Reversible cholinesterase inhibitors |
Myasthenia gravis (MG) is mainly mediated by acetylcholine receptor antibodies. It is an autoimmune disease mediated by
T cell auxiliary antibodies and complement involvement, which mainly affects the acetylcholine receptors on the postsynaptic membrane of the neuromuscular
junction. Its onset is closely related to humoral immunity mediated by acetylcholine receptor autoantibodies (AChR-Ab), and mainly affects the acetylcholine receptors on the
postsynaptic membrane of the neuromuscular junction, resulting in skeletal muscle weakness symptoms. MG not only causes damage to the neuromuscular junction of skeletal muscle,
but also affects many parts of the body. It is a widespread autoimmune disease. The clinical feature of MG is that skeletal muscles are easily fatigued when affected.
This muscle weakness is fluctuating, manifested as worsening after activity and relief after rest, and lighter in the morning and heavier in the evening. MG is chronic and recurrent,
and in severe cases it can cause respiratory muscle paralysis and even threaten life. MG is a curable disease. Immunosuppressants, cholinesterase inhibitors and thymectomy
are the main treatments for MG. The cholinesterase inhibitor pyridostigmine bromide is the most commonly used. If it is treated promptly and reasonably, the symptoms
of most patients can be alleviated or even completely relieved. Pyridostigmine bromide, whose chemical name is 3-dimethylaminoformyloxy-1-methylpyridine bromide, is a reversible
cholinesterase inhibitor (AchE). It can reversibly bind to cholinesterase, reduce the destruction of acetylcholine released by cholinergic nerve endings, accumulate acetylcholine in
the synaptic cleft, and produce muscarinic (M) and nicotinic (N) cholinergic receptor excitation. In addition, it has a direct excitatory effect on nicotinic cholinergic receptors
(N2 receptors) on motor end plates, and can promote the release of acetylcholine from motor nerve endings, thereby increasing the muscle tone of gastrointestinal tract, bronchial
smooth muscle and skeletal muscle throughout the body. It is an ionized, hydrophilic carbamate derivative of a reversible cholinesterase inhibitor. Its chemical structure contains
a positively charged "quaternary ammonium salt" group, which prevents it from passing through the blood-brain barrier, thus limiting its effect in the central nervous system.
It is currently widely used to treat myasthenia gravis, functional flatulence after surgery, and urinary retention. It is similar to neostigmine, with a slightly weaker effect,
but a longer-lasting effect and fewer adverse reactions. In addition, it can also be used to treat organophosphorus poisoning, obesity, poliomyelitis, dementia, and epilepsy.
In 1955, the FDA approved it for the treatment of myasthenia gravis, and it is often used in military medicine to prevent damage from nerve agents such as soman and sarin. |
Pharmacological action |
Pyridostigmine bromide is a reversible anticholinesterase drug that can inhibit the activity of cholinesterase, reduce the destruction of acetylcholine released by
cholinergic nerve endings, accumulate acetylcholine in the synaptic cleft, and cause muscarinic (M) and nicotinic (N) cholinergic receptor excitation. In addition,
it has a direct excitatory effect on nicotinic cholinergic receptors (N2 receptors) on motor end plates, and can promote the release of acetylcholine from motor nerve endings,
thereby increasing the muscle tension of gastrointestinal tract, bronchial smooth muscle and skeletal muscle throughout the body. |
Dosage form research |
Currently, the only dosage form of pyridostigmine bromide (PB) used clinically in China is tablets (60 mg/tablet).
There are many types of dosage forms abroad, mainly ordinary tablets: 60 mg/tablet; sustained-release tablets: 180 mg/tablet;
injection (sterile powder): 1 mg/tube, 5 mg/tube, 10 mg/tube; syrup: 12 mg/ml. |
1. Rapid-release preparations PB has a short biological half-life. Patients with myasthenia gravis often experience dysphagia in clinical practice. Therefore, PB is prepared as a rapid-release preparation,
dissolved or suspended before oral administration, which is convenient for patients to swallow and has good clinical application value. Orally disintegrating tablets are suitable for patients with dysphagia and both young and old patients.
They have a fast disintegration rate, fast drug dissolution rate, fast absorption and onset, high bioavailability, and an increased drug surface area, which allows them to be distributed over a large area in the gastrointestinal tract,
which can reduce local irritation of the drug to the gastrointestinal tract. In addition, PB dispersible tablets can be prepared by the β-cyclodextrin inclusion method, aiming to provide a new dosage form for the elderly,
children and patients with dysphagia. When the ratio of drug to β-cyclodextrin is 1:3 (m/m), the bitter taste of the drug can be masked by combining flavoring agents and effervescent agents,
and PB dispersible tablets with a short disintegration time and partial taste masking can be prepared. |
2. Sustained-release preparations: At present, research on sustained-release dosage forms mainly focuses on sustained-release microparticles,
sustained-release pellets and sustained-release tablets. Preparing PB as a sustained-release preparation not only facilitates patients' medication,
but also reduces adverse reactions caused by fluctuations in blood drug concentrations, which has important clinical significance for improving patients' compliance with medication.
1) Sustained-release microparticles Sustained-release microspheres: The natural polymer material bovine serum albumin is selected as the carrier material, sorbitan monooleate and polysorbate 80 are used as mixed emulsifiers, and glutaraldehyde saturated toluene solution is used as the curing agent. The PB albumin microspheres are prepared by emulsification curing method. The microspheres have a round appearance, high encapsulation rate and drug loading. When preparing albumin microspheres by emulsification curing method, factors such as the ratio of drug amount to albumin amount (drug-to-mass ratio), the amount of cross-linking agent and additives, curing time, curing temperature, stirring speed, etc. may affect the quality of the microspheres.
In another study, polylactic acid (PLA) was used as the carrier material to prepare PB into biodegradable microspheres. The results showed that the release behavior of PB polylactic acid microspheres in different media was similar, and they had a good sustained-release effect. In addition, the PB API was dispersed in an acrylic polymer solution,
and the PB microparticles were prepared by spray drying technology, which had a certain sustained release effect. Liposomes:
Encapsulating drugs in carriers to prepare liposomes can improve the bioavailability of drugs. The chemical book preparation process of liposomes has a great influence
on the particle size and encapsulation rate of the prepared liposomes. According to the physicochemical properties of PB, making it into liposomes can improve its bioavailability
and effectively improve its absorption in the body. N-methyl chitosan (TMC60) was used as the coating material, and the reverse phase evaporation method was used to prepare cationic PB
liposomes. The results showed that the coated liposomes had a significant in vitro sustained release effect. Further studies showed that the stability of TMC60 coated liposomes was good,
but the encapsulation rate of the optimal formulation of the liposomes was (63.36±0.27)%, which did not reach the minimum limit (80%) specified in the 2010 edition
of the "Chinese Pharmacopoeia" (Part II). Nanoparticles: PB phospholipid complexes were prepared by solvent evaporation method, and dispersed in hydroxypropyl methylcellulose (HPMC)
solution to obtain PB phospholipid complex nanoparticles. The PB phospholipid complex prepared in this study has changed the physicochemical properties and biological characteristics
of the parent (PB) drug to a certain extent, and the obtained nanoparticles have a certain sustained release effect in different media. |
2) Sustained-release micropellets: After mixing microcrystalline cellulose, HPMC and PB, a binder is added to granulate,
and the micropellet core is made by extrusion-spheronization technology. After drying, the HPMC, polyvinyl alcohol and other concentrated liquids are respectively
wrapped on the outside of the pellet core by fluidized bed coating technology to form a sealing layer, a sustained-release layer and a waterproof layer. The study showed that the
release rate of the drug increased after the micropellets were wrapped with a waterproof layer.
3) Sustained-release tablets: In order to improve patient compliance, PB sustained-release tablets were prepared using a hydrophilic gel skeleton and film coating.
The sustained-release tablet uses HPMC as a sustained-release material to prepare a hydrophilic gel skeleton tablet core, and then ethyl cellulose is used as a film coating material
to coat the tablet core. The pharmacokinetic study of this sustained-release tablet shows that the sustained-release tablet has a significant sustained-release effect when taken once a day.
In order to reduce the adverse reactions of PB and improve patient compliance, PB sustained-release preparations were prepared using wet granulation technology with HPMC,
carnauba wax and calcium phosphate as sustained-release skeleton materials, and the process was optimized to obtain the optimal PB sustained-release
tablets (with commercially available sustained-release tablets of 180 mg/tablet as a reference). Pharmacokinetic studies showed that its release
model was consistent with the Higuchi model. |
Precautions |
1. Use with caution in patients with arrhythmia (especially atrioventricular block), postoperative atelectasis or pneumonia.
2. There are obvious individual differences in the absorption, metabolism and excretion of this product.
The dosage and time of use should be
determined according to the effects after taking the medicine.
3. After taking the medicine, pregnant women may suffer from premature birth due to uterine contraction.
The FDA classifies the pregnancy safety of this drug as Class C.
4. This drug can be secreted into breast milk in small amounts. |
Adverse reactions |
1. Mild anticholinesterase toxicity may occur, such as abdominal pain, diarrhea, increased salivation, increased tracheal mucus secretion,
sweating, miosis, decreased blood pressure and bradycardia, which generally disappear on their own.
2. Bromide reactions may occur, such as Chemicalbook rash, fatigue, nausea and vomiting. The reversible cholinesterase inhibitors, pharmacological effects,
precautions, drug interactions, etc. of pyridostigmine bromide are edited and compiled by Wang Xuyan of chemicalbook. (2016-7-18) |
Drug interactions |
1. It can inhibit the activity of cholinesterase in plasma, making the hydrolysis of ester local anesthetics in the body slow and easy to cause poisoning reactions.
Therefore, it is advisable to use amide local anesthetics during the use of this drug.
2. Aminoglycoside antibiotics, capreomycin, lincomycin, polymyxin, lidocaine intravenous injection or quinine intramuscular
injection can act on the neuromuscular
junction to weaken the tension of skeletal muscles, so they can produce different degrees of antagonism to the effect of this drug.
3. It can weaken the muscle relaxant effect of inhaled general anesthetics such as ether, enflurane, isoflurane, methoxyflurane, and cyclopropane.
4. Antihypertensive drugs that block sympathetic ganglia (such as guanethidine, mecamylamine and imifen) can weaken the effect of this drug.
5. Even drugs with weak antimuscarinic effects (such as procainamide, quinidine, etc.) can weaken the efficacy of this drug on myasthenia gravis,
so it is not suitable for combined use.
6. Atropine acts on M cholinergic receptors and can reduce the adverse reactions of overdose of cholinesterase inhibitors.
Therefore, when this drug is used to antagonize non-depolarizing muscle relaxants, it can be used in combination with atropine. |
Chemical properties |
Light yellow to colorless liquid, soluble in ethanol and water. |
Uses |
Anticholinesterase drug, used for myasthenia gravis, postoperative functional intestinal flatulence and urinary retention |
