Neostigmine
Encyclopedia
Neostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor
.
Neostigmine is made by first reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms a dimethylcarbamate. Next, that product is alkylated using dimethylsulfate, which forms neostigmine.
, neostigmine indirectly stimulates
both nicotinic
and muscarinic receptor
s. Unlike physostigmine
, neostigmine has a quaternary nitrogen; hence, it is more polar and does not enter the CNS. Its effect on skeletal muscle is greater than that of physostigmine, and it can stimulate contractility before it paralyzes. Neostigmine has moderate duration of action, usually two to four hours. Neostigmine binds to the anionic site of cholinesterase. The drug blocks the active site of acetylcholinesterase so the enzyme can no longer break down the acetylcholine molecules before they reach the postsynaptic membrane receptors. This allows for the threshold to be reached so a new impulse can be triggered in the next neuron. In myasthenia gravis there are too few acetylcholine receptors so with the acetylcholinesterase blocked, acetylcholine can bind to the few receptors and trigger a muscular contraction.
and routinely, in anesthesia
at the end of an operation, to reverse the effects of non-depolarizing
muscle relaxant
s such as rocuronium
and vecuronium
, usually in a dose of 25 to 50 mcg per kilogram.
It can also be used for urinary retention
resulting from general anesthesia and to treat curariform
drug toxicity.
Another indication for use is the Ogilvie syndrome
which is a pseudoobstruction of the colon in critically ill patients.
Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration of neostigmine can provoke menstrual bleeding. Modern tests which rely on detecting hCG
in urine have rendered this application obsolete.
Though one of only two treatments available for myasthenia gravis this drug is no longer available to anyone using the Medicare Part D
program.
Neostigmine will cause slowing of the heart rate (bradycardia
), for this reason it is usually given along with a parasympatholytic
drug such as atropine
or glycopyrrolate
.
Gastrointestial symptoms occur earliest after ingestion and include anorexia, nausea and vomiting, abdominal cramps and diarrhea.
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 3.8ppm and 3.1ppm are due to the electronic withdrawing nature of the tertiary and quarterary nitrogen, respectively.
Acetylcholinesterase inhibitor
An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...
.
Synthesis
Neostigmine was first synthesized by Aeschlimann and Reinert in 1931.Neostigmine is made by first reacting 3-dimethylaminophenol with N-dimethylcarbamoyl chloride, which forms a dimethylcarbamate. Next, that product is alkylated using dimethylsulfate, which forms neostigmine.
Pharmacology
By interfering with the breakdown of acetylcholineAcetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, neostigmine indirectly stimulates
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
both nicotinic
Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
and muscarinic receptor
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s. Unlike physostigmine
Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
, neostigmine has a quaternary nitrogen; hence, it is more polar and does not enter the CNS. Its effect on skeletal muscle is greater than that of physostigmine, and it can stimulate contractility before it paralyzes. Neostigmine has moderate duration of action, usually two to four hours. Neostigmine binds to the anionic site of cholinesterase. The drug blocks the active site of acetylcholinesterase so the enzyme can no longer break down the acetylcholine molecules before they reach the postsynaptic membrane receptors. This allows for the threshold to be reached so a new impulse can be triggered in the next neuron. In myasthenia gravis there are too few acetylcholine receptors so with the acetylcholinesterase blocked, acetylcholine can bind to the few receptors and trigger a muscular contraction.
Clinical uses
It is used to improve muscle tone in people with myasthenia gravisMyasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
and routinely, in anesthesia
Anesthesia
Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...
at the end of an operation, to reverse the effects of non-depolarizing
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which 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 therapeutic groups: neuromuscular blockers and spasmolytics...
s such as rocuronium
Rocuronium
Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...
and vecuronium
Vecuronium
Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
, usually in a dose of 25 to 50 mcg per kilogram.
It can also be used for urinary retention
Urinary retention
Urinary retention, also known as ischuria, is a lack of ability to urinate. It is a common complication of benign prostatic hyperplasia , although it can also be caused by nerve dysfunction, constipation, infection, or medications...
resulting from general anesthesia and to treat curariform
Curare
Curare is a common name for various arrow poisons originating from South America. The three main types of curare are:* tubocurare...
drug toxicity.
Another indication for use is the Ogilvie syndrome
Ogilvie syndrome
Ogilvie syndrome is the acute pseudoobstruction and dilation of the colon in the absence of any mechanical obstruction in severely ill patients....
which is a pseudoobstruction of the colon in critically ill patients.
Historically, it has been used as a test for early pregnancy. In a non-pregnant female whose menstrual period is delayed, administration of neostigmine can provoke menstrual bleeding. Modern tests which rely on detecting hCG
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
in urine have rendered this application obsolete.
Though one of only two treatments available for myasthenia gravis this drug is no longer available to anyone using the Medicare Part D
Medicare Part D
Medicare Part D is a federal program to subsidize the costs of prescription drugs for Medicare beneficiaries in the United States. It was enacted as part of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 and went into effect on January 1, 2006.- Eligibility and...
program.
Side effects
Neostigmine can induce generic occular side effects including: headache, brow pain, blurred vision, phacodonesis, pericorneal injection, congestive iritis, various allergic reactions, and rarely, retinal detachment.Neostigmine will cause slowing of the heart rate (bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
), for this reason it is usually given along with a parasympatholytic
Parasympatholytic
A parasympatholytic agent is a substance or activity that reduces the activity of the parasympathetic nervous system. A parasympatholytic agent is a substance or activity that reduces the activity of the parasympathetic nervous system. A parasympatholytic agent is a substance or activity that...
drug such as atropine
Atropine
Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
or glycopyrrolate
Glycopyrrolate
Glycopyrrolate is a medication of the muscarinic anticholinergic group. It does not cross the blood brain barrier and consequently has no to few central effects. It is a synthetic quaternary amine...
.
Gastrointestial symptoms occur earliest after ingestion and include anorexia, nausea and vomiting, abdominal cramps and diarrhea.
Spectral data
Neostigmine shows notable UV/VIS absorption at 261nm, 267nm, and 225nm.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 3.8ppm and 3.1ppm are due to the electronic withdrawing nature of the tertiary and quarterary nitrogen, respectively.
Chemistry
Neostigmine, N,N,N-trimethyl-meta-(dimethylcarbomoyloxy)-phenylammonium methylsulfonate, 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 dimethylsulfate forming the desired compound.- 43. J.A. Aeschlimann, (1933).