Acetylcholinesterase (AChE) inhibitors will prevent the breakdown of acetylcholine (ACh) and so increase ACh levels. Increased ACh levels at autonomic nervous system ganglia should activate both the sympathetic and parasympathetic nervous systems. However, the adverse effects of AChE inhibitors outside of the CNS are mostly parasympathomimetic. Why do AChE inhibitors not stimulate the sympathetic nervous system as well?

Acetylcholinesterase (AChE) inhibitors increase the concentration of acetylcholine (ACh) at synapses by blocking its breakdown. This will activate both the sympathetic and parasympathetic systems, as the preganglionic neurons in both systems release ACh.

However, the impact of AChE inhibitors is more prominent on the parasympathetic nervous system for several reasons:

  •  Target Organs and Tissues: Unlike the sympathetic system, the parasympathetic system primarily uses ACh as the neurotransmitter not just at the ganglia (like the sympathetic system) but also in the target organs and tissues. This means that AChE inhibitors significantly enhance the effects of parasympathetic activation all the way to the target tissues, unlike in the sympathetic system, where norepinephrine (NE) is released at the target organs and tissues and is not impacted by AChE inhibitors.
  • Desensitization: Increased ACh levels due to AChE inhibitors will eventually lead to overstimulation of nicotinic receptors at the ganglia of both systems. This causes depolarizing block and desensitization of these receptors, essentially causing them to “shut down” temporarily. This means the impact on both sympathetic and parasympathetic systems at the ganglionic level becomes blunted.
  • Parasympathomimetic Persistence: Even after the desensitization at the ganglia, the parasympathetic effects continue to be felt at the target tissues because of increased levels of ACh there. This “overrules” the sympathetic nervous system because the sympathetic neurotransmitters (norepinephrine and epinephrine) are not increased by AChE inhibitors.

So, while theoretically, AChE inhibitors could have an initial impact on both systems, in practical terms, their effect is skewed toward a parasympathomimetic outcome for the reasons listed above. This explains why using AChE inhibitors often leads to symptoms like bradycardia (slow heart rate), increased gastrointestinal motility, and other signs of heightened parasympathetic activity rather than a balanced activation of both autonomic branches.