Clinical Pharmacokinetics

, Volume 41, Issue 10, pp 719–739 | Cite as

Clinical Pharmacokinetics and Pharmacodynamics of Cholinesterase Inhibitors

  • Michael W. JannEmail author
  • Kara L. Shirley
  • Gary W. Small
Review Article Drug Disposition


Cholinesterase inhibitors are the ‘first-line’ agents in the treatment of Alzheimer’s disease. This article presents the latest information on their pharmacokinetic properties and pharmacodynamic activity.

Tacrine was the first cholinesterase inhibitor approved by regulatory agencies, followed by donepezil, rivastigmine and recently galantamine. With the exception of low doses of tacrine, the cholinesterase inhibitors exhibit a linear relationship between dose and area under the plasma concentration-time curve. Cholinesterase inhibitors are rapidly absorbed through the gastrointestinal tract, with time to peak concentration usually less than 2 hours; donepezil has the longest absorption time of 3 to 5 hours. Donepezil and tacrine are highly protein bound, whereas protein binding of rivastigmine and galantamine is less than 40%. Tacrine is metabolised by hepatic cytochrome P450 (CYP) 1A2, and donepezil and galantamine are metabolised by CYP3A4 and CYP2D6. Rivastigmine is metabolised by sulfate conjugation.

Two cholinesterase enzymes are present in the body, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Tacrine and rivastigmine inhibit both enzymes, whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapse. These different pharmacological profiles provide distinctions between these agents. Cholinesterase inhibitors show a nonlinear relationship between dose and cholinesterase inhibition, where a plateau effect occurs. Cholinesterase inhibitors display a different profile as each agent achieves its plateau at different doses.

In clinical trials, cholinesterase inhibitors demonstrate a dose-dependent effect on cognition and functional activities. Improvement in behavioural symptoms also occurs, but without a dose-response relationship. Gastrointestinal adverse events are dose-related. Clinical improvement occurs with between 40 and 70% inhibition of cholinesterase. A conceptual model for cholinesterase inhibitors has been proposed, linking enzyme inhibition, clinical efficacy and adverse effects. Currently, measurement of enzyme inhibition is used as the biomarker for cholinesterase inhibitors. New approaches to determining the efficacy of cholinesterase inhibitors in the brain could involve the use of various imaging techniques.

The knowledge base for the pharmacokinetics and pharmacodynamics of cholinesterase inhibitors continues to expand. The increased information available to clinicians can optimise the use of these agents in the management of patients with Alzheimer’s disease.


Cholinesterase Fluvoxamine Cholinesterase Inhibitor Rivastigmine Tacrine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Kara L. Shirley, Pharm.D., at the time of this paper was the Novartis Fellow in Clinical Neuropsychopharmacology, and received only salary support from Novartis for her training. Michael W. Jann, Pharm.D., has received research grant support from Novartis and Janssen, Otsuka, Bristol Myers Squibb, Solvay, Glaxo Smith Kline, Lipocine, Lilly and Pfizer Pharmaceuticals.


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Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Michael W. Jann
    • 1
    Email author
  • Kara L. Shirley
    • 1
    • 2
  • Gary W. Small
    • 3
  1. 1.Department of Clinical and Administrative Sciences, Southern School of PharmacyMercer UniversityAtlantaUSA
  2. 2.Department of Pharmacy PracticeAlbany College of PharmacyAlbanyUSA
  3. 3.Department of Psychiatry and Biobehavioral Sciences, Center on Aging and Alzheimer’s Disease Research CenterUniversity of CaliforniaLos AngelesUSA

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