption	↓ HF hospitalization and death	Genital yeast infections, UTIs, euglycemic DKA, volume depletion
Hydralazine + nitrate	Afterload plus preload reduction	↓ Mortality, especially in Black patients	Headache, reflex tachycardia, lupus
Loop diuretic	NKCC2 blockade	Symptom relief only	Hypokalemia, ototoxicity
Digoxin	Na+/K+-ATPase inhibition	Symptom relief only	Narrow therapeutic window

Aldosterone antagonists. Spironolactone also blocks androgen receptors, causing gynecomastia; eplerenone is selective and spares this effect. Both can cause dangerous hyperkalemia, especially with ACE inhibitors or kidney disease.

SGLT2 inhibitors. The -flozins (dapagliflozin, empagliflozin) reduce heart failure events with both reduced and preserved EF; the resulting glucosuria explains the genital and urinary infections.

Digoxin. Inhibiting the Na+/K+-ATPase raises intracellular Na+, which slows the Na+/Ca2+ exchanger and raises intracellular Ca2+ for positive inotropy; increased vagal tone slows AV conduction for rate control in atrial fibrillation. Toxicity: nausea, yellow-green vision (xanthopsia), and arrhythmias; treat with digoxin-specific antibody fragments (Fab).

Hypokalemia (often from loop diuretics) potentiates digoxin toxicity because less K+ competes for the pump's binding site. Renal failure and verapamil, amiodarone, or quinidine also raise digoxin levels.