Week 8 - Chapter 15 (Cholinesterase Inhibitors) Flashcards Preview

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Flashcards in Week 8 - Chapter 15 (Cholinesterase Inhibitors) Deck (19):
1

Cholinergic Crisis

Cholinesterase inhibitor toxicity can cause a life-threatening cholinergic crisis. (muscle weakness, paralysis --> respiratory problem)

2

Cholinesterase Inhibitor

drugs that prevent the degradation of acetylcholine by acetylcholinesterase (also known simply as cholinesterase).

3

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.

4

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.

5

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.

6

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.

7

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.

8

Neostigmine category

Reversible Cholinesterase Inhibitor

9

Physostigmine category

Reversible Cholinesterase Inhibitor

10

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.

11

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

12

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

13

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.

14

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.

15

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.

16

Physostigmine use

used to treat poisoning by atropine and other drugs that cause muscarinic blockade

17

Physostigmine mechanism of action

physostigmine is identical to that of neostigmine—except that physostigmine readily crosses membranes, whereas neostigmine does not. In contrast to neostigmine, physostigmine is not a quaternary ammonium compound and hence does not carry a charge. Because physostigmine is uncharged, the drug crosses membranes with ease.

18

Physostigmine adverse effects

combined with tricyclic antidepressants causes a risk of causing seizures and cardiotoxicity

19

Myasthenic crisis V.S. Cholinergic crisis

Distinguishing myasthenic crisis from cholinergic crisis
>Challenging dose of edrophonium, also a cholinesterase inhibitor. If symptoms get better then it's myasthenia gravis, if they get worst it's cholinergic crisis. (Atropine and oxygen should be given)
>History of medication use or signs of excessive muscarinic stimulation assist with differential diagnosis
>Identification by the patient

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