From the Guidelines
Mestinon (pyridostigmine) causes bradycardia due to its inhibition of acetylcholinesterase, leading to increased acetylcholine levels that stimulate muscarinic receptors in the heart, slowing the heart rate. This effect is a result of the parasympathetic stimulation of the heart, which opposes sympathetic stimulation that would increase heart rate. The bradycardia caused by Mestinon is dose-dependent, making it more likely to occur with higher doses 1.
Mechanism of Action
The mechanism by which Mestinon causes bradycardia involves the inhibition of acetylcholinesterase, the enzyme responsible for breaking down acetylcholine. With less acetylcholine being broken down, its levels increase at cholinergic synapses throughout the body, including those in the heart. In cardiac tissue, the increased acetylcholine activates muscarinic receptors, particularly M2 receptors in the sinoatrial node, the heart's natural pacemaker. Stimulation of these receptors results in a decrease in the firing rate of pacemaker cells and a slowing of conduction through the atrioventricular node, ultimately leading to bradycardia.
Clinical Considerations
Patients taking Mestinon should be monitored for signs of excessive slowing of the heart rate, especially those with pre-existing cardiac conditions or those taking other medications that can slow heart rate. While this effect can be utilized therapeutically in certain cases, severe bradycardia can become problematic and may require treatment, such as with atropine, as recommended in guidelines for the management of symptomatic bradycardia 1.
Treatment of Bradycardia
In cases where Mestinon-induced bradycardia becomes symptomatic, treatment guidelines suggest the use of atropine as a first-line agent, with doses of 0.5 to 1 mg IV repeated every 3 to 5 minutes as needed, up to a total of 1.5 to 3 mg. The use of atropine should be cautious, especially in patients with acute coronary ischemia or myocardial infarction, as increased heart rate may worsen ischemia or increase infarct size 1.
From the Research
Mechanism of Bradycardia
- Mestinon (Pyridostigmine) causes bradycardia due to its effect on the cardiac parasympathetic pathway, which is mediated by the inhibition of cholinesterase activity and the direct activation of cholinergic receptors 2.
- The bradycardic effect of pyridostigmine is not clearly related to the degree of cholinesterase activity and has a low sensitivity to nicotinic and muscarinic M1 receptor antagonists, but a high sensitivity to muscarinic M2 receptor antagonists 2.
Comparison with Other Cholinesterase Inhibitors
- Neostigmine, another cholinesterase inhibitor, produces a dose-dependent decrease in heart rate, which is poorly correlated with cholinesterase inhibition and has a higher sensitivity to muscarinic receptor antagonists compared to edrophonium 3.
- Edrophonium, on the other hand, produces a dose-dependent decrease in heart rate that is highly correlated with cholinesterase inhibition and is blocked by muscarinic antagonists at similar doses to those that block the bradycardia produced by vagus nerve stimulation 3.
Clinical Implications
- The use of pyridostigmine can lead to bradycardia and AV block, particularly in patients with myasthenia gravis, and may require treatment with muscarinic antagonists such as hyoscyamine to resolve the condition 4.
- Glycopyrrolate and atropine are safe and effective in preventing heart rate slowing induced by neostigmine, with glycopyrrolate being more conducive to maintaining a stable heart rate in patients 5.