Week 8 - Chapter 15 (Cholinesterase Inhibitors) Flashcards
Cholinergic Crisis
Cholinesterase inhibitor toxicity can cause a life-threatening cholinergic crisis. (muscle weakness, paralysis –> respiratory problem)
Cholinesterase Inhibitor
drugs that prevent the degradation of acetylcholine by acetylcholinesterase (also known simply as cholinesterase).
Irreversible Cholinesterase Inhibitor
highly toxic. These agents are employed primarily as insecticides. During World War II, huge quantities of irreversible cholinesterase inhibitors were produced for possible use as nerve agents, but were never deployed. Today, there is concern that these agents might be employed as weapons of terrorism. The only clinical indication for the irreversible inhibitors is glaucoma.
Myasthenic Crisis
Patients who are inadequately medicated may experience myasthenic crisis, a state characterized by extreme muscle weakness caused by insufficient acetylcholine at the NMJ. Left untreated, myasthenic crisis can result in death from paralysis of the muscles of respiration. A cholinesterase inhibitor (eg, neostigmine) is used to relieve the crisis.
Organophosphate Cholinesterase Inhibitor
All irreversible cholinesterase inhibitors contain an atom of phosphorus, because of the phosphorus they are called Organophosphate Cholinesterase Inhibitor. Almost all irreversible cholinesterase inhibitors are highly lipid soluble. As a result, these drugs are readily absorbed from all routes of administration. They can even be absorbed directly through the skin. Easy absorption, coupled with high toxicity, is what makes these drugs good insecticides—and gives them potential as agents of chemical warfare. Once absorbed, the organophosphate inhibitors have ready access to all tissues and organs, including the CNS.
Quaternary
Structural formulas of reversible cholinesterase inhibitors. Note that neostigmine and edrophonium are quaternary ammonium compounds (+ charge), but physostigmine is not. Because physostigmine is uncharged, the drug crosses membranes with ease.
Reversible Cholinesterase Inhibitor
the normal function of cholinesterase is to break down acetylcholine into choline and acetic acid. (This process is called a hydrolysis reaction because of the water molecule involved.) The overall reaction between acetylcholine and cholinesterase is extremely fast. As a result, one molecule of cholinesterase can break down a huge amount of acetylcholine in a very short time. The reaction between neostigmine and cholinesterase is much like the reaction between acetylcholine and cholinesterase. The only difference is that cholinesterase splits neostigmine more slowly than it splits acetylcholine. Hence, once neostigmine becomes bound to cholinesterase, the drug remains in place for a relatively long time. Because cholinesterase remains bound until it finally succeeds in degrading neostigmine, less cholinesterase is available to catalyze the breakdown of acetylcholine. As a result, more acetylcholine is available to activate cholinergic receptors.
Neostigmine category
Reversible Cholinesterase Inhibitor
Physostigmine category
Reversible Cholinesterase Inhibitor
Myasthenia Gravis Pathology
Myasthenia gravis (MG) is a neuromuscular disorder characterized by fluctuating muscle weakness and a predisposition to rapid fatigue. Common symptoms include ptosis (drooping eyelids), difficulty swallowing, and weakness of skeletal muscles. Patients with severe MG may have difficulty breathing owing to weakness of the muscles of respiration. Symptoms of MG result from an autoimmune process in which the patient's immune system produces antibodies that attack nicotinicM receptors on skeletal muscle. As a result, the number of functional receptors at the NMJ is reduced by 70% to 90%, causing muscle weakness.
SLUDGE and Killer B’s
Mnemonic for Cholinergic crisis: S alivation L agrimation U ruination D iaphoresis/ D diarrhea G gastrointestinal cramping E mesis B radycardia B bronchospasm B ronchorrhea
DUMBELS
Mnemonic for Cholinergic crisis: D iaphoresis/ D diarrhea U ruination M iosis B radycardia, B ronchospasm, B ronchorrhea; E mesis L agrimation S alivation
Neostigmine use
aka [Bloxiverz, Prostigmin]:
Prostigmin’s principal indication is management of myasthenia gravis. Bloxiverz is used to reverse the actions of nondepolarizing neuromuscular blockade following surgery.
Neostigmine mechanism of action
Neostigmine and the other reversible cholinesterase inhibitors act as substrates for cholinesterase.The reaction between neostigmine and cholinesterase is much like the reaction between acetylcholine and cholinesterase. The only difference is that cholinesterase splits neostigmine more slowly than it splits acetylcholine. Hence, once neostigmine becomes bound to cholinesterase, the drug remains in place for a relatively long time. Because cholinesterase remains bound until it finally succeeds in degrading neostigmine, less cholinesterase is available to catalyze the breakdown of acetylcholine. As a result, more acetylcholine is available to activate cholinergic receptors.
Neostigmine adverse effects
Excessive Muscarinic Stimulation (increased salivation, gastric secretions, tone and motility of the Gi tract,urinary urgency, bradycardia, sweating, miosis, and spasm with accommodation. It can also cause neuromuscular blockade in toxic doses which can cause fatal respiratory paralysis.
