deck_1019816 Flashcards
Where is AChE found and what are its charactersitics & function?
its bound to a membrane, it will be RELATIVELY specific for ACh (rapid hydrolsis at cholinergic synapse)
What are the two forms of cholinesterase?
acetylcholinesterase and pseudocholinesterase
What is the main function of AChE?
to hydrolysize ACh at the cholinergic synapse
What is the commerical name for ambemonium?
Mytelase oral
What is important about the sturcture of both ambemonium and demecarium?
both compounds have a quaternary amine linked together; the second amine stabilizes the binding to the AChE enzyme
What is significant about the structure of demecarium alone?
it has 2 neostigmine molecules connected by a series of 10 CH_3 groups
What is ambemonium?
it is an AChE inhibitor and a carbamate
What is amebmonium used to treat?
myasthenia gravis
What is the mechanism of action and side effects of ambemonium and demecarium?
they will be similar to other carbamates
Where is pseudocholinesterase found?
its in the plasma and many tissues (especially the liver); its made in the liver
What is the commerical name for demecarium?
Humorsal opthalmic
What are Ache inhibitors such as organophosphates used to treat?
What is the main function of pseudocholinesterase?
it can break down different chemical substrates such as cocaine and succinylcholine
What is demecarium used to treat?
for the treatment of:
1) chronic open angle glaucome after other treatments have failed
3) closed angle glaucome after iridectomy
3) diagnosis and treatment of accommodative esotropia (crossed eyes during near vision focus)
What is the important treatment used for alzheimers and why is this treatment effective
used to improve cognitive function
because in alzheimers there is a decrease in the choline acetyltransferase and other markers of cholinergic neuron activity. Eventually cholinergic, neurons die or are destroyed; therefor these patients are very sensitive to the CNS toxcities of drugs with anti-muscarinic effects
Where is AChE location relative to a synapse?
acetylcholinesterase if in the basal lamina of the synapse– on the postsynaptic cell
Name four prototypes of AChE inhibitors that work centrally
1) Tacrine (Cognex)
2) Donepezil (Aricept)
3) Rivastigmine (Exelon)
4) Galantamine (Reminyl)
If AChE is inhibited what can happen?
it will allow ACh to accumulate in the synapse
What has happened to the use of tacrine and donepezil and why?
diminished due to side effects associated w/ them
example tacrine- hepatoxicity manifested as abnormal liver function test
What is AChe some times called and how is it formed?
at the synapse AChE is called “true” cholinesterase or erythocyte cholinesterase
its made in the neuronal cell bodies and then transported to the synapse by axonal transport
What is a side effect associated with the use of tacrine?
hepatoxicity of liver
Where are AChE found but where is its highest enzyme activity?
acetylcholinesterase is found in four places:
neuromuscular junction, erythrocyte membranes, brain and spinal cord
It has the highest enzyme activity at the sympathetic and parasympathetic ganglia.
What are galatamine and rivastigmine used to treat?
new agents used to treat alzheimer’s disease-more commonly used
What is the function of the AChE aromatic pocket?
the quanternary amine of ACh will bind to the aromatic pocket by electrostatic interaction
What are organophosphates?
AChE inhibitors that are irreversible agents
Once ACh is bound to AChE what happens?
the acetyl carbon of ACh undergoes nucleophilic attack by a serine hydroxyl and a tetrahedral intermediate is formed.
The intermediate breaks down to acetyl enzyme conjugate and choline
The deacetylation step is the rate limiting.
What is the important characteristics of organophosphates ?
these are pentavalent phosphorus compounds with labile groups such as flouride or an organic group; the labile group is released, leaving the residue of the molecule covalently attached (via the phosphorous group) to serine -OH group of the enzyme
What is the rate limiting step in the reaction between ACh and AChE?
deacetylating step
What is important to know about the structures of organophosphates ?
its has a labile group
What are the intermediates in the reaction of ACh and AChE?
acetyl enzyme conjugate and choline
what are the major uses of organophosphates?
war gases—during WWII
pesticides
sometime therapeutically
What are the three types of AChE inhibitors and what are their functions?
short acting agents- edrophonium
medium acting agents- neostigmine, physostigmine
irreversible agents- organophosphats, ecothiophate
differ only in ther interaction with the active site of cholinesterase
What are irreversible cholinesterase inhibitors?
1) isoflurophate
2) soman
3) echothiphate
4) parathion—> paraoxon
5) malathion—> malaoxon
What are the five reversible AChE inhibitors?
acetylcholine
neostigmine
carbaryl
physostigmine
edrophonium
What do the dashed lines on the figure page 10 represent?
1
What type of inhibitor is edrophonium?
its an alcohol based inhibitor
What is ecothiophate?
its an AchE inhibitor—-and an organophosphate
What is the use of edrophonium?
myasthenia gravis in emergencies
reversal of neuromuscular blockade produced by non-depolarizing blockers (recall it will stop the break down of ACh allowing it to work on receptor–reserves neuromusular block)
What is another name for ecothiophate?
phospholine iodine– only used in the USA
What characteristics (molecular structure) of edrophonium allow it to interact with AChE and how does it work?
edrophonium has a quanternary amine will allow it interact with the aromatic pocket of AChE
but also the phenol moiety (portion of the molecule) allows it to hydrogen bodn with the enzyme
How is edrophonium given?
parenterally, the quaternary amine allows for slow absorption
What is the duration of action of edrophonium?
5-15 minutes
How does edrophonium work and why is effective with muscle paralysis?
it prolongs the duration of action of ACh at the neuromuscular junction –increases muscle strength for patients with myasthenia gravis
therefore, a higher ACh concentration @ NMJ will over come reversible neuromuscular blockers and stop muscle paralysis
When is edrophonium contraindicated?
for asthmatics and urinary or intestinal obstruction
What is another name for isoflurophate?
floropryl; DFP (no longer avaliable)
What is isoflurophate?
its an AChE inhibitor–but an organophosphate
How are isoflurophate and ecothiophate used?
given as ophthalmaic solution- but can enter systemic circulation
What is the use of isoflurophate and ecothiophate?
treatment:
1) glaucoma- chronic open angle (refractory to other treatments)
2) closed angle glaucome after iridectomy
3) diagnosis of accommodative estropia
What is an important property of isoflurophate?
its highly lipophilic
What are the side effects of isoflurophate and ecothiophate?
essentially the same as other AChE inhibitors and direct acting agonist.
What are the contraindictions of isoflurophate and ecothiophate?
those with
1) uveitis
2) iridocytis
3) retinal detachment
What are the side effects of edrophonium:Hint: GI (5)Glands(3)Cardiac (1) Pulmonary (2)
similar to direct acting agonist:
GI- cramps, nausea, vomitting, diarrhea, and urge to urinate
glands- sweating, watering eyes and mouth
cardiac- bradycardia
pulmonary- shortness of breath, wheezing
What are the drug interactions w/ other AChE inhibitor and NMJ blocker succinylcholine?
may prolong phase I block
What is physostigmine?
A carbamate; its a teritary amine carbamyl ester
Why are benefits of long acting Ache inhibitors?
prolong the action and concentration of AChE
in the case of the eye induces miosis(pupil contraction) and reduction in intraocular pressure–will last for 7-14 days
What is physostigmine used to treat?
open angle glaucoma (can use with beta blockers)
used systemically to reverse the effects of muscarinic blockade
Describe the neurotoxicity of AChE inhibitors.
happens from accidental exposure (use and manufacture of pesticides)
exposure will usually be pulmonary or transdermally
the agents have been used in suicides and homicides
How does physostigmine work (its route in the body)?
absorbed from GI tract—> mucosal membranes
if applied to conjunctival—> crosses blood brain barrier
Describe the acute toxicity of AChE inhbitors
the classic muscarinic and nicotinic agonist side effects- at the locus of contact w/ the vapors and/or aerosol of the agents
can get systemic effects from ingesting and follow peripheral exposure.
What are the first signs of AChE inhibitors?
ocular browache, lacrimation and miosis
pulmonary signs: wheezing and tightness in chest
If AChE inhibitors are ingested what can occur?
vomitting and diarrhea
If AChE inhibitors are given transdermally what can happen?
localized sweating and muscle fasciculations (random contractions)
How is physostigmine metabolized and how long does it work?
its metabolized by plasma cholinesterases and is active for 0.5-2 hours
How does physostigmine work in the eye?
high levels of ACh—> contraction of the iris sphincter and ciliary muscle—> flow of aqueous humor into the canal of schlemn—> intraocular pressure goes down
How does physostigmine work at the synpase?
reverse muscarinic blockage—> increases concentration of ACh and competes with the other antagonist to reverse toxicity
What are the side effects of physostigmine?
same as edrophonium but will be more intense because of longer duration and potency
What are some VERY dangerous side effects of AChE inhbitors?
if respiratory muscle becomes paralyzed death can occur
Describe the side of AChE inhibitors as given by the acronym d.u.m.b.b.e.l.l.s
Diarrhea
Urination
Miosis
Bronchorrhea
Bronchospasm
Emesis
Lacrimation
Laxation
Salivation
What are the treatment for organophosphate poisoning as shown by A FLOP or A FLOOD?
A-Atropine
Fl-Fluids
O-Oxygen
P-Pralidoxime
A-Atropine
Fl-Fluids
O-Oxygen
O-Oximes
D- Diazepam
Describe the respiratory failure associated with AChE inhibitor toxcity?
At frist skeletal muscle will twitch and fasciculate followed by weakness and paralysis(depolarization block). If respiratory muscle becomes paralyzed death will occur
both muscarinic (increased salivation and bronchoconstriction) and nicotinic (CNS depression) effects
Who should not use physostigmine?
should not be used in patients that are asthmatics, have some form of caridovascular disease and urinary or intestinal block
What type of drug is neostigmine?
its an AChE inhibitor—and a carbamate
Who is neostigmine given?
1
Describe the toxicity associated with CNS caused by AChE inhibitors.
1) confusion
2) ataxia
3) convulsions
4) coma
5) paralysis of central respiratory centers
What is the use of neostigmine?
can be given orally to treat:
1) Myasthenia gravis
can be given parenterally to treat:
1) myasthenia gravis
2) reversal of NMJ blockade
3) treatment and prophylaxis of post-operative urinary retension and ileus (if obstruction is because of handling or anesthesia its not a real blockage)
How is neostigmine given?
can be give parenterally or orally but the oral dose has poor absorption (will be 10-15x the parenteral dose)
How should acute toxcity from AChE inhibitor be treated?
1) removal of exposure
2) start artificial respiration and oxygen
3) stop convulsions with diazepam
4) give atropine- to lower salivation, bronchoconstriction and bradycardia (dose it until toxic symptoms disappear or atropine toxicity appears)
What has better absorption oral or parenteral dose of neostigmine?
well the parenteral dose is more potent
What is chronic exposure of AChE inhibitor?
delayed neurotoxicity in the form of polyneuritis characterized by axonal swelling and segmentation
there will be sensory disturbances, ataxia and weakness—> may progress to paralysis
What are the effects of neostigmine?
1) reverse the myasthenia gravis and neuromuscular blockade (similar to edrophonium)
2) relieves urinary retention and increase tone of detrosor muscle
3) increases gastric tone and motility
How can acetcholinesterase be reactivated and what does this do?
reactivated with oximes such as pralidoxime cholride also knows as (protopam chloride, 2-PAM) and obidoxine
the molecules restore cholinergic transmission, esp. at neuromuscular muscle junction to reverse respiratory paralysis
What are the side effects of neostigmine?
are the same as physostigmine:
no asthmatics, cardiovascular disease, urinary or intestinal block
What is another way reactivation can be done and what does this do?
1
What kind of drug is pyridostigmine?
most widely used anticholinesterase agent for the treatment of myasthenia gravis
What are some benefits of reactivation by oximes? And what are they ineffective against?
it restores cholinergic transmission esp at the neuromuscular junction to reverse respiratory paralysis
What is the main use of pyridostigmine?
1) orally alone for mild muscle weakness
2) in combination with corticosteriods for SEVERE impairment
What are the side effects of oximes?
muscle weakness, blurred vision, headache, nausea, and tachycardia–weak AChE itself
How is pyridostigmine given?
the dosage varies based on indvidual–difference in absorption, metabolism, and excretion
need to figure out the dosage and time of administration empirically
Why will doses of pyridostigmine vary?
depends on the person
What is a cholineasetarse inhibitor that is an alcohol, carbamate, and organophosphate?
alcohol: edrophonium
carbamates: neostigmine, pyridostigmine, physostigmine, ambenoium, demacurium
organophosphates: echothiophate
What is the duration of action for pyridostigmine?
3-6 hours
What is the use of edrophonium and whats its duration of action?
1
What war was pyridostigmine used in and what was so important about it?
during the Gulf War and one of the suspected agent in the Persian Gulf War syndrome
what is myasthenia gravis and what are its characteristics?
its an auto immune disorder–loss of nicotinic ACh receptors from neuromuscular junction
characterized by progressive weakness of the skeletal muscle as a result of an impairment of the neuromuscular junction
What is the use of neostigmine and what is its duration of action?
1) myasthenia gravis
2) ileus
duration of action: 0.5-2 hours
What is the use of pyridostigmine and what is its duration of action?
Use: myasthenia gravis
duration of action-3-6 hours
What is the use of physostigmine and what is its duration of action?
Uses: glacoma
Duration of action: 0.5-2 hours
What is the use of ambenonium and what is its duration of action?
Uses: myasthenia gravis
Duration of Action: 4-8 hours
What is the use of demacurium and what is its duration of action?
used to treat:
1) glaucoma ( chronic open angle—after other treaments have failed)
2) closed angle glaucoma after iridectomy
3) treatment of accommodative esotropia (crossed eye during near vision focus)
Duration of action: 4-6 hours
What is the use of echothiophate and what is its duration of action?
used in the treatment:
1) glaucoma–chronic open angle refractory
2) closed angle glaucoma—after iridectomy
3) diagnosis of accommodative esotropia
duration of action : 100 hours
What are cholinesterases?
they are serine hydrolases
What is the benefit of pseudocholinesterase?
it has a broader spectrum of chemical substrates that it can metabolize including cocaine and succinylcholine
What is the drug interaction of edrophonium with other AChE inhibitors?
they potentiate the effects- can cause onset of cholinergic crisis
What is drug interaction between edrophonium and digitalis?
addative vagalmimetic effect may slow the heart
What an important structural characteristic of ecothiophate?
less lipid soluble due to charged amine groups
What are skeletal muscle responses to AChE inhibitors toxicity?
skeletal muscle will twitch and fasciculate initially followed by weakness and paralysis (depolarization block)
How are oximes administered and whaat is the onset of action?
its a nucleophilc agent that is usually given parenterally via IV BUT can be given orally
the onset of action is within minutes
What is important to remember about to the structure of oximes and how does this effect their action?
charged nitrogen prevents entry into the CNS —most effective at the neuromuscular junction and not CNS
What are oximes ineffective against?
oximes are ineffective against carbamylated AChE inhibitors
