Is it possible to use cholinesterase inhibitors safely in patients with cardiac conduction defects

Fråga: Is it possible to use cholinesterase inhibitors safely in patients with cardiac conduction defects and arrhythmias?

The question concerns two patients. One is a 76-year old man with post-polio syndrome, AV-block I, right-bundle fascicular block, and Alzheimer´s disease (AD). Treatment with a cholinesterase-inhibitor is being considered. The AV-block has a PQ-time of 0.24 seconds but there are no clinical signs of coronary impairment. The other patient has pre-excitation and suspicion of Wolff-Parkinson-White syndrome. FASS 2001 recommends precaution when the patient has problems with cardiac conductivity.

Sammanfattning: Cholinesterase-inhibitors are the only treatment used today for Alzheimer´s disease. The effect varies between individuals and is considered to be overall clinically significant. However, there are several potentially serious side effects. In patients with pre-existing cardiac conductivity disorders treatment with cholinesterase-inhibitors requires particular caution and the clinical benefit has to be weighed against the potential cardiac risks.

Svar: Cholinesterase-inhibitors improve symptoms of Alzheimer´s disease in a dose-dependent manner and are the only possible treatment today (1). The response varies between patients but some may gain substantially from the treatment and further deterioration of symptoms may even be halted during treatment (2). The cholinesterase-inhibitors used today have a high CNS-selectivity but there are still many dose-dependent adverse events due to peripheral cholinergic activity (1). Bradycardia is a known side effect and also the most frequently reported adverse effect (3). Bradycardia may, with excessive dosage, proceed to dysrythmia and even asystole (4). In the clinical trial of galanthamine (Reminyl) an initial exclusion criterion was a heart rate below 50 but it changed to 45 later in the study (5). In the clinical trials with donepezil (Aricept), syncope (2 cases) but not bradycardia were reported as side effects (6). The most frequent cardiac adverse effects reported in Sweden are asystole, bradycardia, and atrial fibrillation but single reports of Torsades de Pointes, ventricular tachycardia, and arrhythmias are found (7). Half of the patients who were reported with adverse drug reactions had pre-existing cardiac problems (7).

There is little data in the literature on treatment of patients with pre-existing cardiac problems. In the galanthamine trial AV-block I was not an exclusion-criterion (5).

Due to the paucity of data on treatment with cholinesterase-inhibitors in patients with conduction defects and arrhythmias no general recommendation can be given. In each case the possible benefit on the cognitive function has to be weighed against these, potentially serious, side effects. 1 McGleenon BM, Dynan KB, Passmore AP. Acetylcholinesterase inhibitors in Alzheimer´s disease. Br J Clin Pharmacol 1999;48:471-80. 2 Schneider LS. Treatment of Alzheimer´s disease with cholinesterase inhibitors. Clin Geriatr Med 2001;17:337-58. 3 Intdis (International Drug Information System): WHO:s adverse drug reactions database 4 Dukes MNG, Aronson JK, editor. Meyler´s Side effects of drugs. 14th ed. Amsterdam: Elsevier; 2000. p. 435-6. 5 Personal communication with Bo Eriksson, Janssen-Cilag. September 2001 6 Personal communication with Owe Luhr, Pfizer AB. Sepember 2001 7 Swedis (The Swedish Drug Information System)