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50 Chapter 2 of antiarrhythmic drugs—the type and degree of blockade of chan-nels, antagonistic and agonistic effects on receptors, effects on the sodium–potassium pump, the time constants of binding to cellular sites, effects on second messengers, and the affinity for binding on the basis of whether the cell is in an active or inactive state. The resultant schema is shown in Figure 2.7. Drug Channels Receptors Pumps Cunical effects Cunical effects Lidocaine Mexiletine Tocainide Moricizine Procainamide Disopyramide Quinidine Propafenone Flecainide Encainide Na Fast Med Slow Ca k a I A A A A A A Left ver- Na-k ticular Sirus Extra 2 ATPase function Rate cardiac Bepridil ? Verapamil Diltiazem Bretylium Sotalol Amiodarone Alinidine ? Nadolol Propranolol Atropine Adenosine ? Digoxin Relative potency of block: Low = Agonist Moderate High = Agonist/Antagonist A = Activated state blocker I = Inactivated state blocker Figure 2.7 The Sicilian Gambit, a schema listing all major known proper-ties of antiarrhythmic drugs. Effects of each drug on channels, receptors, and pumps are shown, as are some of the clinical effects. (Reproduced with permission from Members of the Sicilian Gambit. Antiarrhythmic Therapy: A Pathophysiologic Approach. Armonk, NY: Futura, 1994:94). Introduction to antiarrhythmic drugs 51 Two major differences exist between the Vaughan-Williams scheme and the Sicilian Gambit approach. First, the Sicilian Gambit is far more thorough than the Vaughan-Williams system in describ-ing the precise actions of antiarrhythmic drugs. Second, inasmuch as each drug is essentially in its own class (since no two drugs are exactly alike in all the ways listed), the Sicilian Gambit is not a true classificationsystem.Instead,itisatabularlistofvirtuallyeverything known about each drug. This is not to say that the Sicilian Gambit is not useful. It is, in fact, useful to have a complete tabulation of all known effects of antiarrhythmic drugs. Such a table allows one to easily compare the recognized similarities and differences among drugs. Further, when the mechanisms of arrhythmias have become more precisely delin-eated, precise knowledge of individual drugs may help in formu-lating more accurate guesses as to effective pharmacologic therapy (which was a specific goal in devising the Sicilian Gambit), although it is likely to be always true that nearly identical patients with nearly identical arrhythmias often respond differently to the same drug. In addition, a tabulated system is certainly helpful to basic researchers. However, because the Sicilian Gambit is not a true classification system, it does not offer much help to the average clinician in learn-ing about or communicating about antiarrhythmic drugs. Nor does it aid in formulating practical generalizations about these drugs. Es-pecially for the nonexpert, the Vaughan-Williams system, with all its limitations, remains the most useful means of categorizing an-tiarrhythmic drugs; it is the system that will be used throughout this book. Part 2 Clinical features of antiarrhythmic drugs CHAPTER 3 Class I antiarrhythmic drugs The feature that gains an antiarrhythmic drug admission into Class I is blockade of the rapid sodium channel. Yet, because of their varied effects on the sodium channel and the potassium channel, drugs assigned to Class I can behave very differently from one another. On the basis of their sodium and potassium effects, Class I drugs have been subclassified into groups IA, IB, and IC. The major clinical features, electrophysiologic properties, and adverse effects of Class I antiarrhythmic drugs are summarized in the accompanying tables. Class IA ClassIAdrugscanbethoughtofasall-purposeantiarrhythmicagents because they are moderately effective in treating most types of tach-yarrhythmias. Unfortunately, they are also moderately effective in causing both major varieties of side effects—end-organ toxicity and proarrhythmias. As shown in Figure 3.1, Class IA drugs block the rapid sodium channel (slowing the upstroke of the cardiac action potential and therefore slowing conduction velocity) and the potassium channel (prolonging the duration of the action potential and prolonging re-fractoriness). These electrophysiologic effects are manifested in both atrial and ventricular tissue, and therefore Class IA drugs have the potential of treating both atrial and ventricular tachyarrhythmias. ThemajorclinicalfeaturesofClassIAantiarrhythmicdrugsaresum-marized in Table 3.1, and the major electrophysiologic features are summarized in Table 3.2. Quinidine Quinidine is the D-isomer of the antimalarial quinine, a drug that was noted to be effective in the treatment of palpitations as long 55 56 Chapter 3 Figure 3.1 Effect of Class IA drugs on the cardiac action potential. Baseline action potential is displayed as a solid line; the dashed line indicates the effect of Class IA drugs. ago as the eighteenth century. Quinidine itself was recognized as an effective antiarrhythmic agent in the early twentieth century. Clinical pharmacology Quinidine is administered orally as one of three salts (quinidine sul-fate, quinidine gluconate, or quinidine polygalacturonate). All three forms of the drug have been made available because some patients tolerate one salt better than another. Approximately 80–90% of the sulfate preparation is absorbed after oral administration, and peak plasma concentrations are reached within 2 hours. The gluconate and polygalacturonate preparations are absorbed more slowly and less completely than the sulfate formulation. Quinidine is 80–90% protein bound in the circulation and has a large volume of distribu-tion. The concentration of the drug is 4–10 times higher in the heart, liver, and kidneys than it is in the circulation. The drug is eliminated mainly through hepatic metabolism. Its elimination half-life is 5–8 hours but may be prolonged in patients with congestive heart failure or in the elderly. Electrophysiologic effects Quinidine blocks the sodium channel and slows the rate of depo-larization of the action potential. Like all Class IA drugs, quinidine ... - tailieumienphi.vn
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