CARDIOVASCULAR SYSTEM PART 1

Anti-Ischemic Drug Therapy  Anti-ischemic drug therapy during anesthesia is indicated whenever evidence of myocardial ischemia exists. The treatment of ischemia during anesthesia is complicated by the ongoing stress of surgery, blood loss, concurrent organ ischemia, and the patient’s inability to interact with the anesthesiologist. Nonetheless, the fundamental principles of treatment remain the same as in the unanesthetized state. All events of myocardial ischemia involve an alteration in the oxygen supply/demand balance

Nitroglycerin Nitroglycerin (NTG) is clinically indicated as initial therapy in nearly all types of myocardial ischemia. Chronic exertional angina, de novo angina, unstable angina, Prinzmetal’s angina (vasospasm), and silent ischemia respond to NTG

 administration. During intravenous therapy with NTG, if blood pressure (BP) drops and ischemia is not relieved, the addition of phenylephrine will allow coronary perfusion pressure (CPP) to be maintained while allowing higher doses of NTG to be used for ischemia relief. If reflex increases in heart rate (HR) and contractility occur, combination therapy with β-adrenergic blockers may be indicated to blunt this undesired increase in HR. Combination therapy with nitrates and calcium channel blockers may be an effective anti-ischemic regimen in selected patients; however, excessive hypotension and reflex tachycardia may be a problem, especially when a dihydropyridine calcium antagonist is used. Mechanism of Action NTG enhances myocardial oxygen delivery and reduces myocardial oxygen demand. NTG is a smooth muscle relaxant that causes vasculature dilation.2 Nitrate-­mediated vasodilation occurs with or without intact vascular endothelium. Nitrites, organic nitrites, nitroso compounds, and other nitrogen oxide–containing substances (e.g., nitroprusside) enter the smooth muscle cell and are converted to reactive nitric oxide (NO) or S-nitrosothiols, which stimulate guanylate cyclase metabolism to produce cyclic guanosine monophosphate (cGMP GMP-dependent protein kinase is stimulated with resultant protein phosphorylation in the smooth muscle. This leads to a dephosphorylation of the myosin light chain and smooth muscle relaxation. Vasodilation is also associated with a reduction of intracellular calcium. Sulfhydryl (SH) groups are required for formation of NO and the stimulation of guanylate cyclase. When excessive amounts of SH groups are metabolized by prolonged exposure to NTG, vascular tolerance occurs. The addition of N-acetylcysteine, an SH donor, reverses NTG tolerance. The mechanism by which NTG compounds are uniquely better venodilators, especially at lower serum concentrations, is unknown but may be related to increased uptake of NTG by veins compared with arteries.3 Physiologic Effects Two important physiologic effects of NTG are systemic and regional venous dilation. Venodilation can markedly reduce venous pressure, venous return to the heart, and cardiac filling pressures. Prominent venodilation occurs at lower doses and does not increase further as the NTG dose increases. Venodilation results primarily in pooling

β-Adrenergic Blockers β-Adrenergic blockers have multiple favorable effects in treating the ischemic heart during anesthesia

They reduce oxygen consumption by decreasing HR, BP, and myocardial contractility. HR reduction increases diastolic CBF. Increased collateral blood flow and redistribution of blood to ischemic areas may occur with β-blockers. More free fatty acids may be available for substrate consumption by the myocardium. Microcirculatory oxygen delivery improves, and oxygen dissociates more easily from hemoglobin after β-adrenergic blockade. Platelet aggregation is inhibited. β-Blockers should be started early in ischemic patients in the absence of contraindications. Many patients at high risk of perioperative cardiac morbidity should be started on β-blocker therapy before surgery and continued on this therapy for up to 30 days after surgery. Perioperative administration of β-adrenergic blockers reduces both mortality and morbidity when given to patients at high risk for coronary artery disease who must undergo noncardiac surgery.4 These data suggest that intermediate- and high-risk patients presenting for noncardiac surgery should receive perioperative β-adrenergic blockade to reduce postoperative cardiac mortality and morbidity. Recommendations on the perioperative use of β-adrenergic blockade for noncardiac surgery are given


Physiologic Effects anti-ischemic effects β-Blockade on the ischemic heart may result in a favorable shift in the oxygen demand/ supply ratio.5 The reductions in the force of contraction and HR reduce myocardial oxygen consumption and result in autoregulatory decreases in myocardial blood flow. Several studies have shown that blood flow to ischemic regions is maintained with propranolol. antihypertensive effects Both β1- and β2-receptor blockers inhibit myocardial contractility and reduce HR; both effects should reduce BP. No acute decrease in BP occurs during acute administration of propranolol. However, chronic BP reduction has been attributed to a chronic reduction in cardiac output (CO). Reductions in high levels of plasma renin have been suggested as effective therapy in controlling essential hypertension. electrophysiologic effects Generalized slowing of cardiac depolarization results from reducing the rate of diastolic depolarization (phase 4). Action potential duration and the QT interval may

shorten with β-adrenergic blockers. The ventricular fibrillation threshold is increased with β-blockers. These antiarrhythmic actions of β-blockers are enhanced in settings of catecholamine excess, such as in pheochromocytoma, acute myocardial infarction, the perioperative period, and hyperthyroidism. Pharmacology of Intravenous β-Adrenergic Blockers propranolol Propranolol has an equal affinity for β1- and β2-receptors, lacks intrinsic sympathomimetic activity (ISA), and has no α-adrenergic receptor activity. It is the most lipidsoluble β-blocker and generally has the most central nervous system side effects. First-pass liver metabolism (90%) is very high, requiring much higher oral doses than intravenous doses for pharmacodynamic effect. The usual intravenous dose of propranolol initially is 0.5 to 1.0 mg titrated to effect. A titrated dose resulting in maximum pharmacologic serum levels is 0.1 mg/kg. The use of continuous infusions of propranolol has been reported after noncardiac surgery in patients with cardiac disease. A continuous infusion of 1 to 3 mg/hr can prevent tachycardia and hypertension but must be used cautiously because of the potential of cumulative effects

metoprolol Metoprolol was the first clinically used cardioselective β-blocker. Its affinity for β1-receptors is 30 times higher than its affinity for β2-receptors, as demonstrated by radioligand binding. Metoprolol is lipid soluble, with 50% of the drug metabolized during first-pass hepatic metabolism and with only 3%
excreted renally. Protein binding is less than 10%. Metoprolol’s serum half-life is 3 to 4 hours. As with any cardioselective β-blocker, higher serum levels may result in greater incidence of β2-blocking effects. Metoprolol is administered intravenously in 1- to 2-mg doses, titrated to effect. The potency of metoprolol is approximately one half that of propranolol. Maximum β-blocker effect is achieved with 0.2 mg/kg given intravenously. esmolol Esmolol’s chemical structure is similar to that of metoprolol and propranolol, except it has a methylester group in the para position of the phenyl ring, making it susceptible to rapid hydrolysis by red blood cell esterases (9-minute half-life). Esmolol is not metabolized by plasma cholinesterase. Hydrolysis results in an acid metabolite and methanol with clinically insignificant levels. Ninety percent of the drug is eliminated in the form of the acid metabolite, normally within 24 hours. A loading dose of 500 μg/kg given intravenously, followed by a 50- to 300- μg/kg/min infusion, will reach steadystate concentrations within 5 minutes. Without the loading dose, steady-state concentrations are reached in 30 minutes. Esmolol is cardioselective, blocking primarily β1-receptors. It lacks ISA and membrane-stabilizing effects and is mildly lipid soluble. Esmolol produced significant reductions in BP, HR, and cardiac index after a loading dose of 500 μg/kg and an infusion of 300 μg/kg/min in patients with coronary artery disease, and the effects were completely reversed 30 minutes after discontinuation of the infusion. Initial therapy during anesthesia may require significant reductions in both the loading and infusion doses. Hypotension is a common side effect of intravenous esmolol. The incidence of hypotension was higher with esmolol (36%) than with propranolol (6%) at equal therapeutic endpoints. The cardioselective drugs may cause more hypotension because of β1-induced myocardial depression and the failure to block β2 peripheral vasodilation. Esmolol appears safe in patients with bronchospastic disease. In another comparative study with propranolol, esmolol and placebo did not change airway resistance whereas 50% of patients treated with propranolol developed clinically significant bronchospasm. labetalol Labetalol provides selective α1-receptor blockade and nonselective β1- and β2-blockade. The potency of β-adrenergic blockade is 5- to 10-fold greater than α1-adrenergic blockade. Labetalol has partial β2-agonist effects that promote vasodilation. Labetalol is moderately lipid soluble and is completely absorbed after oral administration. First-pass hepatic metabolism is significant with production of inactive metabolites. Renal excretion of the unchanged drug is minimal. Elimination half-life is approximately 6 hours. In contrast to other β-blockers, clinically, labetalol should be considered a peripheral vasodilator that does not cause a reflex tachycardia. BP and systolic vascular resistance decrease after an intravenous dose. Stroke volume (SV) and CO remain unchanged, with HR decreasing slightly. The reduction in BP is dose related, and acutely hypertensive patients usually respond within 3 to 5 minutes after a bolus dose of 100 to 250 μg/kg. However, the more critically ill or anesthetized patients should have their BP titrated beginning with 5- to 10-mg intravenous increments. Reduction in BP may last as long as 6 hours after intravenous dosing. Summary β-Adrenergic blockers are first-line agents in the treatment of myocardial ischemia. These agents effectively reduce myocardial work and oxygen demand. There is growing evidence that β-adrenergic-blocking agents may play a significant role in reducing perioperative cardiac morbidity and mortality in noncardiac surger