Heart Antianginal Agents (Chapter 46)

Overview

• Antianginal agents aim to improve blood delivery to the heart muscle in two main ways:

  • Dilating blood vessels (increase coronary blood flow and reduce afterload effects)

  • Decreasing the work of the heart, thereby reducing oxygen requirements

• Major classes of antianginal agents:

  • Nitrates

  • Beta-adrenergic blockers

  • Calcium channel blockers

  • Piperazine acetamide (ranolazine)

• Key overarching concepts:

  • The goal is to increase myocardial oxygen supply or decrease demand to relieve angina symptoms and prevent myocardial ischemia.

  • Choice of agent depends on angina type (stable vs variant), comorbid conditions (e.g., HF), and tolerability; some agents are specifically contraindicated in certain conditions (e.g., non-dihydropyridine CCBs in HF).

  • Practical considerations include onset/duration of action, routes of administration, and potential drug interactions or adverse effects (e.g., tolerance, QT prolongation).

Nitrates

• Drugs: isosorbide dinitrate, isosorbide mononitrate, nitroglycerin

• Mechanism of action:

  • Act directly on smooth muscle to cause relaxation and decreased muscle tone

  • Do not repair damaged vessels; instead improve flow in surrounding vessels where relaxation can occur

  • Main effect is a drop in blood pressure (BP) due to vasodilation

  • Resulting hemodynamic changes: decreased preload and decreased afterload, which reduces cardiac workload and myocardial oxygen demand

• Role in therapy:

  • Acute angina attacks: sublingual or buccal tablets, translingual spray, IV (bolus or infusion) for rapid relief

  • Prevention or prophylaxis: topical ointment or patch, transdermal systems; slow-release formulations for maintenance

  • Isosorbide dinitrate/mononitrate are often used orally for longer-term control

• Available forms and form-dependent kinetics (nitroglycerin):

  • Sublingual or buccal tablet

  • Translingual spray

  • IV forms: bolus or infusion

  • Transdermal patch

  • Topical ointment or paste

  • Transmucosal agent

  • Slow-release forms are also available

  • Onset of absorption, onset of action, and duration depend on the form used

• Isosorbide dinitrate and isosorbide mononitrate (oral forms):

  • Onset: 14 ext{--}45 ext{ minutes} (up to 4 ext{ h} with sustained release [SR])

  • Duration: 4 ext{--}6 ext{ h} (SR 6 ext{--}8 ext{ h})

• Contraindications/Cautions:

  • Anemia, hypotension, hypovolemia

  • Head trauma or cerebral hemorrhage

• Drug interactions:

  • Ergot derivatives decrease the effect of nitrates

  • Nitrates decrease effects of heparin

  • PDE-5 inhibitors: risk of significant hypotension and cardiovascular events when combined

• Side effects/Adverse effects (vasodilation-related):

  • CNS: headache (HA), dizziness, weakness

  • GI: nausea, sometimes other GI symptoms

  • Cardiovascular: hypotension, reflex tachycardia, possible angina during dose changes

  • Skin: flushing, pallor; transdermal patches may cause contact dermatitis

  • Others: tolerance can develop with continual use

• Interventions with nitrate administration:

  • Sublingual administration protocol:

  • Have the patient lie down or sit

  • Moisten the mouth

  • Place tablet under the tongue

  • Ensure the tablet fizzles (activation)

  • Dosing strategy for acute attacks: may repeat every 5 ext{ minutes}, up to 3 doses

  • Form-specific administration techniques should be followed

  • Acute attacks: sublingual/buccal tablets or translingual spray

  • Prevention: topical ointment or patch

  • Unstable angina or acute myocardial infarction (MI): IV forms are preferred

• Practical/clinical notes:

  • Avoid abrupt withdrawal to prevent angina rebound

  • Monitor BP and heart rate during titration, especially with IV forms

  • Consider nitrate tolerance; implement nitrate-free intervals when appropriate if clinically needed

• Special considerations:

  • Nitrates are often used in combination with other antianginals depending on patient profile and tolerance

Beta-Adrenergic Blockers (beta-blockers)

• Drugs: atenolol, metoprolol, propranolol, nadolol

• Mechanism of action:

  • Decrease cardiac output and cardiac oxygen consumption

  • Lower blood pressure (BP)

  • Reduce heart rate and myocardial contractility, thereby lowering oxygen demand

• Role in therapy:

  • Primarily for long-term management of stable angina

  • Not used for Prinzmetal (variant) angina

• Dosing and tolerability:

  • Generally, used at lower doses for angina prevention compared to hypertension (HTN)

  • Lower doses often lead to fewer side effects in angina management than HTN management

• Side effects/adverse effects (sympathetic blockade):

  • Fatigue, bradycardia, hypotension

  • Bronchospasm risk with non-selective agents in COPD/asthma (e.g., propranolol)

  • Potential sexual dysfunction; masking of hypoglycemia symptoms in diabetics (especially non-selective agents)

• Practical notes:

  • Assess comorbid conditions (asthma/CAD/diabetes) before initiating

  • Titrate slowly to minimize adverse effects; monitor HR and BP

Calcium Channel Blockers (CCBs)

• Drugs: amlodipine, diltiazem, nicardipine, nifedipine, verapamil

• Classes and distinctions:

  • Non-dihydropyridine CCBs: diltiazem, verapamil

  • Dihydropyridine CCBs: amlodipine, nifedipine, nicardipine

• Important note on HF: HF patients should avoid non-dihydropyridine CCBs due to further decreases in myocardial function

• Mechanism of action:

  • Decrease both preload and afterload, leading to reduced myocardial workload and oxygen consumption

• Indications/uses:

  • Useful for Prinzmetal (vasospastic) angina and chronic stable angina

• Side effects/adverse effects:

  • CNS: dizziness, fatigue, depression, headaches

  • GI effects (nausea, constipation in some agents)

  • Other: edema, flushing, palpitations; potential conduction abnormalities with certain agents

• Practical considerations:

  • Dihydropyridines are more vasodilatory and may cause edema; non-dihydropyridines have more effect on heart rate and conduction

  • Monitor for heart block or bradycardia with non-dihydropyridines, especially in combination with beta-blockers

Piperazine Acetamide Agent (Ranolazine)

• Drug: ranolazine (Ranexa) – extended-release (ER) tablet form

• Classification: Also a Class Id antiarrhythmic (see Chapter 45)

• Therapeutic role:

  • Antianginal benefits beyond traditional agents; can be used as add-on therapy for chronic angina

  • Additional metabolic effects: may decrease blood glucose levels in diabetic patients

  • Cardiovascular benefits: may decrease incidence of ventricular fibrillation (V-fib), atrial fibrillation (A-fib), and bradycardia in patients with chronic angina

• Mechanism of action:

  • Decreases workload of the heart, but exact mechanism is not well understood

• Cardiac electrophysiology considerations:

  • Prolongs the QT interval; avoid in patients with a prolonged QT or in combination with other QT-prolonging drugs

• Interactions/contraindications:

  • Caution with CYP3A inhibitors (P450) and combinations that affect ranolazine metabolism

• Practical notes:

  • Monitor QT interval and adjust concomitant QT-prolonging meds accordingly

  • Consider metabolic interactions in patients with diabetes or those taking multiple antiarrhythmic agents

Connections to foundational principles and real-world relevance

• The concept of reducing oxygen demand (via decreased preload/afterload and heart rate) complements strategies to increase oxygen supply (vasodilation and improved coronary flow).

• Choice of agent often reflects patient-specific factors: comorbid HF, risk of tachyarrhythmias, need for rapid symptom relief, likelihood of interactions with concomitant therapies (e.g., PDE-5 inhibitors, CYP enzyme inhibitors).

• Variant angina (Prinzmetal) specifically benefits from agents that reduce vasospasm (nitrates, certain CCBs) rather than relying solely on beta-blockers, which may worsen vasospasm in some cases.

• Practical pharmacotherapy considerations include monitoring for tolerance with nitrates, bradycardia with beta-blockers or non-dihydropyridine CCBs, and QT prolongation with ranolazine or other QT-prolonging drugs.

• Ethical/practical implications include ensuring proper patient education on routes of administration, recognizing potential for overdose or rebound angina, and balancing symptom relief with adverse effect profiles to maximize adherence and quality of life.

Notable numerical references (recap)

• Nitrate isosorbide dinitrate/mononitrate oral onset: 14 ext{--}45 ext{ minutes}

• Nitrate oral duration: 4 ext{--}6 ext{ hours} (SR: 6 ext{--}8 ext{ hours})

• Acute nitroglycerin dosing (sublingual): up to 3 imes 5 ext{ minutes} intervals if needed

• General concept: vasodilation leads to decreased preload and afterload, reducing myocardial oxygen demand

If you want, I can reorganize these notes into a printable one-page reference or expand any section with more examples or clinical scenarios to aid memorization.