Ch. 15: Cholinesterase Inhibitors & Use for Myasthenia Gravis
Terms in this set (119)
its a neuromuscular disease
what kind of condition is Myasthenia Gravis?
these are drugs that prevent the breakdown of acetylcholine by acetylcholinesterase (aka: cholinesterase)
these drugs increase the amount of acetylcholine available to activate receptors - thus this enhances cholinergic action when these receptors are activated.
By preventing the breakdown of acetylcholine, what is the effect that cholinesterase inhibitors cause?
1. reversible inhibitors - produce effects of moderate duration
2. irreversible inhibitors - effects of long duration
there are 2 categories of cholinesterase inhibitor drugs:
This drug is the prototype drug that represents the group of reversible cholinesterase inhibitors
These drugs are viewed as indirect-acting cholinergic agonists
They lack selectivity & bc they lack this selectivity, they have limited therapeutic applications
Why can cholinesterase inhibitors result in transmission at all cholinergic junctions; muscarinic, ganglionic, neuromuscular ..?
What do Cholinesterase Inhibitors treat???
There is Neosigmine (Bloxiverz, Prostigmin)
Blox = reverses effects of NBA after surgery
Prosti=manages myasthenia gravis
this is the prototype drug for "Reversible" cholinesterase inhibitors - if patients adhere to their meds
these drugs act as substrates for cholinesterase - whose job is to break down acetylcholine into choline and acetic acid
describe the mechanism of action for Neostigmine and other reversible cholinesterase inhibitors
to break down acetylcholine into choline and acetic acid
what is the normal function of cholinesterase ?
B/c more acetylcholine is available, this can intensify transmission at virtually all junctions where acetylcholine is the NT.
Pharmacologic effects: Because Cholinesterase inhibitors breakdown acetylcholine - these drugs make more acetylcholine available --- what can this do?
-more acetylcholine available for usage
-skeletal muscle stimulation
-activation of peripheral muscarinic receptors
-activation of cholinergic receptors in the CNS
*when used THERAPEUTICALLY - These drugs affect only muscarinic receptors on organs, and nicotinic receptors of the neuromuscular junction
In sufficient doses, cholinesterase inhibitors can produce what effects?
cholinesterase inhibitors - Neostigmine
what drug class treats myasthenia gravis?
-same effects as muscarinic agonists ***
-bc muscarinic agonists MIMIC the affects of acetylcholine
-cholinesterase inhibitors BLOCK THE BREAKDOWN of acetylcholine, which in turn leaves more available acetylcholine to be used.... effects are:
-bradycardia, bronchial constriction, urinary urgency (contracting bladder smooth muscles), increased glandular secretions, increased tone and motility of GI tract smooth muscles (--> emptying),miosis (pupils are constricting for near vision), contracting ciliary muscles for near vision focus
Muscarinic effects of cholinesteratse inhibitors; or when cholinesterase inhibitors successfully block the breakdown of acetylcholine at muscarinic receptors - what effects occur?
therapeutic = INCREASED force of contraction on skeletal muscles
toxic = REDUCED force of contraction - this gets reduced b/c of the excessive amounts of acetylcholine at the neuromuscular junction keeping the motor endplate in a state of constant depolarization -->depolarizing the neuromuscular blockade---- not need to know .. just extra
Neuromuscular effects: The effects of cholinesterase inhibitors on skeletal muscles are dose dependent.
At therapeutic doses - what happens?
If there's toxic doses?
therapeutic - mild stimulation
toxic - depress CNS
*in order for CNS effects to occur, these drugs must first penetrate thru the BBB, which they can only really do at high concentrations
what are the effects of Choliensterase inhibitors on the CNS???
at therapeutic doses?
at toxic doses?
orally or injection - IM, IV, or subQ
-absorped poorly thru oral route
what route does Neostigmine come in?
this is a major indication for Neostigmine and other reversible cholinesterase inhibitors
-MG & Reversal of neuromuscular blockade from post surgery or overdose
-Bradycardia, increased sections, contractions of smooth muscles, miosis, contraction of ciliary muscle, urinary urgency, increased tone and motility of GI tract to excrete
-Therapeutic doses increase contractions; toxic levels decrease it
-Therapeutic doses cause mild excitement, toxic causes sedation
Oral, injection routes. Poor absorption orally
AE: Due to high amounts of acetylcholine... excessive muscarinic effects (increased secretions, sweating, saliva, tone and motility of Gi tract, urinary urgency, miosis, spasm of accommodation from near vision, bradycardia, etc. & also depolarizing of neuromuscular blockade -- can paralyza the resp. muscles becomes fatal
Reversible Cholinesterase Inhibitor: Neostigmine.
Effects on muscarinic receptors? - their response
with Atropine. Excessive muscarinic effects means there is toxic levels or high concentration of muscarinic agonists or at leas the effects which can mean poisoning. treat with atropine when muscarinic effects become excessive
how can we suppress the adverse effects of excessive muscarinic effects caused by reversible cholinesterase inhibitors' Neostigmine?
atropine will reverse these
what can we give to a patient who is having excessive muscarinic effects
1. Excessive muscarinic stimulation / excessive muscarinic effects (think: increased secretions, bradycardia, increased tone and motility, all these effects intensified causing toxic levels or poisoning - need atropine med to reduce them)
- respiratory depression
TREAMTNET: GIVE ATROPINE
what are the adverse effects of Neostigmine - a reversible cholinesterase inhibitor?
-this is a reversible cholinesterase inhibitor. which means it makes more available acetylcholine to be used in the body..so its effects are similar to muscarinic agonists, whose job is to mimic the effects of acetylcholine.
Contras are: pt with peptic ulcer disease (bc it increases secretions), coronary insufficiency, obstruction of GI tract and urinary bladder (bc it increases pressure, tone motility and contractions to void and empty). asthma (bc it increases and thickens secretions), HYPERTHEYROIDISM. B/c this lowers HR more, which is already lowered bc of the Neostigmine effect
Name the contraindications for giving someone Neostigmine
-Atropine is used to treat the pt when they have an adverse effect from neostigmine of excessive muscarinic stimulation
-In hand, cholinesterase inhibitors can be used to overcome muscarinic blockade caused by atropine...meaning that they will make acetylchline available to actually be used by preventing its breakdown, not blocking it off
What is the drug interaction between Neostigmine and Atropine? (muscarinic antagonists in general)
by neostigmine causing an increased accumulation of acetylcholine at NMJ, the inhibitors can reverse muscle relaxation and paralysis. remember: acetylcholine contracts skeletal muscle. It will help the pt get back to contracting muscles
what is the drug interaction between Neostigmine and other reversible cholinesterase inhibitors and Competitive neuromuscular blockers?
Cholinesterase inhibitors DO NOT REVERSE the effects of Succinylcholine but they will actually INTENSIFY the effects of Succinylcholine
what is the drug interaction / relationship between Neostigmine and Depolaring Neuromuscular blockers (key word: there's a difference between depolarizing and competitive ones)
--will cause the adverse effects of excessive muscarinic stimulation and respiratory depression.
This state produced is cholinesterase inhibitor POISONING, which is called cholinergic crisis
what happens if a patient overdoses on their cholinesterase inhibitor Neostigmine?
when there is cholinesterase inhibitor poisoning....causing resp. despression and excessive muscarinic stimulation
what is a cholinergic crisis
they go into cholinergic crisis - this is life threatening
what happens when a pt has cholinesterase inhibitor poisoning
If patient has cholinesterase poisoning.
*SLUDGE and the killer B's (or 3 B's)
INCREASED: Salivation, Lacrimation, Urination, Diaphoresis, Diarrhea, Gastrointestinal cramping, Emesis, Bradycardia, Bronchospasm, Bronchorrhea
what occurs during a cholinergic crisis. how does this begin?
Patient has cholinesterase inhibitor poisoning, patient is having a cholinergic crisis and needs to be treated with Atropine
Patient exhibits Salivation, Lacrimation, Urination, Diaphoresis, Diarrhea, Gastrointestinal cramping, Emesis, Bradycardia, Bronchospasm, Bronchorrhea.
What is occurring?
-this is a type of poisoning. Remember cholinergic poisoning is only caused by 3 things: mushrooms, cholinesterase inhibitors (which is the cholinergic crisis), and muscarinic agonists. Treatment for any muscarinic poisoning will always be IV ATROPINE bc its a muscarinic ANTAGONIST - will reduce these symptoms
what is the treatment for a cholinergic crisis?
-Treat the muscarinic effects with ATROPINE IV
-Treat respiratory depression with mechanical ventilation with oxygen. Cannot be treated with drugs ***
If Atropine cannot dry up the bronchial secretions, use suction then give oxygen
During a cholinergic crisis, what drug do we give to the patient to manage their respiratory depression?
(think: in this crisis 2 things happen. Increased and excessive muscarinic effects - know all those, and resp. depression)
No, cannot readily cross membrane. So they do not go into the brain - they are POLAR, meaning they cannot cross. So for many this drug may not work for some patients.
Can neostigmine and other reversible cholinesterase inhibitors cross membranes easily?
-other routes: IV, IM, subQ
Neostigmine is absorbed poorly through what route?
minima effects. Bc it cannot readily cross membranes
What kind of effects does Neostigmine have on infants and fetus???
this is a poor substrate for cholinesterase
this drug is given for the management of myasthenia gravis
direct-acting muscarinic agonists
the muscarinic response of Neostigmine is identical to those of ____ what drugs?
increased force of contraction in skeletal muscle ... so there will be an increase in muscle strength, and increase in diaphragm strength to breathe
What is a therapeutic sign that Neostigmine is working to treat myasthenia gravis ??
-excessive muscarinic stimulation
-neuromuscular blockade - resp. depression
treat with Atropine
adverse effects/acute toxicity of Neostigmine - due to accumulation of acetylcholine
-Obstruction of urinary and GI tract
-Peptic ulcer disease
List all the precautions and contraindications for Neostigmine
-Muscarinic antagonists - atropine reduces its adverse effects
-Depolarizing neuromuscular blockers - cannot reverse the effects of Succinylcholine
just list the drug interactions with Neostigmine
another reversible cholinesterase inhibitor
what type of drug is Physostigmine
Physostigmine does NOT carry a charge (whereas neostigmine does), which makes Pysostigmine able to cross membranes with ease
Reversible cholinesterase inhibitors: Physostigmine is identical to Neostigmine In pharmacology-wise, but what is a major difference in the two?
Physostigmine - bc it has no charge
Which reversible cholinesterase inhibitor can cross membranes with ease and why
Neostigmine - reversible cholinesterase inhibitor
this is the drug of choice to manage myasthenia gravis
Physostigmine - reversible cholinesterase inhibitor
so other muscarinic antagonists would be: antihistamines, antipsycotics, but NOT tricylic antidepressants
this is the drug of choice to treat poisoning by Atropine and other drugs that cause muscarinic blockade (so it treats muscarinic antagonist poisoning)
by causing acetylcholine to build up at muscarinic junctions.
-by preventing the breakdown of acetylcholine, this allows it to build up and accumulate interfering with the blockade that muscarinic antagonists perform - this built up acetylcholine competes with the muscarinic blocker for receptor binding and thereby reverses receptor blockade
How does Physostigmine counteract muscarinic antagonist poisoning???
B/c phos does not have a charge,therefore it's able to cross the BBB to reverse muscarinic blockade in the CNS
Why is Physostigmine preferred to use as a reversible cholinesterase inhibitor over Neostigmine??? - in reversing muscarinic blockade
IV or IM
What are the routes for Physostigmine?
for myasthenia gravis
What is this drug indicated for? Pyridostigmine
This drug is used only as a test and is given to patients to test for myasthenia gravis. When given if their muscles get strong they have the condition
-They are reversible cholinesterase inhibitors
-With all three benefits derive from inhibiting cholinesterase in the CNS.
*** Rivastigmine is also used to treat dementia from Parkinson's disease
What are these drugs used for? What class of drugs are they?
Donepezil, Galantamine, Rivastigmine
signs of an increase in muscle strength
what is the therapeutic sign that Neostigmine is effective in treating Myasthenia Gravis?
-There's not enough dosage of the drug being given if those muscles are still showing weakness
-Contact HCP, increase the dosage
what does the nurse do if the patient taking Neostigmine is having difficulty swallowing?
Because the diaphragm can get so weak it may become paralyzed
If left untreated, why might Myasthenia Gravis lead to death as a result?
they should be wearing a medical alert bracelet and adhering to their medication
what is important education to teach the patient with myasthenia gravis in their every day lives?
this is what happens in a cholinergic crisis; poisoning of cholinesterase inhibitor drugs; Neostigmine overdose!
what drug overdose can cause these effects?
-Excessive muscarinic stimulation
Reversible cholinesterase inhibitors *** is the class.
Drug indicated to treat it is Neostigmine to increase muscle strength by preventing breakdown of acetylcholine, more is available to fight for receptors and contract muscles
what is the mainstay of therapy for Myasthenia Gravis? what drug class
IRREVERSIBLE cholinesterase inhibitors are much much more toxic - they're made from insecticides - these drugs may be used as weapons of terrorism
which cholineresterase inhibitor category is more toxic than the other? Reversible or Irreversible
to treat Glaucoma
The ONLY clinical indication for irreversible cholinesterase inhibitors is ??
-Myasthenia Gravis& & for reversal of competitive nondepolarizing neuromuscular blockade, can be used to treat Alzheimers
(All treatments of Cholinesterase inhibitors include: Alzheimers, MG, & Glaucoma. Only irreversible ones are used for glaucoma)
Clinical indications for:
reversible cholinesterase inhibitors?
irreversible cholinesterase inhibitors?
what are irreversible cholinesterase inhibitors used to treaT???
all routes bc they are lipid soluable. they can even be absorbed thru the skin directly. - makes them good agents for insectides and for chemical warfare
what route can irreversible cholinesterase inhibitors be absorbed by?
Irreversible cholinesterase inhibitors, because they can be readily absorbed by any route and are highly toxic
These drugs have a high potential for being used in chemical warfare
-By phosphorus atom
Irreversible cholinesterase inhibitors are highly toxic and were primarily used as ____.
They all contain what atom?
they are highly lipid soluble
Why can Irreversible cholinesterase inhibitors be readily absorbed by all routes?
Irreversible cholinesterase inhibitors
What drug is being described?
-All contain atom of phosphorus
-Highly lipid soluble
-Readily absorbed from several routes
-Potential use in chemical warfare
-primarily used as insecticides
-ONLY used for treatment of Glaucoma
respiratory problems - 1st rule of thumb is to make sure they have an airway!
people with insecticide poisoning, we worry mainly about what?
Irreversible cholinesterase inhibitors
mechanism of action of which drug class?
-These bind to the active center of cholinesterase, preventing the enzyme from hydrolyzing acetylcholine - binding to cholinesterase is irreversible
Irreversible chol. inhibitors
Neostigmine / reversible chol. inhibitors
helps to treat alzheimers and MG
-(type of muscarinic poisoning) Atropine, but give oxygen to treat patient's respiratory depression
Treats muscarinic antagonist poisoning
treats muscarinic agonist poisoning
treats cholinergic crisis
responses to irreversible chol. inhibitors last longer, responses to reversible ones are brief.
Which lasts longer?
Responses to reversible or irreversible cholinesterase inhibitors?
-To treat Glaucoma
Irreversible cholinesterase inhibitors have only one indication, and for this there is only one drug that's available ___
-irreversible cholinesterase inhibitor
what is echothiophate and what does it treat
irreversible - because these have phosphorus in their atoms !!!***
what are organophosphate cholinesterase inhibitors?
irreversible cholinesterase inhibitors - organophosphate chol. inhib.
poisoning from these drugs is possible through direct skin contact or used as instruments for warfare or terrorism
result: cholinergic effects ; characterized by excessive muscarinic stimulation and depolarizing neuromuscular blockade (is this resp. depression)?
What happens when a pt gets toxic doses of irreversible cholinesterase inhibitors ??
--ask why are these different then others.
-increased secretions;salivary and bronchial glands
-involuntary urination and defecation
-neuromuscular blockade can result in paralysis followed by death from apnea. convulsions of CNS will precede these, sue observations.
When irreversible cholinesterase inhibitors become toxic levels --> cholinergic crisis. What are the symptoms of the excessive muscarinic stimulations that will be seen here???
-mechanical ventilation using oxygen to help resp. depression
-Give Atropine to reduce muscarinic stimulation
-GIVE PRALIDOXIME to reverse the inhibition (restriction) of cholinesterase at NMJ
-Give a Benzodiazepine (Diazepam) to suppress convulsions
what is used as treatment for toxicity of irreversible cholinesterase inhibitors??
choline is important in the transport of ___.
cholinesterase hydrolyzes choline
cholinesterase inhibitors restrict these
- mechanical ventilation
-give atropine to reduce muscarinic stimulation
- Pralidoxime to reverse inhibition of cholinesterase at NMJ - but this cannot cross the BBB so it cannot reverse CNS effects, which is why you need a benzo to help with the CNS effects below....
-Diazepam (Valium) (give a Benzo to suppress convulsions)
Toxic effects of Irreversible Cholinesterase Inhibitors. What would be the treatment.
And why would you give these drugs.
Pralidoxime - effectiveness to treatment is determined by early administration
this is the specific antidote to help reverse and treat irreversible cholinesterase inhibitor poisoning
-A Benzo ; Diazepam (Valium)
If a patient is having irreversible cholinesterase inhibitor poisoning, what do you give them as a antidote?
-as a drug to suppress convulsions from the CNS?
this is the specific antidote to poisoning by the irreversible (organophosphate) cholinesterase inhibitors
-reversal is most effective at the NMJ
This drug is given as a antidote as IM or IV and must be infused slowly IV to prevent hypertension. Treats organophate poisoning
It is a neuromuscular disorder characterized by:
Fluctuating muscle weakness &
predisposition to rapid fatigue
what is myasthenia gravis characterized by??
***starts at the mouth with difficulty swallowing
Ptosis (drooping eyelids)
Weakness in skeletal muscles
-patients with severe MG may have difficulty breathing owing to weakness of muscles of respiration
Name the common symptoms of Myasthenia Gravis
remember: nicotinic M receptors are on skeletal muscles! makes sense. --- # of functional receptors is destroyed and reduced causing the muscle weakness
this is an autoimmune disease in which the body's immune system produces antibodies attack Nicotinic M receptors on skeletal muscles --> causing muscle weakness
-symptoms of myasthenia gravis.
-Give them treatment: Neostigmine which is a reversible cholinesterase inhibitor
patient exhibits difficulty swallowing, drooping eyelids, secretions, weakness in their skeletal muscles. What would you prescribe them?
cholintesterase inhibitors *reversible ones. Neostigmine is the mainstay of therapy. - by preventing acetylcholine inactivation and breakdown, these agents intensify the effects of acetylcholine in which this increases muscle strength !!! -this does NOT cure MG, only relieves symptoms. pt needs lifelong treatment
what class of drugs do we use to treat myasthenia gravis?
check the patient's ability to swallow !!! -How? assessment is done by giving the patient a few sips of water. If pt is unable to swallow the water, parenteral medication is substituted for oral
For the patient with Myasthenia Gravis, what should you do before giving ANY oral medication?
these agents will increase muscle strength - therapeutic sign its working
what are the beneficial effects of using reversible cholinesterase inhibitors to treat MG?
well treatment is Neostigmine - a reversible cholinesterase inhibitor that makes more acetylcholine available, so it has same SE as muscarinic agonists....
SE: excessive muscarinic stimulation. If excessive, give pt atropine to reduce them
what are the side effects of treatment for myasthenia gravis?
-start with small dosing and adjust to patient's responses
-may need t omodify dosage in anticipation of exertion
-look for signs of undermedication and overmedication
How do you start off with drugs to treat Myastehnia Gravis?
If pt is having difficulty swallowing and showing ptosis
*solution: increase the dosage of their medication
when treating Myasthenia Gravis, what are signs that the patient is undermedicated?
Patient is now in a toxic state; will have excessive salivation & have excessive other muscarinic responses
****patient will go into crisis
When treating Myasthenia Gravis, what are signs over overmedication ???
when a pt has Myasthenia Gravis, what is the most important thing that we worry about
in a cholinergic crisis- pt will have extreme weakness of muscles, frank paralysis, and excessive muscarinic stimulation of effects
Myasthenia Gravis: what type of crisis is this; Myasehnic or Cholinergic?
Characterized by: extreme muscle weakness or frank paralysis and signs of excessive muscarinic stimulation
Treatment with respiratory support and Give Atropine to reduce excessive muscarinic stimulation effects
In myasthenia gravis: how do you treat a Cholinergic crisis?
Why type of crisis from Myasthenia Gravis is caused by inadequate medication
myasthenic crisis - give higher dose of medication!!
this type of crisis occurring as a result from Myasthenia Gravis is due to not giving enough Neostigmine medication
*think about the treatment drug for this: Neostigmine. It is a reversible cholinesterase inhibitor - which means it prevents the breakdown of acetylcholine so more is available to be used. If not enough of this med is being given, patient does not have enough Ach available and therefore shows signs of myasthenic crisis - extrmeee muscle weakness
What type of crisis is this resulting from Myasethenia gravis?
-extreme muscle weakness
-caused by insufficient Ach at the neuromuscular junction ***
not enough acetylcholine is available
If left untreated, this crisis can result in death as a result of the paralysis of the muscles that work on respirations (diaphragm)
-Atropine (muscarinic antagonist) & respiratory support - excessive muscarinic stimulation, frank paralysis, & extreme muscle weakness
-Give adequate amount of Neostigmine (reversible cholinesterase inhibitor)
-Result from Myasthenia Gravis. Cholinergic crisis comes from too much medication - toxic levels, Myasthenic crisis comes from under-medication
what is used to relieve myasethnic crisis?
what is used to relieve cholinergic crisis?
what do these crises result from?
patient is in a cholinegic crisis
-a myasethnic crisis is due to under medicating
which crisis of myasthenia gravis?
-patient is overmedicated and shows signs of excessive muscarinic stimulation including excess saliva
watch their symptoms
-increase the dose and you'll find out.
-If increased and their muscle weakness is relieved they had a myasethnic crisis.
-If you increase it and muscarinic effects increase, they have a cholinergic crisis and need atropine and a ventilator
If you can't tell what type of crisis your Myasethnia Gravis patient is having, what should you do?
Myasthenic crisis - think of neostigmine preventing the breakdown of ach ...if there's not enough neostigmine, there's not enough ach available - increase the dose !!
This crisis of myasthenia gravis is caused by an insufficient amount of acetylcholine at neuromuscular receptors
myasthenia gravis - fluctuating muscle weakness
patients with this condition have difficulty breathing owing to weakness of diaphragm
no, they give symptomatic relief. patients need lifetime therapy
do cholinesterase inhibitors cure MG?
myasthenic crisis - treat with cholinesterase inhibitors; Neostigmine
This is a state of extreme muscle weakness due to insufficifent amount of Ach at NMJ
Cholinergic crisis - treat with ventiliation support and atropine !
This is a state of extreme muscle weakness, frank paralysis, and excessive muscarinic stimulation
-gather patient's history of medication use or signs of excessive muscarinic stimulation are needed to permit a difference In diagnosis
-if these are inadequate, patient receives a Tensilon test ; give them Endrophonium - which is an ultra short-acting cholinesterase inhibitor
-If the endrophonium induced elevation of acetylcholine levels alleviates symptoms - the crisis is myasthenic (patient had gone under medicated)
How can we tell the difference between a myasthenic crisis from a cholinergic crisis? since their symptoms are similar and they are treated differently?
-means it is a myasthenic crisis
this is an ultra short-acting cholinesterase inhibitor used to distinguish between a myasthenic crisis and a cholinergic crisis.
- if symptoms are relieved after receiving this test, what does this mean?
pt is in acholinergic crisis - over medication from cholinesterase inhibitors caused toxic effects. give atropine and ventilation support IMMEDIATELY after this test result
what happens if Endrophonium is given and it intensifies symptoms, what crisis is the pt in?
B/c of the possibility of cholinergic or myasthenic crises happening and these can be fatal - this is needed to inform emergency medical personnel of their condition
why is it important for patients with Myasthenic Gravis to wear a medical alert bracelet?
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