Antihypertensive Drugs

Overview & Classification

1. Diuretics - deplete sodium, reduce blood volume
2. Renin-Angiotensin System (RAS) Blockers - reduce peripheral vascular resistance and blood volume
3. Direct Vasodilators - relax vascular smooth muscle
4. Sympathoplegic Agents - reduce PVR, inhibit cardiac function, increase venous pooling

1. Diuretics

Mechanism

Types & Uses

• Chlorthalidone has a longer duration of action than HCTZ, though both show comparable cardiovascular outcomes in elderly patients.
• In severe hypertension on multiple drugs, blood pressure becomes very sensitive to volume because vascular responsiveness is blunted.

Adverse Effects

• Hypokalemia, hyperglycemia, hyperuricemia (thiazides) - particularly significant in elderly due to higher prevalence of arrhythmias, diabetes, and gout
• MRAs contraindicated if creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women), or hyperkalemia

2. Renin-Angiotensin System (RAS) Blockers

A. ACE Inhibitors (ACEi)

• Captopril (prototype), Enalapril (prodrug → enalaprilat), Lisinopril (lysine derivative; not a prodrug), Ramipril, Perindopril, Benazepril, Fosinopril, Quinapril, Trandolapril

• Reduce proteinuria and stabilize renal function in CKD and diabetes (by reducing efferent arteriolar resistance and intraglomerular capillary pressure)
• Beneficial in heart failure and post-MI
• Reduce incidence of new-onset diabetes in high cardiovascular risk patients

• Dry cough (due to bradykinin/substance P accumulation) - class effect
• Angioedema - rare but serious
• Hyperkalemia (especially in renal insufficiency or diabetes)
• Acute renal failure in bilateral renal artery stenosis
• Contraindicated in pregnancy (2nd and 3rd trimesters - fetal hypotension, anuria, renal failure, malformations)
• First-dose hypotension in hypovolemic patients

B. Angiotensin Receptor Blockers (ARBs)

C. Direct Renin Inhibitor

• Aliskiren - inhibits renin directly, blocking the first step of the RAS cascade. Generally used as add-on therapy; avoid combining with ACEi/ARBs especially in diabetes or renal disease.

3. Calcium Channel Blockers (CCBs)

Mechanism

Classification

• Effective in elderly and in isolated systolic hypertension
• DHPs especially useful in angina with atherosclerosis
• Non-DHPs (Verapamil, Diltiazem) for AF rate control

• Verapamil/Diltiazem: AV block grade 2-3, severe LV dysfunction, heart failure
• DHPs: Use with caution in tachycardia/arrhythmia

4. Sympathoplegic (Adrenergic) Agents

A. Beta-Blockers (β-Blockers)

• Non-selective: Propranolol, Nadolol, Timolol
• Cardioselective (β₁): Metoprolol, Atenolol, Bisoprolol
• With vasodilating properties: Carvedilol (α+β block), Labetalol (α+β), Nebivolol (NO-mediated vasodilation)

• Post-MI, stable angina, heart failure (Carvedilol, Bisoprolol, Metoprolol succinate)
• Aortic aneurysm (Propranolol)
• AF rate control
• Prevention of AF recurrence

• Asthma - absolute contraindication (bronchoconstriction)
• AV block grade 2-3
• Mask hypoglycemia symptoms in diabetics
• Metabolic syndrome, glucose intolerance (precaution)
• Depression, psoriasis (relative)
• Athletes and physically active patients (reduces exercise tolerance)

B. Alpha-1 Blockers

• First-dose orthostatic hypotension (particularly with Prazosin)
• Contraindicated in heart failure (ALLHAT trial showed worse outcomes)

C. Central Alpha-2 Agonists (Centrally Acting)

• Methyldopa - drug of choice in pregnancy hypertension
• Clonidine - also used for opioid/nicotine withdrawal; patch formulation available
• Guanabenz, Guanfacine

D. Postganglionic Sympathetic Blockers

• Reserpine - depletes catecholamines from vesicles; very inexpensive
• Guanethidine, Guanadrel - block NE release from terminals; rarely used now due to side effects (severe orthostatic hypotension)

5. Direct Vasodilators

A. Hydralazine

• Mechanism: Dilates arterioles (not veins) by unclear mechanism (possible NO-related); causes marked reflex sympathetic activation and sodium retention - must be combined with β-blocker + diuretic.
• Dose: 40-200 mg/day (higher dose increases lupus risk)
• Adverse Effects: Headache, tachycardia, flushing. At ≥400 mg/day: drug-induced lupus (arthralgia, myalgia, skin rash, fever) in ~10-20%, especially in slow acetylators. Peripheral neuropathy (rare).
• Safe in pregnancy (used IV for hypertensive emergencies in pregnancy)

B. Minoxidil

• Mechanism: Opens K⁺ channels in smooth muscle via active metabolite (minoxidil sulfate) → membrane stabilization → reduced contraction. More potent than hydralazine.
• Use: Severe/resistant hypertension, especially in renal failure patients who don't respond to hydralazine. Must be combined with β-blocker + loop diuretic.
• Adverse Effects: Severe fluid retention, tachycardia, hypertrichosis (hair growth - forms basis for topical Rogaine). Pericardial effusion with long-term use.

C. Sodium Nitroprusside

• Mechanism: Releases NO → dilates both arteries and veins → reduces preload and afterload.
• Use: Hypertensive emergencies (IV only); also used in acute heart failure.
• Adverse Effects: Cyanide toxicity with prolonged use (especially renal failure). Requires continuous BP monitoring.

D. Fenoldopam

• Mechanism: D₁-receptor agonist → renal and peripheral vasodilation; increases renal blood flow and sodium excretion.
• Use: Hypertensive emergencies, particularly when renal preservation is desired.

Drug Selection by Compelling Indication

Contraindications Summary

Polypharmacy in Resistant Hypertension

• Most drugs evoke compensatory mechanisms that limit their effect (e.g., vasodilators cause reflex tachycardia + sodium retention)
• Adding a β-blocker prevents tachycardia; adding a diuretic prevents sodium retention
• The classic triple combination: vasodilator + β-blocker + diuretic
• Preferred combination: RAS inhibitor + CCB + thiazide (based on RAAS and ACCOMPLISH trial data)

Note: K.D. Tripathi's Essentials of Medical Pharmacology is not available in the textbook library. The answer below is drawn from Katzung's Basic & Clinical Pharmacology (16th Ed.) and Goodman & Gilman's Pharmacological Basis of Therapeutics - the standard references that cover the same content as Tripathi, often with identical drug classifications and mechanisms. The structure follows the Tripathi-style organization (positive inotropic / non-inotropic; chronic / acute CHF).

Drugs for Congestive Heart Failure (CHF)

Classification of Drugs Used in CHF

DRUGS FOR CHF
│
├── A. POSITIVE INOTROPIC DRUGS
│   ├── 1. Cardiac Glycosides (Digitalis) — Digoxin
│   ├── 2. Beta-Adrenoceptor Agonists — Dobutamine, Dopamine
│   ├── 3. Phosphodiesterase Inhibitors (Bipyridines) — Milrinone, Inamrinone
│   └── 4. Calcium Sensitizers — Levosimendan
│
└── B. NON-INOTROPIC DRUGS (First-line in chronic CHF)
    ├── 1. Diuretics — Furosemide, Spironolactone, Eplerenone
    ├── 2. ACE Inhibitors — Captopril, Enalapril, Ramipril
    ├── 3. Angiotensin Receptor Blockers — Losartan, Valsartan
    ├── 4. ARNI — Sacubitril/Valsartan (Entresto)
    ├── 5. Beta-Blockers — Carvedilol, Bisoprolol, Metoprolol succinate
    ├── 6. Vasodilators — Hydralazine + Isosorbide dinitrate, Nesiritide
    ├── 7. SGLT2 Inhibitors — Empagliflozin, Dapagliflozin
    └── 8. HCN Channel Blocker — Ivabradine

A. POSITIVE INOTROPIC DRUGS

1. Cardiac Glycosides - Digoxin (Digitalis)

• Inhibits Na⁺/K⁺-ATPase (the sodium pump) → intracellular Na⁺ accumulates
• ↑ intracellular Na⁺ reduces Ca²⁺ expulsion via Na⁺/Ca²⁺ exchanger (NCX)
• ↑ intracellular Ca²⁺ is stored in SR → released during systole → positive inotropy

• Mechanical: Increased contractility (positive inotropy)
• Electrical/Electrophysiological:
  • Decreased automaticity of SA node (negative chronotropy)
  • Decreased AV conduction velocity (negative dromotropy) - useful in AF
  • At toxic doses: increased automaticity → arrhythmias
• Indirect (vagal): Bradycardia, decreased AV conduction - mediated via vagus nerve stimulation

• Oral bioavailability: ~70-80%
• Protein binding: ~25% (low)
• Half-life: 36-48 hours (prolonged in renal failure)
• Elimination: primarily renal (dose reduction needed in renal insufficiency)
• Narrow therapeutic index: therapeutic level 0.5-2 ng/mL

• CHF with atrial fibrillation (drug of choice - slows ventricular rate + improves contractility)
• Systolic CHF (HFrEF) - reduces hospitalizations but does not reduce mortality (DIG trial)
• Atrial flutter/fibrillation for rate control

• Hypokalemia (most important - K⁺ competes with digoxin at Na⁺/K⁺-ATPase)
• Hypomagnesemia, hypercalcemia, hypothyroidism
• Renal failure, old age, quinidine co-administration (displaces digoxin)

• Withhold digoxin
• Correct hypokalemia (KCl IV - if K⁺ is low and no AV block)
• Lignocaine / Phenytoin for ventricular arrhythmias
• Atropine for bradycardia
• Digoxin-specific antibody fragments (Digibind/DigiFab) - definitive antidote for severe toxicity

2. Beta-Adrenoceptor Agonists

3. Phosphodiesterase Inhibitors (Bipyridines)

4. Calcium Sensitizers

• Sensitizes troponin complex to Ca²⁺ → enhanced contractility without increasing intracellular Ca²⁺
• Also inhibits PDE and causes vasodilation
• Approved in several countries (not USA) for acute HF
• Advantage: less arrhythmogenic than digitalis

B. NON-INOTROPIC DRUGS (First-line for Chronic CHF)

These are the cornerstone of CHF management and improve survival.

1. Diuretics

• Reduces preload by reducing venous return and blood volume
• Rapid IV action in acute pulmonary edema
• Also causes venodilation (independent of diuresis)

• Block aldosterone receptors → reduce Na⁺ retention, prevent myocardial fibrosis, reduce baroreceptor dysfunction
• Reduce morbidity and mortality in severe CHF (RALES trial for spironolactone, EPHESUS for eplerenone)
• Use in NYHA class II-IV when CrCl >30 mL/min and K⁺ <5 mmol/L
• Finerenone - newer non-steroidal MRA with lower hyperkalemia risk

2. ACE Inhibitors (First-line, All Stages of CHF)

• ↓ peripheral resistance → ↓ afterload (easier for failing heart to pump)
• ↓ aldosterone → ↓ Na⁺/water retention → ↓ preload
• ↓ sympathetic activity (AngII promotes NE release presynaptically)
• Prevent and reverse cardiac remodeling (key long-term benefit)
• Reduce mortality, hospitalizations, and slow progression (CONSENSUS, SOLVD trials)

3. Angiotensin Receptor Blockers (ARBs)

• Used when patients cannot tolerate ACEi (due to cough)
• Similar benefits to ACEi in reducing mortality and hospitalization
• Do not cause cough (no bradykinin effect)
• Do not combine ACEi + ARB in CHF (increased renal adverse effects without added mortality benefit)

4. ARNI - Sacubitril/Valsartan (Entresto) ★ New Standard of Care

5. Beta-Blockers (Paradoxically Beneficial in Chronic CHF)

• Prevent catecholamine-mediated myocardial toxicity and remodeling
• Reduce heart rate → more diastolic filling time
• Anti-arrhythmic (reduce sudden death)
• Reduce wall stress

6. Vasodilators

• Hydralazine: arteriolar dilator → ↓ afterload
• ISDN: venodilator → ↓ preload
• Used particularly in African-American patients with NYHA III-IV on standard therapy (A-HeFT trial)
• Also used when ACEi/ARBs are contraindicated (e.g., renal failure, pregnancy)

• Recombinant BNP → vasodilation + diuresis via ↑ cGMP
• IV use in acute CHF; reduces filling pressures
• Large trials (ASCEND-HF) failed to show mortality reduction; risk of hypotension and renal toxicity - used with caution

7. SGLT2 Inhibitors ★ (Newest Addition)

8. Ivabradine

Treatment Algorithm for HFrEF (Chronic Systolic CHF)

1. ACEi / ARB or ARNI (Sacubitril/Valsartan)
2. Beta-blocker (Carvedilol / Bisoprolol / Metoprolol succinate)
3. MRA (Spironolactone / Eplerenone)
4. SGLT2 inhibitor (Empagliflozin / Dapagliflozin)

Drugs for Acute Decompensated CHF (Acute Pulmonary Edema)

Summary Table: Drugs Improving Survival in CHF