Atropine is of no use to stimulate breathing in cholinergic crisis, and mechanical ventilation is the only option. What potential therapeutic agents can be designed to reverse this phase in critical care practice?
Please check out the following link, it might be helpful.
Regards
http://www.ncbi.nlm.nih.gov/pubmed/22352046
Dear Sidharta,
As you wrote the treatment for this condition is still to be investigated since the anticholinergic agents such as atropine do not give the desired treatment effect.
For contributing to the discussion I present some facts concerning the treatment of cholinergic crisis.
1-Some elements of cholinergic crisis can be treated with antimuscarinic drugs like atropine, but the most important element, respiratory arrest, cannot. The neuromuscular junction, where the brain communicates with skeletal muscle (like the diaphragm, the main breathing muscle), works by acetylcholine activating nicotinic acetylcholine receptors and leading to muscle contraction. Atropine blocks muscarinic acetylcholine receptors (a different subtype than the nicotinic receptors at the neuromuscular junction), so atropine will not improve the muscle strength and ability to breath in someone with cholinergic crisis. Such a patient will require mechanical ventilation support via endotracheal intubation until the crisis resolves on its own. The respiratory compromise from cholinergic crisis unfortunately has no pharmacologic solution or therapy.
2-Nihon Kokyuki Gakkai Zasshi. 2011 Dec;49(12):877-84.
[Acute respiratory failure associated with cholinergic crisis: report of five cases and review of the literature].
[Article in Japanese]
Takahashi M1, Ubukata S, Sato E, Shoji M, Morikawa N, Watanabe H, Takahashi H.
Author information
Abstract
Distigmine bromide is a cholinesterase inhibitor widely used for the treatment of hypotonic neurogenic bladder. However, this drug is also known to cause cholinergic crisis, a rare but serious adverse reaction. Cholinergic crisis is an excessive amount of acetylcholine due to the systemic inhibition of cholinesterase activity, characterized by parasympathetic symptoms such as sweating, salivation, miosis, bradycardia, diarrhea and circulatory and respiratory failure. The incidence of cholinergic crisis has been estimated at approximately 0.2%, and the majority of the patients are elderly with underlying conditions such as cerebrovascular disease. Since 2004, we have encountered 5 cases of acute respiratory failure associated with cholinergic crisis induced by the administration of a normal oral dose of distigmine. We present these cases here and review an additional 23 cases from the literature in Japan. In these 28 cases, mechanical ventilation was required for 57%, with a mean duration of 5.1 days and a mortality rate of 11%. Pneumonia was observed in half of the cases in the acute phase, and relapse due to the readministration of distigmine was reported in 20% of cases. It is important to remember that cholinergic crisis in the elderly is often misdiagnosed and is occasionally treated as simple aspiration pneumonia.
http://www.ncbi.nlm.nih.gov/pubmed/22352046
Hoping this will contribute in the discussion on this very interesting topic,
Rafik
Dear Sidharta,
As you wrote the treatment for this condition is still to be investigated since the anticholinergic agents such as atropine do not give the desired treatment effect.
For contributing to the discussion I present some facts concerning the treatment of cholinergic crisis.
1-Some elements of cholinergic crisis can be treated with antimuscarinic drugs like atropine, but the most important element, respiratory arrest, cannot. The neuromuscular junction, where the brain communicates with skeletal muscle (like the diaphragm, the main breathing muscle), works by acetylcholine activating nicotinic acetylcholine receptors and leading to muscle contraction. Atropine blocks muscarinic acetylcholine receptors (a different subtype than the nicotinic receptors at the neuromuscular junction), so atropine will not improve the muscle strength and ability to breath in someone with cholinergic crisis. Such a patient will require mechanical ventilation support via endotracheal intubation until the crisis resolves on its own. The respiratory compromise from cholinergic crisis unfortunately has no pharmacologic solution or therapy.
2-Nihon Kokyuki Gakkai Zasshi. 2011 Dec;49(12):877-84.
[Acute respiratory failure associated with cholinergic crisis: report of five cases and review of the literature].
[Article in Japanese]
Takahashi M1, Ubukata S, Sato E, Shoji M, Morikawa N, Watanabe H, Takahashi H.
Author information
Abstract
Distigmine bromide is a cholinesterase inhibitor widely used for the treatment of hypotonic neurogenic bladder. However, this drug is also known to cause cholinergic crisis, a rare but serious adverse reaction. Cholinergic crisis is an excessive amount of acetylcholine due to the systemic inhibition of cholinesterase activity, characterized by parasympathetic symptoms such as sweating, salivation, miosis, bradycardia, diarrhea and circulatory and respiratory failure. The incidence of cholinergic crisis has been estimated at approximately 0.2%, and the majority of the patients are elderly with underlying conditions such as cerebrovascular disease. Since 2004, we have encountered 5 cases of acute respiratory failure associated with cholinergic crisis induced by the administration of a normal oral dose of distigmine. We present these cases here and review an additional 23 cases from the literature in Japan. In these 28 cases, mechanical ventilation was required for 57%, with a mean duration of 5.1 days and a mortality rate of 11%. Pneumonia was observed in half of the cases in the acute phase, and relapse due to the readministration of distigmine was reported in 20% of cases. It is important to remember that cholinergic crisis in the elderly is often misdiagnosed and is occasionally treated as simple aspiration pneumonia.
http://www.ncbi.nlm.nih.gov/pubmed/22352046
Hoping this will contribute in the discussion on this very interesting topic,
Rafik
Dear Rafik,
Thanks for your reply. Yes this is an interesting topic since this topic involves intriguing interplay between ACh, muscarinic, and nicotinic receptor actions.
Atropine as we know is a competitive antagonist of ACh at the muscarinic receptors. The muscles of respiration are innervated by cholinergic nicotinic receptors, so atropine is of no use in this sense.
Almost all anticholinesterase agents or cholinesterase inhibitors are contraindicated in cholinergic crisis; distigmine is not an anticholinergic agent rather it is a cholinomimetic drug similar to neostigmine or physostigmine. There's no rational for using muscarinic agonists as well, since most of these agents are cholinomimetic / parasympathomimetic, and dangerous if used in acute respiratory failure due to cholinergic crisis (often on account of organophosphate poisoning [OP]) or due to over-treatment of myasthenia gravis with distigmine (AChI toxicity). One option which could be explored: if any targeted nicotinic receptor analogue which would selectively bind to ACh nicotinic receptors on the diaphragmatic muscles may be of some use. You have very little choice for drug therapeutics in the way of giving anticholinergic agents (atropine, or pralidoxime which is effective only in OP) or experimenting with drugs that block the synthesis of ACh, but this would likely, in any case of MG, would further worsen the symptoms. Transient inhibition of the enzyme choline acetyltransferase would result in motor neuron dysfunctions, so this is not an option as well. Drugs like kainite, or hemicholine which block the reuptake of choline may reduce synthesis of ACh, so may act as an indirect acting anticholinergic agent. But it has got no clinical use.
Regards, Sidharta