Calcium Channel Blockers & Anti-angina Agents PRCL 628: Medical Pharmacology Robert J. DiDomenico, PharmD, FCCP Clinical Associate Professor Cardiovascular.

Calcium Channel Blockers & Anti-angina AgentsPRCL 628: Medical Pharmacology

Robert J. DiDomenico, PharmD, FCCP Clinical Associate Professor

Cardiovascular Clinical Pharmacist

 OBJECTIVES

For each of the anti-angina drugs/drug classes, students should be able to:

1. Describe the mechanism of action.

2. Compare and contrast the pharmacokinetic and drug interaction profiles

within each class.

3. Compare and contrast the clinical effects.

4. List the common and/or serious adverse effects.

Calcium Channel Blockers & Anti-angina AgentsPRCL 628: Medical Pharmacology

Required Reading:

1. Katzung BG. Chapter 12. Vasodilators & the Treatment of Angina Pectoris. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=55821915.

Suggested Reading:

1. Michel T, Hoffman BB. Chapter 27. Treatment of Myocardial Ischemia and Hypertension. In: Knollmann BC, ed. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011. http://www.accessmedicine.com/content.aspx?aID=16667490.

Abrams J. N Engl J Med 2005;352:2524-33

Prinzmetal or Variant Angina

Coronary Artery Vasospasm

http://www.uofmmedicalcenter.org/healthlibrary/Article/40420

Oxygen Supply ≠ / Oxygen Demand

/ Arterial pO2

/ Diastolic filling time Coronary blood flow

/ Heart rate/ Myocardial contractility/ Ventricular wall tension

Chronic Angina

Treatment of Angina

• Nonpharmacologic– Percutaneous coronary

intervention– Correction of anemia– Correction of hypoxemia

• Pharmacologic– Beta-blockers– Calcium channel blockers– Nitrates– Ranolazine

Parker JD, Parker JO. N Engl J Med 1998;338:520-31.

(Nitroglycerin)

Trevor AJ, Katzung BG, Masters SB. Chapter 12. Drugs Used in the Treatment of Angina Pectoris. In: Trevor AJ, Katzung BG, Masters SB, eds. Pharmacology: Examination & Board Review. 9th ed. New York: McGraw-Hill; 2010. http://www.accesspharmacy.com/content.aspx?aID=6543820.

Figure 1. Pathways of organic nitrate bioactivation in vascular cells.

Münzel T et al. Circulation Research 2005;97:618-628

Copyright © American Heart Association

NitratesPharmacodynamic Effects

• Beneficial effects Oxygen demand

Ventricular volume Arterial pressure Ejection time

Perfusion• Coronary vasodilation Collateral blood flow LVEDP

• Deleterious effects Oxygen demand

• Reflex tachycardia• Reflex in contractility

Perfusion Diastolic perfusion

time due to tachycardia

– Nitrate tolerance• Requires 8 – 12 hour

“nitrate-free” interval

Nitrates Adverse Effects & Notable Drug Interactions

• Common adverse effects– Headache– Reflex tachycardia– Orthostatic hypotension

• Drug interactions– Phosphodiesterase

inhibitors• Potentiate effects of nitrates

& may precipitate severe hypotension & MI

– Sildenafil (Viagra, Revatio)

– Vardenafil (Levitra, Staxyn)

– Tadalafil (Cialis, Adcirca)

Pharmacokinetics of Nitrate Dosage Forms

Nitrate Dosage form Onset(minutes)

Duration Common Dose

Short-actingNitroglycerinNitroglycerinNitroglycerin

SublingualTranslingual spray

Intravenous

1 – 31 – 41 – 2

10 – 60 min10 – 60 min3 – 5 min

0.4 – 0.6mg PRN0.4mg/spray PRN

5 – 10mcg/min titrated to effect

Long-actingNitroglycerin

Isosorbide dinitrateIsosorbide mononitrate

Topical ointmentTransdermal patch

OralOral

20 – 6020 - 6015 – 4030 – 60

2 – 8 hours2 – 8 hours2 – 6 hours6 – 8 hours

(Ismo)8 – 12 hours

(Imdur)

0.5 – 1 inch q4-6h0.2 – 0.4 mg/hr5 – 60mg TID

20mg BID

30 – 120mg daily

Figure 2. Molecular mechanisms of nitrate tolerance.

Münzel T et al. Circulation Research 2005;97:618-628

Copyright © American Heart Association

Katzung BG. Chapter 12. Vasodilators & the Treatment of Angina Pectoris. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012. http://www.accessmedicine.com/content.aspx?aID=55821915.

Trevor AJ, Katzung BG, Masters SB. Chapter 12. Drugs Used in the Treatment of Angina Pectoris. In: Trevor AJ, Katzung BG, Masters SB, eds. Pharmacology: Examination & Board Review. 9th ed. New York: McGraw-Hill; 2010. http://www.accesspharmacy.com/content.aspx?aID=6543820.

X

http://www.drugdevelopment-technology.com/projects/istaroxime/istaroxime4.html

Calcium Channel BlockersPharmacodynamic Effects

Myocardial oxygen demand•Smooth muscle relaxation = vasodilation

– Arterioloes > veins• Nimodipine selective for cerebral vessels

Contractility– Nondihydropyridines (diltiazem,

verapamil)– Dihydropyridines (e.g., nifedipine)

• Minimal effect at therapeutic doses

Heart rate– Nondihydropyridines

• Clinical uses– Angina– Hypertension– Raynaud’s

• Dihydropyridines

– Pulmonary HTN• Nifedipine/DHPs

– Supraventricular tachycardias

• Diltiazem• Verapamil

Calcium Channel BlockersPharmacokinetics & Dosing

Drug Dosage form Bioavail-ability

(%)

Onset(minutes)

Half-life

(hours)

Duration(hours)

Common Dose

Diltiazem IR tabletSR capsule

XR/CD capsuleIV

40 – 65 30 – 601 – 2 hrs1 – 2 hrs

3

3 – 10 61224

1 – 3

30 – 90mg q6h60 – 180mg BID120 – 480mg/day

15 – 20mg, 5-15mg/hr

Verapamil IR tabletSR tab/cap

IV

20 – 35 1 – 2 hrs5 – 11 hrs

1 – 5

4 – 12 6 – 812 - 24< 0.5

40 – 160mg TID120-480mg/day

2.5 – 10mg

Nifedipine IR capsuleSR tablet

45 – 70 2030

2 – 7 6 – 824

10 – 30mg q6-8h30 – 240mg daily

Amlodipine Tablet 65 – 90 6 – 12 hrs 30 – 50 24 2.5 – 10mg daily

Felodipine ER tablet 15 – 20 2 – 5 hrs 11 – 16 24 2.5 – 20mg daily

Calcium Channel BlockersAdverse Effects & Notable Drug Interactions

• Adverse effects– Peripheral edema– Flushing– Hypotension– Reflex tachycardia

• Dihydropyridines• Nifedipine > others

– Nondihydropyridines• Bradycardia• Heart block• Heart failure

• Inhibit CYP3A4– Statins– Cyclosporine– Tacrolimus

• Inhibits p-glycoprotein (verapamil)– P-glycoprotein

substrates (e.g., digoxin)

Carbone F, et al. Swiss Med Wkly. 2013;143:w13874.http://www.smw.ch/content/smw-2013-13874/

RanolazineClinical Effects & Precautions

Ventricular wall tension (diastole)

• No effect on heart rate & blood pressure

• Small risk for QTc prolongation

• Drug interactions– Substrate

• CYP3A4, CYP2D6, PGP

– Inhibits• CYP3A4, CYP2D6, PGP

– Avoid/contraindicated• Azole antifungals

• Strong CYP3A4 inducers & inhibitors

• High-risk QTc prolonging drugs

Summary of Anti-Angina Effectson Myocardial Oxygen Supply & Demand

Drug/Class HR BP Wall Tension

Contract-ility

O2 Supply

Beta-blockers / CCBs

Verap/DiltDihydropyridines

/

Nitrates / Ranolazine

Cavallari LH, DiDomenico RJ. Chapter 7: Ischemic Heart Disease In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT, eds. Pharmacotherapy Principles & Practice, 3 rd ed.. Chicago: McGraw-Hill, 2013.

Cavallari LH, DiDomenico RJ. Chapter 7: Ischemic Heart Disease In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT, eds. Pharmacotherapy Principles & Practice, 3rd ed.. Chicago: McGraw-Hill, 2013.

Cavallari LH, DiDomenico RJ. Chapter 7: Ischemic Heart Disease In: Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT, eds. Pharmacotherapy Principles & Practice, 3rd ed.. Chicago: McGraw-Hill, 2013.