What is the difference between muscarinic receptor blockers, cholinergic (parasympathomimetic) agents, anticholinergic (antimuscarinic) agents, and muscarinic receptor inhibitors?

From the Guidelines

Muscarinic blockers, anticholinergics, and muscarinic inhibitors should be avoided in older patients due to their strong anticholinergic effects, which can lead to negative effects on vision, urination, constipation, and cognition, as seen in a 2021 study published in the Mayo Clinic Proceedings 1. When considering the use of muscarinic blockers, anticholinergics, and muscarinic inhibitors, it is essential to weigh the potential benefits against the risks, particularly in older patients. These medications, which include oxybutynin, diphenhydramine, and cyclobenzaprine, can have broad muscarinic receptor blockade effects, leading to adverse outcomes. In contrast, cholinergics, such as bethanechol, pilocarpine, and neostigmine, increase acetylcholine activity and are used to treat conditions like myasthenia gravis, glaucoma, and urinary retention.

Some key points to consider when prescribing these medications include:

• The anticholinergic burden, which refers to the cumulative effect of taking multiple anticholinergic drugs, can adversely affect cognition and functionality in older patients 1.
• The decline in acetylcholine physiology associated with aging can be further blocked by anticholinergics, leading to negative effects on vision, urination, constipation, and cognition.
• The use of anticholinergic medications has been linked to an increased risk of injurious falls, episodes of confusion or delirium, visits to the emergency department, and hospitalizations, ultimately raising the cost of care 1.
• Cholinergics, on the other hand, can be beneficial in treating certain conditions, but their use should be carefully considered in patients with contraindications like asthma.

In terms of specific medications, muscarinic blockers/anticholinergics like atropine, scopolamine, ipratropium, and oxybutynin are used to treat conditions like overactive bladder, COPD, asthma, and motion sickness. However, their use should be approached with caution, particularly in older patients, due to the potential for strong anticholinergic effects. The most recent evidence suggests that deprescribing strongly anticholinergic medications, such as oxybutynin, can help mitigate the negative effects associated with anticholinergic burden in older patients 1.

From the FDA Drug Label

Tolterodine is a competitive muscarinic receptor antagonist. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels.

The main difference between muscarinic blockers, anticholinergics, and muscarinic inhibitors is largely semantic, as they all refer to agents that block the action of acetylcholine at muscarinic receptors.

• Muscarinic blockers and muscarinic inhibitors are terms that specifically refer to the blockade of muscarinic receptors.
• Anticholinergics is a broader term that refers to any agent that blocks the action of acetylcholine, including both muscarinic and nicotinic receptors.
• Cholinergics, on the other hand, are agents that mimic the action of acetylcholine, either by directly stimulating muscarinic or nicotinic receptors, or by increasing the concentration of acetylcholine in the synaptic cleft. In the context of tolterodine, it is a muscarinic blocker or antimuscarinic agent, as it competitively antagonizes muscarinic receptors 2.

From the Research

Muscarinic Blockers vs Cholinergics vs Anticholinergics vs Muscarinic Inhibitors

• Muscarinic blockers, also known as antimuscarinics, are used to treat overactive bladder (OAB) by inhibiting the binding of acetylcholine at muscarinic receptors M(2) and M(3) on detrusor smooth muscle cells and other structures within the bladder wall 3.
• Cholinergics, on the other hand, are agents that mimic the action of acetylcholine, and are not typically used to treat OAB.
• Anticholinergics is another term for antimuscarinics, and refers to the same class of drugs used to treat OAB.
• Muscarinic inhibitors is also another term for antimuscarinics, and refers to the same class of drugs used to treat OAB.

Comparison of Antimuscarinics

• Several antimuscarinic agents are available for the treatment of OAB, including oxybutynin, tolterodine, propiverine, trospium, darifenacin, and solifenacin 4, 3.
• These agents differ in their pharmacokinetic and adverse event profiles, as well as their muscarinic receptor subtype selectivity 3, 5.
• Some antimuscarinics, such as tolterodine and darifenacin, have shown bladder selectivity in animal models, which may improve their tolerability 6.
• Network meta-analyses have compared the efficacy and adverse events of different antimuscarinics, and found that some agents, such as trospium and fesoterodine, have a more favorable balance of efficacy and adverse events 7.

Adverse Events

• Antimuscarinics can cause a range of adverse events, including dry mouth, constipation, blurred vision, and cognitive impairment 4, 3, 7.
• The risk of adverse events can vary depending on the specific antimuscarinic agent, dosage, and formulation used 7.
• Agents with greater M(3) selectivity may have a lower risk of cognitive and cardiovascular adverse events 5.