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Classification of Antihypertensive Drugs

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ANTIHYPERTENSIVE DRUGS - CLASSIFICATION

A. Diuretics

B. Renin-Angiotensin System (RAS) Inhibitors

C. Sympathetic Inhibitors

D. Calcium Channel Blockers (CCBs)

E. Vasodilators

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AT1 Receptor Blockers (ARBs / Sartans) - Detailed Discussion

1. Background and Drugs Available

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2. Mechanism of Action

The Renin-Angiotensin System (RAS) Pathway

Liver → Angiotensinogen
         ↓ (Renin, from kidney)
    Angiotensin I
         ↓ (ACE - in lungs)
    Angiotensin II
         ↓
   AT1 Receptor    +    AT2 Receptor

AT1 Receptor Effects (Harmful - blocked by ARBs)

1. Vasoconstriction - vascular smooth muscle contraction → ↑ peripheral resistance → ↑ BP
2. Aldosterone secretion (adrenal gland) → ↑ Na+ and water retention → ↑ preload → ↑ BP
3. ADH release (posterior pituitary) → water retention
4. Sympathetic stimulation → ↑ heart rate and contractility
5. Cardiac and vascular remodeling - hypertrophy, fibrosis, proliferation, apoptosis

AT2 Receptor Effects (Beneficial - unblocked by ARBs)

• ↑ Bradykinin (BK) → ↑ Nitric Oxide (NO) → ↑ cGMP → Vasodilation
• Natriuresis
• Anti-proliferative and anti-fibrotic effects

Net Result of ARB Action

Key distinction from ACE inhibitors: ACE inhibitors block ALL Ang II production (including via chymase). ARBs selectively block AT1 receptors while allowing residual Ang II to stimulate the beneficial AT2 receptor. They also do NOT accumulate bradykinin, hence no cough.

• Katzung's Basic and Clinical Pharmacology, 16e, p. 482

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3. Pharmacological Effects - Organ by Organ

Blood Vessels

• Vasodilation → ↓ peripheral resistance → ↓ BP
• Reduced vascular remodeling and endothelial dysfunction

Heart

• ↓ Preload (via Na+/water retention blockade) and ↓ afterload (vasodilation)
• ↓ Cardiac workload → reduces symptoms in heart failure
• Anti-remodeling effect: prevents hypertrophy and fibrosis
• Improves heart failure outcomes

Kidneys

• Dilates efferent arterioles > afferent arterioles → ↓ intraglomerular pressure
• ↓ Proteinuria → renoprotective in diabetic nephropathy
• RENAAL trial: Losartan reduced ESKD risk by 28% in type 2 diabetic nephropathy
• IDNT trial: Irbesartan reduced serum creatinine doubling by 33% vs placebo
• Brenner and Rector's The Kidney, p. 2595

Adrenal Gland

• ↓ Aldosterone secretion → ↓ Na+ and water retention, ↓ K+ loss (mild potassium sparing)

Brain

• ↓ Sympathetic outflow
• Possibly beneficial in dementia and stroke prevention (ongoing research)

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4. Clinical Uses

• Braunwald's Heart Disease, p. 1575-1579

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5. Adverse Effects

Advantages over ACE Inhibitors

• No dry cough (most important clinical difference - because no bradykinin accumulation)
• No significant increase in bradykinin
• Much rarer angioedema

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6. Contraindications

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7. Comparison: ARBs vs ACE Inhibitors

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8. Key Points to Remember

1. ARBs block AT1 receptors → prevent ALL harmful effects of Ang II
2. AT2 receptor stimulation remains intact → additional vasodilation and anti-proliferative benefits
3. They do NOT inhibit ACE and do NOT increase bradykinin → no cough (most tested MCQ point)
4. Renoprotection is partially blood-pressure-independent (shown in RENAAL and IDNT trials)
5. Should not be combined with ACE inhibitors routinely - dual RAAS blockade increases adverse effects without adding benefit (ONTARGET trial)
6. Telmisartan has the longest half-life and some PPARγ agonist activity (potential metabolic benefits)

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GTU B.Pharm Pharmacology II (BP502TP)

Q. Classify Antihypertensive Drugs. Discuss in detail the Mechanism of Action, Uses, and Adverse Effects of AT1 Receptor Blockers (Sartans/ARBs).

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PART A: CLASSIFICATION OF ANTIHYPERTENSIVE DRUGS

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I. DIURETICS

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II. RENIN-ANGIOTENSIN SYSTEM (RAS) INHIBITORS

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III. SYMPATHETIC INHIBITORS

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IV. CALCIUM CHANNEL BLOCKERS (CCBs)

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V. VASODILATORS

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PART B: AT1 RECEPTOR BLOCKERS (ARBs / SARTANS)

Definition

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Drugs in this Class (with Duration of Action)

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MECHANISM OF ACTION

Step 1: Understanding the Renin-Angiotensin System (RAS)

LIVER
  ↓ produces
Angiotensinogen
  ↓ Renin (from kidney juxtaglomerular cells)
Angiotensin I
  ↓ ACE (Angiotensin Converting Enzyme, in lungs)
Angiotensin II
  ↓              ↓
AT1 Receptor    AT2 Receptor
(harmful)       (beneficial)

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Step 2: Effects of Ang II via AT1 Receptor (Normal Physiology)

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Step 3: How ARBs Work

Angiotensin II
      ↓
 ARB blocks →  AT1 Receptor  [BLOCKED]
                   ✗
No vasoconstriction
No aldosterone secretion
No ADH release
No sympathetic stimulation
No cardiac remodeling
→ ↓ BP

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Step 4: The AT2 Receptor Advantage (Key Pharmacological Point)

• When AT1 is blocked → renin is disinhibited (feedback mechanism) → Ang II levels RISE in blood
• This excess Ang II now preferentially stimulates the AT2 receptor (which ARBs do NOT block)

AT2 Receptor stimulation
  ↓
↑ Bradykinin (BK) → ↑ Nitric Oxide (NO) → ↑ cGMP
  ↓
Vasodilation + Natriuresis + Anti-proliferation + Anti-fibrosis
  ↓
Additional ↓ BP + Cardioprotection

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Step 5: No Bradykinin Accumulation = No Cough

• ACE inhibitors block ACE → bradykinin is NOT broken down → accumulates → causes dry cough (in 10-20% patients)
• ARBs do NOT block ACE → bradykinin metabolism is unaffected → NO cough

This is the most important clinical difference between ARBs and ACE inhibitors.

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PHARMACOLOGICAL EFFECTS (Summary Table)

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USES / THERAPEUTIC INDICATIONS

1. Hypertension (Primary Use)

• First-line antihypertensive; efficacy equal to ACE inhibitors and CCBs
• Used as monotherapy or in combination with diuretics/CCBs
• Preferred in patients intolerant to ACE inhibitors (due to cough)

2. Heart Failure (HFrEF - Reduced Ejection Fraction)

• Used when ACE inhibitors are not tolerated
• Candesartan (CHARM trial) and Valsartan (Val-HeFT trial) reduce mortality and hospitalizations
• Reduce cardiac remodeling, ↓ preload and afterload

3. Diabetic Nephropathy

• Most important renal indication - reduces proteinuria and slows CKD progression in Type 2 DM
• Losartan - RENAAL trial: reduced ESKD risk by 28%
• Irbesartan - IDNT trial: reduced creatinine doubling by 33%
• Protection is partly independent of BP lowering

4. Chronic Kidney Disease (CKD) with Proteinuria

• Reduces intraglomerular hypertension → slows progression even in non-diabetic CKD

5. Post-Myocardial Infarction with LV Dysfunction

• Valsartan (VALIANT trial) - non-inferior to captopril post-MI
• Indicated when ACE inhibitors not tolerated

6. Left Ventricular Hypertrophy (LVH)

• Causes regression of LVH
• Losartan better than atenolol in regressing LVH (LIFE trial)

7. Prevention of Stroke

• Losartan reduced stroke risk in hypertensive patients with LVH (LIFE trial)

8. Marfan Syndrome

• Losartan reduces aortic root dilation - may be as effective as atenolol

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ADVERSE EFFECTS

Key Differences from ACE Inhibitors:

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CONTRAINDICATIONS

1. Pregnancy - Absolute contraindication (fetotoxic and teratogenic)
2. Bilateral renal artery stenosis - Can cause acute renal failure (↓ efferent tone → ↓ GFR severely)
3. Severe hyperkalemia (K+ >5.5 mEq/L)
4. History of hypersensitivity to any ARB
5. Concurrent use with ACE inhibitor + ARB + Aliskiren (triple RAAS blockade) - Not recommended (↑ adverse effects without added benefit)

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DRUG INTERACTIONS

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IMPORTANT EXAM POINTS (GTU Pharmacology II)

1. ARBs are called "Sartans" - all end in "-sartan"
2. They block AT1 receptor, NOT ACE enzyme
3. They do NOT cause cough (no bradykinin accumulation)
4. They allow beneficial AT2 receptor stimulation
5. Losartan is the prototype ARB
6. Contraindicated in pregnancy (fetotoxic)
7. Main adverse effects: hypotension, hyperkalemia, ↑ creatinine
8. Drug of choice in hypertension with diabetic nephropathy
9. Olmesartan-specific ADR: sprue-like enteropathy
10. NOT combined with ACE inhibitors routinely (dual RAAS blockade = more harm than benefit)

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