Beta-Blockers, Calcium Channel Blockers, Nitrates in CAD Management

General (including evidence of efficacy)

Management of coronary artery disease

Management of coronary artery disease (CAD) is multifaceted, including both invasive and noninvasive approaches. Among the mainstays of pharmacologic treatment, beta-blockers have proven to be both safe and efficacious in both stable CAD and in the treatment of acute coronary syndrome (ACS), reducing both CAD-associated morbidity and mortality.

Both calcium channel blockers and nitrates also are important adjunctive therapies in stable and symptomatic coronary artery disease. In the following, we will describe what a clinician needs to know with each therapy in the setting of stable and symptomatic CAD.

Beta-blockers

• Beta-blockers in the management of acute coronary syndrome (ACS)

  Early use of beta-blockers (i.e., within 24 hours) in the absence of contraindications (below) is recommended in the management of ACS as it decreases morbidity and mortality, reduces infarction size, and prevents ventricular fibrillation. In addition, if early contraindications are present, then readdressing the use of beta-blockers after 24 hours is recommended.

  Contraindications: (1) signs of heart failure or low output state; (2) severe bronchospasm; (3) prolonged P–R interval or advanced heart block

  Related Content

  IV beta blockade is recommended in hypertensive patients or patients with atrial fibrillation and rapid ventricular response presenting with ACS in the absence of the contraindications mentioned above.

  Recommendations

  Early use of beta blockade with the following agents: metoprolol, atenolol (both cardioselective to the beta 1 receptor), or propranolol (nonselective) have been shown to have benefit in both PO and IV forms in the setting of ACS and in the absence of contraindications. IV forms maybe of additional benefit in the setting of ACS and hypertension or atrial fibrillation with rapid ventricular rate. In addition, IV beta blockade is frequently used in ST elevation myocardial infarction (STEMI) and in the absence of contraindications.

  The mentioned medications all do not have intrinsic sympathetic activity, which may increase heart rate at rest and be harmful in this situation.

  Would choose cardioselective beta blockade if patient has comorbid chronic obstructive pulmonary disease (COPD) and/or reactive airway disease

• Beta-blocker in the management of stable coronary artery disease (CAD)

  Beta-blocker have been shown to improve mortality in patients with history of CAD and should be used for at least 3 years (class I recommendation) and potentially for life after an event

  Recommendations

  The type of beta-blocker depends on patient comorbidities, however, would recommend cardioselective beta-blockers (i.e., atenolol or metoprolol) for patients with COPD or reactive airway disease

  Titrate dose of beta-blocker to a resting heart rate of 55 to 60; however, antianginal efficacy is dose-dependent and cardioselective beta-blockers may lose their selectivity at higher doses

  May consider beta-blockers with intrinsic sympathetic activity for patients with resting bradycardia and likely unable to tolerate decreases in heart rate; however, this specific subclass of beta-blockers have been associated with an increase in CAD associated mortality.

Calcium channel blockers (CCB)

Nitrates

• CCBs in the management of acute coronary syndrome (ACS)

  Dihydropyridines (DHPs)

  Nifedipine – short-acting preparation, especially in doses above 60 mg, is contraindicated in ACS because of reflex tachycardia and worsening ischemia. Long-acting preparations do not have the same harmful effects; however, caution should be used in patients with heart failure.

  Amlodipine and felodipine have not been studied in ACS.

  Nondihydropyridine

  Verapamil and diltiazem – has shown greatest benefit in the setting of NSTEMI with preserved ejection fraction. Short-acting and long-acting preparations can be used when beta-blockers are absolutely contraindicated; in the absence of heart failure or AV conduction, abnormalities to control ongoing ischemia or atrial fibrillation/flutter with rapid ventricular rate in the setting of ACS.

  Recommendations

  Avoid nifedipine, especially short-acting preparation, in the setting of ACS

  Reserve use of CCBs to nondihydropyridines in the setting of beta-blocker intolerance/contraindications and (1) NSTEMI and (2) ACS (including STEMI) complicated by atrial flutter/fibrillation PLUS the absence of heart failure or AV conduction abnormalities. CCB in the management of stable CAD

• Nitrates in the management of acute coronary syndrome

  Sublingual nitrates – given in the emergency room setting for suspected acute coronary syndrome. Dosing is 0.4 mg and can be given up to three times, 5 minutes apart. Dosing can be reduced if limited by headache or hypotension.

  Intravenous nitrates – usually given if unresponsive to three doses of sublingual nitrates. Starting dose is 5 mcg/min and can be titrated up every 10 minutes by 5 to 20 mcg/min up to 400 mcg/min as long as systolic blood pressure (SBP) does not drop by 30 mm Hg or fall below 90 mmHg. Also indicated in the setting of ACS with heart failure, hypertension, or persistent chest pain. Can develop nitrate tolerance if given longer than 24 hours; however, prolonged administration is unlikely in the mechanical reperfusion era.

• Nitrates in the management of stable CAD

  Short-acting

  Sublingual nitrates – (onset of action 5 minutes with a 30-minute duration) given in the management of chronic stable angina. Dosing is 0.4 mg and if pain is unrelieved, then they can be given up to three times, 5 minutes apart. However, if pain is unrelieved after first dose, then the recommendation is to present to the nearest medical emergency facility (preferably with percutaneous coronary intervention (PCI) capabilities). Dose can be given prophylactically prior to exertion to increase exercise capacity. It can be given in a tablet or spray form.

  Long-acting

  Isosorbide mononitrate – (onset of action 30 to 60 minutes, immediate release, duration: 6 hours; extended release – duration: 12 to 24 hours). Immediate release dose start at 15 mg to 30 mg and given at least 8 hours apart to decrease tolerance. Extended release start at 30 mg and given daily also to decrease tolerance. Immediate release is limited by nitrate tolerance and rebound angina. Extended release can be used in combination with hydralazine for afterload reduction in cases of systolic dysfunction.

  Isosorbide dinitrate – (onset 15 to 30 minutes, duration 3 to 6 hours). Starting dose is 15 mg and can be given up to three times a day, at least 8 hours apart, to decrease tolerance. Decrease in anginal frequency and an increase in exercise capacity, especially after up to 3-hour doses are given; however, these effects seem to wear off later in the day.

  Transdermal nitroglycerin – (onset of action 30 minutes, duration: 8 to 14 hours). Starting dose is 0.2 mg/hr, and it is recommended to be given intermittently (every 12 hours, with a 12-hour nitrate free period) to decrease nitrate tolerance. Increases in exercise capacity have been observed; however, anginal frequency may increase in the patch free periods.

• Contraindications

  Hemodynamic instability – generally a systolic blood pressure of less than 90 mmHg or blood pressure that is markedly below baseline (>30 mm Hg) is a contraindication for nitrates. In addition signs of impending hemodynamic collapse, such as tachycardia or bradycardia, are also contraindications for nitrates.

  Recent phosphodiesterase inhibitor (PDEi) use—the use of PDEi within the last 24 to 48 hours—is also a contraindication given the resultant hypotension that occurs. Long-acting PDEi, such as tadalafil, should be noted given its relatively longer half-life compared to other PDEi (1/2 life approximately 18 hours)

  Right ventricular myocardial infarction – nitrites should be held in this situation given potential for hypotension/hemodynamic instability

  Left ventricular outflow obstructions – nitrates should be held in comorbid severe aortic stenosis (AS) or hypertrophic cardiomyopathy (HCM) given the potential for worsening outflow obstruction with HCM or hemodynamic collapse with severe AS.

• Recommendations

  Sublingual nitrates are recommended for both ACS and the management of stable CAD; it be used as a prophylactic agent prior to exercise in addition to treating anginal pain. Given its short half-life, it is not subject to tachyphylaxis. The need for more than one dose of sublingual nitroglycerin should be followed up with presentation to the nearest emergency room and further workup.

  Long-acting nitrates in addition are recommended for stable CAD and are all equally effective in increasing exercise time and reducing angina; however, their use is complicated by nitrate tolerance, requirement of nitrate free periods, and subsequent rebound angina/silent ischemia.

Differences between drugs within the class

Beta-blockers

• Cardioselectivity

  Selective for beta 1 receptor compared to nonselective to beta 1, beta 2, and alpha 1 receptors. Beta 1 receptors are located in the SA, AV nodes, and the atria/ventricles and act to decrease heart rate, contractility, and increase AV node conduction when blocked. Beta 2 receptors are located in the vascular and bronchial smooth muscles and increase contractility in their vascular beds when blocked. Cardioselective beta-blockers include atenolol, metoprolol, and nadolol.

• Intrinsic sympathetic activity

  Partial beta agonist activity, which is more pronounced when the patient is at rest, and sympathetic activity is low. It may have theoretical benefit in heart failure (i.e., increases contractility) and patients with bronchospasm; however, it has not been shown to be beneficial and may be harmful given increases in heart rate. Examples include pindolol and labetalol.

• Lipophilic

  Lipophilic has increased ability to cross the blood brain barrier and increases the likelihood of CNS adverse effects. Their half-life and the method of excretion also vary and need to be taken into consideration in the elderly and patients with compromised renal function. Metoprolol and propranolol are considered highly lipophilic, while atenolol is highly hydrophilic. Overall clinical studies have not shown increased incidence of fatigue or depressive symptoms.

• Alpha adrenergic antagonism

  Mainly an alpha 1 antagonism, causing peripheral and coronary vasodilatation. Carvedilol and labetalol are two examples of beta-blockers with alpha adrenergic activity.

Calcium channel blockers

• Dihydropyridine

  Has a higher affinity to the calcium channels in the peripheral vasculature, causing peripheral vasodilation leading to a higher incidence of peripheral edema, flushing, and headaches as a class effect.

  Short-acting nifedipine has a higher incidence of reflex tachycardia than long-acting preparations

  Second generation dihydropyridines (i.e., amlodipine and felodipine) have a lower incidence of the above side effects and are better tolerated.

• Nondihydropyridine

  Verapamil – acts mainly on the myocardial calcium channels, leading to negative inotropy and chronotropy. It may also act on the peripheral vasculature but is not as potent as dihydropyridines.

  Diltiazem – is a less potent vasodilator than DHPs and is a negative chronotrope and inotrope; however, it is not as potent as Verapamil. Therefore it is better tolerated than verapamil.

Nitrates

• Short-acting nitrates

  Lingual (sub, trans) – given in tablet or spray form. Rapid acting (within 3 minutes) and given its short half-life, nitrate tolerance is less likely.

  Intravenous – immediate acting; however, can develop nitrate tolerance if given longer than 24 hours.

• Long-acting nitrates

  Isosorbide mononitrate – immediate release duration of action for 6 hours and extended release acts within 12 to 24 hours

  Isosorbide dinitrate – extended release duration of action for 8 hours

  Transdermal nitroglycerin – duration of action for 12 hours

  All long-acting forms need a nitrate free period to decrease nitrate tolerance; however, there is a risk of rebound angina and silent ischemia

Administration

Beta-blockers

• Cardioselective

  Atenolol – PO, available in extended release (25 mg to 200 mg daily)

  Metoprolol – PO, available in immediate release (25 mg to 400 mg twice daily) or extended release (25 mg to 400 mg daily). IV dosing – 5 mg (can give up to three times during acute MI, 2 minutes apart, and start initial PO dosing if able to tolerate IV doses)

• Nonselective

  Propranolol – PO, available in immediate release (80 mg to 360 mg/day given 2 to 4 times/day). IV dosing – 0.5 to 1 mg, repeating if symptoms are uncontrolled or heart rate not controlled with a maximum dosing of 0.1 mg/kg

• Intrinsic sympathetic activity

  Pindolol – PO, available in immediate release (5 to 40 mg twice daily)

• Alpha adrenergic antagonism

  Carvedilol – PO, available in immediate release (3.125 mg to 25 mg twice daily) and extended release (10 mg to 80 mg daily)

  Labetalol – PO, available in immediate release (100 mg to 1200 mg twice daily). IV dosing – initial dosing 20 mg, if tolerated can give repeat boluses of 40 to 80 mg or infusion (2 mg/min initial infusion dosing). Maximum IV daily dosing is 300 mg/day.

Calcium channel blockers

• Dihydropyridines

  Nifedipine – PO, available in immediate release (20 to 60 mg three times a day) and extended release (60 mg/day to 180 mg/day)

  Nicardipine – PO, available in immediate release (20 to 40 mg three times a day), both extended release and IV formulation are indicated for hypertension and not FDA-approved for the treatment of angina.

  Amlodipine – PO, available in extended release (5 mg/day to 10 mg/day)

  Felodipine – PO, available in extended release (5 mg/day to 10 mg/day); however, it is not FDA-approved for the treatment of angina.

• Nondihydropyridine

  Verapamil – PO available in immediate release (40 mg to 160 mg three times a day) or extended release (180 mg/day to 480 mg/day). IV dosing – initial bolus 2.5 to 5 mg with repeat of 5 to 10 mg in 30 minutes if tolerated. Maximum daily dosing 20 to 30 mg/day.

  Diltiazem – PO available in immediate release (60 mg to 240 mg twice a day) or extended release (120 mg/day to 480 mg/day). IV formation (initial recommended bolus – 15 mg to 20 mg, repeat 20 mg to 25 mg after initial bolus. Initial infusion rate – 5 mg/hr, up to 15 mg/hr; however, infusion not recommended past 24 hours.

Nitrates

• Nitroglycerin

  Sublingual – initial dose 0.4 mg (dose range – 0.2 to 0.6 mg), up to three doses every 5 minutes for persistent symptoms. Dose can be given prophylactically prior to angina inducing activities. Dose can be reduced if not tolerated

  Translingual – 1 to 2 sprays under tongue (0.4 mg metered inhaled doses), up to three doses every 5 minutes for persistent symptoms. Dose can be given prophylactically prior to angina inducing activities.

  Transdermal – 0.2 to 0.4 mg/hr patches for 12 to 14 hours with nitrate free periods or 10 to 12 hours. Can titrate up to 0.4 to 0.8 mg/hr.

  Intravenous – initial 5 mcg/min and can titrate up by 5 mcg/min every 5 minutes up until 20 mcg/min. If 20 mcg/min does not control symptoms then can titrate up by 10 to 20 mcg/min every 5 minutes for a maximum infusion dosing 400 mcg/min.

• Isosorbide mononitrate (PO)

  Regular release – 5 to 20 mg taken 7 hours apart. Extended release – 30 mg to 240 mg daily.

• Isosorbide dinitrate (PO)

  Immediate release – 5 to 80 mg divided into 2 to 3 doses/day. Extended release – 40 mg to 160 mg daily

Pharmacologic action

Beta-blockers

This class of medication blocks the action of catecholamines (i.e., epinephrine and norepinephrine) on beta receptors. There are three different types of beta receptors (types 1-3).

• Beta-1 receptor is primarily located in the myocardium and activation causes an increase in contractility, AV node conduction, and a decrease in AV nodal refractory time leading to increases in heart rate. Blocking the effects of beta-1 leads to a decrease in oxygen demand and a decrease in anginal symptoms. Medications that selectively block the beta-1 receptor are “cardioselective.”

• Beta-2 receptors are located in the bronchial and peripheral smooth muscle cells. Activation causes vasodilation and blocking of this receptor will lead to bronchospasm.

• Beta-3 receptors are also located in the myocardium, but its role is unclear. However, it is thought to reduce inotropy when stimulated by catecholamines.

Calcium channel blockers

Dihydropyridines versus nondihydropyridine: Blocks entry of calcium through the voltage sensitive calcium channel (L type), preventing the influx of calcium into the cardiac myocyte and vascular smooth muscles by binding its alpha 1 subunit, consisting of 4 domains (I – IV) and each domain consists of 6 transmembrane subunits (S1 – S6). Dihydropyridines block the III and IV transmembrane domain while diltiazem blocks the cytoplasmic bridge between domain III and IV. Verapamil blocks domain IV at the S6 transmembrane subunits. Dihydropyridines has more vasodilatory effects while non-dihydropyridine have more negative inotropic and chronotropic effect.

Nitrates

Nitrates act mainly as a vasodilator through its action on the vascular smooth muscle cells (VSMC). Nitrates enter the VSMC and are converted to nitric oxide (NO) in addition to S-nitrosothiols, which activate guanylate cyclase. Guanylate cyclase converts guanosine 5′ triphosphate to cyclic guanosine monophosphate, which in turn acts to relax smooth muscle cells and contributes to vasodilation in the venous, arterial, and coronary vascular beds.

Contraindications and Side Effects

All agents have contraindications during vital sign instability (i.e., hypotension <90 mmHg, tachycardia >100 bpm, bradycardia <50 bpm)

Beta-blockers

Beta-blockers are rarely contraindicated in the setting of stable CAD management. Relative contraindications include:

• Nonselective beta-blockers have a relative contraindication in the setting of active bronchospasm or reactive airway disease

• Starting in the setting of active cocaine use

• Starting in the setting of prolonged P–R interval (>0.24 seconds) or high-degree AV block

• Starting/increasing dose during signs and symptoms of decompensated heart failure (see below)

There is no increased incidence of fatigue, sexual dysfunction, or depressive symptoms noted and beta-blockers are not contraindicated in patients with depression.

Calcium channel blockers

Calcium channel blockers are contraindicated in:

• Starting in the setting of prolonged P–R interval (>0.24 seconds) or high-degree AV block

• Starting/increasing dose during signs and symptoms of decompensated heart failure

Otherwise safe to use in the setting of beta-blocker contraindications (i.e., active bronchospasm or cocaine use) and has no noted potential for depression or fatigue

Nitrates

Nitrates are contraindicated in:

• Recent PDE inhibitor use (i.e., within 24 hours of sildenafil (Viagra) or vardenafil (Levitra) use and 48 hours of tadalafil (Cialis) use)

• Suspected right ventricular infarction

Undesirable effects

Beta-blockers

• Adverse Side Effect of Beta Blockers

  Cardiovascular – Adverse effects including the mentioned worsen bronchospasm, and cardiac output in the setting of heart failure decompensation. Additionally, discontinuation may worsen anginal symptoms.

  Metabolism – Furthermore, use may potentiate hypoglycemic episodes making it difficult to recognize and recover from them.

  CNS – there have been reports of associated depression, fatigue, and sexual dysfunction; however, it is equivocal

Calcium channel blockers

• Adverse Side Effects of CCB

  Edema – Dihydropyridines >> Nondihydropyridines (diltiazem > verapamil). Largely a side effect of dihydropyridine due to its vasodilatory effects.

  Depressed cardiac function – Nondihydropyridines depress cardiac function (diltiazem > verapamil) through slowing cardiac conduction and decreasing inotropy. These medications are relatively contraindicated in systolic dysfunction and may have increased adverse side effects when combined with beta blockers. May also worsen outcomes in the setting of systolic dysfunction post-ACS.

  Reflex tachycardia – short-acting preparation dihydropyridines, especially nifedipine. Contraindicated in ACS, as it may worsen outcomes due to this effect.

Nitrates

• Adverse Side Effects of Nitrate

  Are related to vasodilatory effects and include headache, dizziness, postural hypotension

Alternative approaches

• Alternative approaches include both pharmacologic and percutaneous interventions and are listed below.

  Coronary stents – which include bare metal stents and drug eluting stents; both indicated in the treatment of ACS and stable CAD optimally treated, however when the patient has intolerable anginal symptoms

  Ranolazine: (750 to 1,000 mg BID) inhibitor of late sodium influx channel, is useful in the treatment of angina refractory to above

  Antiplatelets: aspirin 81 to 162 mg/day for stable CAD and clopidogrel 75 mg/day if aspirin allergic; no benefit to dual antiplatelets in setting of stable CAD

  Statins – high potency statins (i.e., atorvastatin, rosuvastatin) with goal of an LDL level <70.

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