Anesthesia Pharmacology and Angina

Anesthesia Pharmacology: Antianginal Drugs

Clinical Pharmacology of Antianginal Agents

Nitrates Beneficial Effects:
- Angina pectoris caused by temporary myocardial ischemia is responsive to treatment by organic nitrates.
- These agents 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.
- Beneficial effects of low dose nitrates occurs primarily as a result of vasodilation.
  - Specifically, venodilation decreases end-diastolic left and right ventricular chamber size and pressures.
  - Some arteriolar dilation,evidenced by flushing and dilation of meningeal arterial vessels, is responsible for headache associated with nitroglycerin 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.
ß-Adrenoceptor Antagonists
- β-adrenoceptor antagonists are beneficial in reducing the frequency and severity of exertional angina attacks, but are not effective in variant angina and may even worsen that condition.
- Propranolol (Inderal), timolol (Blocadren), metoprolol (Lopressor), atenolol (Tenormin) are effective antianginal drugs.
- Antianginal effects of beta-blockers are due to:
  - Decreased heart rate
  - Decreased contractility
  - Decreased blood pressure during exercise (reduced afterload)
Calcium Channel Blockers
- Calcium channel blockers cause vasodilation of the arterial vascular bed, thus reducing afterload and decreasing myocardial wall tension.
  - As a consequence, myocardial oxygen demand decreases.
  - Calcium channel antagonists have minimal effects on venous beds and thus have little effect on preload.
- 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.
- 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.

[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. 774-775]

Some Antianginal Drugs:
- Nitrates and Nitrites:
  - Amyl nitrite
  - Erythrityl tetranitrate
  - Isosorbide dinitrate (Isordil, Sorbitrate)
  - Nitroglycerin
  - Pentaerythritol tetranitrate
- Calcium Channel Blockers:
  - Amlodipine (Norvasc)
  - Bepridil (Vascor)
  - Diltiazem (Cardiazem)
  - Nimodipine (Nimotop)
  - Felodipine (Plendil)
  - Isradipine (DynaCirc)
  - Nicardipine (Cardene)
  - Nifedipine (Procardia, Adalat)
  - Nisoldipine (Sular)
  - Verapamil (Isoptin, Calan)
- ß-Adrenoceptor Antagonists:
  - Atenolol (Tenormin)
  - Metoprolol (Lopressor)
  - Nadolol (Corgard)
  - Propranolol (Inderal)

Isosorbide
- Angina pectoris caused by temporary myocardial ischemia is responsive to treatment by organic nitrates. These agents act primarily by vasodilation (especially venodilation) which reduces myocardial preload and therefore myocardial oxygen demand.
- Isosorbide dinitrate is orally active and only slowly metabolized by the liver.
- Comparisons of nitrates relative to nitroglycerin: isosorbide dinitrates dinitrate is degraded at 1/6 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.
- 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 by increasing the rate of dephosphorylation of myosin light chains.
  - Nitric oxide synthetase produces endogenous nitrates by action on L-arginine.
- Some arteriolar dilation,evidenced by flushing and dilation of meningeal arterial vessels, is responsible for headache associated with nitroglycerin use.
- Adverse Effects
  - 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.
Nitroglycerin
- Sublingual nitroglycerin is used to relieve symptoms of angina or as a prophylactic before exertional activities that would otherwise cause angina.
- Angina pectoris caused by temporary myocardial ischemia is responsive to treatment by organic nitrates.
  - These agents 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.
    - Some arteriolar dilation,evidenced by flushing and dilation of meningeal arterial vessels, is responsible for headache associated with nitroglycerin use.
  - Adverse Effects
    - 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
Nimodipine (Nimotop) and Felodipine (Plendil)
- Calcium channel blockers are effective in treating angina because they reduce peripheral resistance.
- Nimodipine (Nimotop) and felodipine (Plendil) have relatively little effects on reducing myocardial contractility compared to verapamil (Isoptin, Calan) or diltiazem (Cardiazem). 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.
- Adverse Effects
  - SA nodal inhibition may lead to bradycardia or SA nodal arrest. This effect is more prominent if beta adrenergic antagonists are concurrently administered.
  - GI reflux.
  - Negative inotropic are augmented if ß-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.
Diltiazem (Cardiazem)
- Calcium channel blockers are effective in treating angina because because they:
  - Reduce peripheral resistance
  - Reduce dialate coronary vasculature
  - And 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 (Cardiazem) has a direct negative chronotropic effect on the heart sufficient to block reflex-mediated tachycardia secondary to the decrease in peripheral resistance.
- Diltiazem (Cardiazem) also reduces myocardial contractility which may be undesirable in managing angina in patients with congestive heart failure.
- Adverse Effects
  - SA nodal inhibition may lead to bradycardia or SA nodal arrest. This effect is more prominent if beta adrenergic antagonists are concurrently administered.
  - GI reflux.
  - Negative inotropic are augmented if beta-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.
Nisoldipine (Sular)
- Calcium channel blockers are effective in treating angina because reduce peripheral resistance is reduced.
- 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.
- Nisoldipine, a dihydropyridine, is similar to nifedipine but five to ten times more potent as a vasodilator and little effect on myocardial contractility.
- Adverse Effects
  - Dizziness, headache and peripheral edema.
  - Concurrent use of cimetadine, a fatty meal, or grapefruit juice may increase serum concentations and increase toxicity.
Verapamil
- Verapamil: Greatest efficacy among calcium channel blockers for treatment of cardiac arrhythmias
- Useful also in treating angina since it reduces afterload and myocardial contractility.
  - Pharmacokinetics:
    - Route of Administration: IV or oral
    - Extensive hepatic metabolism (following oral administration, bioavailability: 20%)
      - Cautious use in patients with hepatic dysfunction
    - Much larger oral dose required -- reflecting significant hepatic first pass metabolic effect
    - Following IV administration: 70% eliminated by the kidney (15% biliary excretion)
  - Dosage considerations:
    - Suppression of paroxysmal supraventricular tachycardia (5-10 mg IV over 1-3 minutes) -- followed by continues infusion of approximately 5 ug/kg/minute
    - Prior to verapamil administration: 1 g IV calcium gluconate: may decrease verapamil-induced hypotension without affecting verapamil's anti-rhythm it properties
    - Oral verapamil (80-120 mg every 6-8 hours):
      - Suppression of paroxysmal supraventricular tachycardia
      - Control of ventricular rate in atrial fibrillation or atrial flutter
  - Mechanism of Action/Cardiac Effects: Verapamil (and other calcium channel blockers)
    - Coronary artery and systemic arterial vasodilation (Moderate)
    - Diminishes calcium ion flux across slow-type Ca²⁺ channels of smooth muscle and cardiac cells
    - Blocks both activated and inactivated calcium channels -- more effective on:
      - Tissues less completely polarized at rest (may fire more frequently)
      - Tissues the depend on calcium currents for activation: e.g. sinoatrial and atrioventricular nodes
        
        AV nodal conduction (effective refractory period): prolonged
      - Significant AV nodal depression (reduced AV transmission)
    - Reduced Ca²⁺ flux: decreased diastolic depolarization rate (phase 4 depolarization)
    - Negative SA nodal chronotropic effect
  - Clinical Use:
    - Major Use:
      - Reentrant supraventricular tachycardia
        
        Alternative drug: adenosine
        
        Verapamil or adenosine preferable to previous therapy which included:
        
        Propranolol, digoxin, edrophonium (anticholinesterase), vasoconstrictor agents (arrhythmia termination by reflex -- enhancing vagal tone), cardioversion
    - Occasionally useful: conversion of atrial flutter and fibrillation to normal sinus rhythm (NSR)
    - Rarely useful: ventricular arrhythmias
  - Side effects/Toxicities:
    - Cardiac:
      - Dose-related -- often avoidable
      - Common Error: administration of verapamil (IV) to patient with ventricular tachycardia which was misdiagnosed as supraventricular arrhythmia: hypotension and ventricular fibrillation may then occur
      - Exacerbation of left ventricular failure (CHF): due to negative inotropic properties of calcium channel blockers
      - A-V block (with large dose or in the presence of partial A-V block; --treated with atropine, beta adrenergic receptor agonists, or calcium)
      - In patients with sinus node disease, precipitation of sinus arrest may occur
    - Extracardiac:
      - Constipation, nervousness, peripheral edema, lassitude
  [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. 774-775]

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