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2nd MBBS Pharmacology - Cardiovascular Drugs

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics, Lippincott Illustrated Reviews: Pharmacology, Katzung's Basic & Clinical Pharmacology, Braunwald's Heart Disease

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1. Nitroglycerin (Glyceryl Trinitrate / GTN)

Mechanism of Action

1. GTN enters vascular smooth muscle and is converted to NO (bioactivation requires mitochondrial aldehyde dehydrogenase, ALDH2).
2. NO activates soluble guanylyl cyclase (sGC), which converts GTP to cGMP.
3. Elevated cGMP activates protein kinase G (PKG), which:
   • Reduces myosin light chain kinase (MLCK) activity
   • Increases myosin light chain phosphatase activity
   • Reduces intracellular Ca²⁺
4. Result: vascular smooth muscle relaxation and vasodilation

Antianginal MOA - Reduction of O₂ Demand

Key fact: When GTN is injected directly into the coronary artery, it does NOT abort anginal pain, confirming that its major effect is preload reduction, not direct coronary dilation. - Goodman & Gilman

Therapeutic Uses

1. Stable angina (exertional) - sublingual GTN for acute relief
2. Unstable angina (ACS) - IV nitroglycerin for ongoing ischemia
3. Vasospastic (Prinzmetal's) angina - directly relieves coronary spasm
4. Acute left ventricular failure / pulmonary edema - venodilation reduces preload and pulmonary congestion; IV dose 20-400 µg/min
5. Hypertensive emergencies - IV nitroglyerin for BP control
6. Acute MI - reduces preload and myocardial O₂ demand
7. Esophageal spasm - smooth muscle relaxation (diagnostic/therapeutic)

Routes of Administration

Adverse Effects

1. Headache - most common; due to meningeal arterial dilation. Usually decreases after a few days of continued use.
2. Postural hypotension / dizziness / weakness - reflex tachycardia may occur
3. Flushing - facial/neck vasodilation (low doses can cause facial flush without systemic hypotension)
4. Reflex tachycardia - baroreceptor-mediated compensatory response to hypotension
5. Methemoglobinemia - at very high doses (more clinically relevant with sodium nitroprusside/amyl nitrite)
6. Bezold-Jarisch reflex - paradoxical bradycardia and hypotension with sublingual GTN (vagally mediated)
7. Nitrate tolerance - with continuous use (see below)
8. Nitrate dependence - withdrawal angina in industrial workers exposed chronically

Nitrate Tolerance

• Develops with repeated high-dose/continuous exposure
• Mechanisms: depletion of sulfhydryl groups, free radical generation, neurohumoral activation (RAAS, sympathetics), plasma volume expansion, ALDH2 inactivation
• Prevention: Nitrate-free interval of 8-12 hours daily (usually at night for exertional angina)
• Eccentric twice-daily dosing for ISDN maintains efficacy

Precautions and Contraindications

1. Sildenafil (and PDE5 inhibitors) - ABSOLUTE CONTRAINDICATION. Both increase cGMP; combined use causes severe, potentially fatal hypotension.
2. Hypovolemia - preload-dependent states; GTN worsens hypotension
3. Hypotension (SBP <90 mmHg) - contraindicated
4. Right ventricular infarction - RV depends on preload; GTN can cause severe hypotension
5. Hypertrophic obstructive cardiomyopathy (HOCM) - reduces preload, worsens outflow obstruction
6. Increased intracranial pressure / head injury - meningeal vasodilation worsens ICP
7. Closed-angle glaucoma - increases intraocular pressure
8. Autonomic dysfunction (e.g., diabetic autonomic neuropathy) - compensatory sympathetic response impaired; severe hypotension/syncope possible
9. Abrupt withdrawal - can precipitate rebound angina after chronic use

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2. Coronary Steal Phenomenon

Definition

Pathophysiology

• In ischemic zones: arterioles are already maximally dilated due to local autoregulatory factors (adenosine, CO₂, reduced O₂). They cannot dilate further.
• In normal zones: arterioles are not maximally dilated and retain vasodilatory reserve.

• Only the normal-zone vessels respond and dilate further
• Blood is preferentially redirected to the normal zones
• The ischemic zone loses flow → worsening ischemia

Normal zone: vasodilatory reserve present → DILATES → receives MORE blood
Ischemic zone: already maximally dilated → CANNOT dilate → receives LESS blood ("stolen")

Agents That Can Cause Coronary Steal

• Dipyridamole - major clinical example; inhibits adenosine uptake, causing widespread arteriolar dilation. Used in pharmacological stress testing precisely because it causes steal.
• Adenosine and regadenoson - both carry FDA black-box warnings for this effect
• Sodium nitroprusside - non-selective arteriolar/venous dilator; may cause steal in active MI
• Isoflurane - historic controversy in anesthetic practice (largely resolved; steal is possible but uncommon at clinical doses)

Clinical Significance

1. Dipyridamole stress test (pharmacologic stress echo/nuclear scan) exploits coronary steal to provoke ischemia in CAD patients - deliberately induces steal to detect vulnerable myocardium.
2. In unstable angina, inadvertent coronary steal from dipyridamole can precipitate MI.
3. In coronary artery fistulas, the fistula creates a steal by diverting blood away from the myocardium, causing angina.
4. Sodium nitroprusside is not recommended in acute MI patients because its non-selective vasodilation may induce steal.

Precautions

• Avoid dipyridamole in patients with unstable angina or severe CAD outside of controlled diagnostic settings
• Dipyridamole stress testing should be performed with resuscitation facilities available; aminophylline (adenosine receptor antagonist) is the antidote to reverse the effect
• Avoid drugs with non-selective arteriolar dilation in active MI

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3. Nifedipine vs. Verapamil - Compare and Contrast

Basic MOA (Common)

• Nifedipine binds to transmembrane segments of domains III and IV
• Verapamil binds to transmembrane segment 6 of domain IV (IVS6)
• Calcium influx blocked → smooth muscle relaxation (vasodilation) + decreased cardiac contractility/conduction

Comparison Table

Key Distinguishing Points (Exam Focused)

• Nifedipine = "vascular selective" → treats HTN and angina; causes reflex tachycardia; NO antiarrhythmic use
• Verapamil = "cardiac selective" → antiarrhythmic; constipation is hallmark ADR; DO NOT combine with β-blockers or use in AV block
• Verapamil is the prototype Phenylalkylamine; Nifedipine is the prototype Dihydropyridine
• Verapamil blocks both activated and inactivated T-type Ca²⁺ channels - frequency/use-dependent block
• Amlodipine (another DHP) is preferred over short-acting nifedipine in hypertension due to longer t½ (30-50 hours)

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4. Nitrates (as a Class)

Members

MOA (Class)

Therapeutic Uses (Class)

1. Stable angina - acute relief (SL GTN) and prophylaxis (ISDN, ISMN, transdermal GTN)
2. Unstable angina - IV GTN reduces ischemia and preload
3. Prinzmetal's (variant) angina - directly relieves coronary arterial spasm; drug of choice
4. Acute MI - IV GTN in first 24-48 hours reduces preload, wall stress, infarct size
5. Acute decompensated heart failure - venodilation rapidly reduces pulmonary congestion
6. Hypertensive urgency/emergency - IV GTN or ISDN
7. Esophageal spasm - smooth muscle relaxation
8. Pulmonary hypertension - inhaled NO in neonates
9. Anal fissures - topical GTN relaxes internal anal sphincter

Adverse Effects (Class)

Precautions (Class)

Nitrate-Free Interval Strategy

• Exertional angina: remove patch/omit night dose (patient sleeps without nitrate)
• Nocturnal / rest angina: omit daytime dose instead
• Always add another antianginal agent (β-blocker or CCB) to cover the nitrate-free period

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Summary for Exams:

• Nitrates/GTN: NO donor → cGMP → vasodilation (mainly venous); key contraindication = PDE5 inhibitors + RV MI
• Coronary steal: maximum arteriolar dilation in normal zones diverts blood from ischemic zones; caused by dipyridamole, adenosine; used in stress testing; dangerous in unstable angina
• Nifedipine: vascular-selective DHP; reflex tachycardia; no AV node effect; gingival hyperplasia; 18% ADR rate
• Verapamil: cardiac-selective; antiarrhythmic; constipation; AV block risk; dangerous with β-blockers + digoxin; 9% ADR rate