Antiarrhythmic Drugs A practical guide – Part 6

90 Chapter 5 of calcium-channel blockade (a Class IV effect). All these effects can produce antiarrhythmic actions. Clinical pharmacology The clinical pharmacology of amiodarone can be fairly described as being bizarre, complex, and incompletely understood. After an oral dose, 30–50% is absorbed from the gastrointestinal tract. Once ab-sorbed, amiodarone displays a complex pattern of distribution that is usually described as (at least) a three-compartment model. The first, or central, compartment is thought to consist of the intravascular space. With aggressive loading regimens, the central compartment can be largely saturated within 24 hours. The second, or periph-eral, compartment probably consists of most of the body’s organs. It is thought to take 5–7 days to begin to saturate the peripheral compartment by use of a typical regimen for loading amiodarone— an important consideration because the antiarrhythmic effects of amiodarone are thought to require adequate filling of this periph-eral compartment. The third, or deep, compartment consists of the body’s fat. It takes many weeks or months for the third compartment to become saturated, and it may never actually become completely saturated. Because of the depth of this deep compartment, amio-darone has a huge volume of distribution, many times the body’s actual volume; it has been calculated to be as high as 500 L. Tissue concentrations of amiodarone vary markedly from organ to organ and are the highest in organs with high-fat content, such as the liver and the lungs. In vivo, amiodarone is in a state of equilibrium among the three compartments. If the drug is discontinued, the concentra-tion of amiodarone in the central compartment (the serum) falls quickly to low levels, but the low serum levels persist for weeks or months because of the slow leaching of the drug from the peripheral and deep compartments. Amiodarone is metabolized in the liver to desethylamiodarone (DEA),whichdisplayselectrophysiologiceffectssimilartotheparent compound and has similar pharmacologic properties. Very little amiodarone or DEA is excreted in the urine or the stool; essentially, amiodarone is stored, not excreted. Its chief means of elimination may actually be the gradual and natural sloughing of amiodarone-packed epithelial cells. The half-life of the drug has been reported as being between 2 weeks and 3 months in duration. This extraordi-narily long half-life is reflected in the low daily dosage requirement after loading has been achieved. Class III antiarrhythmic drugs 91 Dosage The unusual kinetics of amiodarone dictate the loading schedule. Usually, 1200–1600 mg/day are given orally in divided doses for several days (usually, 5–14 days), followed by 400–600 mg/day for severalweeks,andfinallybyachronicmaintenancedoseof200–400 mg/day. This sort of loading regimen was derived empirically, but it is a logical approach. By giving large doses for days to weeks, one can achieve relatively rapid saturation of the central and peripheral compartments. Achieving a steady state, however, requires filling the deep compartment, which takes many weeks. When treating non-life-threatening arrhythmias or when using amiodarone as prophylaxis against arrhythmias that are not mani-fest, a much gentler loading regimen is often used. Less aggressive loading schedules may avoid some toxicities associated with admin-istering higher doses of the drug but require significantly more time to achieve both an antiarrhythmic effect and a steady state. The use of intravenous amiodarone is generally reserved for the treatment of recurrent life-threatening ventricular tachyarrhyth-mias that have not responded to other therapies. The Class III ef-fects of amiodarone are not seen acutely with IV loading; relatively long-term administration of the drug is necessary before prolonga-tion of refractoriness is seen, just as with oral loading. The imme-diate effects of intravenous amiodarone are limited mainly to its Class II (beta-blocking) actions (Table 5.3), though some Class I ef-fect (sodium-channel blockade) is also seen acutely. Accordingly, the most prominent electrophysiologic effect is prolongation of the Table 5.3 Electrophysiologic effects of IV versus PO amiodarone* Administration PO IV QT interval Increase — AH interval Increase Increase Atrial RP Increase — Ventricular RP Increase — *The AH interval reflects the refractory period of the AV node. PO administration of amiodarone (after sufficient loading) results in prolongation of the action po-tential, as reflected by the resultant increase in the QT interval and in atrial and ventricular refractory periods; acute IV loading does not. The Class III effects of amiodarone are not seen with acute IV loading; instead, the increase in AV nodal refractorinessindicatesthattheClassII(andpossiblyClassIV)effectsofamiodarone predominate. RP, refractory periods. 92 Chapter 5 atrioventricular (AV) nodal refractory periods, and the most promi-nent hemodynamic effect is hypotension. Any immediate antiar-rhythmic efficacy with intravenous amiodarone is likely to be at least partially related to how dependent a patient’s arrhythmias are on catecholamine stimulation. When amiodarone is loaded intravenously, 1 g is delivered during the first 24 hours as follows: 150 mg is infused during the first 10 minutes (15 mg/min), followed by 360 mg during the next 6 hours (1 mg/min), and then followed by 540 mg during the next 18 hours (0.5 mg/min). If intravenous therapy is still desired after the first 24 hours, the infusion can continue at 0.5 mg/min (720 mg/24 h). Indications Amiodarone is a broad-spectrum antiarrhythmic agent. It can be efficacious for virtually any type of tachyarrhythmia, though it is approved by the FDA only for the treatment of ventricular tach-yarrhythmias. Amiodarone is the most effective drug yet developed for recur-rent ventricular fibrillation or hemodynamically unstable ventricu-lar tachycardia. Early studies with amiodarone generally limited its use to patients whose ventricular tachyarrhythmias had proven re-fractory (most often, as documented during electrophysiologic test-ing) to other antiarrhythmic therapy. Even in this difficult-to-treat population, amiodarone reduced the risk of sudden death to about halfthatseenwithmoreconventionaldrugs.Insubsequentrandom-ized trials, however, amiodarone proved to be significantly inferior to the implantable defibrillator in reducing mortality. The main in-dications for oral amiodarone today in the treatment of ventricular arrhythmias are to either reduce the frequency of shocks in patients whohaveimplantabledefibrillatorsorofferatleastpartiallyeffective therapy to patients deemed not to be candidates for an implantable defibrillator. Amiodarone is moderately effective in maintaining sinus rhythm in patients with atrial tachyarrhythmias, including atrial fibrillation and atrial flutter. In patients with heart failure, amiodarone is prob-ably the drug of choice after cardioversion for atrial fibrillation, since it has few adverse hemodynamic effects, and often results in a well-controlled ventricular response should the arrhythmia recur. (The use of antiarrhythmic drugs in the treatment of atrial fibrillation will be discussed in Chapter 11.) Amiodarone is also effective in bypass-tract-mediated tachycardias and AV nodal reentrant tachycardias. Class III antiarrhythmic drugs 93 However, these arrhythmias can almost always be cured with abla-tion procedures, and amiodarone should be used very rarely in their management. Adverse effects and interactions Amiodarone causes a high incidence of side effects, ranging from merelyannoyingtolifethreatening.Manysideeffectsofamiodarone appear to be related to the total lifetime cumulative dose of the drug (rather than to the daily dosage). Even when low daily dosages are used, therefore, significant side effects are seen, and the risk of de-veloping new side effects continues to increase as therapy continues over time. Side effects occur in approximately 15% of patients dur-ing the first year but increase to over 50% with chronic therapy. Ad-verse effects require discontinuation of the drug in approximately 20% of patients. It has been widely speculated that much of the unique organ toxicity seen with amiodarone is related to the io-dine atoms contained in the drug, a feature not shared by any other antiarrhythmic drug. Gastrointestinal side effects are common but, in most cases, are relatively mild. Nausea, vomiting, or anorexia have an incidence of approximately 25% during the high-dose loading phase, but these symptoms often improve with lowering of the daily dosage. Esophageal reflux caused by an amiodarone-induced paralysis of the lower esophageal sphincter is an uncommon but potentially devas-tating side effect. Elevation of hepatic transaminases of up to twice normal values is seen in about 25% of patients treated with amiodarone. In most cases, these elevations return toward normal after a few months, although amiodarone-induced hepatitis has been reported in ap-proximately 3% of patients. When hepatic transaminases remain chronically elevated, the consequences are unclear. Occasional cases of cirrhosis have been reported, however. Pulmonary complications are generally considered the most dan-gerous side effect seen with amiodarone and are the form of toxi-city most likely to prove fatal. Acute adult respiratory distress syn-drome from amiodarone-induced pneumonitis can be seen at any time during therapy, but the time of highest risk is probably immedi-ately after surgery, especially cardiac surgery. The incidence of acute amiodarone-induced pneumonitis is generally reported to be 2–5%, butthecumulativeincidencemaybehigherwithlong-termtherapy. A chronic interstitial fibrosis can also be seen with amiodarone; the 94 Chapter 5 incidence of this problem is unclear. The carbon monoxide (CO) dif-fusingcapacityisalmostalwaysdepressedwithamiodarone-induced pulmonary problems, but this laboratory finding is unfortunately nonspecific—many patients taking amiodarone develop depressed CO diffusing capacities without clinically apparent pulmonary prob-lems. Therefore, routine pulmonary function tests do not appear to help in predicting which patients will eventually develop lung toxicity. Thyroidproblemswithamiodaronearerelativelycommon.Amio-darone reduces peripheral conversion of T4–T3, resulting in some-what increased T4 levels and somewhat decreased T3 levels even in euthyroid patients. Approximately 10% of patients treated with amiodarone eventually develop true hypothyroidism (a low serum T4 level is always significant in patients taking this drug), and a smaller proportion develop hyperthyroidism. Although hypothy-roidism can be treated relatively easily with thyroid-replacement medication, hyperthyroidism represents a difficult clinical problem because of its presentation and its treatment. Amiodarone-induced hyperthyroidism sometimes manifests as an exacerbation of the pa-tient’s underlying ventricular tachyarrhythmias. This is a potentially lethal condition. Further, because amiodarone itself contains a sig-nificant amount of iodine, patients receiving amiodarone have high-iodine stores, which thus precludes the use of radioactive iodine for thyroid ablation. To make matters worse, treating amiodarone-induced hyperthyroidism with antithyroid drugs can be difficult or even impossible. Sometimes thyroidectomy is the only feasible means of controlling amiodarone-induced hyperthyroidism. Cutaneous side effects with amiodarone are relatively frequent. Significant photosensitivity occurs in about 20% of patients taking the drug, and some patients eventually develop a blue-gray discol-oration of sun-exposed skin, which can be quite disfiguring. Neurologic side effects are rare but can include ataxia, tremor, sleep disturbances, and peripheral neuropathy. A proximal myopa-thy can also be seen with amiodarone. Ocular symptoms (most often, poor night vision or halo vision) occasionally accompany the corneal microdeposits seen in virtually all patients taking amiodarone. Multiple drug interactions have been reported with amiodarone. The most common are the potentiation of warfarin and increased digoxin levels. Quinidine, procainamide, phenytoin, and flecainide levels are also increased. As a rule, if amiodarone is given in ... - tailieumienphi.vn