---

Cardiovascular Pharmacology - Complete Notes (2nd Year MBBS)

---

1. Calcium Channel Blockers (CCBs) - Classification, MOA, Adverse Effects, Precautions, Therapeutic Uses

Classification

• Verapamil - prototype; acts on heart > vessels

• Diltiazem - intermediate; acts on heart and vessels equally

• Nifedipine (prototype), Amlodipine, Felodipine, Nicardipine, Nimodipine, Isradipine, Lacidipine

---

Mechanism of Action (MOA)

1. Vascular smooth muscle - Prevents Ca²⁺ influx → vasodilation → reduced afterload
2. Cardiac muscle - Reduces contractility (negative inotropy)
3. SA node - Slows automaticity (negative chronotropy)
4. AV node - Slows conduction (negative dromotropy)

• Reduce afterload (peripheral vasodilation) → reduced O₂ demand
• Dilate coronary arteries (especially epicardial) → increased O₂ supply
• Relieve coronary vasospasm (Prinzmetal angina) - key advantage over beta-blockers
• Non-DHPs (verapamil, diltiazem) also reduce heart rate and contractility, reducing O₂ demand further

---

Compare: Dihydropyridines vs. Non-Dihydropyridines

---

Adverse Effects

• Flushing, headache, dizziness (due to vasodilation)
• Reflex tachycardia (especially short-acting nifedipine - dangerous)
• Peripheral edema (ankle swelling - most common complaint)
• Gingival hyperplasia (especially with nifedipine and amlodipine)

• Constipation (most common - blocks GI smooth muscle Ca²⁺ channels)
• Bradycardia, AV block, heart block
• Negative inotropy - worsens heart failure
• Hypotension

• Intermediate profile; bradycardia, AV block (less than verapamil)
• Ankle edema (less than DHPs)

• Hypotension
• Drug interactions: inhibit CYP3A4 (verapamil, diltiazem) - raises levels of cyclosporine, digoxin, statins

---

Precautions / Contraindications

• Verapamil/Diltiazem: Avoid in sick sinus syndrome, AV block (2nd/3rd degree), HF with reduced EF, combination with beta-blockers (risk of complete heart block)
• Nifedipine (short-acting): Avoid in unstable angina/acute MI - reflex tachycardia can be harmful
• All CCBs: Use with caution in hepatic impairment (high first-pass metabolism)
• Avoid verapamil + beta-blockers IV combination - can cause fatal bradycardia/asystole

---

Therapeutic Uses

1. Angina pectoris - all types (effort-induced + vasospastic)
2. Hypertension - DHPs preferred (amlodipine, felodipine)
3. Supraventricular tachyarrhythmias (SVT) - Verapamil, Diltiazem (IV)
4. Prinzmetal (vasospastic) angina - DHPs of choice
5. Hypertrophic cardiomyopathy - Verapamil
6. Raynaud's phenomenon - Nifedipine
7. Migraine prophylaxis - Verapamil
8. Subarachnoid hemorrhage - Nimodipine (crosses BBB, prevents cerebral vasospasm)
9. Preterm labor (tocolysis) - Nifedipine

---

2. Nitroglycerin (GTN) - MOA, Therapeutic Uses, Routes, Adverse Effects, Precautions

Mechanism of Action

• Predominantly venodilation (at low doses) - reduces preload (venous return) → reduces LV end-diastolic volume and pressure → reduces wall tension (by LaPlace's law) → reduces myocardial O₂ demand
• Arterial dilation (at higher doses) - reduces afterload
• Coronary artery dilation - especially epicardial vessels and collateral vessels → increases O₂ supply
• Redistributes blood flow to ischemic subendocardium

---

Routes of Administration

---

Therapeutic Uses

1. Acute angina attack - sublingual NTG drug of choice
2. Prophylaxis of angina - before exertion (sublingual), long-acting patches/oral forms
3. Acute MI (NSTEMI/STEMI) - IV NTG for ischemia relief (not proven mortality benefit)
4. Acute pulmonary edema - IV NTG (reduces preload)
5. Hypertensive urgency/emergency - IV NTG
6. Congestive heart failure - reduces preload
7. Esophageal spasm - smooth muscle relaxation
8. Anal fissure - topical NTG (relaxes internal anal sphincter)

---

Adverse Effects

1. Headache - most common; due to cerebral vasodilation (throbbing headache)
2. Postural hypotension / syncope - especially with first dose; more prominent on standing
3. Reflex tachycardia - can be prevented by beta-blocker combination
4. Flushing, dizziness
5. Methemoglobinemia - with high doses of IV nitrates (nitrite oxidizes hemoglobin Fe²⁺ to Fe³⁺)
6. Nitrate tolerance - develops with continuous use (transdermal patches, oral long-acting) due to depletion of sulfhydryl (-SH) donors and neurohormonal activation; prevented by nitrate-free interval of 8-12 hours/day (e.g., remove patch at night)

---

Precautions

• ABSOLUTE CONTRAINDICATION with PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) - synergistic hypotension, potentially fatal; minimum 24-48 hour gap required
• Avoid in hypotension (BP < 90 mmHg), hypovolemia
• Caution in right ventricular infarction (preload-dependent; nitrates can cause severe hypotension)
• Avoid in increased intracranial pressure (cerebral vasodilation worsens ICP)
• Caution in aortic stenosis (fixed outflow obstruction; hypotension risk)
• Store sublingual tablets in dark, airtight glass containers (degrade with light, heat, moisture)
• Tolerance management: use lowest effective dose, nitrate-free intervals

---

3. Nitrates - Classify, MOA, Adverse Effects, Precautions, Therapeutic Uses

Classification of Nitrates

• Nitroglycerin (GTN) - sublingual, spray
• Isosorbide dinitrate (ISDN) - sublingual

• Isosorbide dinitrate (ISDN) - oral, slow-release
• Isosorbide mononitrate (ISMN) - oral (active metabolite of ISDN, no first-pass metabolism)
• Nitroglycerin - transdermal patches, ointment, buccal
• Pentaerythritol tetranitrate (PETN)
• Erythrityl tetranitrate

MOA

• ISDN undergoes extensive first-pass metabolism; bioavailability ~25%
• ISMN is the active metabolite; bioavailability ~100%, twice-daily dosing preferred
• ISMN does not require hepatic bioactivation

Adverse Effects, Precautions, Therapeutic Uses

---

4. Nifedipine vs. Verapamil - Compare and Contrast

---

5. Coronary Steal Phenomenon

Definition

Mechanism

1. It dilates normal coronary arteries (which have intact endothelium and can respond to vasodilators)
2. The stenosed vessels and their resistance vessels are already maximally dilated due to ischemia - they cannot dilate further
3. Blood preferentially flows through the low-resistance, dilated normal vessels
4. Pressure in the collateral donor vessels falls → collateral blood flow to ischemic zone decreases
5. The ischemic zone receives less blood than before the vasodilator was given - hence "steal"

Drugs That Cause Coronary Steal

• Dipyridamole - works by increasing endogenous adenosine; classic cause of steal
• Adenosine - used in pharmacological stress testing
• Regadenoson - adenosine receptor agonist used in stress testing
• Hydralazine - less common

Clinical Significance

1. Pharmacological stress testing: Dipyridamole and adenosine are used as pharmacological stress agents (in patients who cannot exercise). They deliberately provoke coronary steal to unmask ischemia - seen as ST-segment depression or perfusion defects on imaging (SPECT, PET)
2. Complication risk: In patients with multivessel disease, these agents can cause severe ischemia or MI if not terminated promptly - hence reversal agent (aminophylline = adenosine antagonist) must be available
3. Explains why certain vasodilators are harmful in IHD: Indiscriminate use of potent non-selective vasodilators in CAD can worsen ischemia rather than relieve it

---

6. Myocardial Infarction - Drug Management (2nd yr MBBS Level)

Definition

Classification

• STEMI - ST elevation MI (complete occlusion, needs immediate reperfusion)
• NSTEMI - Non-ST elevation MI (subtotal occlusion)
• Silent MI - common in diabetics

Drug Management

A. IMMEDIATE (First Hour - "MONA" + antiplatelet mnemonic)

• IV morphine 2-4 mg (repeat as needed)
• Relieves pain and anxiety, reduces sympathetic activation
• Causes venodilation → reduces preload
• Caution: Can cause hypotension, nausea; use with care in RV infarct

• Only if SpO₂ < 90% (avoid routine O₂ as can worsen outcomes)
• High flow in hypoxic patients

• Sublingual NTG immediately
• IV NTG for ongoing ischemia, heart failure, hypertension
• Contraindicated in hypotension, RV infarct, recent PDE-5 inhibitor use

• 325 mg stat (chewed for rapid absorption), then 75-100 mg daily
• Irreversibly inhibits COX-1 → blocks TXA₂-mediated platelet aggregation
• Cornerstone of MI therapy - reduces mortality

• Clopidogrel 300-600 mg loading, then 75 mg/day (irreversible P2Y12 block)
• Ticagrelor 180 mg loading, then 90 mg BD (preferred in STEMI - faster onset, reversible)
• Prasugrel 60 mg loading, then 10 mg/day (avoid if prior stroke/TIA)
• DAPT (aspirin + P2Y12 inhibitor) for at least 12 months post-ACS/stenting

B. REPERFUSION THERAPY (STEMI)

• Streptokinase - 1.5 million units IV over 60 min (fibrin-non-specific, antigenicity)
• Alteplase (t-PA) - fibrin-specific, bolus + infusion
• Tenecteplase (TNK-tPA) - single IV bolus, preferred
• Reteplase - double bolus
• Contraindications: active bleeding, recent surgery, prior hemorrhagic stroke, severe uncontrolled HTN

• Heparin (UFH or LMWH) - anticoagulation during PCI
• GP IIb/IIIa inhibitors - tirofiban, eptifibatide (for high-risk NSTEMI/PCI)

C. ANTICOAGULATION

• Unfractionated heparin (UFH) - weight-based IV bolus + infusion; reversible with protamine
• Low molecular weight heparin (LMWH) - Enoxaparin 1 mg/kg SC BD; preferred for NSTEMI
• Fondaparinux - factor Xa inhibitor; preferred in NSTEMI (reduces bleeding risk)
• Bivalirudin - direct thrombin inhibitor; used during PCI

D. BETA-BLOCKERS

• Start within 24 hours in all STEMI/NSTEMI without contraindications
• Metoprolol, carvedilol, bisoprolol
• Benefits: reduce HR, reduce O₂ demand, anti-arrhythmic, prevent reinfarction, reduce mortality
• Contraindications: bradycardia (<60), hypotension, acute HF (wait for stabilization), AV block, reactive airway disease

E. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BLOCKERS

• ACE inhibitors - Ramipril, Lisinopril; start within 24-48 hr if EF < 40%, anterior MI, hypertension, diabetes
• Reduce LV remodeling, prevent progression to HF, reduce mortality
• ARBs - if ACE inhibitor intolerant (valsartan, losartan)
• Aldosterone antagonists - Eplerenone/spironolactone if EF ≤ 40% + HF symptoms or diabetes, already on ACEI + beta-blocker

F. STATINS (HMG-CoA Reductase Inhibitors)

• High-intensity statin therapy - Atorvastatin 40-80 mg or Rosuvastatin 20-40 mg
• Start immediately regardless of baseline LDL
• Pleiotropic effects (anti-inflammatory, plaque stabilization) + lipid lowering
• Target LDL < 70 mg/dL (< 55 mg/dL in very high risk)

G. ANTIARRHYTHMICS

• Lidocaine - IV for VT/VF not responding to defibrillation (not routine prophylaxis)
• Amiodarone - drug of choice for sustained VT or VF
• Atropine - for symptomatic bradycardia
• Temporary pacing - for complete heart block

H. ALDOSTERONE ANTAGONISTS

• Eplerenone or Spironolactone - within 3-14 days post-MI if EF ≤ 40% with symptoms of HF
• Reduces mortality (EPHESUS trial)

Summary Table - MI Drug Management

---

Quick Reference: Drugs in Angina (KD Tripathi Framework)

---