Block 2 Lecture 1 -- Nicotinics and AChE Flashcards
Where does the agonist of a nAChR bind?
alpha subunit
What are the alpha subunit isoforms?
1-7 + 9
Where are alpha-3 containing nAChRs located?
autonomic ganglia
Where are alpha-4 containing nAChRs located?
most common (in CNS)
Where are alpha-6-containing nAChRs located?
highly expressed in CNS DA neurons
Where are alpha-7-containing nAChRs located?
common throughout body (2nd most common)
Where are alpha-9-containing nAChRs located?
cochlea only
What are the beta nAChR subunits? Function?
2-4, unknown
What are the muscle NMJ nAChR isoforms?
fetal: (a1)2b1gd
adult: (a1)2b1ed
What are the neuronal nAChR isoforms?
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
What changes does the major brain nAChR subtype undergo after chronic nicotine exposure?
(a4)2(b2)3 turns into (a4)3(b2)2
What stimulates the change from fetal NMJ nAChR to adult form?
ACh exposure
Which nAChR subunits have high affinity for Ca permeability?
a7 (homomeric neuronal) and a9 (cochlea)
How many agonist binding sites or are on nAChRs?
2
What subunit-specific nAChRs are mostly located on presynaptic terminal?
a7, 4, 6
Describe the affinity of the NMJ nAChR.
high affinity for ACh
low affinity for nicotine
What are the direct-acting nicotine agonists?
1) nicotine
2) lobeline
3) epibatidine
What are the sources of the direct-acting nicotine agonists?
1) tobacco – nicotine
2) indian tobacco – lobeline
3) south american treefrom – epibatidine
What are common causes of acute nicotine toxicity?
1) pesticides
2) kids eating cigs
3) tobacco harvesting
4) smoking while using patch or e-cig
What level of acute nicotine toxicity causes death?
40 mg nicotine
How does acute nicotine toxicity result in death?
convulsions, MI, respiratory failure
– nicotine activates and desensitizes diaphragmatic nAChRs
How is acute nicotine toxicity treated?
gastric lavage
– add mecamylamine for convulsions
What are the effects of chronic smoking toxicity?
1) lung, mouth, bladder, pancreas cancer
2) COPD
3) CAD
4) PVD
5) accelerated atherosclerosis
What is bupropion’s MoA?
DAT/NET reuptake inhibitor
What are the smoking cessation therapies for smoking addiction?
1) bmod + counseling
2) NRT
3) varenicline
4) bupropion
5) clonidine
6) nicvax
7) ecigs
Describe the efficacy of NRT.
- not effective when compared to cold turkey
- - more effective in men
What is varenicline’s MoA?
partial nAChR agonist
What is a common side effect of varenicline?
bad sleep probs
Describe the effectiveness of bmod + counseling in smoking cessation?
adds 5% chance of quitting to NRT
How is absorption of nicotine from cigs affected?
1) inhalation amount
2) inhalation depth
3) duration
4) pH of smoke
5) patient variability
What is menthol’s role in smoking?
desensitizes sensory airway receptors so you can inhale deeper
How are “lite” cigarettes different?
more holes in paper, air dilutes smoke
– also inhale more unfiltered side-stream smoke
What are the pyrolytic products of smoking a cigarette?
CO2
CO
tar
What are the contents of a cigarette?
1) organic matter
2) nicotinic alkyloids
3) additives
How are indirect-acting nAChR antagonists classified?
CNS-acting
indirect NMJ-acting
What are the CNS-acting indirect-acting nAChR antagonists?
– clonidine, flexeril, valium, baclofen
What are the indirect NMJ-acting indirect-acting nAChR antagonists?
botox
myobloc
What are the “paralytics” otherwise known as?
direct-acting nAChR antagonists
What are the classifications of direct-acting nAChR antagonists?
1) non-depolarizing neuromuscular blockers
2) depolarizing neuromuscular blockers
3) ganglionic blockers
4) venoms
What are the direct-acting, depolarizing NMJ blocking, nAChR antagonists?
d-tubocurare
– also: pancuronium, pipercuronium
What are the direct-acting, non-depolarizing NMJ blocking, nAChR antagonists?
succinylcholine
What are the ADRs of succinylcholine?
1) post-op myalgia
2) hyperkalemia
3) malignant hyperthermia
What are the direct-acting ganglionic-blocking nAChR antagonists?
mecamylamine
hexamethonium is of historical note
What things make nAChR antagonist venoms?
cobra, kraits, piscovorous cone snails, flying darts
What are the ADRs of non-depolarizing neuromuscular blockers?
hypotension, reflex tachycardia
– due to some ganglionic blockade
What is the MoA of tubocurare?
- non-depolarizing NMJ blocker
- competitive
- no effect until 75-80% of binding sites are blocked
- most potent on skeletal nAChR
How are the effects of non-depolarizing neuromuscular blockers (tubocurare) reversed?
AChE with mAChR antagonist
How do non-depolarizing nmj blockers vary?
- mainly in half-life
- - some also cause local histamine release
Why does succinylcholine cause post-op muscle pain?
initial depolarization causes twitching and early fasciculations
Why does succinylcholine cause hyperkalemia?
- causes muscles to release K
- - exacerbated in burn trauma (life threatening)
Why does succinylcholine cause malignant hyperthermia?
- due to autosomal dominant disorder of skeletal muscle
- - when combined with inhalation anesthetic, induces massive Ca release from the SR
How is succinylcholine-induced malignant hyperthermia treated?
1) rapid cooling
2) 100% O2 inhalation
3) dantrolene to block ryanodine receptor in SR
What is the MoA of succinylcholine and other depolarizing nmj blockers?
Phase I: initial NMJ depol
– brief competitive interaction
Phase II: long-lasting ion channel blockade
– prolonged non-competitive interaction
How is succinylcholine metabolized?
plasma cholinesterase
– rapid, no need for AChE-I or mAChR-antagonist
What are the ADRs of mecamylamine and other ganglionic blockers?
1) syncope
2) constipation/urinary retention
3) cycloplegia
4) dry mouth
5) partial mydriasis
describe the structure of AChE
- globular protein with interior serine hydrolase
- anionic site gives electrostatic interaction
- esteric site receives a serine
What are the results of an AchE reaction?
choline + acetic acid
Where is AChE located?
pre- and post-synaptic membranes
What is the role of butyrlcholinesterase?
catabolism of -- food esters/xenobiotics -- inhalation anesthetics -- succinylcholine -- cocaine endogenous ligand unknown
What are therapeutic uses for AChE-Is?
1) recovery from NMJ blockers
2) myasthenia gravis
3) atropine/scopolamine poisoning
4) TCA overdose
5) cognitive impairment (dementia)
What is the MoA of TCAs?
block DAT, NET, SERT
also mAChR antagonist
How are AChE-I’s classified?
1) reversible (BBB x-ing or not)
2) irreversible
What are the reversible AChE-I’s?
carbamates
What carbamates cross the BBB?
physostigmine tetrahydroaccridine (THA) rivastigmine donepezil galanthamine
What is the MoA of galanthamine?
BBB x’ing carbamate that also is an nAChR APL
What carbamates don’t cross the BBB?
1) pyridostigmine
2) edrophonium
3) ambenonium, neostigmine, demecarium
How are the ADRs of carbamates caused?
indirect agonism of nAChR, mAChR in somatic, ANS, and CNS
Where are organophosphates found?
1) chemical weapons (tabun, sarin, soman, VX)
2) insecticides
What are insecticide organophosphates?
1) paraoxon
2) parathion
3) diazinon
4) fenthion
5) malithion
6) chlorpyrifos
How is organophosphate poisoning treated?
1) immediate support (gastric lavage, 100% O2, mechanical ventilation)
2) atropine
3) oximes
- - if prior to “aging”
4) anticonvulsant BZDs
What is an oxime?
nucleophilic agent that dephosphorylates AChE to reactivate
– 2-PAM = pralidoxime
What is myasthenia gravis?
an autoimmune Ab-mediated disorder affecting muscle nAChR’s
How is myasthenia gravis treated?
1) AChE-I
2) corticosteroids
3) plasmaphoresis
4) thymectomy
What is Lambert Eaton Myasthenic Syndrome?
abs to Ca channels (presynaptic problem; can’t release ACh)
Why is the main sx of myasthenia gravis ptosis?
high [nAChR] in eyelids
What are the sxs of persian gulf war syndrome?
1) memory loss
2) lack of concentration
3) neuropathic pain
4) depression
How was persian gulf war syndrome caused?
1) pyridostigmine q day as part of nerve gas prophylaxis
2) AChE-I also used for pest control
What are the stages of AChE inhibition?
1) formation of Michaelis enzyme-substrate complex
2) phosphorylation of enzyme on serine residue
3) aging (attachment of monophosphate group)
When does aging of the Michaelis enzyme-substrate complex occur?
in 24-48 post-exposure
What are the first signs of organophosphate poisoning?
eye and respiratory irritation
When are direct-acting nAChR antagonists?
surgery prep
prior to electroconvulsive therapy
What effects do direct-acting nAChR antagonists have when used prior to surgery?
1) significantly decreased dose of general anesthesia (safety, cost, recovery time)
2) facilitates intubation
3) decreases spontaneous movements
4) reduces excess movement
Why do direct-aging nAChR antagonists not cause anesthesia?
do not cross CNS or placenta
- consciousness maintained and pain felt
- maintain analgesia and anesthesia separately
How does nicotine act as a secretagogue and work toward addiction?
1) acts of DA neurons in Ventral Tegmental Area
2) VTA DA neurons project to NAc
- - NAc is involved in the addiction pathway
How are nAChRs upregulated?
by nAChR agonists AND antagonists
