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PHS 931 > Block 2 Lecture 1 -- Nicotinics and AChE > Flashcards

Block 2 Lecture 1 -- Nicotinics and AChE Flashcards

1
Q

Where does the agonist of a nAChR bind?

A

alpha subunit

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2
Q

What are the alpha subunit isoforms?

A

1-7 + 9

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3
Q

Where are alpha-3 containing nAChRs located?

A

autonomic ganglia

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4
Q

Where are alpha-4 containing nAChRs located?

A

most common (in CNS)

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5
Q

Where are alpha-6-containing nAChRs located?

A

highly expressed in CNS DA neurons

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6
Q

Where are alpha-7-containing nAChRs located?

A

common throughout body (2nd most common)

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7
Q

Where are alpha-9-containing nAChRs located?

A

cochlea only

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8
Q

What are the beta nAChR subunits? Function?

A

2-4, unknown

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9
Q

What are the muscle NMJ nAChR isoforms?

A

fetal: (a1)2b1gd
adult: (a1)2b1ed

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10
Q

What are the neuronal nAChR isoforms?

A

homomeric: all a7 (or a10)
heteromeric: a/b only a2-6
- - major brain subtype: (a4)2(b2)3
- - major ganglion subtype: (a3)2(b4)3

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11
Q

What changes does the major brain nAChR subtype undergo after chronic nicotine exposure?

A

(a4)2(b2)3 turns into (a4)3(b2)2

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12
Q

What stimulates the change from fetal NMJ nAChR to adult form?

A

ACh exposure

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13
Q

Which nAChR subunits have high affinity for Ca permeability?

A

a7 (homomeric neuronal) and a9 (cochlea)

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14
Q

How many agonist binding sites or are on nAChRs?

A

2

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15
Q

What subunit-specific nAChRs are mostly located on presynaptic terminal?

A

a7, 4, 6

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16
Q

Describe the affinity of the NMJ nAChR.

A

high affinity for ACh

low affinity for nicotine

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17
Q

What are the direct-acting nicotine agonists?

A

1) nicotine
2) lobeline
3) epibatidine

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18
Q

What are the sources of the direct-acting nicotine agonists?

A

1) tobacco – nicotine
2) indian tobacco – lobeline
3) south american treefrom – epibatidine

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19
Q

What are common causes of acute nicotine toxicity?

A

1) pesticides
2) kids eating cigs
3) tobacco harvesting
4) smoking while using patch or e-cig

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20
Q

What level of acute nicotine toxicity causes death?

A

40 mg nicotine

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21
Q

How does acute nicotine toxicity result in death?

A

convulsions, MI, respiratory failure

– nicotine activates and desensitizes diaphragmatic nAChRs

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22
Q

How is acute nicotine toxicity treated?

A

gastric lavage

– add mecamylamine for convulsions

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23
Q

What are the effects of chronic smoking toxicity?

A

1) lung, mouth, bladder, pancreas cancer
2) COPD
3) CAD
4) PVD
5) accelerated atherosclerosis

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24
Q

What is bupropion’s MoA?

A

DAT/NET reuptake inhibitor

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25
Q

What are the smoking cessation therapies for smoking addiction?

A

1) bmod + counseling
2) NRT
3) varenicline
4) bupropion
5) clonidine
6) nicvax
7) ecigs

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26
Q

Describe the efficacy of NRT.

A
    • not effective when compared to cold turkey

- - more effective in men

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27
Q

What is varenicline’s MoA?

A

partial nAChR agonist

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28
Q

What is a common side effect of varenicline?

A

bad sleep probs

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29
Q

Describe the effectiveness of bmod + counseling in smoking cessation?

A

adds 5% chance of quitting to NRT

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30
Q

How is absorption of nicotine from cigs affected?

A

1) inhalation amount
2) inhalation depth
3) duration
4) pH of smoke
5) patient variability

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31
Q

What is menthol’s role in smoking?

A

desensitizes sensory airway receptors so you can inhale deeper

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32
Q

How are “lite” cigarettes different?

A

more holes in paper, air dilutes smoke

– also inhale more unfiltered side-stream smoke

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33
Q

What are the pyrolytic products of smoking a cigarette?

A

CO2
CO
tar

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34
Q

What are the contents of a cigarette?

A

1) organic matter
2) nicotinic alkyloids
3) additives

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35
Q

How are indirect-acting nAChR antagonists classified?

A

CNS-acting

indirect NMJ-acting

36
Q

What are the CNS-acting indirect-acting nAChR antagonists?

A

– clonidine, flexeril, valium, baclofen

37
Q

What are the indirect NMJ-acting indirect-acting nAChR antagonists?

A

botox

myobloc

38
Q

What are the “paralytics” otherwise known as?

A

direct-acting nAChR antagonists

39
Q

What are the classifications of direct-acting nAChR antagonists?

A

1) non-depolarizing neuromuscular blockers
2) depolarizing neuromuscular blockers
3) ganglionic blockers
4) venoms

40
Q

What are the direct-acting, depolarizing NMJ blocking, nAChR antagonists?

A

d-tubocurare

– also: pancuronium, pipercuronium

41
Q

What are the direct-acting, non-depolarizing NMJ blocking, nAChR antagonists?

A

succinylcholine

42
Q

What are the ADRs of succinylcholine?

A

1) post-op myalgia
2) hyperkalemia
3) malignant hyperthermia

43
Q

What are the direct-acting ganglionic-blocking nAChR antagonists?

A

mecamylamine

hexamethonium is of historical note

44
Q

What things make nAChR antagonist venoms?

A

cobra, kraits, piscovorous cone snails, flying darts

45
Q

What are the ADRs of non-depolarizing neuromuscular blockers?

A

hypotension, reflex tachycardia

– due to some ganglionic blockade

46
Q

What is the MoA of tubocurare?

A
    • non-depolarizing NMJ blocker
    • competitive
    • no effect until 75-80% of binding sites are blocked
    • most potent on skeletal nAChR
47
Q

How are the effects of non-depolarizing neuromuscular blockers (tubocurare) reversed?

A

AChE with mAChR antagonist

48
Q

How do non-depolarizing nmj blockers vary?

A
    • mainly in half-life

- - some also cause local histamine release

49
Q

Why does succinylcholine cause post-op muscle pain?

A

initial depolarization causes twitching and early fasciculations

50
Q

Why does succinylcholine cause hyperkalemia?

A
    • causes muscles to release K

- - exacerbated in burn trauma (life threatening)

51
Q

Why does succinylcholine cause malignant hyperthermia?

A
    • due to autosomal dominant disorder of skeletal muscle

- - when combined with inhalation anesthetic, induces massive Ca release from the SR

52
Q

How is succinylcholine-induced malignant hyperthermia treated?

A

1) rapid cooling
2) 100% O2 inhalation
3) dantrolene to block ryanodine receptor in SR

53
Q

What is the MoA of succinylcholine and other depolarizing nmj blockers?

A

Phase I: initial NMJ depol
– brief competitive interaction
Phase II: long-lasting ion channel blockade
– prolonged non-competitive interaction

54
Q

How is succinylcholine metabolized?

A

plasma cholinesterase

– rapid, no need for AChE-I or mAChR-antagonist

55
Q

What are the ADRs of mecamylamine and other ganglionic blockers?

A

1) syncope
2) constipation/urinary retention
3) cycloplegia
4) dry mouth
5) partial mydriasis

56
Q

describe the structure of AChE

A
    • globular protein with interior serine hydrolase
    • anionic site gives electrostatic interaction
    • esteric site receives a serine
57
Q

What are the results of an AchE reaction?

A

choline + acetic acid

58
Q

Where is AChE located?

A

pre- and post-synaptic membranes

59
Q

What is the role of butyrlcholinesterase?

A 
catabolism of
-- food esters/xenobiotics
-- inhalation anesthetics
-- succinylcholine
-- cocaine
endogenous ligand unknown
60
Q

What are therapeutic uses for AChE-Is?

A

1) recovery from NMJ blockers
2) myasthenia gravis
3) atropine/scopolamine poisoning
4) TCA overdose
5) cognitive impairment (dementia)

61
Q

What is the MoA of TCAs?

A

block DAT, NET, SERT

also mAChR antagonist

62
Q

How are AChE-I’s classified?

A

1) reversible (BBB x-ing or not)

2) irreversible

63
Q

What are the reversible AChE-I’s?

A

carbamates

64
Q

What carbamates cross the BBB?

A 
physostigmine
tetrahydroaccridine (THA)
rivastigmine
donepezil
galanthamine
65
Q

What is the MoA of galanthamine?

A

BBB x’ing carbamate that also is an nAChR APL

66
Q

What carbamates don’t cross the BBB?

A

1) pyridostigmine
2) edrophonium
3) ambenonium, neostigmine, demecarium

67
Q

How are the ADRs of carbamates caused?

A

indirect agonism of nAChR, mAChR in somatic, ANS, and CNS

68
Q

Where are organophosphates found?

A

1) chemical weapons (tabun, sarin, soman, VX)

2) insecticides

69
Q

What are insecticide organophosphates?

A

1) paraoxon
2) parathion
3) diazinon
4) fenthion
5) malithion
6) chlorpyrifos

70
Q

How is organophosphate poisoning treated?

A

1) immediate support (gastric lavage, 100% O2, mechanical ventilation)
2) atropine
3) oximes
- - if prior to “aging”
4) anticonvulsant BZDs

71
Q

What is an oxime?

A

nucleophilic agent that dephosphorylates AChE to reactivate

– 2-PAM = pralidoxime

72
Q

What is myasthenia gravis?

A

an autoimmune Ab-mediated disorder affecting muscle nAChR’s

73
Q

How is myasthenia gravis treated?

A

1) AChE-I
2) corticosteroids
3) plasmaphoresis
4) thymectomy

74
Q

What is Lambert Eaton Myasthenic Syndrome?

A

abs to Ca channels (presynaptic problem; can’t release ACh)

75
Q

Why is the main sx of myasthenia gravis ptosis?

A

high [nAChR] in eyelids

76
Q

What are the sxs of persian gulf war syndrome?

A

1) memory loss
2) lack of concentration
3) neuropathic pain
4) depression

77
Q

How was persian gulf war syndrome caused?

A

1) pyridostigmine q day as part of nerve gas prophylaxis

2) AChE-I also used for pest control

78
Q

What are the stages of AChE inhibition?

A

1) formation of Michaelis enzyme-substrate complex
2) phosphorylation of enzyme on serine residue
3) aging (attachment of monophosphate group)

79
Q

When does aging of the Michaelis enzyme-substrate complex occur?

A

in 24-48 post-exposure

80
Q

What are the first signs of organophosphate poisoning?

A

eye and respiratory irritation

81
Q

When are direct-acting nAChR antagonists?

A

surgery prep

prior to electroconvulsive therapy

82
Q

What effects do direct-acting nAChR antagonists have when used prior to surgery?

A

1) significantly decreased dose of general anesthesia (safety, cost, recovery time)
2) facilitates intubation
3) decreases spontaneous movements
4) reduces excess movement

83
Q

Why do direct-aging nAChR antagonists not cause anesthesia?

A

do not cross CNS or placenta

    • consciousness maintained and pain felt
    • maintain analgesia and anesthesia separately
84
Q

How does nicotine act as a secretagogue and work toward addiction?

A

1) acts of DA neurons in Ventral Tegmental Area
2) VTA DA neurons project to NAc
- - NAc is involved in the addiction pathway

85
Q

How are nAChRs upregulated?

A

by nAChR agonists AND antagonists

PHS 931 (29 decks)

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