Calcium Channel Blockers & Anti-angina Agents PRCL 628: Medical Pharmacology Robert J. DiDomenico,...
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Transcript of Calcium Channel Blockers & Anti-angina Agents PRCL 628: Medical Pharmacology Robert J. DiDomenico,...
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.