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Final Test: Dynamics II > deck_1019816 > Flashcards

deck_1019816 Flashcards

1
Q

Where is AChE found and what are its charactersitics & function?

A

its bound to a membrane, it will be RELATIVELY specific for ACh (rapid hydrolsis at cholinergic synapse)

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2
Q

What are the two forms of cholinesterase?

A

acetylcholinesterase and pseudocholinesterase

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3
Q

What is the main function of AChE?

A

to hydrolysize ACh at the cholinergic synapse

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4
Q

What is the commerical name for ambemonium?

A

Mytelase oral

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5
Q

What is important about the sturcture of both ambemonium and demecarium?

A

both compounds have a quaternary amine linked together; the second amine stabilizes the binding to the AChE enzyme

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6
Q

What is significant about the structure of demecarium alone?

A

it has 2 neostigmine molecules connected by a series of 10 CH_3 groups

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7
Q

What is ambemonium?

A

it is an AChE inhibitor and a carbamate

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8
Q

What is amebmonium used to treat?

A

myasthenia gravis

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9
Q

What is the mechanism of action and side effects of ambemonium and demecarium?

A

they will be similar to other carbamates

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10
Q

Where is pseudocholinesterase found?

A

its in the plasma and many tissues (especially the liver); its made in the liver

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11
Q

What is the commerical name for demecarium?

A

Humorsal opthalmic

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12
Q

What are Ache inhibitors such as organophosphates used to treat?

A
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13
Q

What is the main function of pseudocholinesterase?

A

it can break down different chemical substrates such as cocaine and succinylcholine

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14
Q

What is demecarium used to treat?

A

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)

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15
Q

What is the important treatment used for alzheimers and why is this treatment effective

A

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

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16
Q

Where is AChE location relative to a synapse?

A

acetylcholinesterase if in the basal lamina of the synapse– on the postsynaptic cell

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17
Q

Name four prototypes of AChE inhibitors that work centrally

A

1) Tacrine (Cognex)
2) Donepezil (Aricept)
3) Rivastigmine (Exelon)
4) Galantamine (Reminyl)

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18
Q

If AChE is inhibited what can happen?

A

it will allow ACh to accumulate in the synapse

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19
Q

What has happened to the use of tacrine and donepezil and why?

A

diminished due to side effects associated w/ them

example tacrine- hepatoxicity manifested as abnormal liver function test

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20
Q

What is AChe some times called and how is it formed?

A

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

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21
Q

What is a side effect associated with the use of tacrine?

A

hepatoxicity of liver

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22
Q

Where are AChE found but where is its highest enzyme activity?

A

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.

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23
Q

What are galatamine and rivastigmine used to treat?

A

new agents used to treat alzheimer’s disease-more commonly used

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24
Q

What is the function of the AChE aromatic pocket?

A

the quanternary amine of ACh will bind to the aromatic pocket by electrostatic interaction

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25
Q

What are organophosphates?

A

AChE inhibitors that are irreversible agents

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26
Q

Once ACh is bound to AChE what happens?

A

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.

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27
Q

What is the important characteristics of organophosphates ?

A

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

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28
Q

What is the rate limiting step in the reaction between ACh and AChE?

A

deacetylating step

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29
Q

What is important to know about the structures of organophosphates ?

A

its has a labile group

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30
Q

What are the intermediates in the reaction of ACh and AChE?

A

acetyl enzyme conjugate and choline

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31
Q

what are the major uses of organophosphates?

A

war gases—during WWII

pesticides

sometime therapeutically

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32
Q

What are the three types of AChE inhibitors and what are their functions?

A

short acting agents- edrophonium

medium acting agents- neostigmine, physostigmine

irreversible agents- organophosphats, ecothiophate

differ only in ther interaction with the active site of cholinesterase

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33
Q

What are irreversible cholinesterase inhibitors?

A

1) isoflurophate
2) soman
3) echothiphate
4) parathion—> paraoxon
5) malathion—> malaoxon

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34
Q

What are the five reversible AChE inhibitors?

A

acetylcholine

neostigmine

carbaryl

physostigmine

edrophonium

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35
Q

What do the dashed lines on the figure page 10 represent?

A

1

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36
Q

What type of inhibitor is edrophonium?

A

its an alcohol based inhibitor

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37
Q

What is ecothiophate?

A

its an AchE inhibitor—-and an organophosphate

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38
Q

What is the use of edrophonium?

A

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)

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39
Q

What is another name for ecothiophate?

A

phospholine iodine– only used in the USA

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40
Q

What characteristics (molecular structure) of edrophonium allow it to interact with AChE and how does it work?

A

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

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41
Q

How is edrophonium given?

A

parenterally, the quaternary amine allows for slow absorption

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42
Q

What is the duration of action of edrophonium?

A

5-15 minutes

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43
Q

How does edrophonium work and why is effective with muscle paralysis?

A

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

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44
Q

When is edrophonium contraindicated?

A

for asthmatics and urinary or intestinal obstruction

45
Q

What is another name for isoflurophate?

A

floropryl; DFP (no longer avaliable)

46
Q

What is isoflurophate?

A

its an AChE inhibitor–but an organophosphate

47
Q

How are isoflurophate and ecothiophate used?

A

given as ophthalmaic solution- but can enter systemic circulation

48
Q

What is the use of isoflurophate and ecothiophate?

A

treatment:
1) glaucoma- chronic open angle (refractory to other treatments)
2) closed angle glaucome after iridectomy
3) diagnosis of accommodative estropia

49
Q

What is an important property of isoflurophate?

A

its highly lipophilic

50
Q

What are the side effects of isoflurophate and ecothiophate?

A

essentially the same as other AChE inhibitors and direct acting agonist.

51
Q

What are the contraindictions of isoflurophate and ecothiophate?

A

those with

1) uveitis
2) iridocytis
3) retinal detachment

52
Q

What are the side effects of edrophonium:Hint: GI (5)Glands(3)Cardiac (1) Pulmonary (2)

A

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

53
Q

What are the drug interactions w/ other AChE inhibitor and NMJ blocker succinylcholine?

A

may prolong phase I block

54
Q

What is physostigmine?

A

A carbamate; its a teritary amine carbamyl ester

55
Q

Why are benefits of long acting Ache inhibitors?

A

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

56
Q

What is physostigmine used to treat?

A

open angle glaucoma (can use with beta blockers)

used systemically to reverse the effects of muscarinic blockade

57
Q

Describe the neurotoxicity of AChE inhibitors.

A

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

58
Q

How does physostigmine work (its route in the body)?

A

absorbed from GI tract—> mucosal membranes

if applied to conjunctival—> crosses blood brain barrier

59
Q

Describe the acute toxicity of AChE inhbitors

A

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.

60
Q

What are the first signs of AChE inhibitors?

A

ocular browache, lacrimation and miosis

pulmonary signs: wheezing and tightness in chest

61
Q

If AChE inhibitors are ingested what can occur?

A

vomitting and diarrhea

62
Q

If AChE inhibitors are given transdermally what can happen?

A

localized sweating and muscle fasciculations (random contractions)

63
Q

How is physostigmine metabolized and how long does it work?

A

its metabolized by plasma cholinesterases and is active for 0.5-2 hours

64
Q

How does physostigmine work in the eye?

A

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

65
Q

How does physostigmine work at the synpase?

A

reverse muscarinic blockage—> increases concentration of ACh and competes with the other antagonist to reverse toxicity

66
Q

What are the side effects of physostigmine?

A

same as edrophonium but will be more intense because of longer duration and potency

67
Q

What are some VERY dangerous side effects of AChE inhbitors?

A

if respiratory muscle becomes paralyzed death can occur

68
Q

Describe the side of AChE inhibitors as given by the acronym d.u.m.b.b.e.l.l.s

A

Diarrhea

Urination

Miosis

Bronchorrhea

Bronchospasm

Emesis

Lacrimation

Laxation

Salivation

69
Q

What are the treatment for organophosphate poisoning as shown by A FLOP or A FLOOD?

A

A-Atropine

Fl-Fluids

O-Oxygen

P-Pralidoxime

A-Atropine

Fl-Fluids

O-Oxygen

O-Oximes

D- Diazepam

70
Q

Describe the respiratory failure associated with AChE inhibitor toxcity?

A

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

71
Q

Who should not use physostigmine?

A

should not be used in patients that are asthmatics, have some form of caridovascular disease and urinary or intestinal block

72
Q

What type of drug is neostigmine?

A

its an AChE inhibitor—and a carbamate

73
Q

Who is neostigmine given?

A

1

74
Q

Describe the toxicity associated with CNS caused by AChE inhibitors.

A

1) confusion
2) ataxia
3) convulsions
4) coma
5) paralysis of central respiratory centers

75
Q

What is the use of neostigmine?

A

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)

76
Q

How is neostigmine given?

A

can be give parenterally or orally but the oral dose has poor absorption (will be 10-15x the parenteral dose)

77
Q

How should acute toxcity from AChE inhibitor be treated?

A

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)

78
Q

What has better absorption oral or parenteral dose of neostigmine?

A

well the parenteral dose is more potent

79
Q

What is chronic exposure of AChE inhibitor?

A

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

80
Q

What are the effects of neostigmine?

A

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

81
Q

How can acetcholinesterase be reactivated and what does this do?

A

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

82
Q

What are the side effects of neostigmine?

A

are the same as physostigmine:

no asthmatics, cardiovascular disease, urinary or intestinal block

83
Q

What is another way reactivation can be done and what does this do?

A

1

84
Q

What kind of drug is pyridostigmine?

A

most widely used anticholinesterase agent for the treatment of myasthenia gravis

85
Q

What are some benefits of reactivation by oximes? And what are they ineffective against?

A

it restores cholinergic transmission esp at the neuromuscular junction to reverse respiratory paralysis

86
Q

What is the main use of pyridostigmine?

A

1) orally alone for mild muscle weakness
2) in combination with corticosteriods for SEVERE impairment

87
Q

What are the side effects of oximes?

A

muscle weakness, blurred vision, headache, nausea, and tachycardia–weak AChE itself

88
Q

How is pyridostigmine given?

A

the dosage varies based on indvidual–difference in absorption, metabolism, and excretion

need to figure out the dosage and time of administration empirically

89
Q

Why will doses of pyridostigmine vary?

A

depends on the person

90
Q

What is a cholineasetarse inhibitor that is an alcohol, carbamate, and organophosphate?

A

alcohol: edrophonium
carbamates: neostigmine, pyridostigmine, physostigmine, ambenoium, demacurium
organophosphates: echothiophate

91
Q

What is the duration of action for pyridostigmine?

A

3-6 hours

92
Q

What is the use of edrophonium and whats its duration of action?

A

1

93
Q

What war was pyridostigmine used in and what was so important about it?

A

during the Gulf War and one of the suspected agent in the Persian Gulf War syndrome

94
Q

what is myasthenia gravis and what are its characteristics?

A

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

95
Q

What is the use of neostigmine and what is its duration of action?

A

1) myasthenia gravis
2) ileus

duration of action: 0.5-2 hours

96
Q

What is the use of pyridostigmine and what is its duration of action?

A

Use: myasthenia gravis

duration of action-3-6 hours

97
Q

What is the use of physostigmine and what is its duration of action?

A

Uses: glacoma

Duration of action: 0.5-2 hours

98
Q

What is the use of ambenonium and what is its duration of action?

A

Uses: myasthenia gravis

Duration of Action: 4-8 hours

99
Q

What is the use of demacurium and what is its duration of action?

A

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

100
Q

What is the use of echothiophate and what is its duration of action?

A

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

101
Q

What are cholinesterases?

A

they are serine hydrolases

102
Q

What is the benefit of pseudocholinesterase?

A

it has a broader spectrum of chemical substrates that it can metabolize including cocaine and succinylcholine

103
Q

What is the drug interaction of edrophonium with other AChE inhibitors?

A

they potentiate the effects- can cause onset of cholinergic crisis

104
Q

What is drug interaction between edrophonium and digitalis?

A

addative vagalmimetic effect may slow the heart

105
Q

What an important structural characteristic of ecothiophate?

A

less lipid soluble due to charged amine groups

106
Q

What are skeletal muscle responses to AChE inhibitors toxicity?

A

skeletal muscle will twitch and fasciculate initially followed by weakness and paralysis (depolarization block)

107
Q

How are oximes administered and whaat is the onset of action?

A

its a nucleophilc agent that is usually given parenterally via IV BUT can be given orally

the onset of action is within minutes

108
Q

What is important to remember about to the structure of oximes and how does this effect their action?

A

charged nitrogen prevents entry into the CNS —most effective at the neuromuscular junction and not CNS

109
Q

What are oximes ineffective against?

A

oximes are ineffective against carbamylated AChE inhibitors

Final Test: Dynamics II (11 decks)

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