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Pharmacology - anticholinesterase drugs and cholinesterase reactivating drugs
The focus of this chapter is ✨Neostigmine and ✨Organophosphorus. Based on the pharmacological effects, we will review the clinical application of neostigmine, adverse reactions, manifestations of organophosphate poisoning, diagnosis and rescue medication principles. ❤️Happy learning to everyone❤️
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Pharmacology - anticholinesterase drugs and cholinesterase reactivating drugs
- bacteria
This is a mind map about bacteria, and its main contents include: overview, morphology, types, structure, reproduction, distribution, application, and expansion. The summary is comprehensive and meticulous, suitable as review materials.
- Plant asexual reproduction
This is a mind map about plant asexual reproduction, and its main contents include: concept, spore reproduction, vegetative reproduction, tissue culture, and buds. The summary is comprehensive and meticulous, suitable as review materials.
- Reproductive development of animals
This is a mind map about the reproductive development of animals, and its main contents include: insects, frogs, birds, sexual reproduction, and asexual reproduction. The summary is comprehensive and meticulous, suitable as review materials.
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Anticholinesterase drugs and cholinesterase reactivating drugs
anticholinesterase drugs
Indirectly acting cholinomimetics
Perpetuates the effects of cholinergic drugs by inhibiting cholinesterase
Refractory anticholinesterase drugs
Mechanism
Quaternary ammonium groups and ester structures bind to cholinesterase and inhibit enzyme activity, but the groups can be slowly hydrolyzed to revive cholinesterase.
Pharmacological effects
Eye
Mimic pupils, lower intraocular pressure, regulate spasm
gastrointestinal tract
neostigmine
Exciting the lower esophagus and promoting peristalsis
Gastric smooth muscle contracts and gastric acid secretion increases
Promote the elimination of intestinal contents (especially the colon)
skeletal muscle nerve junction
Inhibits AchE at the neuromuscular junction, causing skeletal muscle contraction (most)
Neostigmine also has the effect of stimulating joints
Anti-AchE drugs can reverse the skeletal muscle relaxation caused by competitive neuromuscular blocking drugs, but have no obvious antagonistic effect on non-depolarizing neuromuscular blocking drugs.
Large doses can cause muscle fiber tremors and muscle relaxation
cardiovascular function
Sympathetic nerves and parasympathetic nerves have opposite effects on the heart, and both regulate
Parasympathetic nerves dominate the heart
heart rate slows down
Decreased cardiac output
other
increased glandular secretion
Bronchiolar and ureteral smooth muscle contraction
Clinical application
myasthenia gravis
Overview: Autoimmune disease, anti-Nm receptor antibodies can be seen in the serum, which bind to Nm receptors and reduce their number.
Medication
Neostigmine, pyridostigmine, ambucilium chloride
Note: The drug has a short action time and needs to be administered repeatedly.
Bloating, urinary retention
Medication
Neostigmine: subcutaneous or intramuscular injection, 0.5 mg each time
Neostigmine bromide: oral, 15-30 mg, slow onset
glaucoma
Medication
Physostigmine, demethonium bromide
Used for short-term first aid of angle-closure glaucoma and long-term treatment of open-angle glaucoma.
Detoxification in Overdose of Competitive Neuromuscular Blocking Drugs
Medication
Neostigmine, efonolamine, galantamine
Physostigmine can cross the blood-brain barrier and is used to treat central anticholinergic drug poisoning. However, because physostigmine has severe central toxicity, it is only used in patients with elevated body temperature or supraventricular tachycardia.
Alzheimer disease alzheimer disease, AD
Overview: Low cholinergic nerve function in the brain leads to cognitive impairment and symptoms of dementia.
Medications: Tacrine, donepezil, galantamine for the treatment of mild to moderate AD
Common medicines
neostigmine
internal processes
absorb
Oral absorption is less and irregular, and bioavailability is low
distributed
Difficult to enter the center
metabolism
BChE hydrolysis, hepatic metabolism
excretion
Excreted from the bile duct through urine, the original drug can reach 50%
Pharmacological effects
Stimulant effects: skeletal muscle > gastrointestinal smooth muscle > glandular, ocular, cardiovascular and bronchial smooth muscle
Clinical application
Myasthenia gravis, postoperative abdominal distension, urinary retention, intestinal paralysis
Adverse reactions
Cholinergic crisis, nausea and vomiting, abdominal pain, myotremors
Contraindications
mechanical intestinal obstruction, urinary tract obstruction
pyridostigmine
Compared with neostigmine, it has a slower onset of action and a longer duration of action.
internal processes
absorb
Poor oral gastrointestinal absorption
High bioavailability
distributed
Can enter the placenta but not easily enter the central nervous system
metabolism
BChE hydrolysis, hepatic metabolism
excretion
Excreted in urine as unchanged drug and metabolites
Clinical application
Myasthenia gravis, postoperative functional flatulence, urinary retention
Ephronamide
Mainly excites skeletal muscles, with weakened anti-AChE effect, rapid effect, and short action time.
Clinical application
Diagnosis of myasthenia gravis
Administer 2mg, no response is seen for 30-45s
After another injection of 8mg, if the short-term muscle contraction improves and no tongue muscle fiber contraction is seen, the diagnosis is positive.
Prepare atropine to prevent poisoning
ambedium chloride
Lasts longer than neostigmine
Clinical Application: Patients with myasthenia gravis who are intolerant to pyridostigmine or neostigmine
Physostigmine
Alkaloids, easily enter the CNS, excitatory in small doses, depressive in large doses
Pharmacological effects: Inhibit AChE, excite M, N receptors, but cannot directly excite receptors (indirect effect)
Clinical application
Treat acute glaucoma
Strong and long-lasting effect
Quick onset of effect
Very irritating
The inner canthus of the eye should be compressed to avoid poisoning into the nasal cavity
After the symptoms of acute glaucoma are relieved, pilocarpine is used to maintain the therapeutic effect.
Can be used alternately with pilocarpine to enhance mydriasis
Adverse reactions
accommodative paralysis
Large dose poisoning can cause respiratory paralysis
demetonium bromide
Long-lasting effect, lasting more than nine days
Clinical application: Aphakia, open-angle glaucoma and patients who are refractory to other drugs
Irreversible anticholinesterase drugs—organophosphates
Mainly used as agricultural and environmental health pesticides, with little clinical medicinal value, but toxicological significance
poisoning mechanism
Phosphorylated AChE is formed that is difficult to hydrolyze. ACh cannot be hydrolyzed and accumulates in the body. Failure to rescue it in time will cause AChE to age. It is difficult to correct the enzyme activity even with the use of rejuvenation drugs. You need to wait for a few weeks for the rebirth of AChE.
Symptoms of poisoning
acute poisoning
Eye
Significant miosis of pupils, eyeball pain, conjunctival congestion, ciliary muscle spasm, blurred vision, eyebrow pain
respiratory system
A tight feeling in the chest, increased glandular secretion, and dyspnea caused by contraction of bronchial smooth muscles
digestive system
Anorexia, nausea, vomiting, abdominal pain, diarrhea
Cardiovascular System
blood pressure drops, heart rate slows
skin and muscles
Sweating, fasciculations, muscle weakness, muscle paralysis
Central Nervous System
First, excitement and restlessness, followed by convulsions, then depression, confusion, ataxia, delirium, and coma.
Symptoms of severe poisoning
Foaming at the mouth, difficulty breathing, tears, penile erection, profuse sweating, incontinence of urine and feces, slowed heart rate, decreased blood pressure
cause of death
Respiratory failure and secondary cardiovascular dysfunction
chronic poisoning
AChE activity in the blood decreased significantly, manifesting as neurasthenic syndrome, abdominal distension, hyperhidrosis, occasional fasciculations and miosis.
diagnosis
severe acute poisoning
Toxic exposure history and clinical signs
Mild acute poisoning or chronic poisoning
AChE activity in red blood cells and plasma
treat
Prevention first
acute poisoning treatment
eliminate poison
Skin absorption: wash with warm water and soap
Mouth: Extract gastric juice and poisons, use lukewarm 2% sodium bicarbonate solution (except trichlorfon, which can be converted into dichlorvos) or 1% saline to repeatedly gastric lavage until the washout has no pesticide smell, and then use magnesium sulfate for catharsis.
Eyes: Clean with 2% sodium bicarbonate or 0.9% sodium chloride solution for several minutes
Antidote
atropine
Antagonizes the M-like effects of ACh in vivo
Relax smooth muscle
Inhibit glandular secretion
Increase heart rate
dilate pupils
Poor antagonism to central symptoms caused by organophosphates
Use the drug until the symptoms of M choline excitement disappear or symptoms of mild atropine poisoning appear (atropinization)
AChE resurrection drug
Medication principles
Combination medication
Atropine AChE resuscitation drug
Take medication as early as possible
Phosphorylated cholinesterase is prone to aging
Take adequate medication
Indicator of adequate atropine dosage: symptoms of M-like poisoning disappear quickly or appear atropinized: dilated pupils, dry mouth, dry skin, flushed face, reduced crackles in the lungs, and accelerated heart rate
Indicator of sufficient amount of AChE reactivation drug: all symptoms of N-like poisoning disappear, and AChE activity in whole blood or red blood cells recovers to 50-60% or more than 30% respectively.
Repeat medication
Symptomatic treatment
Maintain airway patency: endobronchial suction, artificial respiration, oxygen administration
Diazepam 5-10 mg intravenously to continuously suppress convulsions
Anti-shock
Chronic poisoning treatment
Cholinesterase reactivating drugs are ineffective and there is no effective treatment. Contact with poisons should be avoided.
cholinesterase reactivating drugs
Restore the activity of AChE inhibited by organophosphates, shorten the poisoning process, and rescue severe poisoning cases when combined with atropine
pralidoxime chloride
The aqueous solution is relatively stable and can be injected intramuscularly or intravenously. It has few adverse reactions and is commonly used clinically.
Pharmacological effects
Restore AChE activity
Combined with phosphorylated cholinesterase, cleaved into phosphorylated pralidoxime chloride, free and resurrected cholinesterase
direct detoxification
Directly combines with organic phosphates in the body to form non-toxic phosphorylated pralidoxime chloride and is excreted in the urine
Clinical application
Treating organophosphorus poisoning can significantly reduce N-like effects and significantly inhibit skeletal muscle spasm and fasciculations. It has a certain effect on improving the symptoms of poisoning in the central nervous system Less impact on M-like symptoms
Adverse reactions
Less toxic
Intramuscular injection: mild local pain
Intravenous injection too fast (>500mg/min): headache, dizziness, fatigue, blurred vision, nausea, tachycardia
Excessive dose (>8g/24h): inhibits AChE, neuromuscular conduction block, severe symptoms may include epileptic seizures, convulsions, and respiratory depression.
pralidoxime iodide PAM
The earliest applied AChE reactivation drug, the aqueous solution is unstable
There are differences in efficacy
Good efficacy: systemic phosphorus, malathion, parathion
Slightly less effective: metrelfosate, dichlorvos
Invalid: Dimethoate