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MSK phys > pharm of NMJ - Kruseyyy > Flashcards

pharm of NMJ - Kruseyyy Flashcards

1
Q

Agents that affect the nerve action potential

A

a) Tetrodotoxin

b) Local anesthetics

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2
Q

Agents that affect vesicular acetylcholine release

A

a) Botulinum toxin

b) Tetanus toxin

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3
Q

Agents that affect depolarization

A

a) Neuromuscular blocking drugs
i) Curare alkaloids (
d-tubocurarine)
ii) Succinylcholine

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4
Q

Agents that affect the muscle action potential

A

Tetrodotoxin (also affects nerve AP)

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5
Q

Agents that affect muscle contraction

A

Dantrolene - inhibits ryanodine receptors i nsarcoplasmic reticulum and blocks release of Ca2+
- clinical uses include malignant hyperthermia, spasticity associated with upper motor neuron disorders

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6
Q

activated by ACh and are mostly found in the
membranes of postsynaptic muscle cells (also found
on the prejunctional neuronal membrane)

A

Nicotinic acetylcholine receptors (nAChRs)

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7
Q

axonal conduction

A

The passage of an impulse (action potential) along an axon or muscle fiber

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8
Q

Junctional transmission

A

The passage of an action potential across a synaptic junction

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9
Q

facilitates the transport of choline from the plasma into neurons

A

choline transporter

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10
Q

The choline transport system is dependent on

A

extracellular Na
+ with both choline and
Na+ cotransported at the same time

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11
Q 
Choline acetyltransferase
 (ChAT)  function? where are the substrates coming from?
A

Combines the acetyl moiety of acetyl coenzyme A
with choline in the cytoplasm of the neuron (final step in the synthesis of ACh)
(b) ACh is immediately sequestered within synaptic
vesicles after synthesis
(c) Acetyl CoA is synthesized in the mitochondria a
and choline is taken up via the choline transporter

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12
Q

why are ChAT inhibitors of little use

A

uptake of choline is the rate-limiting step in ACh biosynthesis

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13
Q

ACh is actively taken up by the storage vesicle
s at the nerve terminals by the ATPase-
dependent

A

ACh vesicular transporter

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14
Q

When the action potential reaches the axonal te

rminal,

A 
depolarization causes voltage-
gated calcium (Ca
2+) channels to open and Ca
2+  enters the neuron
(2) Elevated Ca
2+  levels promote the fusion of the vesicular membran
e with the cell 
membrane and exocytosis of ACh occurs
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15
Q

categories of snares, names and function

A
  • vesicle (V-SNAREs) - synaptobrevin/ vesiscle associated membrane protein, VAMP)
  • t-SNARE proteins syntaxin and SNAP-25
    ^ they interact together to form core SNARE complex bringing vescile and presynaptic membranes into clsoe contact
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16
Q

Upon arrival of the action potential in the axonal terminal, calcium rushes in and
interacts with the calcium sensor protein —– on the vesicle membrane,
which triggers vesicle fusion and exocytosis

A

synaptotagmin

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17
Q

After release of ACh into the synaptic cleft, two proteins ( ????) bind to the SNARE complex and disassemble the
SNAREs, which causes
recycling of the vesicle and SNARE proteins

A

(α-SNAP and the ATPase NSF)

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18
Q

ACh diffuses across the synaptic cleft and combines with nAChRs on skeletal muscle fibers, which causes
entration gradients)

A

the receptor channel to open and allow Na+ to enter the muscle fiber and K+ to exit (both traveling down their respective conc. gradient)

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19
Q

cleaves ACh into acetate and choline

A

Acetylcholinesterase

(AChE)

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20
Q

Vesicle formation is initiated a few seconds after each action potential by the appearance of the protein

A

clathrin, a contractile p
rotein that coats the pits and is
involved in endocytosis

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21
Q

as a general rule, nAChRs found in

A

skeletal muscle

22
Q

mAChRs found in

A

smooth and cardiac muscle

23
Q

located in presynaptic axons at both the ganglia and the smooth neuromuscular junction where they are involved in ACh-mediated inhibition of further ACh
release

A

mAChRs!!

opposite of nAChRs action

24
Q

Nm type of nAChRs exist at ?? and lead to ??; subunuits?

A

skeletal neuromuscular junction (postjunctional)
excitatory, contraction
- receptors pre and post junctional
- a, b, d, e, and g subunits

25
Q

Nn type of nAChRs exist at ?? and lead to ??; subunits?

A
  • autonomic ganglia; adrenal medulla
  • excitatory, contraction
  • pre and post junctional
    include a and subunit combinations or all a subunit
26
Q

composition and structure of nACHr, binding sites?

A

2: 1:1:1 arrangemnt of a, b, d, e, subunits leading to pentamer e.g. GABA, glycine receptors
- each subunit has four transmembrane spanning domains
- five subunits arranged around a central pore
- only one a subunit and one adjacent subunit have Ach binding sites; need TWO molecules of ACh, one at each site for receptor channel to open

27
Q

why are negative charged anions unable to pass through open nAChR

A

= strong negative charges at mouth of the channel (aspartic acid and glutamic acid)

28
Q

tetrodotoxin

A

MOA: selectively blocks axonal conduction by blocking voltage-gated Na+ channels
maybe death due to respiratory failure and hypotension
- puffer fish poison

29
Q

batrachotoxin MOA

A

Steroidal alkaloid secreted by South American frogs
- MOA: produces paralysis through a selective increase i
n permeability of voltage-gated Na+ channels, which induces a persistent depolarization
(3) Not used clinically

30
Q

local anaesthetics

A

MOA - block neuronal conduction by inhibitng the voltage-gated Na+ channels
- e.g. lidocaine, bupivacaine, procaine

31
Q

hemicholinium

A

MOA: inhibits choline transporter, blocking reuptake of choline into presynaptic terminal and depleting Ach stores

32
Q

botulinum toxin MOA and clinical

A

MOA: cleaves components of the core SNARE complex involved in exocytosis,
preventing the release of ACh
(a) Botulinum B, D, F, G targets synaptobrevin
(b) Botulinum A, E targets SNAP-25
(c) Botulinium C1 targets syntaxin
- Used clinically in a number of settings, including treatment of strabismus and blepharospasm associated with dystonia; treatment of cervical dystonia; temporary improvement in the appearance of lines/wrinkles of the face; treatment of severe
primary axillary hyperhidrosis; prophylaxis of chronic migraine headache

33
Q

Tetanus toxin

A

Tetanus is a nervous system disorder characterized by muscle spasms that is caused
by the toxin-producing anaerobe Clostridium tetani
-
MOA
: block fusion of synaptic vesicles by targeting synaptobrevin
(a) After binding to the presynaptic membrane of the NMJ, tetanus toxin is internalized and transported retroaxonally to the spinal cord
(b) Spastic paralysis is caused by the toxin’s actions on the spinal inhibitory
interneurons, blocking release of inhibitory neurot
ransmitters that normally serve to relax contracted muscle by inhibiting excitatory motor neurons

34
Q

agonist and antagonist action on nACHR

A

BOTH can prevent synaptic transmisison

  • agonists activate receptor to signal as direct result of binding to it
  • antagonists bind to receptors but do not activate generation of a signal
35
Q

curare alkaloids

A

Prototype:
d-tubocurarine
(b) MOA: competes with ACh for the nAChR on the motor end plate, decreasing the
size of the EPP (nondepolarizing competitive nAChR antagonist)
(c) Inhibition of ACh binding to the nAChR leads to flaccid paralysis of skeletal muscle
(d) Used during anesthesia to relax skeletal muscle
(e) Paralysis reversed by increasing ACh in the NMJ
(by use of an acetylcholine
esterase inhibitor; see below)

36
Q

sucinylcholine

A

OA
: depolarizing neuromuscular blocker that binds to
skeletal muscle nAChRs and
initially causes depolarization (acts as an agonist); continued depolarization leads to
receptor blockade and paralysis
(b) Used as an induction agent for anesthesia
(c) Causes transient muscle fasciculations (muscle
twitch) due to agonist activity
(d) Paralysis reversed by termination of succinylcholine’s effects (i.e., time)
- useful when e.g. intubating one, want short lasting anaesthesia
- drug with unique property of being an agonist but acting as antagonist in its ability to cause paralysis

37
Q

snake a-toxins

A

MOA: competitive antagonists that bind irreversibly to
nAChRs and block function at the neuromuscular junction (e.g., α-bungarotoxin is a selective antagonist of the
α7 nAChR in the brain)

38
Q

AChE inhibitors MOA and clinical

A

inhibits acetylcholinesterase and the hydrolysis
of ACh, increasing ACh
concentration in the NMJ and increasing activation
of AChRs
- Used in the treatment of dementia associated with Alzheimer or Parkinson disease,
myasthenia gravis, reversal of neuromuscular blockade during anesthesia, and
treatment of urinary retention (e.g., from postoperative bladder distention

39
Q

veratridine

A

MOA
: stimulates Na+ passage into cells and leads to increased nerve excitability
- affects muscle AP!

40
Q

dantrolene

A

MOA
: inhibits ryanodine receptors in the sarcoplasmic
reticulum and blocks the release of Ca2+
(2) Used in the treatment of malignant hyperthermia
and spasticity associated with upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple
sclerosis)

41
Q

reduced cerebral production of ChAT in

A

patients with Alzheimer Disease

42
Q

medically you would give AhE inhibitors to

A

myasthenia gravis patients because they have reduced no. of nAChRs
patients who received anesthetics, bringiing them back

43
Q

prejunctionally nAChRs act to

A

gathering of more vesicles near membrane so when another AP comes, more vesicles released

44
Q

fastest synaptic events in the NS involve

A

nAChRs (milliseconds)!!!

mAChRs are seconds or longer

45
Q

botulinum bacteria found in

A

vegetables, fruits, seafood

exist sin soil and marine sediment worldwide

46
Q

botulism s/s

A

acute onset of bilateral cranial neuropathies associated with symmetric descending weakness; no sensory deficits except blurred vision
foodborne s/s - nausea, vomiting, abdominal pain, diarrhea and dry mouth

47
Q

botulinum toxin B,D, F,G and tetanus targets

A

synaptobrevin

48
Q

botulinum A/E targets

A

SNAP-25

49
Q

botulinum C1 targets

A

syntaxin

50
Q

example of depolarizing and nondepolarizing blockers

A

depolarizing - succinylcholine

nondepolarizing - curare

51
Q

bind to ternary SNARE complex and use energy of ATP hydrolysis to disassemble the SNAREs

A

a-SNAP and ATPase NSF

MSK phys (7 decks)

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