Nursing Pharmacology Chapter 9:  Antianginal Drugs

• Nitrates: The nitrates, by reducing myocardial wall tension and oxygen requirements, are very effective antianginal agents.

  • Sublingual nitroglycerin

  • Transdermal nitroglycerin

  • Isosorbide dinitrate, isosorbide-5-mononitrate

    • Other agents include amyl nitrite, erythrityl tetranitrate and pentaerythritol tetranitrate.

  • β-adrenoceptor Antagonists:

    • β-receptor blockers reduce myocardial oxygen demand by reducing the increases in heart rate and contractility due to adrenergic activity.

      • Therefore, during exercise normal positive chronotropic and inotropic responses are blunted.

      • Propranolol, atenolol, and nadolol are examples of β-receptor blockers used in management of chronic, classical angina

  • Calcium channel antagonists:

    • Nifedipine, verapamil, diltiazem are examples of calcium channel blockers that may be effective in chronic treatment of angina.

    • They are coronary vasodilators that reduce arterial pressure and myocardial contractility.

      • Administration of these agents would be expected to reduce myocardial oxygen requirements.

    • Some agents, such as verapamil and diltiazem are more likely to affect cardiac conduction and contractility, while others have more prominent effects on vascular smooth muscle.

      • Variant angina (Prinzmetal's angina) is often effectively managed by calcium channel blockers.

      • Verapamil 

        • Blocks cardiac calcium channels in slow response tissues, such as the sinus and AV nodes.

        • Useful in treating AV reentrant tachyarrhythmias and in management of high ventricular rates secondary to atrial flutter or fibrillation.

        • Useful also in treating angina since it reduces afterload and myocardial contractility.

        • Major adverse effects include: heart block or sinus bradycardia can also occur.

      • Diltiazem

        • Calcium channel blockers are effective in treating angina because because they:

          • Reduce peripheral resistance

          • Reduce dialate coronary vasculature

          • Decrease myocardial contractilty.

        • Arteriolar vascular tone depends on free intracellular Ca²⁺ concentration.

          • Calcium channel blockers reduce transmembrane movement of Ca²⁺

          • Reduce the amount reaching intracellular sites

          • and therefore reduce vascular smooth muscle tone.

        • Diltiazem has a direct negative chronotropic effect on the heart sufficient to block reflex-mediated tachycardia secondary to the decrease in peripheral resistance.

        • Adverse Effects

          • Diltiazem  reduces myocardial contractility which may be undesirable in managing angina in patients with congestive heart failure.

          • SA nodal inhibition may lead to bradycardia or SA nodal arrest.

            • This effect is more prominent if β-adrenergic antagonists are concurrently administered.

          • GI reflux.

          • Negative inotropic effects (reduced myocardial contractility) are augmented if β-adrenergic receptor antagonists are concurrently administered.

          • Calcium channel blockers should not be administered if the patient has SA or AV nodal abnormalities or in patients with significant congestive heart failure.

    • Other Interventions: Non-pharmacological approaches involve mechanical revascularization, typically either percutaneous transluminal coronary angioplasty (angioplasty) or cornary artery bypass grafting.

Selwyn, A.P. and Braunwald, E Ischemic Heart Disease in Harrison's Principles of Internal Medicine (Isselbacher et al., eds) McGraw-Hill, Inc., New York, 1994, p 1082

Pharmacology of the Nitrates

• Overview: Angina pectoris caused by temporary myocardial ischemia is responsive to treatment by organic nitrates.

  • Organic nitrates act primarily by vasodilation (especially venodilation) which reduces myocardial preload and therefore myocardial oxygen demand.

  • Nitrates also promote redistribution of blood flow to relative ischemic areas.

    • The organic nitrates and nitrites are denitrated to produce nitric oxide (NO) which activates guanylyl cyclase.

    • Activation of cyclase results in increased concentrations of cyclic guanosine 3',5'-monophosphate (cyclic GMP) which results in vasodilation.

    • NO activates guanylate cyclase, by binding to iron at the enzyme's heme moiety, causing cyclic GMP (cGMP) synthesis

    • cGMP mediated vasodilation occurs by

      • (1) Decreasing calcium levels in the cell, thus decreasing calcium-calmodulin complex activation of myosin light chain kinase.

      • (2) Inhibition of myosin light chain kinase results in net dephosphorylation of myosin light chain and thus causes relaxation.

      • (3)  cGMP also causes dephosphorylation of myosin light chain by activating other enzyme systems. [Ahlner et al., Pharmacol. Rev., 43 (3): 351-423, 1991] and D.K. Blumenthal, University of Utah]

    • Nitric oxide synthetase produces endogenous nitrates by action on L-arginine.

• Mechanism of Action of Nitrates in Treatment of Angina

  • Beneficial effects of low dose nitrates occurs primarily as a result of peripheral vasodilation.

    1. Venodilation decreases end-diastolic left and right ventricular chamber size and pressures.

    2. Arteriolar dilation, evidenced by flushing and dilation of menningeal arterial vessels, is responsible for headache associated with nitroglycern use.

  • At higher doses, additional venous pooling and arteriolar dilatation decrease blood pressure and cardiac output with attendant sympathetic nervous system activation.

    • Reflex-mediated tachycardia can be produced in this case. If cardiac output and blood pressure are sufficiently reduced, coronary blood flow will be compromised.

    • Tachycardia combined with a reduced coronary flow can in this case aggravate ischemia and induce an anginal attack.

• Nitrate Effects on Regional and Total Coronary Blood Flow

  • In the presence of atherosclerotic disease with significant coronary occlusion proximal to small resistance arterioles, arterioles are maximally dilated by autoregulatory mechanisms.

  • Nitrates may still cause vasodilation of larger capacitance vessels but may exert antianginal activity by promoting coronary blood flow redistribution.

  • With coronary flow partially obstructed, there is a relative reduction in blood flow to the subendocardium.

  • Nitrates tend to redistribute coronary flow to the subendocardial region. Even if there is no significant increase in total coronary blood flow with nitrate administration, more blood may thus be directed to relatively ischemic areas.

  • Spasm of large epicardial vessels is responsible for Prinzmetal's variant angina. Effectiveness of sublingual nitroglycerin in treating this condition is due to direct vasodilation of the large vessel.

[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. 762.

• Smooth Muscle Sites of Action

  • Nitrates (nitrovasodilators) act on nearly all smooth muscle, causing relaxation.  Susceptible non-cardiac smooth muscle include:

    • Bronchiolar

    • Biliary Duct

    • Sphincter of Oddi

    • Smooth muscle of the gastrointestinal tract, including the esophagus

    • Uterine smooth muscle may be relaxed also, but the effects are less predictable compared to the above.

  • Esophageal spasm may produce symptoms similar to angina.

    • These symptoms are often relieved by nitroglycerin.

      • Accordingly, differential diagnosis between angina and "angina" secondary to biliary or esophageal spasm, based solely on response to nitrates may be problematic

• Absorption and Metabolism

  • Organic nitrates are metabolized by reductive hydrolysis in the liver by glutathione-organic nitrate reductase.

  • Reaction products are more water-soluble denitrated compounds and inorganic nitrates.

  • Oral bioavailability and duration of action are determined by hepatic biotransformation.

• Comparisons of nitrates relative to nitroglycerin

  • Erythrityl tetranitrate is degraded 3 times faster.

  • Isosorbide dinitrates dinitrate is degraded at 1/6 the rate

  • Pentaerythritol nitrate is degraded at 1/10 the rate.

  • Isosorbide dintrate has long acting metabolites, isosorbide-2-mononitrate and isosorbide-5-mononitrate, with half-lives of 2 to 5 hours.

    • These metabolites are probably responsible for some of the therapeutic effectiveness of isosorbide-dinitrate.

  • Isosorbide-5-mononitrate may now be directly prescribed and, as expected, has a longer half-life than isosorbide dinitrate

• Toxicities: Side effects are usually secondary to cardiovascular effects of nitrates, notable vasodilation. Adverse effects include:

  • Headache (meningeal vascular dilatation)- decreasing dosage may help.

  • Dizziness, weakness due to postural hypotension.

  • Some incidence of drug rash, especially with pentaerythritol tetranitrate.

[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. 764]