Positive inotropic drugs and drugs used in dysrhythmias

J.K. Aronson

1 7 Positive inotropic drugs and drugs used in dysrhythmias CARDIAC GLYCOSIDES (SED-15, 648; SEDA-29, 182; SEDA-30, 209; SEDA-31, 321) Observational studies Hospital admissions because of digoxin toxicity became signifi­ cantly less common from 1991 to 2004 in the USA and the UK in the former this was associated with a reduction in the use of digoxin, but in the latter there was no such change. However, in both countries, the num­ ber of prescriptions written for a dose of at least 250 micrograms fell (1C). Of 2 987 580 hospital admissions in the Netherlands during 2001–2004 there were 1286 cases of digoxin intoxication (0.04%) (2C). The incidence rate for admission related to digoxin intoxication was 49 per 100 000 prescriptions (95% confidence interval [CI] = 46, 51), corresponding to 1.94 admissions per 1000 treatment-years. Women had a 1.4-fold higher risk of intox­ ication than men (95% CI = 1.3, 1.6). The age- and sex-adjusted relative risk of death in patients with digoxin intoxication com­ pared with those admitted for other reasons was 0.7 (95% CI = 0.5, 0.8). Cardiovascular Digoxin toxicity has again been briefly reviewed in the context of two cases, one associated with sinus bradycardia and ventricular bigemini and one with second-degree heart block (3Ar). Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32017-4
2010 Elsevier B.V. All rights reserved.

Gastrointestinal Non-occlusive mesenteric ischemia secondary to digitalis is rare but has again been reported, in a 76-year-old woman with digoxin intoxication (serum concentration 6.0 µg/l) (4A).

Mortality during treatment of atrial fibrillation with digoxin There have been several studies of the risk of death during treatment of atrial fibrillation with digoxin. In a post-hoc analysis of the results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study, the use of rhythm-control drugs was asso­ ciated with increased mortality after adjust­ ment for the other co-variates (hazard ratio [HR] = 1.49) and digoxin was associated with an increased risk of death (HR = 1.42; 95% CI = 1.09, 1.86) (5c). However, the authors suggested that that may have been caused by the use of digoxin in patients at a higher risk of death, such as those with heart failure, rather than by a deleterious effect of digoxin on survival. They also suggested that there may be other confounding factors in the reasons that physicians choose digoxin. Similarly, the survival of users and non­ users of digitalis has been investigated in a post-hoc analysis of data from the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V studies, in which 7329 patients with atrial fibril­ lation were randomized to warfarin or xime­ lagatran to prevent thromboembolism (6c). Users had a higher mortality than non-users

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(255/3911 versus 141/3418; 6.5% versus 4.1%; HR = 1.58; 95% CI = 1.29, 1.94). However, digitalis users also had more baseline risk fac­ tors, which would have confounded the results, even though after multivariate adjustment, the increased mortality persisted (HR = 1.53; 95% CI = 1.22, 1.92). The authors nevertheless sug­ gested that digitalis may increase mortality in patients with atrial fibrillation. Since both of these studies involved posthoc non-randomized analyses, they should be regarded as merely hypothesis generating. In a 1-year study using data from the Registry of Information and Knowledge about Swedish Heart Intensive care Admissions (RIKS-HIA), mortality was measured among 60 764 patients admitted to coronary care units with atrial fibrillation with or without congestive heart failure during 1995–2003 and adjusted for differences in background characteristics and other medications and treatments by propensity scoring (7c). Among those with atrial fibrillation without congestive heart failure there was a higher mortality rate in those who were discharged taking digoxin than in those who were not (adjusted RR = 1.42; 95% CI = 1.29, 1.56); there was no such difference among those who had con­ gestive heart failure with or without atrial fibrillation. The authors suggested that longterm therapy with digoxin may be an indepen­ dent susceptibility factor for death in patients with atrial fibrillation without congestive heart failure. However, as this study was based on registry data, confounding could have occurred. In 2824 patients with atrial fibrillation, who were studied prospectively for a mean of 4.6 years, information about medications was obtained from the local hospital registry and information about diagnoses, hospitali­ zations, and deaths from national registries (8c). Propensity score matching and Cox regression was used to account for con­ founding. Factors associated with the use of digoxin were permanent atrial fibrillation (HR = 3.2, CI = 2.7, 3.9), absence of a pace­ maker (HR = 2.3, CI = 1.6, 3.2), a history of heart failure (HR = 2.0, CI = 1.7, 2.5), treat­ ment in an internal medicine ward rather than a cardiology ward (HR = 1.6, CI = 1.3, 2.0), female sex (HR = 1.6, CI = 1.3, 1.9), and age 80 years or more (HR = 1.4, CI = 1.1, 1.7).

Chapter 17

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Mortality was higher among those who used digoxin than among those who did not (51% versus 31%); however, after adjustment for co-variates there were no effects of digoxin on all-cause mortality, myocardial infarction, ischemic stroke, time to readmission to hospital, or days spent in hospital per year at risk. The authors concluded that the increased mortality associated with digoxin is attributable to its use in an elderly and frailer subset of patients with atrial fibrillation. Conclusion There is currently no good evi­ dence that the use of digoxin is associated with increased mortality in patients with atrial fibrillation, with or without concurrent congestive heart failure. A proper prospec­ tive randomized study would be necessary to confirm or refute this hypothesis. Susceptibility factors Sex In an analysis of adverse drug reactions in four German pharmacovigilance centres, which resulted in hospitalization of 3092 patients in 2000– 2004, 314 patients were admitted because of adverse effects associated with cardiac gly­ cosides. The incidence of adverse reactions was 1.9 (CI = 1.0, 3.3) per 1000 patients exposed to cardiac glycosides per 3 months exposure. More women were affected than men (244 versus 70) and oral digitoxin was involved in 296 (228 women). Women received significantly higher body weightrelated doses of digitoxin and had signifi­ cantly higher digitoxin plasma concentra­ tions than men. Doses were high (over 1 microgram/kg/day) in 71% of the women but in only 29% of the men. Those who had adverse reactions to cardiac glycosides had a significantly lower body weight and were significantly older than patients with other adverse drug reactions. Drug administration route In a retrospec­ tive analysis of 1795 pregnant women at 17–24 weeks’ gestation who received vary­ ing doses of digoxin by transabdominal intrafetal injection (up to 1.0 mg) or intraamniotic injection (up to 0.5 mg) to obtain fetal death in advance of elective termination in the second trimester, the overall failure

Positive inotropic drugs and drugs used in dysrhythmias

rate was 6.6% (9c). There were no failures using an intrafetal dose of 1.0 mg, but fail­ ures occurred with lower doses. Failure rates were higher with intra-amniotic administration of 0.5 mg (8.3%) than intrafetal administration (3.6%). There were no adverse maternal events. Drug overdose The management of over­ dose with cardiac glycosides when there are serious complications involves the use of Fab fragments of digoxin-specific anti­ bodies. However, in patients with severe renal impairment, the clearance of Fab– digoxin complexes is reduced, and plasma­ pheresis has been used to remove them (10A, 11A), as illustrated by another report (12A). However, it should be remembered that although plasma exchange removes digoxin–Fab complexes and prevents rebound digoxin toxicity, it does not increase the clearance of digoxin, which has a large apparent volume of distribution. Non-fatal self-poisoning with Digitalis purpurea, whose main constituent is digi­ toxin, occurs occasionally (13A, 14A), and unintentional poisoning can occur when the leaves of the plant are mistaken for those of comfrey (Symphytum officinale) (15A, 16A). Fatal self-poisoning with D. pur­ purea has been reported (17Ar). • A 64-year-old man ate a whole D. purpurea plant. He became nauseated and developed a junctional rhythm, with concave up-sloping ST segment depression; he later developed a bradycardia and runs of second-degree atrioventricular block, which rapidly progressed to a sinus pause lasting 3.5 seconds, followed by sinus arrest. The serum potassium concentration was 4.3 mmol/l and the serum glycoside concentration, measured using a digoxin assay, was 36 µg/l. Despite repeated doses of activated charcoal and administration of digoxin-specific antibodies, he had a cardiac arrest and died. At post-mortem examination there were undigested and partially digested foxglove plant parts in the stomach.

The reference to van Gogh in the title of this report is misleading (18r, 19r). Drug–drug interactions Calcium salts Although it has been suggested that intra­ venous calcium should be used to treat the

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hyperkalemia that can occur in digitalis intoxication (20R), this suggestion has been challenged, on the grounds that calcium salts may increase the risk of cardiac dys­ rhythmias in such cases (21r). However, evi­ dence that that is so is anecdotal, and counterexamples have also been published (22A, 23A, 24r). This question has been reviewed in the light of a case in which intravenous calcium gluconate was benefi­ cial in a patient with hyperkalemia and digoxin intoxication (25AR). The authors concluded that digoxin toxicity should be treated with digoxin-specific antibodies, when they are available (as they were not in their case). However, for patients with life-threatening hyperkalemia with loss of P waves, and especially if there is QRS widening, they recommended intravenous calcium. They also recommended that while slow infusion of calcium may be desirable, the speed of infusion should be determined by the urgency of the problem. Proton pump inhibitors There are several ways in which proton pump inhibitors might interact with digoxin. Inhibition of gastric acid secretion prevents hydrolysis of digoxin in the stomach, increasing its sys­ temic availability (26C). In one study ome­ prazole increased the average Cmax and area under curve (AUC) of digoxin by about 10% and slightly shortened the tmax, although in a few patients the effect was larger (up to 30%); the half-life was not changed, suggesting a change in availability rather than clearance (27C). Proton pump inhibitors also cause a transepithelial paracellular leak in the gas­ tric mucosa, which allows molecules as large as 4 kDa to cross (28c), although the effect is specific for certain molecules, as it allows the passage of digoxin but not phenytoin (29E). Omeprazole also inhibits P glycoprotein (30E), inhibition of which in the transepithe­ lial transport of digoxin in the intestine and kidney would reduce its clearance. There has been a single report of digoxin toxicity attributed to an interaction with omeprazole (31A).

336 • A 65-year-old woman developed weakness, loss of balance, nausea, and xanthopsia. She had been taking digoxin 0.0625 mg/day for paroxysmal atrial fibrillation and her serum digoxin concentration had been 1.1 µg/l. Omeprazole 20 mg/day had been added for gastroesophageal reflux disease and her serum digoxin concentration was 3.9 µg/l; renal function was normal. She was given antidigoxin antibody Fab fragments and quickly recovered.

Rabeprazole may also increase the effects of digoxin (32c). However, a single oral of pantoprazole 40 mg had no effect on the pharmacokinetics of oral beta-acetyldigoxin 0.2 mg bd in 18 healthy volunteers or on the electrocardiographic effects of digoxin (33c). Quinine The interaction of digoxin with quinine has only occasionally been described (SED-15, 664). It seems to have the same basis as the interaction of digoxin with quini­ dine. Torsade de pointes has now been attributed to this interaction in a 76-year-old man who was taking digoxin 0.5 mg/day, qui­ nine sulfate 750 mg/day, aspirin 100 mg/day, candesartan 8 mg/day, and amlodipine 10 mg/ day; the plasma digoxin concentration was 5 µg/l (6.4 µmol/l) (34A). Vildagliptin In an open, randomized, three-period, crossover study in 18 healthy subjects during co-administration of vilda­ gliptin 100 mg/day and digoxin (0.5 mg, then 0.25 mg/day on days 2–7), there were no effects on the exposure to either drug, assessed by AUC0!24h and Cmax, or on half-life or clearance (35c).

Chapter 17

J.K. Aronson

Monitoring therapy The reasons for mon­ itoring the plasma digoxin concentration have again been reviewed in the context of a case report (37Ar). In summary: • measure the plasma digoxin concentration to monitor adherence to therapy; • measure it to diagnose toxicity, if indicated by the patient’s clinical state; • measure it to monitor for potential toxicity if renal function changes, or after a change in dosage, or after the addition of another drug that affects the pharmacokinetics of digoxin; • always measure the serum potassium concen­ tration at the same time as the plasma digoxin concentration, because potassium depletion makes the plasma digoxin concentration unin­ terpretable, and toxicity should be assumed in the presence of hypokalemia, whatever the plasma digoxin concentration; • measure the serum potassium and renal function indices at intervals, depending on the patient’s clinical state and other drugs taken; • samples for digoxin measurement should be taken at least 6–12 hours after the last dose (ideally 11 hours); note that steady state takes 8–10 days to reach after any change in dose if renal function is normal, and longer in renal impairment; • plasma concentration monitoring is not necessary in clinically and biochemically stable patients.

OTHER POSITIVE INOTROPIC DRUGS

(SED-15, 2822; SEDA-29, 183; SEDA-30, 212; SEDA-31, 323)

Milrinone (SED-15, 2346; SEDA-29, 183; Management of adverse drug reactions In a retrospective review of the records of 838 patients with raised serum digitalis con­ centration (digoxin > 1.95 µg/l or digitoxin > 23 µg/l), only 67 (8%) had received Fab fragments of antidigoxin antibody (36c). The authors concluded that the antibodies are underused in patients with raised digitalis con­ centrations and especially in those with chronic digitalis intoxication, who had a higher mortality rate than those with acute poisoning. They proposed that there should be identical criteria for the use of antidigoxin antibody after both acute and chronic poisoning.

SEDA-30, 212; SEDA-31, 323) Drug administration route Milrinone by inhalation reduces pulmonary artery pres­ sure and its use has been studied retrospec­ tively in high-risk patients, mean age 64 years, to evaluate their postoperative course (38c). Milrinone 5 mg was given administered before (n = 30) or after (n = 40) cardiopulmonary bypass, which lasted a mean of 145 minutes, with crossclamping for 91 minutes. Those who received inhaled milrinone before the start of cardiopulmonary bypass had a lower

Positive inotropic drugs and drugs used in dysrhythmias

pulmonary artery pressure after bypass and fewer needed emergency reinitiation of bypass after weaning (3% versus 23%). There were no detectable adverse effects.

ANTIDYSRHYTHMIC DRUGS Antidysrhythmic agents of class III have been reviewed, including the newer agents dofetilide, ambasilide, azimilide, chromanol 293B, dronedarone, ersentilide, ibutilide, sematilide, tedisamil, and trecitilide, as well as amiodarone, bretylium, and sotalol (39R).

ADENOSINE RECEPTOR AGONISTS (SED-15, 36; SEDA-29, 185; SEDA-30, 212; SEDA-31, 323)

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adenosine 12 mg, which terminated sponta­ neously after 3 minutes (42A). Although not prolonged, this is longer than one would expect. Prolonged complete heart block requiring intubation and temporary pacing, after the administration of adenosine to a patient with an atrial flutter treated with metoprolol and diltiazem, has also been reported (43A). Accessory conduction pathways can be associated with dysrhythmias after the administration of adenosine. A 79-year-old man developed sustained second-degree atrioventricular block after adenosine infu­ sion for nuclear stress testing and required a permanent pacemaker (44A). In another case a non-sustained polymorphous ventri­ cular tachycardia occurred during adeno­ sine stress perfusion imaging in a patient with a pre-excitation electrocardiographic pattern (45A). Paradoxical coronary artery vasospasm with bursts of polymorphous tachycardia occurred after withdrawal of adenosine following a stress test in a patient with vasospastic angina (46A).

Adenosine and analogues Cardiovascular In a retrospective review of 1948 adenosine stress myocardial perfusion studies, adenosine-induced atrial fibrillation occurred in eight (0.41%) cases 90–170 seconds after the infusion (40Ac). Three had a history of atrial fibrillation, two had a his­ tory of coronary artery disease, and seven had more than one risk factor for coronary artery disease. In three cases, the dysrhyth­ mia was preceded by bradycardia, adenosineinduced second-degree atrioventricular block, or sinus pauses. All converted spon­ taneously to sinus rhythm after 15 seconds to 6 hours. Pre-excited atrial fibrillation occurred in a 31-year-old woman with Wolff–Parkinson– White syndrome after the administration of adenosine (41A). The adverse effects of adenosine are usually transient, because it has a half-life of a few seconds. One patient developed a monomorphic ventricular tachycardia after termination of an atrioventricular nodal re-entrant tachycardia with intravenous

Dyspnea and bronchospasm associated with adenosine Asthma is a contraindication to the use of adenosine, which can cause bronchospasm in susceptible patients. In one case aden­ osine, 140 micrograms/kg/minute for 1 min­ ute, caused severe bronchospasm in a 78­ year-old woman with pre-existing chronic obstructive pulmonary disease (COPD), but no evidence of reversible obstruction; it did not respond to repeated doses of inhaled salbutamol 100 micrograms but did respond to intravenous theophylline 50 mg (47A). However, the authors stressed that they did not want to discourage the use of adenosine in patients with COPD but no evidence of pre-existing reversible airway obstruction, as this adverse effect is rare in such patients. In another case, adenosine caused respiratory arrest in a patient with asthma (48A). In patients with a history of COPD or asthma, who were given adenosine

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140 mg/kg/minute for 4 minutes for stress myocardial perfusion scintigraphy, those with a history of asthma were given an inhaled bronchodilator before the administration of adenosine (49A). Most of the patients (24/46) did not have any dyspnea or chest pain during adenosine infusion. However, 14 had chest discomfort during adenosine and 9 complained of dyspnea. None required aminophylline or resuscitation. In a case-control study, patients with known or suspected mild asthma or COPD were pre­ treated with an inhaled beta2-adrenoceptor agonist and adenosine titrated up to a max­ imum of 140 micrograms/kg/minute over 6 minutes (50C). Of 1261 patients, 124 had known or suspected airway disease and 72 who were suitable for adenosine stress testing were compared with 72 controls. The most common adverse effects were dyspnea and chest pain; the former was significantly more common in those with asthma (38 versus 25 controls) but not the latter (14 versus 16 con­ trols); these effects were mostly mild and well tolerated. Bronchospasm occurred in five patients with asthma/COPD but resolved shortly after the end of the adenosine infusion; aminophylline was not required in any case. Because of the association of adenosine with bronchospasm, beta2-adrenoceptor agonist-induced supraventricular tachycardia in patients with asthma poses a therapeutic problem. In two boys with exacerbations of asthma and salbutamol-induced supraventri­ cular tachycardia, adenosine converted the rhythm without worsening the asthma (51A). This confirms previous reports that adenosine may be safe in such cases (52Ar, 53c). However, adenosine can cause dyspnea in the absence of bronchospasm, perhaps through stimulation of vagal C fibers in the airways and lungs. In 12 healthy subjects, mean age 32 years, intravenous adenosine 10 mg was given after inhalation of aerosoli­ zed lidocaine or placebo on two separate days (54C). After about 20 seconds, adenosine caused dyspnea, increased minute ventilation and caused transient bradycardia followed by tachycardia. The intensity of the dyspnea was markedly reduced by lidocaine, but the increased minute ventilation and heart rate responses were not affected.

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Of 54 patients, 7 of whom had mild COPD, 36 developed dyspnea during adenosine infu­ sion (55c). In those with mild COPD, respira­ tory resistance was significantly higher (0.48 versus 0.27 kPa/l/second), but neither those with nor those without COPD had a signi­ ficant increase in respiratory resistance during adenosine infusion. Respiratory resistance in those with dyspnea was insignificantly lower than in those without dyspnea. The authors concluded that bronchospasm had not been the cause of the dyspnea that their patients had suffered.

Adenosine receptor agonists (SEDA-30, 213; SEDA-31, 324) Observational studies In an open, rando­ mized, parallel-group, multicenter study in 133 adults who had completed diagnostic cardiac catheterization, the selective A2A adenosine receptor agonist binodenoson 0.3, 0.5 or 1 micrograms/kg/minute for 3 minutes or as a bolus injection of 1.5 or 3 micrograms/kg caused dose-related coron­ ary hyperemia within seconds (56c). All doses transiently caused reduced blood pressure, increased heart rate and an increased rate–pressure product. There were no adverse effects on the electrocardiogram. In an open dose-escalation study, the selective A2A adenosine receptor agonist regadenoson 10–500 micrograms by rapid intravenous bolus dose-relatedly increased peak intracoronary blood flow velocity in 34 subjects by up to 3.4 times (57c). Regade­ noson 400–500 micrograms increased heart rate by a mean of 21/minute and reduced systolic blood pressure by 5–24 mmHg and diastolic blood pressure by 8–15 mmHg. In another four subjects aminophylline 100 mg attenuated the increase in peak flow velocity but not the tachycardia caused by 400 micrograms of regadenoson. Adenosine and regadenoson in stress myocardial perfusion imaging have been compared in a database study of 2015 patients; regadenoson caused less chest pain, flushing, and throat, neck, or jaw

Positive inotropic drugs and drugs used in dysrhythmias

pain, but more headache and gastrointestinal discomfort (58c). Placebo-controlled studies In a crossover, randomized, double-blind, placebo-controlled trial, patients with asthma were challenged with adenosine monophosphate after rega­ denoson or placebo pretreatment (59C). The forced expiratory volume in 1 second (FEV1) was significantly higher at baseline at 10–60 minutes after treatment with regadenoson, but one patient had a 36% asymptomatic reduction in FEV1, which resolved spontaneously. The most common adverse events with regadenoson were tachy­ cardia (66%), dizziness (53%), headache (45%), and dyspnea (34%). Regadenoson increased the mean heart rate significantly (maximum 10/minute) compared with placebo. In a randomized, double-blind, placebocontrolled, crossover trial of regadenoson in 38 patients with moderate COPD and 11 patients with severe disease, there were no differences between regadenoson and pla­ cebo on multiple lung function parameters, including FEV1 and forced vital capacity, respiratory rate and oxygen saturation (60C). The mean maximum falls in FEV1 were 0.11 and 0.12 liters in patients who received regadenoson and placebo, respec­ tively, and there was new-onset wheezing in 6% and 12%. No patient required acute treatment with bronchodilators or oxygen.

Amiodarone

(SED-15, 148; SEDA-29, 185; SEDA-30, 213; SEDA-31, 324)

Enhanced eryptosis as a possible mechanism of action of amiodarone Eryptosis is a process of suicidal cell death undergone by erythrocytes, in which the pro­ cess known as scrambling of the cell mem­ brane occurs; erythrocyte shrinkage, exposure of membrane-bound phosphatidylserine, and annexin binding occur, mimicking features of

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apoptosis in nucleated cells (61R). The phos­ pholipids in erythrocyte plasma membranes are asymmetrically distributed; sphingo­ myelin and phosphatidylcholine are predomi­ nantly in the outer leaflet of the bilayer and phosphatidylserine and phosphatidylethano­ lamine in the inner leaflet. Alteration (‘scram­ bling’) of this asymmetry is an important feature of eryptosis. Eryptosis can be triggered by activation of calcium-permeable cation channels (62E–64E), with entry of calcium, which activates calcium-dependent potassium channels, leading to egress of potassium, chloride, and water, and thus to cell shrinkage (65E, 66E). These effects can be stimulated by the calcium ionophore iono­ mycin and by osmotic shock, oxidative stress, and glucose depletion. They are inhibited by inhibitors of the channels involved, such as amiloride and its analo­ gue ethylisopropylamiloride, charybdo­ toxin, chloride channel blockers such as niflumic acid, and antisense oligonucleo­ tides against the small-conductance cal­ cium-activated potassium channel isoform hSK4 (KCNN4); some of these effects are inhibited by phenylephrine, dobutamine, dopamine, catecholamines, and erythropoie­ tin. Calcium further triggers calcium-sensi­ tive scrambling of the cell membrane, causing breakdown of phosphatidylserine asymmetry, thought to result from activation of a so-called scramblase, which is sensitive to the intracellular concentration of free calcium (67E), with translocation of plasma membrane phospholipids and exposure of phosphatidylserine at the erythrocyte sur­ face. Cell membrane scrambling is also trig­ gered by ceramide (acylsphingosine) (68E). Erythrocytes in which membrane phosphati­ dylserine is exposed are rapidly eliminated from the blood, being engulfed by circulating macrophages (69E). Drugs that can stimulate eryptosis include chlorpromazine (70E), ciclosporin (71c), and paclitaxel (72c). Exposure of erythrocytes to lead (73E) and mercury (74E) does likewise. Several diseases are associated with acceler­ ated eryptosis, including sickle cell disease, thalassemia, and glucose-6-phosphate dehy­ drogenase deficiency (75c), hemolytic–uremic

340

syndrome (76c), malaria (77E), in which it may contribute to accelerated removal of the erythrocytic form of the parasite (78E), sepsis (79c), phosphate depletion (80E), iron deficiency (81E), Wilson’s disease (82E), and amyloidosis (83E). When erythrocytes from healthy volun­ teers were exposed to amiodarone 1 µmol/l, the intracellular calcium concentration rose and annexin V binding was triggered (84E). However, amiodarone did not significantly affect ceramide formation, which is a feature of eryptosis. Amiodarone also increased annexin binding after hypertonic shock by the addition of sucrose 550 mmol/l but did not significantly alter the enhanced annexin binding after chloride removal by replace­ ment with gluconate. Thus, amiodarone appears to produce some of the effects that are associated with eryptosis and triggers phosphatidylserine exposure. However, it is not clear that the concentrations that produce this effect in vitro are relevant to in vivo therapy with amiodarone and specifically its adverse effects on the blood. Because eryptosis may be a mechanism whereby the clearance of Plasmodiuminfected erythrocytes are cleared, the effect of amiodarone on phosphatidylserine expo­ sure in Plasmodium-infected erythrocytes has been studied, in case it might affect the course of malaria (85E). Human erythro­ cytes were infected in vitro with Plasmodium falciparum, which increased annexin V bind­ ing, and this effect was significantly increased by amiodarone 10 µmol/l. Amiodarone also significantly reduced intraerythrocytic DNA/ RNA content and in vitro parasitemia. Fol­ lowing infection of mice with Plasmodium berghei, amiodarone 50 mg/kg significantly reduced the parasitemia and increased the survival of infected mice (from 0% to 70% 26 days after infection). Amiodarone also significantly increased the percentage of infected erythrocytes. Thus, amiodarone inhibited the intra-erythrocytic growth of Plasmodium falciparum, enhanced the suicidal death of infected erythrocytes, reduced parasitemia after Plasmodium bergheiinfection and supported host survival during malaria.

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Cardiovascular In the context of a case report it has been suggested that prolonga­ tion of the QT interval by amiodarone is the result of combined block of the rapid and slow components of the outward potassium current (IKr and IKs) in cardiac cells (86Ar). It has been proposed that activation of the IKs channel, for example with isoprenaline, could mitigate this adverse effect of amio­ darone (87A). The importance of susceptibility factors for cardiac dysrhythmias has been stressed in two cases. In one case intravenous amio­ darone unmasked congenital prolongation of the QT interval in a 62-year-old man with new-onset atrial fibrillation and no history of other dysrhythmias (88A). In another case torsade de pointes occurred in a 72-year­ old woman with pre-existing QT interval prolongation after the administration of amiodarone 300 mg/h for 3 hours (89A). Sinus bradycardia has been studied in 477 patients, mean age 49 years, taking amio­ darone, mean loading dose 809 mg/day, mean maintenance dosage 263 mg/day, mean duration of follow-up 21 months (90c). There was sinus bradycardia in 32% and 11% of patients during loading with amiodarone and maintenance treatment respectively. Phlebitis is a common complication when amiodarone is infused into a peripheral blood vessel, and although it may be possi­ ble to reduce the risk by using a low con­ centration (e.g. less than 2 mg/ml), the risk is still relatively high and has been esti­ mated at 14% (95% CI = 2.6, 25%) in a study in 273 patients, of whom 36 developed phlebitis (91c). When possible a large vein should be used for infusion of amiodarone. Respiratory Amiodarone-associated pneu­ monitis has again been reviewed in the context of case reports (92Ar, 93Ar). The hypothesis that aryl radical forma­ tion is involved in the adverse effects of amiodarone has been tested (94E). Photo­ lysis of anerobic aqueous solutions of amio­ darone and N-desethylamiodarone resulted in the formation of an aryl radical, as deter­ mined by spin-trapping and electron para­ magnetic resonance (EPR) spectroscopy.

Positive inotropic drugs and drugs used in dysrhythmias

The non-iodinated analogue, didesiodo­ amiodarone, did not form aryl radicals under identical conditions. The cytotoxicity of these compounds was also studied in human lung epithelioid HPL1A cells. Desethylamiodarone had a more rapid and potent effect (LC50 8 µmol/l) than amio­ darone (LC50 146 µmol/l), and dides­ iodoamiodarone was intermediate (LC50 26 µmol/l), suggesting that the iodine atoms play a minor part. Incubation of human lung epithelial cells with the spintrapping nitrones alpha-phenyl-N-t-butyl­ nitrone 10 mmol/l and alpha-(4-pyridyl N-oxide)-N-t-butylnitrone 5.0 mmol/l did not significantly protect against cytotoxicity. Intratracheal administration of amiodarone to hamsters produced pulmonary fibrosis by day 21, which was not prevented by 4 days of treatment with the spin-trapping nitrones. The authors suggested that although amiodarone can generate an aryl radical photochemically, its in vivo forma­ tion may not be a major contributor to toxicity. The mechanisms of amiodarone-induced lung toxicity have been studied in relation to interferon gamma, which inhibits pul­ monary fibroblast proliferation, and inter­ leukin-4 (IL-4), which increases fibroblast growth and collagen production (95c). The ratio of interferon gamma to interleukin-4 produced by activated peripheral cluster of differentiation 4 (CD4) T cells increased during treatment with amiodarone in 26 patients, 6 of whom had lung toxicity. The serum concentration of desethylamiodar­ one was lower in those with lung damage and was inversely proportional to the ratio of interferon gamma to interleukin, which was the most powerful indicator of amiodar­ one lung toxicity in a multilogistic regression analysis. In an analysis of 237 cases of amiodarone­ associated pulmonary toxicity (described as interstitial lung disease, pulmonary fibrosis, pulmonary infiltrates, pleural effusion, alveolitis fibrosis, pneumonitis, bronchiolitis obliterans organizing pneumonia, or crypto­ genic organizing pneumonia), only age and duration of therapy significantly affected the risk (96c). The authors suggested that

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targeted monitoring of patients aged over 60 years and those who have taken amio­ darone for 6–12 months may minimize the risk of morbidity and mortality secondary to lung complications. In the context of three men, all smokers, aged 75, 93, and 85 years, who developed diffuse interstitial pneumonitis after taking amiodarone 200 mg/day for an average of 6.6 months, the authors suggested that old age and pre-existing lung abnormalities caused by smoking could be associated with amio­ darone-related pulmonary toxicity (97Ar). In a patient with peripheral edema and respiratory crackles on auscultation, a diag­ nosis of cardiac failure was made. However, there was platypnea rather than orthopnea, and a computed tomography (CT) scan showed an interstitial pneumonitis, which was attributed to amiodarone (98A). In 15 patients with raised serum globulin concentrations who were taking amiodar­ one the serum globulin concentrations nor­ malized after drug withdrawal; 11 of these patients had amiodarone toxicity according to the authors, and 9 had amiodarone-asso­ ciated pneumonitis (99c). A pleural effusion has been attributed to the combination of amiodarone and hypo­ albuminemia in a patient with severe burns (100A), but could have been due to the hypoalbuminemia alone. There have been rare reports of isolated lung masses attributed to amiodarone, and another case has been reported (101A). The mass contained myofibroblasts, aggregates of foamy macrophages containing multiple lamellar bodies (typical of amiodarone), and chronic interstitial inflammatory cells. The lesion resolved completely within 3 months of amiodarone withdrawal. Following reports that the adverse effects of amiodarone on the lungs can occur after relatively short-term therapy (SEDA-30, 214; SEDA-29, 186), a prospective study has been conducted in 102 patients, who were admitted to an intensive care unit (ICU) after cardiac surgery and who received short-term prophylactic amiodar­ one if they were thought to be at high risk of atrial fibrillation (102c). They were given 900 mg/day intravenously for the first 2 days

342

and 600 mg/day thereafter. There were no significant effects of amiodarone on respira­ tory function. In contrast, a rapidly fatal case of lung damage has been reported in a man who was given intravenous amiodarone. • A 72-year-old man who developed atrial fibrillation after three-vessel coronary artery bypass grafting was given an intravenous loading dose of amiodarone 5 mg/kg over 20 minutes and then an infusion at a rate of 750 mg/day. Sinus rhythm was restored after 2 hours, but he became increasingly breathless, with an oxygen saturation of 85% on oximetry. His breath sounds were reduced at the lung bases and there were bibasilar râles. Arterial blood gases showed a respiratory acidosis. His erythrocyte sedimentation rate was 156/hour and the leukocyte count was 16.5  109/l. A chest X-ray showed bilateral alveolo­ interstitial infiltrates. A CT scan showed prominent bilateral densities, mainly at the perihilar space, radiating to the periphery, with a ground-glass appearance. He died after an episode of ventricular fibrillation. Post­ mortem examination showed a diffusely deranged lung parenchyma with foamy cells typical of amiodarone toxicity, interstitial and intra-alveolar edema, and hyaline membranes with diffuse dilatation of the airways and hyperplasia of the alveolar cells.

In 500 consecutive Japanese patients tak­ ing amiodarone who were retrospectively evaluated, the mean follow-up period was 48 months and the mean maintenance dosage was 141 mg/day (103c). The cumula­ tive incidences of lung damage at 1, 3, and 5 years were 4.2%, 7.8%, and 11% respec­ tively. Multivariate analysis showed that age at the start (HR = 1.48; 95% CI = 1.13, 1.93) was a significant pretreatment suscept­ ibility factor. Age (HR = 1.64; 95% CI =1.29, 2.09), maintenance dosage (HR = 1.90; 95% CI = 1.45, 2.49) and plasma monodesethylamiodarone concen­ tration (HR = 1.30; 95% CI = 1.08, 1.58) were susceptibility factors during treatment. The diagnostic sensitivity and specificity of percent predicted diffusion capacity of carbon monoxide were 68% and 69% for at least a 15% reduction and 59% and 74% for at least a 20% reduction. The diagnostic sensitivity and specificity of a serum KL-6 concentration of at least 500 U/ml were 25% and 91% respectively. The authors

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concluded that amiodarone can cause sub­ stantial pulmonary toxicity even at low doses, particularly in older patients. Nervous system Cerebellar ataxia, with a wide-based gait, bilateral dysdiadochokinesia, and bilateral nystagmus, has been reported in a 95-year-old woman who had taken amio­ darone 200 mg/day for 8 months (104A). Sensory systems Eyes In vivo confocal microscopy has been performed in 20 eyes of 10 patients (6 men and 4 women) at different stages of amiodarone-induced ker­ atopathy (105c). There were brilliant intra­ cellular inclusions with high reflectivity in the basal epithelium layer in all cases. Patients with stage 2 and 3 changes had all corneal layers affected. There was thinning and increased tortuosity of the corneal nerves in patients with stage 2 and 3 changes. The authors concluded that the basal epithelium was most affected at any stage of keratopathy; in stage 1 only the superficial and basal epithelium are affected, while in stages 2 and 3 all the corneal layers are affected. With advancing keratopathy the corneal nerves became thinner and tortuous. Rarely, keratopathy can affect the whole cornea (106A). Amiodarone can cause optic neuropa­ thies (107Ar). The question of whether it can cause a non-arteritic anterior ischemic optic neuropathy at all has been briefly discussed (108r, 109r), and ischemic optic neuropathy has again been reported (110A). In a prospective, double-masked, rando­ mized study of amiodarone (n = 837) or pla­ cebo (n = 832) with a median follow-up in survivors of 46 months, there were no cases of bilateral visual loss (111C). The authors calculated that the maximum possible annual incidences of bilateral visual loss in subjects taking amiodarone continuously for 4 to over 60 months in daily doses of > 2.0 mg/kg (n = 696), > 3.0 mg/kg (n = 559), or > 4.0 mg/kg (n = 219) were 0.23%, 0.29%, and 0.74% respectively. Smell Anosmia has been attributed to amiodarone in a 66-year-old man who took amiodarone 200 mg/day for 3 years;

Positive inotropic drugs and drugs used in dysrhythmias

the symptom abated when the dosage was reduced to 100 mg/day (112A). Endocrine Thyroid There are two types of amiodarone-induced thyrotoxicosis: type 1 occurs in those with latent disease and is due to the iodine that amiodarone contains; type 2 is due to a destructive thyroiditis in a previously normal gland. The incidence and predictability of amiodarone-induced thyrotoxicosis and hypothyroidism have been studied in 72 patients with cardiomyopathy during a median follow-up period of 8 months (113c). The prevalence of thyroid dysfunc­ tion before the start of amiodarone therapy was 38% (n = 27), with almost equal distri­ bution between hypothyroidism and hyperthyroidism (n = 14 and 13). After treatment with amiodarone, thyroid dys­ function was diagnosed in 25 of the 44 patients without pre-existing dysfunction. Of these, nine developed either subclinical or overt hypothyroidism and 16 developed either subclinical or overt hyperthyroidism. Factors such as 99mTc-pertechnetate scan uptake, thyroid autoimmunity, age, thyroid autonomy, or abnormal thyroid morpho­ logy were not significantly associated with the development of thyroid dysfunction The usefulness of thyroid scintigraphy has been assessed in 27 consecutive patients (mean age 65 years, 13 women) with amio­ darone-associated hyperthyroidism (114c). All underwent 99mTc-pertechnectate thyroid scintigraphy and were classified according to the qualitative estimation of radiotracer uptake. Type 1, defined by increased/normal uptake, occurred in nine patients, all of whom responded to antithyroid drugs or radioiodine, except one with subclinical hyperthyroidism, who received no therapy. Type 2, defined by very low or undetectable uptake, occurred in 13 patients, 11 of whom responded to withdrawal of amiodarone or prednisone therapy. Hyperthyroidism was resistant in two patients and required antithyroid drugs or potassium perchlorate. The authors concluded that thyroid scinti­ graphy can establish the correct therapeutic approach in most cases of amiodarone­ induced hyperthyroidism.

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The usefulness of Doppler scanning in differentiating the two types has been eval­ uated in 84 healthy subjects, 30 euthyroid patients taking amiodarone, 14 patients with type 1 thyrotoxicosis, and 9 with type 2 thyrotoxicosis (115c). The two types were classified by 131I uptake and the clinical out­ come. The authors suggested that systolic peak velocity in the thyroid arteries could differentiate the two types of thyrotoxicosis. In another study of the usefulness of colorflow Doppler sonography, amiodarone­ associated thyrotoxicosis was classified as type 1 if there was increased blood flow (n = 11) and as type 2 if there was low or no blood flow (n = 10). Ten of the 11 patients in the first group had a hypervascular nodular pattern and one had a hypervascular parenchymal pattern; the clinical diagnoses were toxic nodular goiter and Graves’ disease respectively. Of the 10 patients in the second group, 6 had a normal thyroid volume, 3 a small diffuse goiter, and one a small multinodular goiter (116c). In a retrospective analysis of the preva­ lence and relative proportions of type 1 and type 2 amiodarone-associated thyrotoxico­ sis in 215 patients seen over 27 years in an Italian centre, type 1 was more frequent (60%) at the start but became less frequent with time; the annual mean number of patients with type 1 thyrotoxicosis was 3.6 at the beginning of the study period and 2.5 during the later years (117c). In contrast, the mean annual number of new cases of type 2 thyrotoxicosis progressively increased from 2.4 to 13. Likewise, the proportion of cases of type 2 thyrotoxicosis increased linearly, and by the end of the study was accounting for 89% of the cases. Patients with type 2 thyrotoxicosis were preponderantly male, had a higher serum free T4/free T3 (FT4/ FT3) ratio and lower 3 hour and 24 hour thyroid radioactive iodine uptake, and had taken a higher cumulative dose of amiodarone. The long-term risk of amiodarone­ induced thyroid dysfunction has been studied in 612 men who had taken part in a prospective, randomized, placebocontrolled trial of amiodarone and sotalol for persistent atrial fibrillation (118C).

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Subclinical hypothyroidism, with thyroidstimulating hormone (TSH) concentrations of 4.5–10 mU/L, occurred in 26% of those taking amiodarone and only 6.6% of the controls, and overt hypothyroidism (TSH > 10 mU/l) in 5.0% versus 0.3%; 94% of the cases of overt hypothyroidism were detected by 6 months, suggesting an inter­ mediate time-course. There was a trend towards a greater frequency of hyperthyr­ oidism (TSH < 0.35 mU/l) in those who took amiodarone (5.3% versus 2.4%). The histopathology of amiodarone-asso­ ciated hypothyroidism in a 66-year-old Japanese woman has been reported (119A). Most of the thyroid follicles were enlarged with dense colloid substance and lined by flattened follicular cells (involuted follicles). A few damaged follicles were infiltrated by macrophages, which were immunopositive for HAM56. Sudan IV staining showed many lipid droplets in folli­ cular cells. Ultrastructurally, the follicular cells contained large residual bodies com­ posed of abundant electron-lucent lipid dro­ plets of variable sizes. The methods by which different endocrin­ ologists manage amiodarone-induced thyr­ oid disease vary (SEDA-29, 186). In a questionnaire study the methods used by North American specialists (n = 115) have been compared with those of European specialists from a previous study (n = 101) (120c). Amiodarone-induced hyperthyroid­ ism was less frequent than amiodarone­ induced hypothyroidism in North America (34% and 66% of all cases of amiodarone­ induced thyroid dysfunction respectively, versus 75% and 25% in Europe). When hyperthyroidism is suspected, in North America hormonal assessment is mostly based on serum free T4 and TSH measure­ ments, and serum FT3 determination is requested less often than in Europe; thyr­ oid autoimmunity is included in the initial assessment less often than in Europe. The most commonly used other diagnostic pro­ cedures include, as in Europe, thyroid color-flow Doppler sonography, and to a lesser extent radioactive iodine uptake and thyroid scanning. Withdrawal of amioda­ rone is more often considered unnecessary

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in North America (21% versus 10% in type 1 hyperthyroidism and 34% versus 20% in type 2). In type 1, thionamides are the treatment of choice by both groups, but they are used as monotherapy in North America in 65% of cases com­ pared with 51% in Europe, where potas­ sium perchlorate is more often considered as a useful addition (31% versus 15% in North America). Glucocorticoids are the treatment of choice for type 2 hyperthyr­ oidism, alone (62% versus 46% in Europe) or in association with thionamides (16% versus 25% in Europe). After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 hyperthyroidism less often in North America. If amiodar­ one therapy needs to be reinstituted, pro­ phylactic thyroid ablation is advised by 76% in type 1 hyperthyroidism, while a wait-and-see strategy is adopted by 61% in type 2 hyperthyroidism, similar to the European approach. The effects of potassium perchlorate on thyroid function have been retrospectively studied in 10 patients with amiodarone­ induced thyrotoxicosis without underlying thyroid disease while they continued to take amiodarone (121c). Potassium perchlorate restored euthyroidism in all patients within 28 (range 15–45) days, but after it was with­ drawn all the patients became thyrotoxic again after 45 (range 30–60) days. One patient developed a mild leukopenia and one had a slight increase in serum creatinine, which normalized after withdrawal of potas­ sium perchlorate. The authors recommended that potassium perchlorate should not be used as a first-line treatment for thyrotoxi­ cosis if amiodarone needs to be continued. The use of radioactive iodine to cause thyroid ablation has been studied in four patients with type 2 amiodarone-induced thyrotoxicosis who either were poor candi­ dates for surgery or had refused it (122c). They had been initially treated with thion­ amides and glucocorticoids and all but one had become euthyroid. All four patients received one dose of radioactive iodine (range 29–80 mCi) and were followed up for 12 months. There were no exacerbations of

Positive inotropic drugs and drugs used in dysrhythmias

thyrotoxicosis, but hypothyroidism occurred in three patients in the first 6 months. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hyponatremia due to SIADH has again been attributed to amiodarone (123A, 124A). Hematologic Amiodarone-associated bone marrow granulomata have been reviewed in the light of two further cases, in an 81-year-old man who developed leukopenia, thrombo­ cytopenia, and hepatosplenomegaly after tak­ ing amiodarone for 2 years and an 80-year-old man who developed pancytopenia after 2.5 years; both patients had non-caseating granulomata in the bone marrow (125Ar). The authors reviewed eight other published cases, one of which also featured hepatic granulomata. Liver Intravenous amiodarone can rarely cause acute hepatitis, and further cases have been reported, associated with very high rises in serum transaminases (126A, 127A). It is not clear whether this effect is due to the amiodarone itself or to the vehicle in which it is formulated, polysorbate (Tween) 80. The PPAR-Iþ/- gene may be a susceptibility factor. Pancreas Pancreatitis, a rare adverse effect of amiodarone, has again been reported (128Ar). • A 66-year-old woman who had taken amiodar­ one 200 mg/day for 1 month developed epigas­ tric pain radiating to both flanks associated with a raised serum lipase but a normal serum amylase. Endoscopic ultrasonography suggested pancreatitis. There were no asso­ ciated causal factors, such as biliary stones, hypertriglyceridemia or excess alcohol con­ sumption. Amiodarone was withdrawn. Her symptoms quickly resolved and the serum lipase activity fell. Three months later the abdominal pain had not recurred.

Urinary tract Renal damage associated with amiodarone-induced phospholipidosis has been reported; a renal biopsy showed lamellar lipid inclusions typical of amiodar­ one and there were also corneal microdepo­ sits (129A).

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Skin The blue-grey skin pigmentation in sun-exposed areas associated with amiodarone has been presumed to be due to deposition of lipofuscin. However, electron microscopy and high-performance liquid chromatogra­ phy have shown deposits of amiodarone in a sample of skin from a patient with such pigmentation, and no lipofuscin (130A). The authors therefore suggested that amiodar­ one-related skin pigmentation should be considered a skin storage disease that is secondary to drug deposition, i.e. a betweenthe-eyes reaction of type 1 (131H). Sexual function Another case of epididy­ mitis, a rare adverse effect of amiodarone, has been reported (132Ar). Immunologic The immunomodulatory properties of amiodarone in the inflamma­ tory response induced by cardiac surgery with cardiopulmonary bypass have been investigated in a double-blind, placebocontrolled trial in 20 patients (133c). They were given amiodarone 600 mg/day for 7 days orally before surgery and 45 mg/hour intravenously for 48 hours postoperatively. Fibrinogen formation was significantly increased by amiodarone, and plasma fibri­ nogen concentrations more than doubled by 96 hours after the start of surgery. The secretion of monocyte chemoattractant protein 1 transiently increased 4 hours after the start of surgery but rapidly fell there­ after; it was not affected by amiodarone. The plasma concentrations of C-reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), and interleu­ kin-10 (IL-10) changed significantly, but were not altered by amiodarone. Although the authors suggested that amiodarone is associated with some proinflammatory actions, the data were not convincing. A hypersensitivity reaction to oral amio­ darone occurred in a patient who had had a previous urticarial reaction to an iodinated radiocontrast agent (134A). • A 55-year-old man developed facial urticaria after intra-arterial injection of iohexol during coronary angiography and was successfully treated with intravenous hydrocortisone and promethazine. Two subsequent episodes of

346 fast atrial fibrillation were treated with intravenous amiodarone, which was followed by oral therapy. Within 1 hour after the first oral dose of 400 mg, he developed lip swelling and tingling, which was treated with intravenous promethazine. Amiodarone was withdrawn. The Naranjo scale suggested a probable adverse reaction.

Death In a post-hoc analysis of the effects of amiodarone in 364 patients (155 of New York Heart Association [NHYA] class II and 209 of class III) from among 3029 patients with chronic heart failure who were randomized to carvedilol or metoprolol and followed for a median of 58 months, mortality was higher than in those who did not take amiodarone: 39% and 59% of those who used amiodarone in NYHA classes II and III þ IV died compared with 26% and 43% of those who did not use amiodarone (135c). This difference was maintained in a multivariate analysis (HR = 1.5; 95% CI = 1.2, 1.7). The difference was explained by an increased risk of death due to circula­ tory failure (HR = 2.4; CI = 1.9, 3.1). Sudden death was not different (HR = 1.07; CI = 0.8, 1.4). The authors concluded that amiodarone was associated with an increased risk of death from circulatory failure independent of functional class. However, analyses of this sort often prove to be wrong because of confounding factors. In another example of this type of posthoc analysis, an apparent association between the use of amiodarone and death has been reported in a study that was designed for a completely different purpose (136c). The study was a randomized com­ parison of valsartan, captopril, or both in patients with acute myocardial infarction with heart failure and/or left ventricular sys­ tolic dysfunction. In 825 patients who were taking amiodarone at randomization and 13 875 patients who were not, amiodarone was associated with a significant increase in mortality during three of the four study periods: HR = 1.5 (95% CI = 1.1, 2.0) for days 1–16; 2.1 (1.5, 2.9) for days 17–45; 1.1 (0.83, 1.46) for days 46–198; and 1.4 (1.2, 1.6) for days 199–1096. However, the patients who were treated with amiodarone were older, had higher Killip class, and were

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more likely to have a history of diabetes mellitus and hypertension. Although the analysis was adjusted for baseline predictors of mortality, it is highly likely that other confounders were not allowed for. Only proper prospective randomized stu­ dies can be relied upon to answer the ques­ tions posed by these post-hoc analyses. Fetotoxicity Amiodarone can cause transi­ ent congenital hypothyroidism after gesta­ tional exposure, as has again been reported in two cases (137Ar). The neonatal TSH concentrations were 78 and 134 mU/l (reference range <15 mU/l). Both were successfully treated with levothyroxine 50 micrograms/day, which was withdrawn at 16 and 10 months, respectively. They had normal growth and mental development. Drug–drug interactions Clozapine An interaction of amiodarone with clozapine has been described (138A). • A 75-year-old man with schizophrenia was well managed with clozapine 300 mg/day and divalproex sodium 1000 mg/day. When he later developed a ventricular tachycardia he was given intravenous magnesium and amiodarone 150 mg, and sinus rhythm was restored within 10 minutes. Amiodarone 400 mg/day was con­ tinued and a few weeks later his serum cloza­ pine concentration was 1580 ng/ml (combined clozapine plus norclozapine 1786 ng/ml), sig­ nificantly higher than the prehospital value of 242 ng/ml. The dosage of clozapine was halved to 150 mg/day, and the serum clozapine con­ centration fell to 355 ng/ml after 2 weeks. The dosage of divalproex was not changed during this time.

Clozapine is primarily metabolized by cyto­ chrome P450 1A2 (CYP1A2), of which desethylamiodarone is a potent inhibitor, and the authors proposed this as the mechanism of this interaction. Rosuvastatin An interaction of amiodarone with rosuvastatin has been proposed in a patient whose serum transaminases rose when amiodarone was added to rosuvastatin therapy and normalized when the rosuvastatin was withdrawn (139A). This effect could equally have been due to the rosuvastatin alone.

Positive inotropic drugs and drugs used in dysrhythmias

Monitoring drug therapy The reasons for monitoring amiodarone therapy have again been reviewed, in the context of a case report (37Ar). In summary: • monitor liver function tests and thyroid and renal function at baseline and every 6 months in patients taking amiodarone if the values are within the population reference range:  thyroid profile should include TSH, FT4, and FT3;  liver enzymes (AsT);  renal function (creatinine and electrolytes); • annual chest X-ray, electrocardiogram, and clinical assessment; • monitor the prothrombin ratio weekly during the first 7 weeks of warfarin treatment, after which the dose of warfarin should be adjusted depending on the response.

Managing adverse drug reactions Photothermolytic treatment using a Q-switched ruby laser has been used successfully to treat amiodarone-induced facial discolora­ tion (140A).

Cibenzoline

(SED-15, 740; SEDA-30, 217; SEDA-31, 330)

Neuromuscular function Myasthenia has been attributed to cibenzoline in a patient with chronic renal insufficiency (141A). • A woman in her late sixties with chronic kidney disease took cibenzoline 300 mg/day for 3 days and developed blepharoptosis. Anti-acetylcholine receptor antibody and edrophonium tests were negative. After another 4 days she developed pneumonia with a pleural effusion and had gradually worse blepharoptosis, dull headache, weakness, difficulty in chewing and dyspnea. Cibenzoline was withdrawn and she improved. The blood concentration of cibenzoline immediately after withdrawal was extremely high at 2448 µg/l.

Drug overdose A case of cibenzoline overdose has been reported in a patient with progressive renal insufficiency (142A). Combined hemoperfusion and hemodialysis was used and was associated with a rapid fall in plasma cibenzoline concentration and clinical improvement. However, only 29 mg of an estimated body load of ciben­ zoline (447–807 mg) was removed during

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the 8 hours of treatment. It is not clear to what extent hemoperfusion and hemodia­ lysis were beneficial in this case, since ciben­ zoline has a very large volume of distribution (about 4000 l). The plasma clearance of cibenzoline after intravenous administration in healthy subjects is about 700 ml/minute and the half-life is 7 hours (143C); in renal insufficiency the clearance falls to 224 ml/minute and the half-life increases to 22 hours and hemodialysis accounts for only 13% of drug clearance.

Disopyramide Neuromuscular function Worsening of pre-existing myasthenia gravis has been attributed to disopyramide (144A). • A 63-year-old woman with ocular myasthenia gravis and an anti-acetylcholine receptor antibody concentration of 16 nmol/l responded to a cholinesterase inhibitor and prednisolone 10 mg/day. When she developed atrial fibrillation and heart failure, she was given disopyramide 300 mg/day and furosemide 20 mg/day. Within 6 weeks she developed an aspiration pneumonia secondary to dysphagia with bulbar paralysis-like symptoms. A myasthenic crisis was excluded, since the antiacetylcholine receptor antibody concentration was 0.3 nmol/l. The electrocardiogram showed QTc interval prolongation (549 ms) and she developed torsade de pointes. Despite correction of hypokalemia, administration of magnesium and a continuous intravenous infusion of lidocaine, the tachydysrhythmia did not improve, but it was resolved by intravenous verapamil. All medications were withheld and after 4 days her spontaneous respiration and muscle weakness improved. She eventually died with sepsis and disseminated intravascular coagulation from acute enteritis.

Dofetilide

(SED-15, 1173; SEDA-27, 195; SEDA-29, 187; SEDA-30, 217)

Cardiovascular Cardiac dysrhythmias are common during treatment with dofetilide and can be life-threatening (145A, 146Ar). In a retrospective review of 34 patients with symptomatic paroxysmal atrial fibrilla­ tion, normal left ventricular function, and no

348

significant valvular disease, who were given dofetilide, 9 had to withdraw because of cardiac dysrhythmias; 3 withdrew before discharge from hospital (2 with QT interval prolongation and 1 with supraventricular tachycardia); and 6 withdrew later (3 with ventricular tachycardias, 1 with QT interval prolongation, and 2 with supraventricular tachycardias) (147c). Treatment with dofeti­ lide was successful in less than 1 in 5 patients. Drug overdose A case of intentional over­ dose of dofetilide has been reported (148A). • A 33-year-old man with a history of cocaine abuse took about 5 mg of dofetilide in a suicide attempt and came to the emergency department about 45 minutes after ingestion. His QTc interval was about 570 ms. He was treated with activated charcoal and sorbitol by nasogastric tube and received aggressive supplementation with potassium and magnesium. He was monitored for several days and responded well.

Flecainide

(SED-15, 1370; SEDA-29, 188; SEDA-30, 217; SEDA-31, 330)

Cardiovascular Flecainide usually does not cause cardiac dysrhythmias in patients with no structural cardiac abnormality, but rare reports do appear, as in a case of a 77­ year-old woman whose only cardiac struc­ tural abnormality was atrial dilatation and who developed bradydysrhythmias, prolon­ gation of the QT interval and torsade de pointes 10 days after starting treatment with flecainide 100 mg bd (149A). In another case, episodes of syncope asso­ ciated with marked QRS widening in a 63-year-old man taking flecainide 100 mg bd were precipitated by hypokalemia due to bendroflumethiazide (150A). • A 32-year-old man who was taking flecainide 200 mg/day and bisoprolol 5 mg/day for atrial fibrillation developed rapidly worsening nausea and dyspnea (151A). His systolic blood pressure was 70–85 mmHg and his pulse was irregular. Echocardiography showed no specific acute abnormalities, but the electrocardiogram showed broad complexes and 2:1 heart block. The flecainide concentration was very high at 8.4 µmol/l (usual target range 0.4–2.1).

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Nervous system Central nervous system adverse effects are commonly associated with flecainide, but are rarely severe. A patient with end-stage renal failure developed a paranoid psychosis and myoclonus, which resolved after withdrawal of flecainide (152A). Drug overdose Flecainide overdose can cause severe cardiovascular collapse and dysrhythmias, but responds to hypertonic sodium bicarbonate, as another report has emphasized (153A).

Pilsicainide Pilsicainide is a class IC antidysrhythmic drug, widely used in Japan. It inhibits the fast inward sodium current with slow kinetic properties (154R). It reduces intra-atrial con­ duction and prolongs the atrial effective refractory period. It increases heart rate and mean pulmonary arterial pressure and reduces stroke volume index (155R). It pro­ longs the PQ interval, QRS width, and QT interval; prolongation of the PQ interval correlates with plasma pilsicainide concentrations. The plasma concentration associated with suppression of supraventri­ cular tachycardia is about 0.5 mg/l. The pharmacokinetics of a single oral dose of pilsicainide 50 mg have been studied in 32 patients with varying degrees of renal impairment (156c). The apparent volume of distribution at steady state was 1.48 l/kg, clearance 5 ml/minute/kg and half-life 3.4 hours. Pilsicainide is about 90% eliminated unchanged by the kidneys, by glomerular fil­ tration and tubular secretion, and the half-life was prolonged to 24 hours in severe renal failure. Pilsicainide is bound in plasma to alpha1-acid glycoprotein (CRP), increased concentrations of which cause increased bind­ ing and therefore reduced clearance (157C). Observational studies Single oral doses of pilsicainide have been evaluated in 34 patients (aged 48–81, mean 66 years, 26 men) who had 42 episodes of supraventricular dysrhythmias after coronary artery bypass grafting, most within 2–4 days, classified as

Positive inotropic drugs and drugs used in dysrhythmias

follows: paroxysmal atrial fibrillation (n = 34), paroxysmal atrial flutter (6), and sinus tachy­ cardia (2) (158c). Sinus rhythm was restored in 32 episodes by a single oral dose of pilsi­ cainide 50–100 mg, within 90 minutes in 44% and within 3 hours in 56% of episodes (mean conversion time 119 minutes). There were no significant changes in blood pressure and no significant adverse effects. The pharmacokinetics of pilsicainide have been studied in 16 healthy Korean men (mean age 25 years, weight 72 kg, height 177 cm) and 16 healthy Japanese men (age 25 years, weight 60 kg, height 172 cm) (159c). The AUC and Cmax of pilsicainide increased in proportion to dose. There were no differ­ ences in the kinetics between the two groups. There were nine adverse events in seven of the Korean subjects; all were mild and they included dizziness, a feeling of being hot, somnolence, and atrioventricular block. Two of the 16 Japanese subjects had a total of four adverse events; one had a reduced blood pressure, a sense of discomfort, and PR interval prolongation, and the other had extra ventricular beats. Placebo-controlled studies The effects of a single oral dose of pilsicainide have been evaluated in a double-blind, placebo-con­ trolled study in 75 patients (51 men) with recent-onset atrial fibrillation (160C). There was conversion to sinus rhythm within 90 minutes in 18 of the 40 patients who received pilsicainide and in 3 of the 35 who received placebo. The mean times to conversion were 37 minutes with pilsicainide and 50 minutes with placebo. In 30 patients whose pilsicai­ nide concentrations were determined, the mean plasma concentration was 1.05 ng/l at 90 minutes; there was no significant differ­ ence in the plasma concentrations between 15 responders and 15 non-responders (1.07 ver­ sus 1.03 ng/l). Pilsicainide increased the QRS duration at 40–90 minutes after administra­ tion. There was a sinus pause of 8 seconds after termination of atrial fibrillation in one patient with Wolff–Parkinson–White syn­ drome who received pilsicainide, and in one non-responder there was conversion to atrial flutter with 2:1 atrioventricular conduction but without hemodynamic deterioration.

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In a placebo-controlled study 62 patients with chronic atrial fibrillation were given oral placebo (n = 10) or pilsicainide 150 mg/day (n = 52) for 4 weeks before elec­ trical cardioversion (161C). Before cardio­ version, 11 of those who were given pilsicainide reverted to sinus rhythm com­ pared with none in the placebo group. Of 51 patients in whom direct current cardiover­ sion was performed, 8 were not converted to sinus rhythm (5 pilsicainide and 3 placebo) and 3 needed intracardiac cardioversion. There were asymptomatic bradydysrhythmias in 5 of those who were given pilsicainide. Cardiovascular Of 35 patients, 11 without ST segment depression were given pilsicai­ nide; 24 had ischemic ST segment depres­ sion, of whom 9 were given pilsicainide; they were compared with 16 age-matched controls (162C). The QRS duration was mea­ sured at rest and at heart rates of 80, 100, and 120/minute during exercise. There were no changes in the QRS duration as heart rates increased in the controls. However, ischemia independently caused a significant increase in QRS duration at a heart rate of 120/min­ ute. Pilsicainide produced a rate-dependent prolongation of the QRS duration in patients without ST segment depression as the heart rate increased to 100/minute. The combina­ tion of ischemia þ pilsicainide led to a much greater rate-dependent prolongation of the QRS duration. The authors concluded that the combination of a class IC drug and acute ischemia could lead to additive rate-depen­ dent ventricular conduction slowing, and that such an effect could have explained the increased mortality in the Cardiac Arrhyth­ mia Suppression Trial (CAST). In a study of the electrophysiological mechanisms of the adverse effects of class I antidysrhythmic drugs of different subtypes (cibenzoline, disopyramide, pilsicainide, and procainamide) in 14 patients (mean age 37 years, 10 men) who had inducible atrio­ ventricular re-entrant tachycardias, the drugs induced unidirectional conduction block in the accessory pathway (antegrade conduction block associated with preserved retrograde conduction) and enhanced the induction of the tachycardia with atrial extrastimulation

350

in 4 of 6 patients with a manifest accessory pathway; in 8 patients with a concealed acces­ sory pathway, there was outward or inward expansion of the tachycardia induction zone in patients who had greater prolongation of the conduction time than the refractory period of the retrograde accessory pathway after class I drugs (163c). During ventricular extrastimulation, induction of bundle branch re-entry after class I drugs initiated the tachy­ cardia in patients with both types of accessory pathway. The authors concluded that the adverse effects of all class I drugs, regardless of subtype, are mainly due to induction of unidirectional retrograde conduction in the manifest accessory pathway and greater prolongation of the retrograde conduction time in the concealed accessory pathway than the refractory period. Delayed conduction has been attributed to pilsicainide (164A). • A 74-year-old man with atrial fibrillation was given pilsicainide 50 mg tds and 2 days later he suddenly lost consciousness. He was cyanotic, with an irregular pulse and a systolic blood pressure below 50 mmHg. An electrocardiogram showed a heart rate of less than 40/minute, with sinus pauses, ventricular escape beats, an extremely long PQ interval, and broad QRS complexes. He responded to intravenous dopamine 15 micrograms/kg/ minute), dobutamine 15 micrograms/kg/minute and atropine sulfate 1 mg and reverted to atrial fibrillation with a broad QRS complex and a systolic blood pressure of 100 mmHg. Pilsicainide was withdrawn and 2 days later the rhythm was atrial flutter/fibrillation and the QRS complex was normal.

In 89 patients (aged 62 years, 72 men) with episodes of atrial fibrillation (65 with parox­ ysmal, 11 with persistent, and 13 with perma­ nent atrial fibrillation) who were given oral pilsicainide for 4 weeks, the dose was increased in those who did not develop atrial flutter; those who did have atrial flutter underwent ablation (165c). Pilsicainide caused atrial flutter in 17 patients, in whom the pilsicainide plasma concentration was significantly higher than in those without atrial flutter (0.79 versus 0.51 mg/l). Like other class IC antiarrhythmic drugs with slow kinetics, pilsicainide can cause Brugada­ like changes on the electrocardiogram,

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mimicking acute inferior myocardial infarc­ tion (166A). • An 81-year-old woman with normal renal func­ tion developed pilsicainide intoxication asso­ ciated with dehydration after taking pilsicainide 100 mg/day for paroxysmal A atrial fibrillation (167 ). Electrocardiography showed atrioventricular dissociation, idioventri­ cular rhythm with marked QRS widening and QTc interval prolongation. The plasma concen­ tration of pilsicainide was 6.2 mg/l (usual target range 0.25–1.0). Rehydration with intravenous saline caused reversion to sinus rhythm after 2 hours and the QRS and JT intervals gradually normalized.

In a 17-year-old man with Brugada syn­ drome intravenous pilsicainide caused further ST segment elevation in the inferior leads, new ST segment depression in leads V2–V6 and two distinct forms of ventricular extra beats, which triggered short runs of poly­ morphous ventricular tachycardia; an infusion of isoprenaline suppressed the dysrhythmias and normalized the ST segment (168A). In another case a 65-year-old man with a Brugada-type electrocardiogram developed chest pain, palpitation, and faintness while taking pilsicainide; intravenous pilsicainide caused ST segment elevation in V1–V4 and vasospasm of the right coronary artery (169A). In a patient with a ventricular pacemaker, ventricular pacing failure occurred immediately after a single oral dose of pilsicainide (170A). Ventricular dysrhythmias have been attributed to pilsicainide, including ventricu­ lar tachycardia in an 88-year-old man taking pilsicainide 100 mg/day for atrial fibrillation (plasma pilsicainide concentration 2.42 mg/l) (171A), ventricular fibrillation in a 56-year­ old man with Brugada syndrome taking pil­ sicainide 150 mg/day for paroxysmal atrial fibrillation syndrome (172A), and ventricular tachycardia originating from the right ventri­ cular outflow tract (173A). Ventricular dysrhythmias due to pilsicai­ nide have been examined in 28 patients with Brugada-type electrocardiographic abnorm­ alities (174c). In all patients, pilsicainide increased the ST segment elevation and accentuated type 1 electrocardiographic changes. Ventricular tachycardia developed in three patients and ventricular extra beats

Positive inotropic drugs and drugs used in dysrhythmias

in two other patients. These 5 patients had higher ST segment elevation in lead V2 at baseline and after pilsicainide and a longer QTc interval after pilsicainide than the other 23 patients. However, there was no difference between the two groups in the incidence of prior cardiac events, the results of signalaveraged electrocardiography, HV interval, inducibility of ventricular fibrillation by pro­ grammed electrical stimulation or QRS duration. In one patient, ventricular extra beats originated from three sites, two of which triggered polymorphous ventricular tachycardia. The right ventricular outflow tract was the origin of two types of ventricu­ lar extra beats, and other sites were the ori­ gins of five other types. Breast feeding In a healthy nursing mother who took oral pilsicainide 50 mg, the pilsi­ cainide concentration in milk was higher than that in plasma at all times up to 12 hours, with an average ratio of 1.75:1; how­ ever, the estimated daily amount of drug that a baby who takes 150 ml/kg/day of breast milk would ingest would be very low (0.06 mg) (175A). Susceptibility factors Sex In a population pharmacokinetic study of intravenous pilsi­ cainide 10 mg in 91 patients with cardiac dysrhythmias, plasma concentrations were 50% lower in women than in men (176c). Drug overdose Fatal poisoning has been attributed to an overdose of the combination of pilsicainide and atenolol, with high plasma concentrations of both (177A). • A 34-year-old man took an overdose of pilsicainide hydrochloride (2500 mg) with suicidal intent (178A). His consciousness was impaired and there was circulatory failure. His systolic blood pressure was 74 mmHg. He had a ventricular tachycardia, and since cardioversion was ineffective, he was given intravenous magnesium sulfate, which resulted in immediate reversion to normal rhythm, although the PQ and QRS intervals remained prolonged, consistent with the effects of a class IC sodium channel blocker. The blood pressure rose to over 100 mmHg and his circulatory and respiratory functions improved immediately. The plasma concentration of pilsicainide was high (7.22 mg/l). Hemoperfusion was performed

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but the plasma pilsicainide concentration did not fall satisfactorily.

Drug–drug interactions Cetirizine An interaction of cetirizine with pilsicainide has been described in an anecdotal report, a small clinical study, and an in vitro study, (179AcE). A 72-year-old woman with renal insufficiency who was taking oral pilsicai­ nide 150 mg/day felt faint 3 days after starting to take oral cetirizine 20 mg/day. She had a wide QRS wave with bradycardia, and her symptoms were relieved by withholding pilsi­ cainide. The plasma cetirizine concentration fell when pilsicainide was withdrawn. In a pharmacokinetic study in six healthy men after a single dose of either cetirizine 20 mg, pilsicainide 50 mg, or both, the renal clearance of each drug was significantly reduced during co-administration (from 475 to 279 ml/minute for pilsicainide and from 189 to 118 ml/minute for cetirizine). In vitro studies using Xenopus oocytes with micro-injected human organic cation transporter 2 and renal cells transfected with human multidrug resistance protein 1 showed that transport of the substrates of these transporters was inhibited by both cetir­ izine and pilsicainide. Cimetidine In nine healthy men aged 21–38 years, oral cimetidine 800 mg increased the AUC of oral pilsicainide 50 mg by a mean of 33%, prolonged its half-life by a mean of 24% (from 5 to 6.2 hours), reduced its apparent oral clearance by a mean of 26% (from 245 to 180 ml/minute), and reduced its renal clearance by a mean of 28% (from 197 to 142 ml/minute); the net renal clearance by tubular secretion was significantly reduced by a mean of 38% (from 151 to 93 ml/min­ ute) (180c). In the same study, oral probene­ cid 1500 mg had no effect on cimetidine kinetics. The authors concluded that pilsicai­ nide is secreted by the active transport system for organic bases in the proximal renal tubule.

Propafenone (SED-15, 2939; SEDA-30, 218; SEDA-31, 331) Cardiovascular ‘Cardiac memory’ is the phenomenon whereby T wave changes

352

persist after aberrant ventricular activation. Propafenone toxicity has been reported to cause cardiac memory after QRS widening and markedly abnormal ventricular activa­ tion in a 74-year-old woman (181A). Propafenone can cause Brugada-like changes on the electrocardiogram (182A), which can be mistaken for acute myocardial infarction (183A). Drug–drug interactions Citalopram Epi­ sodes of chest tightness and dizziness, which occurred when citalopram was added to the regimen of a woman, an inter­ mediate to the extensive cytochrome P450 2D6 (CYP2D6) metabolizer, who was tak­ ing a large number of other drugs, including propafenone, were unconvincingly attribu­ ted to the latter (184A). Lithium Electrocardiographic changes compatible with type 1 Brugada syn­ drome occurred when a patient with Wolff–Parkinson–White syndrome who was taking lithium, with serum concentrations within the usual target range, was given propafenone (185A). The authors suggested that the electrocardiographic changes had occurred because of synergistic blocking effects of the two drugs on sodium channels. Venlafaxine An interaction of propafenone with venlafaxine has been hypothesized (186A). • An 85-year-old woman who was taking propafenone 150 mg bd, ramipril, ticlopidine, torsemide, theophylline, paracetamol, and triazolam developed a mood disorder and was found to have cortical atrophy. She was given modified-release venlafaxine 75 mg/day and 4 weeks later the dosage was increased to

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150 mg/day. After 10 days she developed bouts of visual hallucinations lasting about 2 hours, especially at night, and psychomotor agitation. Venlafaxine was withdrawn and the hallucinations and psychomotor agitation resolved in about 4 days. She was given citalopram instead, without adverse effects.

As venlafaxine is metabolized primarily by CYP2D6 and is a substrate of P glycopro­ tein, both of which propafenone inhibits, the authors proposed that propafenone had increased venlafaxine plasma concen­ trations, causing the hallucinations.

Quinidine and derivatives (SED-15, 2997; SEDA-29, 189; SEDA-30, 219; SEDA-31, 332) Immunologic Antiphospholipid antibodies have been reported in patients taking quinidine (SEDA-20, 179). A 68-year-old woman with easy bruising and hematomas provoked by minimal trauma, who had been taking quinidine for 18 years, had antiphospholipid antibodies and antiprothrom­ bin antibodies (187A). Susceptibility factors Genetic In a doubleblind, crossover, randomized study of the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in 13 healthy Caucasians and 24 Koreans, there were no pharmacokinetic differences, but the QTc intervals in the Caucasians were longer than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations, and in women; in an Emax model, E0 was related to sex, and DEmax was related to ethnicity (188C).

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