Angina is chest pain or chest discomfort due to an imbalance between myocardial oxygen supply and demand.^1,2 Angina is a predictor of future cardiovascular events; therefore, angina treatment goals are to prevent myocardial infarction (MI) and death, and to alleviate symptoms of angina.^1-3 Antianginal drugs work by correcting the myocardial oxygen supply and demand ratio.³

This article focuses on antianginal drug classes and oral antianginal drugs used to treat angina. Additional therapies to prevent cardiovascular events should be started according to guidelines.¹

Antianginal Drugs: Beta Blockers

Antianginal beta blockers decrease myocardial oxygen demand by decreasing contractility and heart rate and reducing total peripheral resistance.⁴ Beta blockers are classified as either cardio-selective or non-selective. Cardio-selective beta blockers have a greater affinity for beta₁ receptors with additional beta₂ receptor inhibition at higher doses while non-selective options have an affinity for beta₁, beta₂, and alpha₁ receptors.⁵

Beta blockers are effective in treating stable angina; however, not all beta blockers are FDA approved for this indication.² Beta blockers can worsen symptoms of vasospastic angina and severe peripheral arterial disease.⁴

Side effects include hypotension, exercise intolerance, bradycardia, fatigue, and insomnia.^3,4,5 Beta blockers can mask the symptoms of hypoglycemia in people with diabetes.^3,4,5Bronchospasm can occur, therefore use cautiously in individuals with severe obstructive airway disease.^5,6 Taper beta blockers to avoid beta-blocker withdrawal, which increases the risk of an acute MI.⁴

Beta blockers are contraindicated in those with Raynaud’s phenomenon, pre-existing heart block, sinus bradycardia, cardiogenic shock, sick sinus syndrome without a pacemaker, and heart failure.^4,7,9,11 Beta blockers in combination with verapamil or diltiazem can cause symptomatic bradycardia, excessive fatigue, and heart block.^4,6,9

Cardio-selective Antianginal Beta blockers

Atenolol

Atenolol is not metabolized by the liver.⁹ Dosing starts at 50 mg orally once a day and can be titrated up to 200 mg daily.⁹ Atenolol is renally excreted requiring dose adjustments for CrCl < 35.⁹

In addition to the class side effects of beta blockers, atenolol can also cause cold extremities, dizziness, and depression.⁹ Atenolol crosses the placenta and can harm the fetus; therefore, it is pregnancy category D.⁹ Use caution in nursing mothers as atenolol is excreted in breast milk.⁹

Metoprolol

Metoprolol is hepatically metabolized through CYP2D6.^6,10 Medications that inhibit or induce this enzyme system will alter plasma concentrations of either drug, which may require dose adjustments. Metoprolol is contraindicated in those that have, or are suspected to have, pheochromocytoma.^6,10

Metoprolol can mask clinical signs of hyperthyroidism. People who are at risk of developing thyrotoxicosis should be managed carefully as abrupt discontinuation can precipitate a thyroid storm.^6,10

Additional adverse events include dizziness, depression, cold extremities, diarrhea, and rash.
Dosing recommendations are:

Metoprolol tartrate⁸: 100 to 400 mg orally daily in divided doses
Metoprolol succinate¹⁰: 100 to 400 mg orally once daily

Regardless of the formulation, doses should be titrated up as tolerated. People may experience worsening cardiac failure during the titration.¹⁰

Non-selective Beta blockers

Propranolol

Propranolol is hepatically metabolized through CYP2D6,1A2 and 2C19.^7,11Propranolol may cause impotence, vivid dreams, and worsen symptoms of depression.^7,11

Dosing recommendations differ based on the formulation:

Immediate release⁵: 80 to 320 mg orally daily in divided doses 2 to 4 times per day
Extended release⁷: 80 to 320 mg orally once a day

Antianginal Drugs: Calcium Channel Blockers

Calcium channel blockers decrease myocardial oxygen demand and increase oxygen supply by causing coronary artery vasodilation, reducing total peripheral resistance, and decreasing heart rate and ventricular contractility.^4,12

Calcium channel blockers are classified as either non-dihydropyridine or dihydropyridines. Non-dihydropyridines have a greater effect on the myocardium compared to dihydropyridines.^3,4Calcium channel blockers treat stable and vasospastic angina; however, not all calcium channel blockers are FDA-approved for these indications.^2,12

Calcium channel blockers are contraindicated in sick sinus syndrome without a pacemaker, severe hypotension, acute MI, and pulmonary congestion.¹² Peripheral edema is common, especially when starting therapy.^4,12

Dihydropyridine Calcium Channel Blockers

Dihydropyridine calcium channel blockers mainly cause peripheral vasodilation.¹³ Side effects include lightheadedness, headache, and flushing.^4,12,13

Monitor individuals with severe obstructive coronary artery disease closely during initiation and dose titration due to the increased risk of worsening angina or acute MI.^13,14 Beta blockers can be used to help overcome dihydropyridine-induced tachycardia.^3,4

Amlodipine

Amlodipine has a long half-life, 30 to 50 hours, which increases in individuals with hepatic impairment.¹³ Steady state is reached in 7 to 8 days of consecutive dosing.¹³ Higher doses had more incidences of headache and edema compared to lower ones.¹³ Other side effects include fatigue, nausea, somnolence, and abdominal pain.¹³

Amlodipine dosing is 5 to 10 mg orally once a day, with a lower starting dose of 2.5 mg in individuals with hepatic impairment, and in the elderly.¹³ Amlodipine is pregnancy category C and is not recommended when nursing.¹³

Nifedipine

Nifedipine is hepatically metabolized through CYP3A4.¹⁴ Administration with strong CYP3A4 inducers is not recommended. Nifedipine should not be used in cardiogenic shock. Peripheral edema, the most common adverse event, is dose related to higher doses having more incidents.¹⁴ Fatigue, weakness, nausea, and constipation are other common adverse events.¹⁴

Dosing for the extended-release formulation is 30 to 60 mg orally once daily.¹⁴ Monitor patients for excessive hypotension during initiation and dose titration, especially if the individual is also on a beta blocker.¹⁴ Nifedipine is pregnancy category C and is not recommended when breastfeeding.¹⁴

Short-acting nifedipine should be avoided due to increased risk of cardiac events and death when used.^1,4,16

Non-dihydropyridine Calcium Channel Blockers

Non-dihydropyridines slow myocardial conduction and contractility due to inhibition at the SA and AV nodes.¹²Because of these actions, non-dihydropyridines can worsen cardiac output and bradycardia, thus avoid in those with 2^ndand 3^rd-degree heart block and heart failure with a reduced ejection fraction.^3,4,12 Concurrent use with a beta-blocker is not recommended.^4,6,8

People with Wolff Parkinson White syndrome or wide complex tachycardia should not receive verapamil or diltiazem.^15,17 Although rare, incidents of gingival hyperplasia have been reported.²

Verapamil

Verapamil can be used to treat unstable angina.¹⁵ There have been reports of verapamil causing 1^st-degree heart block.¹⁵ Use caution in people with hypertrophic cardiomyopathy with an outflow tract obstruction especially those with high gradients, sinus bradycardia, and advanced heart failure.¹⁵ Verapamil can cause hypotension and thus should be avoided in people who are severely hypotensive (systolic blood pressure < 90 mmHg) or those in cardiogenic shock.¹⁵

Additional adverse events include severe constipation, dyspnea, peripheral edema, and fatigue.^2,15 Angina dosing for verapamil is 80 to 160 mg orally three times a day of the immediate release formulation.¹⁵ Verapamil is metabolized by the liver; therefore, those with liver impairment should start at a lower dose and titrated up as tolerated.¹⁵Verapamil, pregnancy category C, can cross the placenta causing adverse effects on the fetus.¹⁵

Diltiazem

Diltiazem is a potent coronary artery vasodilator and is hepatically metabolized through CYP3A4.^3,17,18 Acute hepatic injuries have been reported which resolved with drug discontinuation.¹⁷ Diltiazem is contraindicated in severe hypotension and acute MI with pulmonary edema.^17,18

Although rare, erythema multiforme and/or exfoliative dermatitis have been reported.¹⁸ More common side effects include headaches, edema, nausea, dizziness, weakness, and generalized rash.^17,18

Diltiazem is available in multiple dosage forms and strengths with pharmacokinetics differing for each one. It is recommended to refer to specific product information as dosing varies.

Antianginal Drugs: Nitrates

Low-dose nitrates cause venodilation, thus decreasing preload while high doses lead to arterial vasodilation.³ The latter mechanism decreases afterload, with both mechanisms resulting in a reduction in myocardial oxygen demand.^1,4 Nitrates effectively treat all forms of angina.⁴

Headache, palpitations, flushing, and hypotension are side effects.⁴ Reflex tachycardia can occur due to reduction of afterload.³ Nitrates should be avoided in people with severe aortic valvular stenosis and used cautiously with those in hypertrophic obstructive cardiomyopathy.^1,4

People who take long-acting nitrates must have a nitrate-free period of 10 to14 hours per day to help prevent tolerance.^4,19 Anginal symptoms may occur during that time.²⁰ Abrupt discontinuation can intensify angina.⁴

Short-acting Antianginal Nitrates

Short-acting nitroglycerin is available as sublingual tablets, sprays, ointments, and powders, and is used for prevention and treatment of acute anginal symptoms.^1,2,4,8 Onset of action is 2 to 5 minutes with effects lasting 15 to 30 minutes.⁴ Nitrate tolerance doesn’t develop with short-acting products.⁴ Dosing varies depending on the product.

Long-acting Antianginal Nitrates

Long-acting nitrates in combination with 5-PDE inhibitors such as sildenafil, can cause excessive hypotension.^2,4 Nitroglycerin is available as extended-release capsules and patches for treating angina.⁴

Isosorbide

Isosorbide should not be used in individuals who have an allergy to another nitrate and people with right ventricular infarction or hypertrophic cardiomyopathy since isosorbide decreases the preload.²⁰

In addition to the above side effects, isosorbide can cause nausea, vomiting, dizziness, lightheadedness, and syncope.²⁰ There are two salt formulations of isosorbide available that differ in pharmacokinetics and dosing.

Isosorbide dinitrate has an onset of 15 to 30 minutes with effects lasting 4 to 6 hours.²⁰ Dosing for the dinitrate formulation is 10 to 40 mg orally three times a day.²⁰

Isosorbide mononitrate, an active metabolite of isosorbide dinitrate, has an onset of 30 minutes with effects lasting 6 to 10 hours.^4,20 Dosing for isosorbide mononitrate depends on formulation:

Immediate release: 20 mg orally twice daily
Extended release: 30 to 120 mg orally once a day

Antianginal Drugs: Late Sodium Current Blockers

Ranolazine, a late sodium current-blocker, reduces oxygen demand by indirectly decreasing myocardial calcium influx thus reducing ventricular wall tension.^{4, 21}Ranolazine has minimal effects on blood pressure and heart rate.^4,21 Side effects include constipation, nausea, headache, and dizziness.^4,19 Although rare, ranolazine-induced myopathy can occur.²¹

Ranolazine is hepatically metabolized through CYP3A4 and 2D6.^4,19 Hepatic impairment and renal failure (CrCl < 30) increases ranolazine concentrations warranting discontinuation or a dose adjustment.⁴ Ranolazine can prolong the QT interval.^4,19Ranolazine is started at 500 mg orally twice a day. Dose can be titrated up to 1000 mg twice daily if tolerated and there are no antianginal drugs interactions limiting max dose.^19,21

Antianginal Drugs in Summary

In summary, antianginal drugs vary in mechanism of action, side effects, and contraindications. Angina treatment with antianginal drugs should be individualized based on the patient’s medical history and drug-specific information.⁸

References

1. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM Guidelines for Management of Patients with Chronic Stable Angina: Executive Summary and Recommendations. Circulation. 1999;99:2829-2848.

2. Kloner RA, Chaitman B. Angina and its Management. J Cardiovascular Pharmacology and Therapeutics. 2017;22(3):199-209.

3. Balla C, Pavasini R, Ferrari R. Treatment of Angina: Where are we? Cardiology. 2018;140:52-67.

4. Fihn, SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164.

5. Khashayar F, Arif J. Beta Blockers. In:StatPearls. NCBI Bookshelf version. StatPearls Publishing; 2022. Accessed September 9, 2022.

6. Lopressor (metoprolol tartrate). Package Insert. In: Novartis Pharmaceutical Corp.;2008.

7. Propranolol. Package Insert. In: Akrimax Pharmaceuticals;2010.

8. Rousan TA, Thadani U. Stable Angina Medical Therapy Management Guidelines: A Critical Review of Guidelines from the European Society of Cardiology and National Institute of Health and Care Excellence. Eur Cardiol Rev. 2019;14(1):18-22.

9. Tenormin (atenolol). Package Insert. In: AstraZeneca; 2011.

10. Toprol XL (metoprolol succinate). Package Insert. In: AstraZeneca;2009.

11. Propranolol hydrochloride extended release capsules. Package Insert. In: Rouses Point Pharmaceuticals;2010.

12. McKeever RG, Hamilton RJ. Calcium channel blockers. In:StatPearls. NCBI Bookshelf version. StatPearls Publishing; 2022. Accessed September 9, 2022.

13. Amlodipine. Package Insert. In: Pfizer; 2011.

14. Nifedipine. Package Insert. In: Cadila Healthcare limited;2019.

15. Fahie S, Cassagnol M. Verapamil. In:StatPearls. NCBI Bookshelf version. StatPearls Publishing; 2022. Accessed September 9, 2022.

16. Kannam JP, Aroesty JM, Gersh BJ. Chronic Coronary Syndrome: Overview of Care. UptoDate, June 3, 2021. Accessed: September 8, 2022.

17. Talreja O, Cassagnol M. Diltiazem. In:StatPearls. NCBI Bookshelf version. StatPearls Publishing; 2022. Accessed September 9, 2022.

18. Diltiazem. Package Insert. In: Valeant Pharmaceuticals;2014.

19. Ranolazine. Package Insert. In: Gilead Sciences, Inc;2010.

20. Balasubramanian S, Chowdhury YS. Isosorbide. In:StatPearls. NCBI Bookshelf version. StatPearls Publishing; 2022. Accessed September 9, 2022.

21. Reed M, Kerndt CC, Gopal S, Nicolas D. Ranolazine. In:StatPearls. NCBI Bookshelf version. StatPearls Publishing; 2022. Accessed September 9, 2022.

Author Bio

Emilie White, PharmD is a residency trained, clinical pharmacist and medical writer. She has practiced pharmacy for over a decade in various hospital settings. Her clinical practice areas of interest include critical care, infectious diseases, and autoimmune disorders.