Cardiac Pharmacology

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A member of the larger family of cardiac glycosides, digitalis was originally derived from the plant foxglove. It was not until the late s, however, that its positive inotropic effects were first discovered. The potential benefit of digoxin therapy in patients with chronic heart failure results from both an overall increased myocardial inotropic state and resulting decreases in ventricular pressures 16, Most recent evidence suggests that positive inotropic effects of digitalis glycosides result from altered excitation-contraction coupling.

In humans, calcium enters myocardial cells via slow calcium channels during the plateau phase of the myocardial action potential, a process that triggers the release of intracellular calcium from the sarcoplasmic reticulum and results in activation of contractile proteins. In general, many excitable cell-membrane proteins are responsible for calcium entry into myocardial cells; these include a slow calcium channel, fast calcium channel, nonspecific cation channel, sodium-calcium exchanger, Na-K-ATPase, sodium-hydrogen exchanger, sarcoplasmic-reticulum ATP-dependent calcium pump, and the ryanodine-sensitive sarcoplasmic- reticulum calcium-release channel.

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Na-K-ATPase activity mediates the active transport of sodium and potassium ions against their respective concentration gradients. Cardiac glycosides bind to the extracellular surface of the subunit of myocardial Na-K-ATPase and inactivate this enzyme system. Blockade of Na-K-ATPase prevents the pumping of sodium and potassium against their concentration gradients, leading to increased sodium-calcium exchange. The resulting increase in intracellular calcium activates the slow calcium channel and is therefore thought to mediate increased myocardial inotropy.

Interestingly, genes encoding four distinct forms of this subunit vary considerably in their ability to bind digitalis 18 , perhaps accounting for some of the variability seen in the effectiveness of digitalis therapy and possibly toxicity. A more detailed account of this mechanism of action of digitalis glycosides can be found in other articles 16, In one study, inhibition of Na-K-ATPase by digitalis preparations was shown to have effects on neurotransmitter exocytosis and neuronal catecholamine transport systems in the heart as well One of the most potentially life-threatening side effects of digitalis therapy is arrhythmia.

This may seem ironic, because digitalis is classically used to treat atrial fibrillation by slowing ventricular response to rapid atrial rates see Chapter 4. However, increased intracellular calcium concentrations mediating digitalis-induced increases in inotropy may also lead to arrhythmias. In addition to side effects directly attributable to inhibition of the sodium pump by inhibiting Na-K-ATPase such as changes in membrane depolarizations, conduction, automaticity, and excitability , delayed afterpotentials and mechanical aftercontractions have been demonstrated with digitalis and may lead to ventricular arrhythmias.

Because atrial tissue depends on the entry of the slow inward current of calcium for depolarization, increased digitalis concentrations and associated increases in intracellular calcium may slow depolarization and result in sinus exit block. Atrioventricular AV block may also result from accumulation of potassium inside the cell and sodium outside the cell. Bolus infusion of digoxin has been shown to induce epicardial coronary artery vasoconstriction, a process not mediated via activation of coronary -ARs and easily reversible by nitrate therapy Massive digitalis overdoses may lead to widespread inhibition of Na-K-ATPase, even in noncardiac tissues; this may result in extracellular hyperkalemia, a process that may slow conduction and lead to reentrant arrhythmias.

Effects of digitalis on chemoreceptors in the area postrema of the medulla in the central nervous system mediate the anorexia, nausea, and vomiting frequently associated with digitalis toxicity. Poor correlation between clinical symptoms and the presence of toxic digitalis levels makes clinical detection of toxicity difficult. Clearly serum digoxin concentrations should be followed regularly; patients with congestive heart failure receiving digoxin therapy have been shown to have serum concentrations of approximately 1.

In addition to decreases in renal function and overdosing regimens, digoxin serum concentrations are affected by several drugs. Digitalis levels have been reported to be acutely elevated with administration of quinidine at least partly as a result of displacement of digitalis-binding sites in tissues. Succinylcholine has the propensity for increasing serum potassium levels acutely, which in turn can increase digitalis arrhythmias. Procainamide, an antiarrhythmic agent that can be used to treat digitalis toxicity, also has the potential in the presence of disturbances of AV conduction to cause asystole or ventricular fibrillation.

Because hypercalcemia predisposes to digitalis arrhythmias, acute bolus administration with calcium intraoperatively must be done with caution in patients receiving chronic digitalis therapy. Several agents have the potential for increasing serum levels by decreasing renal clearance of digitalis; they include calcium channel antagonists, spironolactone, amiloride, and triamterene.

Major classes of cardiovascular medications

Both hyperkalemia and hypokalemia may aggravate digitalis toxicity. On the other hand, some drugs are able to enhance the metabolism of digitalis preparations and hence decrease serum digitalis levels by increasing hepatic microsomal enzyme activity. These agents include phenylbutazone, phenobarbital, phenytoin, and rifampin. However, -AR antagonists do not abolish the inotropic action of digitalis on heart muscle.

Although it is not relevant for acute intraoperative management, one should note that aminoglycoside antibiotics decrease absorption of digitalis oral doses. In light of potential toxicity associated with digitalis glycosides, it may be surprising that controversy exists regarding the effectiveness of digitalis therapy in patients with congestive heart failure in the absence of atrial arrhythmias Although many measures of myocardial function both invasive and noninvasive document increased myocardial inotropy with digitalis therapy even in the absence of atrial arrhythmias, clinical response appears to depend somewhat on the type of congestive failure present.

For example, patients with dilated cardiomyopathy, impaired systolic function, and an associated S 3 gallop frequently benefit from digitalis therapy, whereas patients with elevated myocardial filling pressure but relatively preserved systolic function do not A question is frequently raised regarding administration of digitalis on the morning of surgery. Because digitalis toxicity is related to plasma concentration, the digitalis level should be evaluated preoperatively in patients receiving oral digitalis preparations.

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The presence or absence of a clinical history of nausea and vomiting should be established because these can be symptoms of digitalis toxicity, even in the face of "normal" therapeutic digitalis serum concentrations. There is probably no harm in administering the patient's usual dose of digitalis on the day of surgery as long as no evidence of toxicity is present.

However, if the serum digitalis concentration is elevated, it is prudent to hold the morning dose on the day of surgery. Perhaps instead of worrying whether digitalis glycosides should be given on the day of surgery, one should concentrate on keeping the extracellular serum potassium concentration in the normal range perioperatively in patients receiving digitalis, to prevent arrhythmias associated with this drug.

Nitrates have been used as therapy for ischemic heart disease since the late s. Sublingual nitroglycerin tablets have been and remain the mainstay of medical therapy for acute coronary artery insufficiency, only recently being replaced by sublingual spray nitroglycerin and longer acting preparations, such as nitropaste and nitropatches. Nitroglycerin, the active ingredient in dynamite, was invented by Alfred Nobel, who ultimately endowed the Nobel Prize.

Anesthesiologists have used nitrovasodilators such as nitroglycerin and sodium nitroprusside for more than 20 years. The mechanism of action of these compounds, however, has only recently been described. Nitroglycerin and other organic nitrates penetrate the endothelium, where they act as the substrate for formation of NO. NO then binds to the NO receptor, which is an iron group in the enzyme guanylate cyclase.

NO binding to this iron-containing heme group causes a 3D change that results in the production of 3',5'-cyclic guanosine monophosphate cGMP from GTP Nitrovasodilators act on different arterial beds, with sodium nitroprusside affecting predominantly systemic vasculature particularly arteries and arterioles and nitroglycerin acting on venous capacitance vessels. With increasing doses, these relatively selective effects disappear.

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Because these effects are clearly demonstrated with acute intravenous administration of sodium nitroprusside and nitroglycerin, this aspect of nitrate therapy is examined in more detail in the acute vasodilator therapy section of this chapter. However, sublingual or topical administration of nitrates for acute anginal episodes is addressed in this section. Beneficial effects of nitroglycerin therapy for acute angina result predominantly from the effects of nitrates on coronary arteries.

Specific coronary artery effects of nitrates include dilation of epicardial conduit coronary arteries, dilation of coronary collaterals, reversal and prevention of coronary spasm and vasoconstriction, and perhaps most importantly dilation of atherosclerotic coronary artery stenosis, including those with eccentric lesions 32, Hence, an overall redistribution of myocardial blood flow to areas of ischemia occurs.

In addition, acute venodilation may result in decreased venous return, lower ventricular volumes, and therefore lower wall tension; the net result decreases myocardial oxygen consumption. Although decreased ventricular volume may be beneficial, it may also decrease cardiac output see Starling's law described in the discussion under Intraoperative Acute Cardiac Medications , so nitroglycerin should be administered cautiously. Even sublingual administration of nitrates may occasionally result in syncope secondary to acute venodilation.

Sublingual nitroglycerin is rapidly absorbed from the sublingual mucosa with onset of action within 2 to 5 minutes, maximal effect at 3 to 15 minutes, and little remaining activity after 30 minutes. All nitrate esters produce the same physiologic effects as nitroglycerin, with varying onset and duration depending on the preparation. Nitroglycerin and nitrate esters are rapidly metabolized in the liver by the enzyme glutathione organic nitrate reductase, and metabolites have no residual cardiovascular activity.

Although nitrate therapy is usually well tolerated, the most frequent side effects include dizziness, headaches, and postural hypotension. Virtually no interactions occur with preoperative nitrates and anesthetic agents as long as adequate volume status is maintained. Indeed, because tolerance to nitrate therapy is a fairly common phenomenon, abruptly stopping nitrate therapy may result in acute myocardial ischemia.

Therefore, nitrate therapy should be continued perioperatively in patients already receiving these medications. Potential side effects of acute administration of nitrates intraoperatively are addressed in more detail in the acute vasodilator therapy section further on. As stated in the earlier discussion under Adrenergic Receptors, most currently available drugs used to rapidly modulate the cardiovascular system heart and vessels mediate their action via ARs.

The predominant ARs in human myocardium are -ARs, both 1 and 2 subtypes. Although 2 -AR agonists are classically thought to mediate increases in inotropy and chronotropy, and 2 -AR agonists to mediate smooth-muscle relaxation both bronchial and vascular , it is now clear that both 1 -AR and 2 -AR subtypes are important in mediating myocardial inotropic responses and increases in heart rate to both exogenous and endogenous catecholamines and to synthetic catecholamine derivatives.

Because increases in both inotropic state and heart rate increase myocardial oxygen demand a condition not well tolerated in patients with coronary artery disease , -AR antagonists are frequently used therapeutically to decrease overall myocardial oxygen demand and hence to decrease frequency of angina attacks.

Because -AR antagonists inhibit responses to endogenous catecholamines, and because many anesthetic agents particularly the inhalation agents are known to depress myocardial function, it is theoretically possible to predict that withholding -AR antagonists preoperatively might provide a more stable course intraoperatively.

This hypothesis came to the fore in the early s, and generally anesthesiologists held the morning dose of -AR antagonists. However, instead of improving intraoperative stability, acutely withholding -AR antagonists preoperatively was found to increase the incidence of myocardial ischemia and infarction. We now know that chronic administration of -AR antagonists up-regulates -ARs.

Hence, in the presence of antagonists, -AR number actually increases. Because the half-life of most -AR antagonists in the early s was approximately 3 to 6 hours, holding the morning dose in effect resulted in almost no -AR antagonist concentration during surgery. Because many stimulating events occur during surgery including intubation, incision, sternotomy, and extubation , the resulting surge in endogenous catecholamines during these stressful events resulted in rapid activation of more than the normal number of myocardial -ARs.

Acute increases in myocardial inotropic state resulted, often precipitating angina and myocardial infarction. This syndrome was recognized many years ago, and it is now routine to continue -AR antagonists throughout the perioperative period. If -AR antagonists need to be discontinued, the patient should be monitored closely during gradual tapering of the dose for at least 1 to 2 weeks.

Structurally, -AR agonists and antagonists are very similar. The basic structure consists of a benzene ring and an ethylamine side chain For -AR agonists and antagonists, the levo stereoisomer has much greater affinity for the receptor and is considered the active form; however, the dextro isomer binds weakly and has all of the usual -AR antagonist properties.

Interestingly, most clinical preparations are mixtures of both isomers. Other medical conditions in which -AR antagonists should be avoided include sinus bradycardia, greater than first-degree conduction block, cardiogenic shock, and overt cardiac failure although low-dose -AR antagonists have been used for some forms of congestive heart failure. Treatment with -AR antagonists may mask the symptoms of hyperthyroidism.

Table lists several commonly used -AR antagonists, their relative -AR subtype selectivity, and dosing information. A rapid-acting -AR antagonist with a short half-life, esmolol, is now available intravenously.


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Hence, rapid titration of -AR antagonist effects can be performed using a continuous infusion of esmolol intraoperatively. In general, the cardiovascular effects of -AR antagonists include decreased resting and exercise heart rate, decreased resting and exercise blood pressure, decreased resting and exercise cardiac output, and decreased contractility. The presence or absence of intrinsic sympathetic activity can slightly modify these effects, as can concurrent therapy with an -AR antagonist.

Hence, when -AR antagonists are administered acutely intravenously or for the first time orally, careful monitoring of blood pressure and cardiac output should occur.

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Concurrent use of -AR antagonists and calcium channel antagonists may lead to severe hypotension, although ironically this combination is frequently used in patients with myocardial ischemia and angina. The advantage of using -AR antagonists is that resulting decreases in heart rate, blood pressure, cardiac output, and contractility in general decrease myocardial oxygen consumption and therefore decrease angina frequency.

Noncardiac side effects such as general malaise and impotence occasionally limit the use or patient compliance of -AR antagonist therapy. However, despite these caveats, -AR antagonists remain one of the major classes of drugs in the armamentarium of the cardiovascular clinician.


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One of the most interesting developments in the use of -AR antagonists is their effectiveness in preventing death. Although at first it seems paradoxical that an agent with negative inotropic properties would be given to patients with heart failure, these drugs have been shown to be effective presumably due to changes in -ARs associated with congestive heart failure.

During congestive heart failure, elevated systemic catecholamine levels result in desensitization or dampening of -AR function. Use of low-dose -AR antagonists prevents desensitization and improves congestive heart failure class. Often initiation of -AR antagonist therapy requires hospitalization and careful slow titration of drug Calcium is a major component in excitation-contraction coupling in both myocardial cells and vascular smooth muscle. Calcium fluxes into these cells via calcium channels mediate calcium-induced calcium release from the sarcoplasmic reticulum; this rapidly mobilized calcium from internal stores is critically important for muscle contraction.

Calcium channel antagonists have been used extensively over the years by cardiologists for the treatment of hypertension and ischemic heart disease. Many patients with cardiovascular disease scheduled for surgery, however, will be receiving calcium channel antagonists chronically General properties of calcium channels must be reviewed for a full understanding of this class of drugs.