Pyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier

Blood-brain barrier

The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

, except possibly in stressful conditions.

Mode of action

In a synapse

Synapse

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

, action potential

Action potential

In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...

s are conducted along motor nerves to their terminals where they initiate a Ca2+ influx and the release of acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 (ACh). The ACh diffuses across the synaptic cleft and binds to receptors on the post synaptic membrane, causing an influx of Na

Sodium

Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

+ and K

Potassium

Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

+ ions, resulting in depolarization. If large enough, this depolarization results in an action potential. To prevent constant stimulation once the ACh is released, an enzyme called acetylcholinesterase

Acetylcholinesterase

"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...

 is present in the endplate membrane close to the receptors on the post synaptic membrane, and quickly hydrolizes ACh.

Pyridostigmine inhibits acetylcholinesterase in the synaptic cleft, thus slowing down the hydrolysis of acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

. It is a quaternary carbamate inhibitor of cholinesterase that does not cross the blood-brain barrier, and is taken daily in anticipation of an attack, which carbamylates about 30% of peripheral cholinesterase enzyme. The carbamylated enzyme eventually regenerates by natural hydrolysis and excess ACh levels revert to normal.

Clinical uses

Pyridostigmine is used to treat muscle weakness in people with myasthenia gravis

Myasthenia gravis

Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...

 and to combat the effects of 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. Pyridostigmine bromide has been FDA approved for military use during combat situations as an agent to be given prior to exposure to the nerve agent Soman

Soman

Soman, or GD , is an extremely toxic chemical substance. It is a nerve agent, interfering with normal functioning of the mammalian nervous system by inhibiting the cholinesterase enzyme. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations according to UN...

 in order to increase survival. Used in particular during the first Gulf War

Gulf War

The Persian Gulf War , commonly referred to as simply the Gulf War, was a war waged by a U.N.-authorized coalition force from 34 nations led by the United States, against Iraq in response to Iraq's invasion and annexation of Kuwait.The war is also known under other names, such as the First Gulf...

, pyridostigmine bromide has been implicated as a causal factor in Gulf War syndrome

Gulf War syndrome

Gulf War syndrome or Gulf War illness describes a medical condition that affected veterans and civilians who were near conflicts during or downwind of chemical weapons depot demolition, after the 1991 Gulf War. A wide range of acute and chronic symptoms have included fatigue, musculoskeletal...

.

Pyridostigmine is now also used to treat orthostatic hypotension

Orthostatic hypotension

Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...

.

Pyridostigmine bromide is available under the trade names Mestinon (Valeant Pharmaceuticals

Valeant Pharmaceuticals International

Valeant Pharmaceuticals International, Inc. is a pharmaceutical company with activities spanning the drug discovery pipeline from target identification through clinical trials and commercialization. The focus of the company is on neurology, dermatology and infectious disease with several drugs in...

) and Regonol.

Contraindications

Pyrostigmine bromide is contraindicated in cases of mechanical intestinal or urinary obstruction and should be used with caution in patients with bronchial asthma.

Side effects

Common side effects include:

• Sweating
• Diarrhea
• Nausea
• Vomiting
• Abdominal cramps
• Increased salivation

• Tearing
• Increased bronchial secretions
• Constricted pupils
• Facial flushing due to vasodilation
• Erectile dysfunction

Chemistry

Pyridostigmine, 3-[(dimethylaminocarbonyl)oxy]-1-methyl pyridinium bromide, is synthesized from 3-hydroxypyridine, which is reacted with dimethylaminocarbamoyl chloride, which gives 3-(dimethylaminocarbamoyl)pyridine. The last is reacted with methylbromide, giving pyridostigmine.

• R. Urban, (1951).

Related publications

1. Brenner, G. M. (2000). Pharmacology. Philadelphia, PA: W.B. Saunders Company. ISBN 0-7216-7757-6
2. Canadian Pharmacists Association (2000). Compendium of Pharmaceuticals and Specialties (25th ed.). Toronto, ON: Webcom. ISBN 0-919115-76-4
3. Neal, M.J. (2002). Medical Pharmacology at a Glance (5th ed.). London, England: Blackwell Publishing. ISBN 1405133600