Ipratropium is a muscarinic antagonist used as a bronchodilator in the treatment of chronic obstructive pulmonary disease and asthma. Parasympathetic nervous system activation of M2 receptors in the heart slows the heart but the adverse effects of the muscarinic receptor antagonist, ipratropium, reported by patients can include bradycardia (slowing of the heart). How is this possible?
The parasympathetic nervous innervation of the heart releases acetylcholine, which acts at M2 receptors to slow the heart rate. Thus, muscarinic acetylcholine receptors antagonists, such as atropine, are expected to induce tachycardia (increase the heart rate). Indeed, they do this at high doses. However, there is a balance between the sympathetic and parasympathetic branches of our autonomic nervous system. If we block the parasympathetic nervous system with a muscarinic receptor antagonist, such as atropine, our body tries to compensate by down-regulating the sympathetic nervous system. With low doses of muscarinic receptor antagonists, this compensatory down-regulation of the sympathetic nervous system can be sufficient or even overshoot resulting in bradycardia. However, at higher doses of muscarinic receptor antagonists, the compensatory effect is no longer enough, and the parasympatholytic tachycardia dominates.
When delivered by inhalation for the relief of bronchoconstriction, very little ipratropium escapes into the systemic circulation. Thus, the doses reaching the heart are low doses. The compensatory mechanism is in action, and we may see compensatory bradycardia rather than tachycardia. In fact, in normal clinical use, so little inhaled ipratropium escapes into the systemic circulation that even bradycardia is a rare side effect. Of course, in patients with other risk factors, at higher doses, or if administered orally, we need to look out for the risk of tachycardia.