Title:Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment
Volume: 15
Issue: 4
Author(s): Ondrej Soukup, Michael Winder, Uday Kumar Killi, Vladimir Wsol, Daniel Jun, Kamil Kuca*Gunnar Tobin*
Affiliation:
- Biomedical Research Centre, University Hospital Hradec Kralove,Czech Republic
- Institute of Neuroscience and Physiology, Department of Pharmacology, the Sahlgrenska Academy at the University of Gothenburg,Sweden
Keywords:
Acetylcholine, acetylcholinesterase, muscarinic receptor subtypes, pharmacotherapy.
Abstract: Background: Pharmaceuticals with targets in the cholinergic transmission have been used
for decades and are still fundamental treatments in many diseases and conditions today. Both the
transmission and the effects of the somatomotoric and the parasympathetic nervous systems may be
targeted by such treatments. Irrespective of the knowledge that the effects of neuronal signalling in
the nervous systems may include a number of different receptor subtypes of both the nicotinic and
the muscarinic receptors, this complexity is generally overlooked when assessing the mechanisms of
action of pharmaceuticals.
Methods: We have search of bibliographic databases for peer-reviewed research literature focused on
the cholinergic system. Also, we have taken advantage of our expertise in this field to deduce the
conclusions of this study.
Results: Presently, the life cycle of acetylcholine, muscarinic receptors and their effects are reviewed
in the major organ systems of the body. Neuronal and non-neuronal sources of acetylcholine are
elucidated. Examples of pharmaceuticals, in particular cholinesterase inhibitors, affecting these
systems are discussed. The review focuses on salivary glands, the respiratory tract and the lower
urinary tract, since the complexity of the interplay of different muscarinic receptor subtypes is of
significance for physiological, pharmacological and toxicological effects in these organs.
Conclusion: Most pharmaceuticals targeting muscarinic receptors are employed at such large doses
that no selectivity can be expected. However, some differences in the adverse effect profile of
muscarinic antagonists may still be explained by the variation of expression of muscarinic receptor
subtypes in different organs. However, a complex pattern of interactions between muscarinic
receptor subtypes occurs and needs to be considered when searching for selective pharmaceuticals. In
the development of new entities for the treatment of for instance pesticide intoxication, the
muscarinic receptor selectivity needs to be considered. Reactivators generally have a muscarinic M2
receptor acting profile. Such a blockade may engrave the situation since it may enlarge the effect of
the muscarinic M3 receptor effect. This may explain why respiratory arrest is the major cause for
deaths by esterase blocking.
