Neostigmine

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Neostigmine
Neostigmine.svg
Neostigmine ball-and-stick.png
Clinical data
Trade names Bloxiverz, Prostigmin, Vagostigmin, others
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration
Intramuscular, intravenous, subcutaneous, by mouth
Drug class Cholinesterase inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Unclear, probably less than 5%
Metabolism Slow hydrolysis by acetylcholinesterase and also by plasma esterases
Onset of action Within 10-20 min (injection), [3] with 4 hrs (by mouth) [ citation needed ]
Elimination half-life 50–90 minutes
Duration of action up to 4 hrs [3]
Excretion Unchanged drug (up to 70%) and alcoholic metabolite (30%) are excreted in the urine
Identifiers
  • 3-{[(Dimethylamino)carbonyl]oxy}-N,N,N-trimethylbenzenaminium
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.305.602 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C12H19N2O2+
Molar mass 223.296 g·mol−1
3D model (JSmol)
  • CN(C)C(=O)OC1=CC=CC(=C1)[N+](C)(C)C
  • InChI=1S/C12H19N2O2/c1-13(2)12(15)16-11-8-6-7-10(9-11)14(3,4)5/h6-9H,1-5H3/q+1 Yes check.svgY
  • Key:ALWKGYPQUAPLQC-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [3] [4] It is also used in anaesthesia to end the effects of non-depolarising neuromuscular blocking medication. [3] It is given by injection either into a vein, muscle, or under the skin. [3] After injection effects are generally greatest within 30 minutes and last up to 4 hours. [3] [5]

Contents

Common side effects include nausea, increased saliva, crampy abdominal pain, and slow heart rate. [3] More severe side effects include low blood pressure, weakness, and allergic reactions. [3] It is unclear if use in pregnancy is safe for the baby. [3] Neostigmine is in the cholinergic family of medications. [3] It works by blocking the action of acetylcholinesterase and therefore increases the levels of acetylcholine. [3]

Neostigmine was patented in 1931. [6] It is on the World Health Organization's List of Essential Medicines. [7] The term is from Greek neos, meaning "new", and "-stigmine", in reference to its parent molecule, physostigmine, on which it is based. [8] It is available as a generic medication. [9]

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. [10] [11]

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. [12]

Neostigmine is often prescribed for underactive urinary bladder. [13]

Hospitals sometimes administer a solution containing neostigmine intravenously to delay the effects of envenomation through snakebite. [14] 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. [15]

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. [16] Gastrointestinal symptoms occur earliest. [17] :109

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. [18]

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. [17] :114

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. [10]

Unlike physostigmine, neostigmine has a quaternary nitrogen; hence, it is more polar. It does not cross the blood–brain barrier and enter the CNS. [19]

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. [10] Neostigmine has moderate duration of action – usually two to four hours. [20] It is metabolized by enzymes in the liver and excreted in the urine. [10]

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. [21]

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. [22]

History

Neostigmine was first synthesized by Aeschlimann and Reinert in 1931 [23] and was patented by Aeschlimann in 1933. [24]

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. [17] :103

Related Research Articles

<span class="mw-page-title-main">Acetylcholine</span> Organic chemical and neurotransmitter

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.

<span class="mw-page-title-main">Suxamethonium chloride</span> Chemical compound

Suxamethonium chloride, also known as suxamethonium or succinylcholine, or simply sux in medical abbreviation, is a medication used to cause short-term paralysis as part of general anesthesia. This is done to help with tracheal intubation or electroconvulsive therapy. It is administered by injection, either into a vein or into a muscle. When used in a vein, onset of action is generally within one minute and effects last for up to 10 minutes.

<span class="mw-page-title-main">Pancuronium bromide</span> Aminosteroid muscle relaxant

Pancuronium is an aminosteroid muscle relaxant with various medical uses. It is used in euthanasia and is used in some states as the second of three drugs administered during lethal injections in the United States.

Anticholinergics are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central and peripheral nervous system.

<span class="mw-page-title-main">Edrophonium</span>

Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction. It is sold under the trade names Tensilon and Enlon.

A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acetylcholine (ACh) is the neurotransmitter used by the PSNS. Chemicals in this family can act either directly by stimulating the nicotinic or muscarinic receptors, or indirectly by inhibiting cholinesterase, promoting acetylcholine release, or other mechanisms. Common uses of parasympathomimetics include glaucoma, Sjögren syndrome and underactive bladder.

<span class="mw-page-title-main">Physostigmine</span> Chemical compound

Physostigmine is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and the fruit of the Manchineel tree.

<span class="mw-page-title-main">Pyridostigmine</span> Medication used to treat myasthenia gravis and chronic Orthostatic Hypotension

Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is typically given by mouth but can also be used by injection. The effects generally begin within 45 minutes and last up to 4 hours.

<span class="mw-page-title-main">Vecuronium bromide</span> Muscle relaxant

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 intubation; however, agents such as suxamethonium (succinylcholine) or rocuronium are generally preferred if this needs to be done quickly. It is given by injection into a vein. Effects are greatest at about 4 minutes and last for up to an hour.

<span class="mw-page-title-main">Glycopyrronium bromide</span> Chemical compound

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 given by mouth, via intravenous injection, on the skin, and via inhalation. It is a synthetic quaternary ammonium compound. The cation, which is the active moiety, is called glycopyrronium (INN) or glycopyrrolate (USAN).

<span class="mw-page-title-main">Neuromuscular-blocking drug</span> Type of paralyzing anesthetic including lepto- and pachycurares

Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.

A cholinergic crisis is an over-stimulation at a neuromuscular junction due to an excess of acetylcholine (ACh), as a result of the inactivity of the AChE enzyme, which normally breaks down acetylcholine.

<span class="mw-page-title-main">Rocuronium bromide</span> Non-depolarizing neuromuscular blocker

Rocuronium bromide 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 required for surgery or mechanical ventilation. It is used for standard endotracheal intubation, as well as for rapid sequence induction (RSI).

<span class="mw-page-title-main">Sugammadex</span> Selective relaxant binding agent

Sugammadex, sold under the brand name Bridion, is a medication for the reversal of neuromuscular blockade induced by rocuronium and vecuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA). It is marketed by Merck.

<span class="mw-page-title-main">Acetylcholinesterase inhibitor</span> Drugs that inhibit acetylcholinesterase

Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors. Acetylcholinesterase is the primary member of the cholinesterase enzyme family.

<span class="mw-page-title-main">Cholinesterase inhibitor</span> Chemicals which prevent breakdown of acetylcholine and butyrylcholine

Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. This increases the amount of the acetylcholine or butyrylcholine in the synaptic cleft that can bind to muscarinic receptors, nicotinic receptors and others. This group of inhibitors is divided into two subgroups, acetylcholinesterase inhibitors (AChEIs) and butyrylcholinesterase inhibitors (BChEIs).

Autonomic drugs are substances that can either inhibit or enhance the functions of the parasympathetic and sympathetic nervous systems. This type of drug can be used to treat a wide range of diseases an disorders, including glaucoma, asthma, and disorders of the urinary, gastrointestinal and circulatory systems.

<span class="mw-page-title-main">Cholinergic blocking drug</span> Drug that block acetylcholine in synapses of cholinergic nervous system

Cholinergic blocking drugs are a group of drugs that block the action of acetylcholine (ACh), a neurotransmitter, in synapses of the cholinergic nervous system. They block acetylcholine from binding to cholinergic receptors, namely the nicotinic and muscarinic receptors.

Neostigmine/glycopyrronium bromide, sold under the brand name Prevduo , is a fixed-dose combination medication used for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. It contains neostigmine as the methylsulfate, a cholinesterase inhibitor, and glycopyrronium bromide, an antimuscarinic agent.

<span class="mw-page-title-main">Neuromuscular drug</span>

Neuromuscular drugs are chemical agents that are used to alter the transmission of nerve impulses to muscles, causing effects such as temporary paralysis of targeted skeletal muscles. Most neuromuscular drugs are available as quaternary ammonium compounds which are derived from acetylcholine (ACh). This allows neuromuscular drugs to act on multiple sites at neuromuscular junctions, mainly as antagonists or agonists of post-junctional nicotinic receptors. Neuromuscular drugs are classified into four main groups, depolarizing neuromuscular blockers, non-depolarizing neuromuscular blockers, acetylcholinesterase inhibitors, and butyrylcholinesterase inhibitors.

References

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