Calcium Channel Blockers: Mechanism, Indications & Treatment Principles

1. Chapter 19 Calcium Channel Blockers

2. Drug Overview • Calcium Channel Blockers • dihydropyridine (does not affect cardiac conduction system) • nifedipine (ER), amlodipine, felodipine, nicardipine, etc. • phenylalkylamine • verapamil • benzothiazepine • diltiazem • diarylaminopropylamine • bepridil

3. Drug Overview • Dihydropyridines Do Not Affect Cardiac Conduction System • Bepridil Is the Newest Drug in This Class • Indicated for patients with angina who do not respond to other drugs • 1% develop a new, serious ventricular arrhythmia • Not commonly used in outpatients

4. Indications • Hypertension • Short-acting nifedipine should not be used • For acute reduction of blood pressure • In control of essential hypertension • Immediately after MI • In acute coronary artery syndrome • 36 hours prior to surgery • Vasospastic angina • Arrhythmias

5. Mechanism of Action • All Block the Inward Movement of Calcium Through the Slow Channels of Cell Membranes of Cardiac and Smooth Muscle Cells • Various Drugs Differ in Their Location of Action • Myometrium • Cardiac conduction system • Vascular smooth muscle

6. Mechanism of Action • Myometrium • Decrease force of contraction by blocking inward flow of Ca++ into the cells • This fails to trigger the release of large amounts of Ca++ from the sarcoplasmic reticulum • Free Ca++ is needed for excitation-contraction coupling • Results in a negative inotropic effect, which influences cardiac output

7. Mechanism of Action • Cardiac Conduction System • Ca++ blockers decrease automaticity in the SA node and decrease conduction in the AV node • Results in a negative chronotropic effect through the SA node • Results in a negative chronotropic effect through the AV node and prolongs AV refractory time • Fewer atrial impulses reach the ventricles, slowing the ventricular rate

8. Mechanism of Action • Vascular Smooth Muscle • Decreased force of smooth muscle contraction results in coronary artery dilation • Lowers coronary resistance and improves blood flow through collateral vessels and oxygen delivery • Dilation of main coronary arteries/arterioles in both normal and ischemic areas • Reduces arterial pressure at rest and during exercise by dilating peripheral arterioles • Reducing afterload

9. Mechanism of Action • Vascular Smooth Muscle (cont’d) • Potent inhibitor of coronary artery spasm • Increases myocardial oxygen delivery • Responsible for effectiveness in vasospastic angina

10. Mechanism of Action • nifedipine • Potent dilator of vascular smooth muscle • Mild negative inotropic effect • Small increase in HR • No tendency to prolong AV conduction, prolong SA node recovery time, or slow sinus rate

11. Mechanism of Action • verapamil • Vascular smooth muscle dilator • Less potent than nifedipine • Significant negative inotropic effect • Slows conduction in the SA and AV nodes • Greater effect on AV node

12. Mechanism of Action • diltiazem • Less negative inotropic effect than verapamil • Less peripheral vasodilation than nifedipine • Selectively has greater effect on cardiac muscle than on peripheral vascular smooth muscle • Slows conduction through the SA/AV nodes, but not as much as verapamil • bepridil • Inhibits fast sodium channels and slows Ca++ channels • Class I antiarrhythmic properties

13. Treatment Principles • Nifedipine and Related Drugs Cause Potent Peripheral Vasodilation • More effective for HTN, but more likely to cause peripheral edema • No potential for arrhythmias

14. Treatment Principles • verapamil and diltiazem • Significant effect on cardiac conduction • Antihypertension properties as well • Less likely to cause hypotension than nifedipine and related drugs • More likely to cause conduction problems • Caution: Use with β-blockers

15. Treatment Principles • Ca++ Blockers • Not recommended in CHF • ACC/AHA 2005 Update did not recommend use of this class in heart failure • Not been shown to improve exercise tolerance, quality of life, or survival

16. Treatment Principles • Vasospastic Angina • Treatment of choice • Dihydropyridines, verapamil, diltiazem, and nitrates all are effective as first-line therapy • Both classes reduce vasoconstriction and promote vasodilation in coronary arteries • Dosing is patient specific

17. Treatment Principles • Chronic Stable Angina • Effective in relieving symptoms and increasing exercise tolerance in formal testing • Reduce ST-segment changes on ambulatory ECG monitoring • Nitrates and β-blockers remain first-line therapy • Reserved for patients with contraindications or adverse reactions to β-blockers or nitrates, and when symptoms are not well controlled with first-line agents • Long-acting diltiazem, verapamil, amlodipine, or felodipine should be used

18. Treatment Principles • Hypertension • Diuretics and β-blockers remain first-line therapy based on JNC7 • Patients unable to tolerate first-line drugs may tolerate Ca++ channel blockers • Ca++ channel blockers do not produce hyperlipidemia, insulin resistance, sedation, or sexual dysfunction • Long-acting diltiazem or verapamil or a dihydropyridine should be used

19. How to Monitor • Weekly or biweekly while dosage is titrated • Once stable, monitor periodically (q3-6 mo) for adverse responses and control of disease process • Obtain and monitor serum digoxin levels if Ca++ channel blockers are initiated in patients on digoxin • Renal and hepatic function periodically

20. Patient Variables • Geriatrics • Use lower dosages • Generally well tolerated • Often the drug of choice in elderly patients • Pediatrics • Safety has not been established • Increasing experience with long-acting Ca++ channel blockers in children with essential HTN; has been shown safe and effective

21. Patient Variables • Pregnancy and Lactation • Category C • verapamil, diltiazem, and nifedipine are excreted in breast milk • Race and Gender • No gender differences have been noted • More effective in African American patients

22. Patient Education • Advise patients of potential hypotensive effects during dose titration • Report signs of CHF, irregular HR, nausea, constipation, dizziness, or hypotension • Nitrate therapy with Ca++ channel blockers may cause dizziness • If extended-release tablets are taken, inert shell may pass in feces

23. Patient Education • Do Not Take with Grapefruit Juice • Interferes with drug metabolism by interacting with the cytochrome P450 enzyme system • Inhibits CYP 450 metabolism of CCBs in the intestinal wall • Absorption is enhanced, and a greater pharmacologic effect results • Most common with dihydropyridine CCBs (nisoldipine, nifedipine, felodipine) • CCBs that exhibit the greatest interactions are those that have low bioavailability

24. Dihydropyridines • nifedipine • Contraindications • Hypersensitivity • Nicardipine: Advanced aortic stenosis • Warnings • Hypotension may occur and is more common in patients taking concomitant β-blockers; monitor closely • CHF may develop rarely; usually when used in combination with a β-blocker

25. Dihydropyridines • nifedipine • Warnings (cont’d) • Abrupt withdrawal may cause increased frequency and duration of chest pain; gradually taper dosage • CCBs do not prevent β-blocker withdrawal symptoms; taper β-blocker when a CCB is started • Hepatic dysfunction extends the half-life of nifedipine; use with caution in patients with impaired liver function • Increased angina or MI: Those with severe obstructive coronary disease

26. Dihydropyridines • nifedipine (cont’d) • Precautions • Acute hepatic injury with elevation in LFTs has occurred with nifedipine and nimodipine • Mild to moderate peripheral edema in lower extremities occurs in about 10% of patients

27. Dihydropyridines • nifedipine (cont’d) • Drug interactions • Combination of CCBs and β-blockers is usually well tolerated but may increase likelihood of CHF, severe hypotension, or exacerbation of angina • Many CCBs are cytochrome P450 3A4 substrates • Interactions vary by individual drug • See Table 19-7

28. Dihydropyridines • nifedipine (cont’d) • Dosage and administration (see Table 19-8) • nifedipine: Avoid administration with grapefruit • nisoldipine: Avoid administration with a high-fat meal • nicardipine: Immediate release has prominent peak effects • Increases risk of adverse reactions

29. Phenylalkylamine • verapamil hydrochloride • Contraindications • Hypersensitivity, sick sinus syndrome or second- or third-degree heart block (except in patients with functioning pacemaker) • Hypotension 90 mm Hg • Patients with atrial flutter/fibrillation and an accessory AV pathway • May develop rapid ventricular response or V-fib

30. Phenylalkylamine • verapamil hydrochloride (cont’d) • Warnings • Hypotension with initial dosing or dosage increases; patients taking concomitant β-blockers • Caution with use in patients with heart failure • Negative inotropic effect may initiate CHF • Cardiac conduction: May cause first-degree AV block and transient bradycardia • Elevated LFTs have been reported; monitor • Renal function impairment: 70% is excreted as metabolites in urine; administer with caution

31. Phenylalkylamine • verapamil hydrochloride • Warnings (cont’d) • Antiplatelet effects: Bruising, petechiae, and bleeding have occurred • Patients with IHSS may experience pulmonary edema and severe hypotension with verapamil • Abrupt withdrawal may cause increased frequency and duration of chest pain • Drug interactions (see Table 19-7) • CYP 450 3A4 substrate