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Pharmaceutical Acetylcholinesterase Inhibitors (7)

To read the first article in this series, click here.

To read the previous article in this series, click here.

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There are two man-made reversible inhibitors of note: donepezil and rivastigmine. Donepezil is the world’s best-selling treatment for the symptoms of Alzheimer’s disease. First approved by the FDA in 1996, the blockbuster drug is produced by Eisai and Pfizer under the brand name Aricept[1]. Interestingly, aside from improving cognitive function, it also reduces sleep apnea in AD patients. Unlike the selective donepezil, rivastigmine blocks both acetylcholinesterase and butyrylcholinesterase. It is also prescribed for the treatment of AD in the US and Europe, though it is not as well tolerated as donepezil.

Galantamine, sold under the brand names Reminyl, is an alkaloid isolated from Amaryllidaceae plant family, originally used in Bulgarian and Turkish folk medicines for the treatment of neurological conditions. It was first isolated by the Bulgarian Soviet scientist Dimitar Paskov in 1956[2]. Galantamine has a dual pharmacological effect. It not only reversibly inhibits acetylcholinesterase, but it also binds to allosteric sites of cholinergic receptors, increasing their affinity for acetylcholine. This dual effect of increasing acetylcholine activity and improving receptor sensitivity to it would be more attractive if the drug was well tolerated.


All the acetylcholinesterase inhibitor drugs are dosed in a titrating fashion, because side effects decline with time on the drug, though the cognitive benefits do not. But in the case of galantamine, side effects of nausea and vomiting are particularly pronounced[3]. AD patients begin with 4 mg twice a day. After 4 weeks they usually double the dose, and then after another four weeks they increase it to 12 mg twice a day. Empirically, 16-24mg a day is considered the optimal dose. Strikingly, in studies on mild cognitive impairment, individuals treated with galantamine had higher mortalities[4], though this was not observed in studies on AD patients[5].

Note that acetylcholinesterase inhibitors have been mysteriously shown to reduce dopamine-dependent addictive behavior in animal studies, including with morphine and cocaine in rodents[6][7], and amphetamines in monkeys[8], though results in humans have been mixed[9][10][11][12].

To continue to the next blog post in this series, click here.

To return to an overview of the blog series on the cholinergic system, click here.

[1] Colovic, M. B., Krstic, D. Z., Lazarevic-Pasti, T. D., Bondzic, A. M., & Vasic, V. M. (2013). Acetylcholinesterase inhibitors: pharmacology and toxicology. Current neuropharmacology, 11(3), 315-335. [2] Kostadinova, I., & Danchev, N. (2019). 4-aminopyridine–the new old drug for the treatment of neurodegenerative diseases. Pharmacia, 66, 67. [3] Colovic, M. B., Krstic, D. Z., Lazarevic-Pasti, T. D., Bondzic, A. M., & Vasic, V. M. (2013). Acetylcholinesterase inhibitors: pharmacology and toxicology. Current neuropharmacology, 11(3), 315-335. [4] Mayor, S. (2005). Regulatory authorities review use of galantamine in mild cognitive impairment. BMJ, 330(7486), 276. [5] López-Pousa, S., Olmo, J. G., Franch, J. V., Estrada, A. T., Cors, O. S., Nierga, I. P., & Gelada-Batlle, E. (2006). Comparative analysis of mortality in patients with Alzheimer’s disease treated with donepezil or galantamine. Age and ageing, 35(4), 365-371. [6] Grasing, K., He, S., & Yang, Y. (2009). Long-lasting decreases in cocaine-reinforced behavior following treatment with the cholinesterase inhibitor tacrine in rats selectively bred for drug self-administration. Pharmacology Biochemistry and Behavior, 94(1), 169-178. [7] Hikida, T., Kitabatake, Y., Pastan, I., & Nakanishi, S. (2003). Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine. Proceedings of the National Academy of Sciences, 100(10), 6169-6173. [8] Andersen, M. B., Werge, T., & Fink-Jensen, A. (2007). The acetylcholinesterase inhibitor galantamine inhibits d-amphetamine-induced psychotic-like behavior in Cebus monkeys. Journal of Pharmacology and Experimental Therapeutics, 321(3), 1179-1182. [9] Grasing, K., Mathur, D., Newton, T. F., & DeSouza, C. (2010). Donepezil treatment and the subjective effects of intravenous cocaine in dependent individuals. Drug and alcohol dependence, 107(1), 69-75. [10] De La Garza II, R., Mahoney III, J. J., Culbertson, C., Shoptaw, S., & Newton, T. F. (2008). The acetylcholinesterase inhibitor rivastigmine does not alter total choices for methamphetamine, but may reduce positive subjective effects, in a laboratory model of intravenous self-administration in human volunteers. Pharmacology Biochemistry and Behavior, 89(2), 200-208. [11] De La Garza, R., Shoptaw, S., & Newton, T. F. (2008). Evaluation of the cardiovascular and subjective effects of rivastigmine in combination with methamphetamine in methamphetamine-dependent human volunteers. International Journal of Neuropsychopharmacology, 11(6), 729-741. [12] Winhusen, T. M., Somoza, E. C., Harrer, J. M., Mezinskis, J. P., Montgomery, M. A., Goldsmith, R. J., ... & Berger, P. (2005). A placebo‐controlled screening trial of tiagabine, sertraline and donepezil as cocaine dependence treatments. Addiction, 100, 68-77.

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