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Antihypertensive Drugs: Classification, ACE Inhibitors (Enalapril), and Hypertensive Crisis Management

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PART 1 - Classification of Antihypertensive Drugs

A. Diuretics

1. Thiazide diuretics - Hydrochlorothiazide, Chlorthalidone, Indapamide
2. Loop diuretics - Furosemide, Bumetanide, Torsemide
3. Potassium-sparing diuretics - Spironolactone, Eplerenone, Amiloride, Triamterene

B. Drugs Acting on the Renin-Angiotensin-Aldosterone System (RAAS)

1. ACE Inhibitors (ACEIs) - Enalapril, Captopril, Lisinopril, Ramipril, Perindopril, Fosinopril
2. Angiotensin II Receptor Blockers (ARBs) - Losartan, Valsartan, Candesartan, Olmesartan, Telmisartan
3. Direct Renin Inhibitors - Aliskiren
4. Aldosterone Antagonists - Spironolactone, Eplerenone

C. Adrenergic Receptor Antagonists

1. Beta-blockers (non-selective) - Propranolol, Nadolol, Carvedilol
2. Beta-blockers (cardioselective) - Atenolol, Metoprolol, Bisoprolol, Nebivolol
3. Alpha-1 blockers - Prazosin, Doxazosin, Terazosin
4. Alpha-2 agonists (central) - Clonidine, Methyldopa, Guanfacine
5. Combined alpha+beta blockers - Labetalol, Carvedilol

D. Calcium Channel Blockers (CCBs)

1. Dihydropyridines (vascular selective) - Amlodipine, Nifedipine, Felodipine, Nicardipine, Clevidipine
2. Non-dihydropyridines (cardiac) - Verapamil (phenylalkylamine), Diltiazem (benzothiazepine)

E. Direct Vasodilators

1. Arteriolar - Hydralazine, Minoxidil, Diazoxide
2. Arteriolar + Venous - Sodium Nitroprusside
3. Nitrates - Nitroglycerin (primarily venodilator)

F. Centrally Acting Drugs

• Clonidine, Methyldopa, Moxonidine, Rilmenidine

G. Miscellaneous / Newer Agents

• Endothelin antagonists - Bosentan (pulmonary hypertension)
• Dopamine-1 agonists - Fenoldopam (hypertensive emergencies)
• Vasopeptidase inhibitors / neprilysin inhibitors - Sacubitril (in combination as Sacubitril/Valsartan for HFrEF)

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PART 2 - Enalapril (ACE Inhibitor): Complete Pharmacological Profile

Prototype Drug

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Mechanism of Action (MoA)

1. Blocks conversion of Angiotensin I → Angiotensin II: Angiotensin II is a potent vasoconstrictor and stimulates aldosterone release. By blocking its formation, ACEIs cause:
   • Vasodilation (decreased peripheral resistance)
   • Reduced aldosterone secretion → decreased sodium and water retention → reduced preload
   • Decreased sympathetic nervous system activity
2. Inhibits breakdown of bradykinin (a potent vasodilator): Bradykinin accumulation contributes to additional vasodilation and also stimulates release of prostaglandins (PGI2, PGE2) and nitric oxide - further lowering BP.

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Pharmacological Actions

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Therapeutic Uses

1. Hypertension - First-line agent, especially in patients with:
   • Diabetes mellitus (with or without nephropathy)
   • Chronic kidney disease / proteinuria
   • Heart failure with reduced ejection fraction (HFrEF)
   • Post-myocardial infarction with LV dysfunction
   • High cardiovascular risk patients
2. Chronic Heart Failure (HFrEF) - Reduces morbidity and mortality; indicated in all patients with EF <40% unless contraindicated. Classic trials: CONSENSUS-1 (enalapril vs placebo in NYHA Class IV), SOLVD (HF and asymptomatic LV dysfunction)
3. Post-MI LV Dysfunction - Reduces post-infarction remodeling and mortality
4. Diabetic Nephropathy - Slows progression even in normotensive patients; reduces proteinuria
5. Chronic Kidney Disease - Renoprotective by reducing intraglomerular hypertension
6. Prevention of cardiovascular events in high-risk patients (secondary prevention; shown in HOPE trial with ramipril)
7. Hypertensive Emergency - Enalaprilat IV (active form): given as slow IV infusion for 5 minutes; onset 15 min, peak effect 1-4 hours, duration ~6 hours. Initial dose no more than 0.625 mg in CKD patients. Particularly useful in scleroderma renal crisis (first-choice drug).

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Adverse Effects

• Braunwald's Heart Disease notes: "The decreases in blood pressure and mild azotemia often seen during initiation of therapy are, in general, well tolerated and do not require a decrease in the dose of the ACEI." - Braunwald's Heart Disease, 2 Vol Set, p. 150

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Drug Interactions

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PART 3 - Drugs Used in Management of Hypertensive Crisis

Definitions

• Hypertensive Urgency: SBP/DBP ≥ 180/120 mmHg with NO evidence of acute end-organ damage. Managed with oral agents, outpatient.
• Hypertensive Emergency: Same BP threshold WITH evidence of acute, ongoing end-organ damage (encephalopathy, acute MI, aortic dissection, acute pulmonary edema, acute kidney injury, eclampsia, stroke). Requires IV agents, inpatient/ICU management.

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Drugs Used in Hypertensive Emergency (IV Agents)

1. Sodium Nitroprusside

• Most potent parenteral vasodilator - dilates both arterioles AND venous capacitance vessels
• Onset: immediate; Duration: extremely short (allows minute-to-minute titration)
• Mechanism: releases NO, interferes with calcium-mediated excitation-contraction coupling
• Toxicity: Metabolized to cyanide and thiocyanate via reaction with hemoglobin; risk if >48 hours infusion or rate >2 mcg/kg/min. Signs: air hunger, confusion, seizures, lactic acidosis
• Use: Most hypertensive emergencies; Avoid in pregnancy, high ICP

2. Nitroglycerin (IV)

• Primarily venodilator at low doses; arterial dilation at high doses
• Also dilates epicardial coronary vessels - preferred in acute coronary syndrome/MI
• Onset: immediate; rapidly metabolized
• Caution: adsorbed by PVC tubing; use non-PVC sets and glass bottles

3. Labetalol (IV)

• Combined alpha + beta-adrenergic blocker
• Reduces BP without reflex tachycardia
• Useful in: aortic dissection, hypertension in pregnancy, post-operative hypertension
• Avoid in: acute heart failure, severe asthma/COPD, bradycardia

4. Esmolol (IV)

• Ultra-short-acting cardioselective beta-1 blocker
• Used in: aortic dissection (combined with nitroprusside or nicardipine), perioperative hypertension

5. Nicardipine (IV)

• Dihydropyridine calcium channel blocker
• Dose-dependent BP reduction; onset within minutes
• Safe and effective in pediatric hypertensive emergencies
• Useful in: most emergencies, especially neurological emergencies and post-op hypertension

6. Clevidipine (IV)

• Dihydropyridine CCB; lipid emulsion formulation
• Ultra-short-acting: half-life ~1 min; hydrolyzed by plasma esterases
• Rapid BP reduction (≥15% from baseline within <6 minutes)
• Safety comparable to nitroprusside and nitroglycerin
• Common AEs: sinus tachycardia, headache, nausea

7. Fenoldopam (IV)

• Dopamine D1-receptor agonist - dilates peripheral arteries and renal vasculature
• Increases renal blood flow and sodium excretion - preferred in renal emergencies
• First-choice for hypertensive emergencies with acute kidney involvement

8. Enalaprilat (IV)

• Active metabolite of enalapril; ACE inhibitor given IV
• Onset: 15 minutes; Peak: 1-4 hours; Duration: ~6 hours
• Dose: ~25% of oral enalapril dose (max 0.625 mg initial dose in CKD)
• First-choice in scleroderma renal crisis; second-line in pulmonary edema

9. Phentolamine (IV)

• Non-selective alpha-adrenergic antagonist
• Drug of choice for pheochromocytoma crisis
• Onset: rapid (IV bolus or infusion); Duration: 10-15 min; Half-life: 19 min

10. Hydralazine (IV)

• Direct arteriolar vasodilator; causes reflex tachycardia
• Useful in eclampsia/pre-eclampsia (established safety record in pregnancy)
• Avoid in: aortic dissection, coronary ischemia

11. Diazoxide (IV)

• Direct arteriolar vasodilator; rapid onset
• Less commonly used now; generally avoided in CAD and aortic dissection

12. Methyldopate (IV)

• Central alpha-2 agonist; delayed and unpredictable onset
• Limited use; mainly historical or in specific pregnancy scenarios

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Summary Table: Drug Choice by Hypertensive Emergency Type

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• ACEIs are contraindicated in bilateral renal artery stenosis, pregnancy, and history of angioedema
• The cough from ACEIs is a class effect - switching within the class will not resolve it; switch to ARB
• In hypertensive emergencies, the general goal is to reduce BP by no more than 25% in the first hour, then gradually toward normal over 24-48 hours - except in aortic dissection (target SBP <120 mmHg within 1 hour) and stroke (where overcorrection is harmful)
• Diuretics and CCBs are particularly effective in Black/African-American patients; ACEIs/ARBs are less effective as monotherapy in this population but remain preferred when heart failure, CKD, or proteinuria is present