Published: June 2005

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Syncope and Dementia Treatment - Catching the Falls

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Prescriber Update 26(1): 7-8
June 2005

Medsafe Pharmacovigilance Team

Acetylcholinesterase inhibitors, used to treat dementia of the Alzheimer-type, are associated with syncopal adverse events.  This risk can be minimised by prudent management including gradual dose increments and obtaining a pre-treatment ECG.  Prescribers are reminded that alternative causes of syncope should be considered including dementia and other disease states.  Concurrent medicines can also increase the risk of syncope in dementia patients on acetylcholinesterase inhibitors.

AChEIs help improve cognitive function in dementia

Acetylcholinesterase inhibitors (AChEIs) are indicated for the treatment of the symptoms of mild to moderately severe dementia of the Alzheimer-type.  The AChEIs currently available in New Zealand are donepezil (Aricept^®), galantamine (Reminyl^®), memantine (Ebixa^®) and rivastigmine (Exelon^®).  These medicines work by inhibiting the breakdown of acetylcholinesterase in the synapses, thus increasing the amount of acetylcholine available at post-synaptic neurons.  The resultant increase in central cholinergic neuronal activity is thought to mediate benefits in cognitive and behavioural functions in patients with dementia.^1,2  The goal of treatment in patients with Alzheimer's disease is stabilisation of cognitive, behavioural and functional status; at best, some increase in cognitive function may be achieved.¹

The adverse reactions of the AChEIs are generally mild and transient, and can be limited by introducing dose increases slowly.  Gastrointestinal events such as nausea, vomiting and diarrhoea are most common.  These can be minimised by taking doses with food, as well as ensuring adequate hydration and gradual dose increments.^1,2

Post-marketing reports of syncope with AChEIs

Internationally, there have been several published reports of syncope occurring in patients taking donepezil.^3-7  In New Zealand, adverse reaction reports of syncope associated with AChEIs include the following:

• A 77-year-old female, who had been on donepezil for more than five years, experienced syncope along with somnolence, dysphasia and dehydration.
• A 73-year-old woman prescribed rivastigmine had a syncopal episode and a non-specified arrhythmia within a month of starting treatment.
• A 63-year-old woman taking donepezil experienced syncope and bradycardia.  It was not known how long she had been on donepezil.

Syncope can also be due to other causes

In patients with dementia, syncope can be caused by a number of factors including use of AChEIs, the dementia itself or other not necessarily related disease states, making it difficult to identify the causal factor.  Syncope, repeated falls and transient loss of consciousness may be associated with all forms of dementia, but are more commonly associated with specific sub-types, e.g. dementia with Lewy bodies.⁸  There are a number of other pathologies that may be potential causes of syncope.  Orthostatic hypotension may be responsible for syncope in up to 30% of the elderly; co-administration of antihypertensives may be a contributor in these patients.  Carotid sinus hypersensitivity, cardiac arrhythmia and seizures should also be considered as differential diagnoses when determining the likely cause of syncope.⁹  Age-related falls in patients with dementia are common, and may be related to the high prevalence of orthostatic hypotension and carotid sinus hypersensitivity in patients with Alzheimer's disease and dementia with Lewy bodies.¹⁰

Syncope is known to occur with memantine (in up to 2% of patients), donepezil (2%), rivastigmine (0.1-1%) and galantamine (0.01-0.1%).^11-14  Other cardiovascular adverse events of the AChEIs include bradycardia and dizziness, mainly mediated by a vago-tonic effect on the heart due to muscarinic stimulation.^2,10  Consequently, caution is advised when prescribing AChEIs to patients with sick sinus syndrome, or other supraventricular cardiac conduction conditions, such as sinoatrial or atrioventricular block.^11-14  Obtaining an ECG prior to starting AChEIs in any patient would be a prudent measure to reduce the risk of syncope, and will assist in excluding or identifying other causes of syncope.

Interactions may increase risk of syncope

An additional risk factor for syncopal episodes with AChEIs is interactions with other medicines.^1,2  In particular, concurrent medicines with bradycardic or cholinergic effects should be used with caution, as they may further increase the risk of syncope; such medicines include beta-blockers, digoxin, neostigmine, succinylcholine and pyridostigmine.^12-14  There is also a potential interaction between donepezil and inhibitors of the cytochrome P450 isoenzymes 3A4 or 2D6 (e.g. ketoconazole, itraconazole, erythromycin, quinidine and fluoxetine), resulting in increased blood concentrations of donepezil;¹² this could increase the risk of syncope.

The risk of AChEI-induced syncope can be minimised by gradual upward dose titration until the maintenance dose is reached.  Similarly, if treatment is interrupted for longer than several days, it should be re-initiated with the lowest daily dose.^12-14  When adding in other medicines, be aware of the potential for increased syncopal risk.  Should syncopal episodes persist, consider stopping or reducing either the dose of the AChEI or any concurrent medicines that may be compounding the risk of syncope.

Competing interests (authors): none declared.

References:

1. Bonner LT, Peskind ER. Pharmacologic treatments of dementia. The Medical Clinics of North America 2003;86:657-674.
2. Gauthier S. Cholinergic adverse effects of cholinesterase inhibitors of Alzheimers disease. Drugs Aging 2001;18(11):853-862.
3. Newby VJ, Kenny RA, McKeith IG. Donepezil and cardiac syncope: case report [Letter]. International Journal of Geriatric Psychiatry 2004;19(11): 1110-1112.
4. Bordier P, Garrigue S, Barold SS, et al. Significance of syncope in patients with Alzheimer's disease treated with cholinesterase inhibitors. Europace 2003;5(4):429-431.
5. Springuel P. Donepezil: suspected adverse reactions. Canadian Adverse Drug Reaction Newsletter 1998;8(3):3-4.
6. Paleacu D, Mazeh D, Mirecki I, et al. Donepezil for the treatment of behavioural symptoms in patients with Alzheimer's disease. Clinical Neuropharmacology 2002;25(6):313-317.
7. Greenberg SM, Tennis MK, Brown LB, et al. Donepezil therapy in clinical practice. Arch Neurol 2000;57:94-99.
8. O'Brien J, Ames D, Burns A (Eds). Dementia 2^nd Edn. 2000: London, p. 691.
9. Kasper DL, Braunwald E, Fauci AS, et al (Eds). Harrison's Principles of Internal Medicine 16th Edn. 2005: The McGraw-Hill Companies Inc, United States of America (on-line version accessed)
10. McLaren AT, Allen J, Murray A, et al. Cardiovascular effects of donepezil in patients with dementia. Dement Geratr Cogn Disord 2003;15:183-188.
11. Pfizer Laboratories Ltd. Aricept data sheet. 26 February 2003. www.medsafe.govt.nz/profs/Datasheet/a/Aricepttab.htm
12. Novartis New Zealand Ltd. Exelon data sheet. 10 July 2002. www.medsafe.govt.nz/profs/Datasheet/e/Exeloncap.htm
13. Janssen-Cilag Pty Ltd. Reminyl data sheet. 4 January 2005. www.medsafe.govt.nz/profs/Datasheet/r/Reminyltab.htm
14. Healthcare Logistics. Ebixa data sheet. 30 March 2004. www.medsafe.govt.nz/profs/Datasheet/e/Ebixatabsoln.htm