32.3 Cardiovascular Pharmacology II: Antihypertensives and Diuretics, Hypertensive Emergencies, Vasopressors and Inotropes in Shock, Heart Failure GDMT and Digoxin, and Lipid-Lowering Therapy

Why this area matters

The TOS asks for drug treatment of:

• hypertension and hypertensive emergencies;
• hypotension and shock;
• heart failure;
• dyslipidemia.

Hypertension is one of the most common reasons for consultation in the Philippines and a leading risk factor for stroke and heart disease. Guidelines emphasize lifestyle change plus combination therapy to reach blood pressure targets, usually below 130/80 mmHg for most adults at high risk.

Antihypertensive Pharmacology & Diuretic Regimens

Renin-Angiotensin-Aldosterone System (RAAS) Blockers

• ACE Inhibitors (Captopril, Enalapril, Lisinopril, Ramipril):
  • Mechanism: Inhibit Angiotensin-Converting Enzyme (ACE / Kininase II), preventing the conversion of Angiotensin I to the potent vasoconstrictor Angiotensin II. Simultaneously inhibit the enzymatic breakdown of bradykinin and substance P.
  • Hemodynamic & Renal Effects: Decreases systemic vascular resistance (afterload reduction) without reflex tachycardia. Selectively dilates the efferent arteriole of the renal glomerulus, lowering intraglomerular capillary hydrostatic pressure; this slows long-term renal microalbuminuria and diabetic nephropathy, but causes a transient, anticipated initial dip in GFR ($< 30\%$ rise in serum creatinine is acceptable).
  • Adverse Effects:
    1. Persistent Dry Cough ($5\text{--}20\%$): Mediated by pulmonary accumulation of bradykinin and substance P.
    2. Angioedema ($0.1\text{--}0.5\%$): Life-threatening, non-pitting swelling of lips, tongue, pharynx, and larynx mediated by bradykinin accumulation (not histamine-mediated; epinephrine/antihistamines are ineffective; requires airway protection and C1-esterase inhibitor or icatibant if available).
    3. Hyperkalemia: Due to reduced aldosterone-mediated potassium excretion.
    4. Acute Kidney Injury in Bilateral Renal Artery Stenosis: In bilateral stenosis, glomerular filtration is maintained by Angiotensin II-mediated efferent arteriolar constriction; ACE inhibitors abolish this autoregulation, causing acute prerenal azotemia.
    5. Teratogenicity: Category D; causes fetal renal dysgenesis, oligohydramnios, pulmonary hypoplasia, and neonatal anuria (Potter sequence).
• Angiotensin Receptor Blockers (ARBs: Losartan, Valsartan, Candesartan, Telmisartan):
  • Mechanism: Competitively block Angiotensin II Type 1 ($AT_1$) receptors, preventing Angiotensin II-induced vasoconstriction and aldosterone secretion.
  • Distinction from ACEi: ARBs do not inhibit kininase II and do not increase bradykinin levels. Therefore, ARBs do not cause dry cough and carry a vastly lower incidence of angioedema. Indicated as first-line alternatives for patients who cannot tolerate ACE inhibitors due to cough. Share identical risks of hyperkalemia, acute kidney injury in bilateral renal artery stenosis, and fetal teratogenicity.

Calcium Channel Blockers (CCBs)

Block voltage-gated L-type calcium channels ($Cav1.2$) in vascular smooth muscle and cardiac myocytes, inhibiting intracellular calcium influx and excitation-contraction coupling.

• Dihydropyridines (Amlodipine, Nifedipine, Nicardipine, Felodipine):
  • Tissue Selectivity: High vascular selectivity (vascular smooth muscle $\gg$ myocardium).
  • Clinical Effects: Potent peripheral arteriolar vasodilation; minimal direct effect on cardiac conduction or contractility. Short-acting nifedipine can trigger dangerous reflex sympathetic tachycardia (avoided in acute coronary syndromes).
  • Adverse Effects: Dependent peripheral ankle edema (caused by preferential precapillary arteriolar dilation increasing capillary hydrostatic pressure, not fluid retention; unresponsive to loop diuretics), lightheadedness, facial flushing, and gingival hyperplasia.
• Non-Dihydropyridines (Verapamil, Diltiazem):
  • Tissue Selectivity: Cardiac myocytes and nodal tissue $\ge$ vascular smooth muscle. Verapamil is cardioselective (heart $>$ vessels); Diltiazem has intermediate balanced selectivity.
  • Clinical Effects: Suppress SA node automaticity (negative chronotropy), slow AV node conduction velocity (negative dromotropy), and depress myocardial contractility (negative inotropy). Used for rate control in atrial fibrillation and supraventricular tachycardias.
  • Adverse Effects & Contraindications: Constipation (most prominent with verapamil due to colonic smooth muscle relaxation), bradycardia, heart block, and worsening of heart failure. Strictly contraindicated in patients with Heart Failure with Reduced Ejection Fraction (HFrEF) and second- or third-degree AV block.

Diuretic Classes: Thiazide, Loop & Potassium-Sparing

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Heart Failure Guideline-Directed Medical Therapy (GDMT)

Modern management of Heart Failure with Reduced Ejection Fraction ($LVEF \le 40\%$) centers on foundational Quadruple Therapy, which reverses adverse neurohormonal cardiac remodeling and drastically reduces cardiovascular hospitalization and all-cause mortality.

The Four Pillars of HFrEF Quadruple Therapy

1. Angiotensin Receptor-Neprilysin Inhibitor (ARNI: Sacubitril-Valsartan):
   • Mechanism: Sacubitril is a prodrug whose active metabolite inhibits neprilysin (neutral endopeptidase), preventing the enzymatic degradation of beneficial endogenous natriuretic peptides (ANP, BNP), bradykinin, and adrenomedullin. Valsartan concurrently blocks the $AT_1$ receptor, counteracting angiotensin II.
   • The 36-Hour Washout Rule: Because both ACE and neprilysin degrade bradykinin, co-administering an ACE inhibitor with an ARNI leads to massive, synergistic bradykinin accumulation and catastrophic, fatal angioedema. Clinical guidelines strictly mandate a 36-hour washout period between the last dose of an ACE inhibitor and the initiation of sacubitril-valsartan. (No washout is required when transitioning from an ARB to an ARNI).
2. Evidence-Based Beta-Blockers (Carvedilol, Metoprolol Succinate, Bisoprolol):
   • Only three beta-blockers possess proven mortality benefit in chronic HFrEF: Carvedilol (non-selective beta plus $\alpha_1$ blocker), Metoprolol succinate (extended-release $\beta_1$ blocker; not short-acting metoprolol tartrate), and Bisoprolol.
   • Initiated at low starting doses in clinically stable, euvolemic patients and slowly titrated upward to target doses. Blunt chronic sympathetic hyperactivation, prevent arrhythmia-induced sudden cardiac death, and reverse ventricular remodeling.
3. Mineralocorticoid Receptor Antagonists (MRAs: Spironolactone or Eplerenone):
   • Inhibit aldosterone binding in renal collecting ducts and myocardial interstitium, suppressing cardiac collagen synthesis, myocardial fibrosis, and vascular remodeling (RALES, EPHESUS trials). Serum potassium and renal function must be monitored.
4. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors (Dapagliflozin or Empagliflozin):
   • Promotes osmotic diuresis, decreases ventricular preload and afterload, improves myocardial energetics, and preserves renal function. Proven to reduce cardiovascular mortality and heart failure hospitalizations in HFrEF regardless of whether the patient has diabetes mellitus (DAPA-HF, EMPEROR-Reduced trials).

Digoxin: Inotropy, Parasympathomimetic Action & Toxicity

• Mechanism of Inotropy: Reversibly inhibits the myocardial sarcolemmal $Na^+/K^+$ ATPase pump. This causes intracellular $[Na^+]$ to rise, reducing the inward sodium electrochemical gradient that drives the $Na^+/Ca^{2+}$ exchanger (NCX). Consequently, calcium extrusion is diminished, and intracellular $[Ca^{2+}]$ accumulates within the sarcoplasmic reticulum. Upon subsequent depolarization, augmented calcium release drives enhanced cross-bridge formation, yielding positive inotropy.
• Electrophysiological Effects: Stimulates central vagal nuclei, increasing parasympathetic tone at the AV node. This prolongs AV nodal refractoriness and slows ventricular response in atrial fibrillation (negative dromotropy).
• Mortality Reality: Digoxin improves clinical symptoms, exercise tolerance, and reduces heart failure hospitalizations, but does not reduce all-cause mortality (DIG trial).
• Digoxin Toxicity Profile:
  • Narrow Therapeutic Window: Target level $0.5\text{--}0.9\text{ ng/mL}$; toxicity frequently manifests at levels $> 2.0\text{ ng/mL}$.
  • Precipitating Factors: Hypokalemia (potassium competes with digoxin for the $Na^+/K^+$ ATPase binding site; when potassium is low, digoxin binding and toxicity are markedly increased), hypomagnesemia, hypercalcemia, and renal failure.
  • Clinical Manifestations: Gastrointestinal distress (anorexia, nausea, vomiting, abdominal pain), central neuropsychiatric disturbances (lethargy, confusion, weakness), and unique ocular changes (xanthopsia—yellow-green halos around lights, blurred vision).
  • Cardiac Arrhythmias: Can cause virtually any arrhythmia: frequent premature ventricular contractions (PVCs, most common), paroxysmal atrial tachycardia with AV block, junctional escape rhythms, and fatal bidirectional ventricular tachycardia.
  • Management of Severe Toxicity: Discontinue digoxin; normalize serum potassium and magnesium; administer Digoxin-specific antibody fragments (DigiFab) for life-threatening arrhythmias, severe hyperkalemia ($K^+ > 5.0\text{ mEq/L}$ in acute ingestion), or massive overdose; temporary cardiac pacing or atropine for severe refractory bradycardia.

Choosing antihypertensives

• First-line classes: ACE inhibitor or ARB, calcium channel blocker, and thiazide or thiazide-like diuretic. Combinations (often single-pill) are used when BP is far above target.
• Compelling indications:
  • diabetes with albuminuria or CKD: ACE inhibitor or ARB;
  • heart failure: ACE inhibitor or ARNI, beta-blocker and MRA;
  • after MI: beta-blocker and ACE inhibitor;
  • pregnancy: methyldopa, labetalol or nifedipine (never ACE inhibitors or ARBs);
  • BPH: an alpha-blocker as an add-on;
  • isolated systolic hypertension in older adults: a CCB or thiazide.
• Combinations to avoid: never combine an ACE inhibitor with an ARB (more renal failure and hyperkalemia). Beta-blockers are not first-line for uncomplicated hypertension.
• Monitoring: check creatinine and potassium 1 to 2 weeks after starting or increasing an ACE inhibitor, ARB or MRA. A rise in creatinine of up to 30% is acceptable.

Hypertensive emergencies

• Definition: severely raised BP (often 180/120 mmHg or more) with acute target-organ damage: encephalopathy, stroke, ACS, acute pulmonary edema, aortic dissection, acute kidney injury or eclampsia.
• Initial target: lower mean arterial pressure by no more than about 25% in the first hour, then toward 160/100 over the next 2 to 6 hours. Too-rapid lowering causes cerebral, coronary or renal ischemia.
• Exceptions:
  • aortic dissection: systolic below 120 mmHg within 20 minutes, with beta-blockade first (esmolol or labetalol), then a vasodilator;
  • acute ischemic stroke: lower only if BP is above 185/110 before thrombolysis, or above 220/120 otherwise;
  • eclampsia and preeclampsia: labetalol, hydralazine or nifedipine plus magnesium.
• IV drugs:
  • nicardipine or clevidipine (dihydropyridine CCBs);
  • labetalol;
  • esmolol;
  • nitroglycerin, for ACS and pulmonary edema;
  • sodium nitroprusside, a potent arteriovenous dilator. Its cyanide and thiocyanate toxicity with prolonged use or renal failure causes metabolic acidosis and confusion, and is treated with hydroxocobalamin or sodium thiosulfate.
• Hypertensive urgency (high BP without organ damage): resume or adjust oral therapy and reduce BP over days. Avoid sublingual nifedipine.

Hypotension and shock

• Adverse effects of vasopressors: tachyarrhythmias, limb and gut ischemia, and tissue necrosis on extravasation, treated with local phentolamine.
• Infusions: give them through a central line when possible.
• Dopamine causes more arrhythmias than norepinephrine in septic shock.

Lipid-lowering therapy

• Statin intensity: high-intensity statins are indicated for established ASCVD, LDL of 190 mg/dL or more, and diabetic or high-risk patients.
• Monitoring: check the lipid profile 4 to 12 weeks after starting, and check CK only if there are muscle symptoms.
• Interactions: CYP3A4 inhibitors (macrolides, azoles, grapefruit) raise simvastatin and atorvastatin levels and myopathy risk.
• Severe hypertriglyceridemia (above 500 to 1,000 mg/dL) is treated with a fibrate and diet to prevent pancreatitis.