Medical Pharmacology  Chapter 9:  Antianginal Drugs

• Calcium Channel Blockers: Vascular Effects

  • Calcium channel blockers cause vasodilation of the arterial vascular bed, thus:

    • Reducing afterload

    • Decreasing myocardial wall tension.

    • Afterload reduction: myocardial oxygen demand decreases.

    • Calcium channel antagonists have minimal effects on venous beds and thus have little effect on preload.

  • Calcium channel blockers cause vasodilation of the arterial vascular bed, thus:

    • Calcium channel blockers cause coronary arterial dilatation and have negative inotropic action.

    • Antianginal efficacy in exertional angina thus may result from a decrease in myocardial oxygen demand and an increase in coronary arterial blood flow

[Robertson, R. M. and Robertson, D., Drugs Used for the Treatment of Myocardial Ischemia In:Goodman and Gilman's The Pharmacological Basis of Therapeutics (Hardman et al., eds),McGraw-Hill, New York, 1996, p. 767-773]

• Mechanism of Vascular Smooth Muscle Contraction

  • Three calcium-dependent mechanisms appear to be involved in vascular smooth muscle contraction:

    1. Voltage-sensitive Ca²⁺ channels open following membrane depolarization and calcium ions, moving down its electrochemical potential, enter the cell.

       • Calcium channel blockers work at this step

    2. Agonist-induced contractions occur without membrane depolarization but involves formation of inositol trisphosphate (IP₃), a second messenger, from membrane phosphatidylinositol. Inositol trisphosphate causes release of Ca²⁺ from the sarcoplasmic reticulum.

    3. Receptor-mediated Ca²⁺ channel activation as a function of receptor occupancy

  • The elevation of intracellular calcium results in:

    • Enhanced binding to calmodulin.

    • Calcium-calmodulin complex activates the enzyme myosin light-chain kinase.

    • Activated myosin light-chain kinase phosphorylates light-chain myosin.

    • Phosphorylated light-chain myosin favors actin and myosin interaction which results in smooth muscle contraction.

[Robertson, R. M. and Robertson, D., Drugs Used for the Treatment of Myocardial Ischemia In:Goodman and Gilman's The Pharmacological Basis of Therapeutics (Hardman et al., eds),McGraw-Hill, New York, 1996, p. 767-773]

• Effects on Cardiac Cells:

  • In vascular smooth muscle, the major depolarizing current is due to Ca²⁺ .

  • In the heart, the "fast" response is mediated by Na⁺ whereas the slow response is Ca²⁺ mediated.

    • Note that in the specialized conduction system tissue, the SA and AV nodal tissue, depolarization is mainly due to calcium ion movement

  • In the cardiac myocyte, Ca²⁺ binds to troponin and reduces inhibitory effects of troponin on contraction, favoring muscle contraction.

  • However, calcium channel blockers reduce free intracellular calcium and therefore reduce contractility. Accordingly, calcium channel blockers are negative inotropic drugs.

  • Predominately Cardiac Effects:

    • Diltiazem (Cardiazem),Verapamil (Isoptin, Calan)

      • Moderate vasodilation

      • Moderate decreased contractility

  • Predominately Vascular Effects:

    • Amlodipine (Norvasc), Nicardipine (Cardene), Nifedipine (Procardia, Adalat)

      • Marked vasodilation

      • Minimal effects on contractility

      • Minimal or no effects on AV conduction

• Absorption, Metabolism, Excretion

  • Calcium channel blockers are well absorbed after oral administration.

  • Bioavailability varies among these drugs due to varying degrees of first-pass hepatic metabolism.

  • Usually drug effects are seen with one hour; however, amlodipine (Norvasc), isradipine (DynaCirc) and felodipine (Plendil) are more slowly absorbed and are longer-acting.

• Toxicity:  In patients with liver cirrhosis half lives and bioavailability may be increased and dosages may have to be reduced.

  • Most common side effects caused by calcium channel blockers administration are secondary to excessive vasodilatation including dizziness, hypotension, flushing,  and nausea.

  • Less commonly patients experience constipation, peripheral edema, coughing, pulmonary edema or wheezing.

    • Relatively uncommon side effects include: rash, somnolence and liver function test changes.

  • Worsening of myocardial ischemia may be observed with dihydropyridines (e.g. amlodipine (Norvasc), felodipine (Plendil), nicardipine (Cardene), nitrendipine, nimodipine (Nimotop), nifedipine (Procardia, Adalat)) since these agents are more likely to produce excessive vasodilatation and reflex mediated tachycardia.

    • Mechanisms which may be responsible for worsening ischemia include:

      • Hypotension causing decreased coronary perfusion

      • Increasing coronary blood flow in non-ischemic regions at the expense of coronary flow in ischemic areas

    • Increase in myocardial oxygen demand due to tachycardia caused by reflex sympathetic stimulation.

  • Myocardial ischemia secondary to the use of calcium channel blockers is less frequently seen with verapamil and diltiazem since they are less likely to cause excessive arteriolar dilation.

    • If SA or AV nodal conduction disease is present, i.v. verapamil may cause bradycardia or transient asystole.

    • Intravenous verapamil (Isoptin, Calan) is contraindicated if administered with β-adrenoceptor antagonists because of increased likelihood of AV block and suppression of myocardial contractility

    •  Both verapamil (Isoptin, Calan) or diltiazem (Cardiazem) should not be used in patients with ventricular dysfunction, SA or AV nodal conduction abnormalities, and systolic blood pressure below 90 mm Hg.

• Therapeutic Uses of Calcium Channel Blockers

  • Variant Angina:

    • Calcium Channel Blockers are effective in treating variant angina (Prinzmetal's angina).

    • Variant angina is caused by coronary vasospasm that reduces coronary flow.

    • Calcium channel blockers exert their beneficial effects by direct coronary vasodilation (vasorelaxation), as opposed to peripheral hemodynamic effects.

  • Exertional Angina:

    • Calcium channel blockers are effective in managing exercise-induced angina probably by decreasing oxygen demand (decreased afterload and contractility) and/or increasing coronary blood flow.

  • Cardiac Arrhythmias: Discussed elsewhere

  • Cerebral Vasospasm: Nimodipine is approved for use in those patients with CNS deficits after rupture of congential intracranial aneurysm.

  • Raynaud's Disease (calcium channel antagonists provide symptomtic relief)

    • Nifedipine (Procardia, Adalat)

    • Diltiazem (Cardiazem)

    • Felodipine (Plendil)

 

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