Safety of Cholinesterase Inhibitors and NMDA Receptors Antagonists for the Treatment of Patients with Dementia

For the treatment of dementia and Alzheimer’s disease, acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or the non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDA receptors) memantine are currently used. The administration of these drugs can help temporarily improve or stabilize memory impairments and other cognitive functions, regress behavioral disorders, reduce the patient’s dependence on others, but at the same time can lead to the development of adverse drug reactions. The aim of this study was to analyze the information on the safety of acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the non-competitive inhibitor of NMDA receptors used to treat dementia. It was shown that stimulation of cholinergic receptors can lead to adverse drug reactions as contraction and narrowing of the pupil (miosis), an increase in lens curvature, accommodation spasm (visual impairment and an increased risk of falls), a decrease in heart rate (bradycardia) and inhibition of conduction of impulses through the conducting system heart, increased tone of the bronchi, gastrointestinal tract, gall and bladder, decreased tone of the sphincters of the digestive tract and bladder, increased secretion of exocrine and glands of the stomach, agitation, confusion. Blockade of NMDA receptors due to impairment of glutamate metabolism in the central nervous system may be the cause of neurotoxicity of NMDA receptor antagonists, and also causes dizziness, feeling of tiredness, hallucinations, drowsiness, and confusion. In case of development of adverse reactions, if possible, it is necessary to stop using the drug or reduce its dose, in case of an overdose or other need, prescribe symptomatic therapy. Information on the safety of cholinesterase inhibitors and NMDA receptor antagonists presented in the article is of practical importance for healthcare professionals, as it allows them to assess the possible risks associated with the use of drugs of these groups more accurately. In addition, the information can be used to optimize and individualize the pharmacotherapy regimens for patients with dementia, including the development of domestic protocols for the deprescribing of drugs (evidence-based practice of withdrawal, replacement or gradual dose reduction) in the elderly. 

1. Qiu C, Kivipelto M, Von Strauss E. Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialogues Clin Neurosci. 2009;11(2):111–28.

2. Crow TJ, Grove-White IG. An analysis of the learning deficit following hyoscine administration to man. Br J Pharmacol. 1973;49(2):322–7. https://doi.org/10.1111/j.1476-5381.1973.tb08379.x

3. Ridley RM, Murray TK, Johnson JA, Baker HF. Learning impairment following lesion of the basal nucleus of Meynert in the marmoset: modification by cholinergic drugs. Brain Res. 1986;376(1):108–16. https://doi.org/10.1016/0006-8993(86)90904-2

4. Easton A, Ridley RM, Baker HF, Gaffan D. Unilateral lesions of the cholinergic basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere produce severe learning impairments in rhesus monkeys. Cereb Cortex. 2002;12(7):729–36. https://doi.org/10.1093/cercor/12.7.729

5. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51(1):7–61.

6. Liu Y, Zhang J. Recent development in NMDA receptors. Chin Med J. 2000;113(10):948–56.

7. Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol. 2007;7(1):39–47. https://doi.org/10.1016/j.coph.2006.08.011

8. Olney JW, Labruyere J, Price MT. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science. 1989;244(4910):1360–2. https://doi.org/10.1126/science.2660263

9. Hargreaves RJ, Hill RG, Iversen LL. Neuroprotective NMDA antagonists: the controversy over their potential for adverse effects on cortical neuronal morphology. Acta Neurochir Suppl. 1994;60:15–9.

10. Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2018;(6):CD001190. https://doi.org/10.1002/14651858.CD001190.pub3

11. Loy C, Schneider L. Galantamine for Alzheimer’s disease and mild cognitive impairment. Cochrane Database Syst Rev. 2006;(1):CD001747. https://doi.org/10.1002/14651858.CD001747.pub3

12. Birks JS, Chong LY, Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2015;(4):CD001191. https://doi.org/10.1002/14651858.CD001191.pub4

13. Birks JS. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev. 2006;(1):CD005593. https://doi.org/10.1002/14651858.CD005593

14. McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;(2):CD003154. https://doi.org/10.1002/14651858.CD003154.pub5

15. Jones RW. A review comparing the safety and tolerability of memantine with the acetylcholinesterase inhibitors. Int J Geriatr Psychiatry. 2010;25(6):547–53. https://doi.org/10.1002/gps.2384

16. McShane R, Westby MJ, Roberts E, Minakaran N, Schneider L, Farrimond LE, et al. Memantine for dementia. Cochrane Database Syst Rev. 2019;(3):CD003154. https://doi.org/10.1002/14651858.CD003154.pub6

17. Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R. Adverse effects of cholinesterase inhibitors in dementia, according to the pharmacovigilance databases of the United-States and Canada. PLoS One. 2015;10(12):e0144337. https://doi.org/10.1371/journal.pone.0144337

18. Lim EY, Yang DW, Kim JS, Cho AH. Safety and efficacy of anti-dementia agents in the extremely elderly patients with dementia. J Korean Med Sci. 2018;33(19):e133. https://doi.org/10.3346/jkms.2018.33.e133

19. Stella F, Radanovic M, Canineu PR, de Paula VJR, Forlenza OV. Anti-dementia medications: current prescriptions in clinical practice and new agents in progress. Ther Adv Drug Saf. 2015;6(4):151–65. https://doi.org/10.1177/2042098615592116

20. Park YH. Oldest old patients should be recruited more in clinical trials of dementia. J Korean Med Sci. 2018;33(19):e146. https://doi.org/10.3346/jkms.2018.33.e146

21. Hernández MH, Mestres C, Modamio P, Junyent J, Costa-Tutusaus L, Lastra CF, Mariño EL. Adverse drug events in patients with dementia and neuropsychiatric/behavioral, and psychological symptoms, a one-year prospective study. Int J Environ Res Public Health. 2019;16(6):934. https://doi.org/10.3390/ijerph16060934

22. Cui CC, Sun Y, Wang XY, Zhang Y, Xing Y. The effect of anti-dementia drugs on Alzheimer disease-induced cognitive impairment: a network meta-analysis. Medicine. 2019;98(27):e16091. https://doi.org/10.1097/MD.0000000000016091