Neostigmine

Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage.<ref name=AHFS2016/><ref name=WHO2008>Template:Cite book</ref> It is also used in anaesthesia to end the effects of non-depolarising neuromuscular blocking medication.<ref name=AHFS2016/> It is given by injection either into a vein, muscle, or under the skin.<ref name=AHFS2016/> After injection effects are generally greatest within 30 minutes and last up to 4 hours.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include nausea, increased saliva, crampy abdominal pain, and slow heart rate.<ref name=AHFS2016/> More severe side effects include low blood pressure, weakness, and allergic reactions.<ref name=AHFS2016/> It is unclear if use in pregnancy is safe for the baby.<ref name=AHFS2016/> Neostigmine is in the cholinergic family of medications.<ref name=AHFS2016/> It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine.<ref name=AHFS2016/>

Neostigmine was patented in 1931.<ref name=Fis2006>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> The term is from Greek neos, meaning "new", and "-stigmine", in reference to the alkaloid, physostigmine, which inspired its design.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is available as a generic medication.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

It is used to improve muscle tone in people with myasthenia gravis, and also to reverse the effects of non-depolarizing muscle relaxants such as rocuronium and vecuronium at the end of an operation.<ref name = "Neely_2022">Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Another indication for use is the conservative management of acute colonic pseudo-obstruction, or Ogilvie's syndrome, in which patients get massive colonic dilatation in the absence of a true mechanical obstruction.<ref>Template:Cite journal</ref>

Neostigmine is often prescribed for underactive urinary bladder.<ref>Template:Cite journal</ref>

Hospitals sometimes administer a solution containing neostigmine intravenously to delay the effects of envenomation through snakebite.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Some promising research results have also been reported for administering the drug nasally in order to buy time if anti-venom is not immediately available.<ref name="pmid30154870">Template:Cite journal</ref>

Side effects

Neostigmine has a wide variety of side-effects due to its action that increases acetylcholine (ACh) binding muscarinic receptors on exocrine glandular cells throughout the body, cardiac muscle cells, and smooth muscle cells. These effects include: salivation, lacrimation, diarrhea, bradycardia, and bronchoconstriction.<ref>Template:Cite book</ref> Gastrointestinal symptoms occur earliest.<ref name = "Gilman_1980" />Template:Rp

For this reason, it is usually given along with an anti-cholinergic drug such as atropine or glycopyrrolate which act only on muscarinic receptors while permitting neostigmine action at nicotinic receptors.<ref>Template:Cite journal</ref>

Neostigmine can also induce generic ocular side effects including: headache, brow pain, blurred vision, phacodonesis, pericorneal injection, congestive iritis, various allergic reactions, and rarely, retinal detachment.<ref name = "Gilman_1980">Template:Cite book</ref>Template:Rp

Pharmacology

Acetylcholine is metabolized by the enzyme acetylcholinesterase that cleaves acetylcholine in the neuromuscular junction into acetate and choline. Neostigmine is an inhibitor of acetylcholinesterase. Neostigmine binds to the anionic and ester site of acetylcholinesterase, which blocks the enzyme from breaking down the acetylcholine molecules before they reach the postsynaptic membrane receptors. Its action leads to the accumulation of acetylcholine in the neuromuscular junction that compete with the non-depolarizing blocker agent bound to the acetylcholine receptors. By interfering with the breakdown of acetylcholine, neostigmine indirectly stimulates both nicotinic and muscarinic receptors.<ref name = "Neely_2022" />

Unlike physostigmine, neostigmine has a quaternary nitrogen; hence, it is more polar. It does not cross the blood–brain barrier and enter the CNS.<ref>Template:Cite journal</ref>

Neostigmine is administered intravenously. The drug should be administered when a peripheral nerve stimulator shows a second twitch is present or when the first twitch response is considerably above 10% of baseline. Peak effect is at 7 to 10 minutes.<ref name = "Neely_2022" /> Neostigmine has moderate duration of action – usually two to four hours.<ref>Template:Cite book</ref> It is metabolized by enzymes in the liver and excreted in the urine.<ref name = "Neely_2022" />

Chemistry

Neostigmine, which can be viewed as a simplified analog of physostigmine, is made by reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms the dimethylcarbamate, and its subsequent alkylation using dimethyl sulfate forming the desired compound.

Spectral data

Neostigmine shows notable UV/VIS absorption at 261 nm, 267 nm, and 225 nm.<ref name="pmid4034636">Template:Cite journal</ref>

Neostigmine's ¹H NMR Spectroscopy reveals shifts at: 7.8, 7.7, 7.4, 7.4, 3.8, and 3.1 parts per million. The higher shifts are due to the aromatic hydrogens. The lower shifts at 3.8 ppm and 3.1 ppm are due to the electronic withdrawing nature of the tertiary and quaternary nitrogen, respectively.<ref name="pmid8103105">Template:Cite journal</ref>

History

Neostigmine was first synthesized by Aeschlimann and Reinert in 1931<ref>Template:Cite book</ref> and was patented by Aeschlimann in 1933.<ref>Template:Cite patent</ref>

Neostigmine is made by first reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms a dimethylcarbamate. Next, that product is alkylated using dimethyl sulfate, which forms neostigmine.<ref name = "Gilman_1980" />Template:Rp

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