1 Anti-Angina

Review Materials: Antianginal Drugs

I. Overview

- Atherosclerotic disease of the coronary arteries is the most common cause of mortality worldwide.

- Coronary artery disease (CAD) or ischemic heart disease (IHD) can lead to stable angina or acute coronary
syndrome.

- Stable angina is characterized by sudden, severe chest pain that may radiate to other areas.

- Lifestyle modifications and management of risk factors are essential in reducing cardiovascular morbidity and
mortality.

- Medications used for the management of stable angina include b blockers, calcium channel blockers, organic
nitrates, and ranolazine.

II. Types of Angina

A. Stable Angina

- Common form characterized by short-lasting chest pain.

- Can present atypically in certain populations.

- Caused by reduced coronary perfusion due to atherosclerosis and increased myocardial oxygen demand.

- Promptly relieved by rest or nitroglycerin.

B. Unstable Angina

- Chest pain that occurs with increased frequency, duration, and intensity.

- Can be precipitated by progressively less effort.

- Symptoms not relieved by rest or nitroglycerin.

- Requires hospital admission and aggressive therapy to prevent progression to myocardial infarction (MI) and
death.

C. Prinzmetal Angina

- Uncommon pattern of episodic angina that occurs at rest.

- Due to decreased blood flow caused by coronary artery spasm.

- Promptly responds to coronary vasodilators like nitroglycerin and calcium channel blockers.

D. Acute Coronary Syndrome

- Emergency condition resulting from plaque rupture and thrombosis of a coronary artery.

- Can lead to necrosis of the cardiac muscle if left untreated.

- Classified as ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, or

III. Treatment Strategies

- Four types of drugs commonly used to manage stable angina: b blockers, calcium channel blockers, organic
nitrates, and ranolazine.

- These drugs help balance cardiac oxygen supply and demand.

- Treatment may vary based on concomitant diseases, and a treatment algorithm can guide therapy decisions for
stable angina.

Review Materials: Antianginal Drugs (Continued)

IV. β-Adrenergic Blockers

- β1-adrenergic blockers decrease myocardial oxygen demands by blocking β1 receptors, resulting in decreased
heart rate, contractility, cardiac output, and blood pressure.

- These agents reduce the frequency and severity of angina attacks.

- They are recommended as initial antianginal therapy in all patients, except those with vasospastic angina.

- β-Blockers also reduce the risk of death and myocardial infarction (MI) in patients with prior MI and improve
mortality in heart failure with reduced ejection fraction.

- Agents with intrinsic sympathomimetic activity (ISA) should be avoided in patients with angina and a history of
MI.

- Propranolol is the prototype, but cardioselective β-blockers like metoprolol and atenolol are preferred.

- β-Blockers should be avoided in severe bradycardia but can be used in patients with diabetes, peripheral
vascular disease, and chronic obstructive pulmonary disease, with close monitoring.

- Nonselective β-blockers should be avoided in patients with asthma, and discontinuation should be tapered
gradually over 2 to 3 weeks to avoid rebound angina, MI, and hypertension.

V. Calcium Channel Blockers

- Calcium channel blockers inhibit calcium influx into cardiac and smooth muscle cells, protecting the tissue.

- They primarily affect peripheral and coronary arteriolar smooth muscle, reducing vascular resistance and
afterload.

- Calcium channel blockers are effective in effort-induced angina by reducing myocardial oxygen consumption.

- They also relax coronary arteries, making them effective in vasospastic angina.

- Verapamil primarily affects the myocardium, while amlodipine has a greater effect on smooth muscle in the
peripheral vasculature. Diltiazem has intermediate actions.

- All calcium channel blockers lower blood pressure.

- Dihydropyridine calcium channel blockers include amlodipine and nifedipine. Short-acting dihydropyridines
should be avoided in coronary artery disease (CAD).

- Nondihydropyridine calcium channel blockers include verapamil and diltiazem. They slow atrioventricular
conduction, decrease heart rate, and have vasodilatory effects.

- Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction

- Diltiazem is useful in patients with variant angina but should be avoided in heart failure patients due to its
negative inotropic effects.
3 Anti-Angina

Review Materials: Antianginal Drugs (Continued)

VI. Organic Nitrates

- Organic nitrates are effective in stable, unstable, and variant angina.

A. Mechanism of Action

- Organic nitrates are converted to nitric oxide, which activates guanylate cyclase and increases cyclic guanosine
monophosphate (cGMP) synthesis.

- Elevated cGMP leads to vascular smooth muscle relaxation, reducing myocardial oxygen demand and dilating
coronary vasculature.

B. Pharmacokinetics

- Onset of action varies among nitrates, with sublingual nitroglycerin having the fastest onset.

- Nitroglycerin is commonly administered sublingually or transdermally to avoid hepatic first-pass effect.

- Isosorbide mononitrate has improved bioavailability and longer duration of action due to stability against
hepatic breakdown.

C. Adverse Effects

- Headache is the most common adverse effect.

- High doses can cause postural hypotension, facial flushing, and tachycardia.

- Combination with phosphodiesterase type 5 inhibitors is contraindicated due to the risk of dangerous
hypotension.

- Tolerance to nitrates develops rapidly, but it can be overcome by providing a daily "nitrate-free interval" to
restore sensitivity to the drug.

VII. Sodium Channel Blocker

- Ranolazine inhibits the late phase of the sodium current (late INa), improving the oxygen supply and demand
equation.

- It reduces intracellular sodium and calcium overload, improving diastolic function.

- Ranolazine has antianginal and antiarrhythmic properties.

- It is used when other antianginal therapies have failed.

- The antianginal effects of ranolazine are less in women than in men, but the reason for this difference is
unknown.

- Ranolazine is extensively metabolized in the liver and is subject to numerous drug interactions.

- It can prolong the QT interval and should be avoided with other drugs that cause QT prolongation.

Drug Class: β-Blockers

- Atenolol, Metoprolol, Propranolol

- Common Adverse Effects: Bradycardia, worsening peripheral vascular disease, fatigue, sleep disturbance,
depression, blunted awareness of hypoglycemia, inhibition of β2-mediated bronchodilation in asthma.

- Drug Interactions: Blunted effect with β2 agonists, additive effects with non-dihydropyridine calcium channel
blockers.

- Notes: β1 selective agents (atenolol, metoprolol) preferred, avoid agents with intrinsic sympathomimetic
activity (ISA) for angina therapy (pindolol).

Drug Class: Dihydropyridine Calcium Channel Blockers

- Amlodipine, Felodipine, Nifedipine

- Common Adverse Effects: Peripheral edema, headache, flushing, rebound tachycardia (immediate-release
formulations), hypotension.

- Drug Interactions: CYP3A4 substrate (increases drug concentration).

- Notes: Avoid short-acting agents as they can worsen angina (use extended-release formulations).

Drug Class: Nonhydropyridine Calcium Channel Blockers

- Diltiazem, Verapamil

- Common Adverse Effects: Bradycardia, constipation, exacerbation of heart failure, gingival hyperplasia
(verapamil), edema (diltiazem).

- Drug Interactions: CYP3A4 substrate (increases drug concentration), increases digoxin levels, additive effects
with β-blockers and other drugs affecting AV node conduction.

- Notes: Avoid in patients with heart failure, adjust the dose of both agents in patients with hepatic dysfunction.

Drug Class: Organic Nitrates

- Isosorbide dinitrate, Isosorbide mononitrate, Nitroglycerin

- Common Adverse Effects: Headache, hypotension, flushing, tachycardia.

- Drug Interactions: Contraindicated with PDE5 inhibitors (sildenafil and others).

- Notes: Ensure a nitrate-free interval to prevent tolerance.

Drug Class: Sodium Channel Inhibitor

- Ranolazine

- Common Adverse Effects: Constipation, headache, edema, dizziness, QT interval prolongation.

- Drug Interactions: Avoid use with CYP3A4 inducers (phenytoin, carbamazepine, St. John's wort) and strong
inhibitors (clarithromycin, azole antifungals) and agents that prolong QT interval (citalopram, quetiapine, and
others).

- Notes: No effect on hemodynamic parameters.

Additional Information:

- Anti-anginal drugs include β-blockers, calcium channel blockers, organic nitrates, and sodium channel blockers.

- Each drug class has specific medications with their respective brand names listed.
5 Anti-Angina

- The blood flow in a partially blocked coronary artery is explained in relation to angina.

- Various scenarios with different levels of obstruction are provided to understand angina development.