Neostigmine, sold under the brand name Bloxiverz, among others, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

used to treat myasthenia gravis,

Ogilvie syndrome Ogilvie syndrome is the acute dilatation of the colon in the absence of any mechanical obstruction in severely ill patients. Acute colonic pseudo-obstruction is characterized by massive dilatation of the cecum (diameter > 10 cm) and right c ...

, and

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of bladd ...

without the presence of a blockage. It is also used in anaesthesia to end the effects of non-depolarising neuromuscular blocking medication. It is given by injection either into a vein, muscle, or under the skin. After injection effects are generally greatest within 30 minutes and last up to 4 hours. Common side effects include nausea, increased saliva, crampy abdominal pain, and

slow heart rate Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

. More severe side effects include

low blood pressure Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...

, weakness, and

allergic reactions Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

. It is unclear if use in

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

is safe for the baby. Neostigmine is in the

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cati ...

family of medications. It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine. Neostigmine was patented in 1931. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. The term is from Greek ''neos'', meaning "new", and "-stigmine", in reference to its parent molecule,

physostigmine Physostigmine (also known as eserine from ''éséré'', the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean a ...

, on which it is based.

Medical uses

It is used to improve muscle tone in people with myasthenia gravis, and also to reverse the effects of non-

depolarizing In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therap ...

s such as

rocuronium Rocuronium bromide (brand names Zemuron, Esmeron) is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly r ...

and

vecuronium Vecuronium bromide, sold under the brand name Norcuron among others, is a medication used as part of general anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. It is also used to help with endotracheal in ...

at the end of an operation. Another indication for use is the

conservative management Conservative management is a type of medical treatment defined by the avoidance of invasive measures such as surgery or other invasive procedures, usually with the intent to preserve function or body parts. For example, in appendicitis, conservati ...

of acute colonic pseudo-obstruction, or Ogilvie's syndrome, in which patients get massive colonic dilatation in the absence of a true mechanical obstruction. Neostigmine is often prescribed for underactive urinary bladder. Hospitals sometimes administer a solution containing neostigmine intravenously to delay the effects of

envenomation Envenomation is the process by which venom is injected by the bite or sting of a venomous animal. Many kinds of animals, including mammals (e.g., the northern short-tailed shrew, ''Blarina brevicauda''), reptiles (e.g., the king cobra), spiders ...

through

snakebite A snakebite is an injury caused by the bite of a snake, especially a venomous snake. A common sign of a bite from a venomous snake is the presence of two puncture wounds from the animal's fangs. Sometimes venom injection from the bite may occu ...

. Some promising research results have also been reported for administering the drug nasally as a snakebite treatment.

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. Gastrointestinal symptoms occur earliest. For this reason, it is usually given along with an anti-cholinergic drug such as atropine or

glycopyrrolate Glycopyrronium bromide is a medication of the muscarinic anticholinergic group. It does not cross the blood–brain barrier and consequently has few to no central effects. It is available in oral, intravenous, topical, and inhaled forms. It is a ...

which act only on muscarinic receptors while permitting neostigmine action at nicotinic receptors. 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.

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 Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

from breaking down the acetylcholine molecules before they reach the

postsynaptic membrane Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

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 Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

and

muscarinic receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several r ...

s. Unlike

, neostigmine has a quaternary nitrogen; hence, it is more polar. It does not cross the blood–brain barrier and enter the CNS. However, it does cross the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

. 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. Neostigmine has moderate duration of action – usually two to four hours. It is metabolized by enzymes in the liver and excreted in the urine.

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. 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.

History

Neostigmine was first synthesized by Aeschlimann and Reinert in 1931 and was patented by Aeschlimann in 1933. 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.

References

External links

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