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MSK II: Test 1 > Pharm: Agents that act on NMJ > Flashcards

Pharm: Agents that act on NMJ Flashcards

1
Q

cistracurium

A
  • nondepolarizing nACHR antagonist : isoquinolone derivative

- intermediate duration of action 20- 45 mins

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2
Q

tubocurarine

A

Prototype- nondepolarizing nACHR antagonist : isoquinolone derivative

no longer used: isolated from curare poinson

MOA: competitive antagonist at both presynaptic and postsynaptic nACH receptors

  • Interferes with ACh mobilization at the nerve ending
  • Prevents membrane depolarization and muscle contraction

rule: larger mm. are more resistant to blockade and recover more rapidly

** has more severe AE’s, not used anymore!

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3
Q

pancuronium

A
  • nondepolarizing nACHR antagonist : steroid derivative

** long acting: 1-2 hours

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4
Q

rocuronium

A
  • nondepolarizing nACHR antagonist : steroid derivative

- intermediate duration of action 20- 45 mins, very fast onset!

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5
Q

vecuronium

A
  • nondepolarizing nACHR antagonist : steroid derivative

- intermediate duration of action 20- 45 mins, very fast onset!

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6
Q

succynylcholine

A

-depolarizing NM blocking agent

** super short acting (5-8 mins), fastest onset = good for rapid sequence intubation

Ultra-short duration of action is due to rapid hydrolysis and inactivation by butyrylcholinesterase (aka, pseudocholinesterase or plasma cholinesterase) - Not effectively metabolized at the NMJ by acetylcholinesterase

MOA:
Phase 1 depolarizing block:
- mimics the effects of endogenous ACh, but duration is longer
- blocker binds to channel, sodium enters channel and membrane is depolarized, and stays depolarized
- flaccid paralysis results d/t lack of repolarization
- enhanced by cholinesterase inhibitors (increased ACh)

Phase 2 desensitizing block:

  • Membrane becomes repolarized
  • Desensitized receptors cannot be depolarized again
  • nAChR behaves as if in a prolonged closed state (similar behavior to nondepolarizing block)
  • Antagonized by AChE inhibitors (decreased ACh)

AE:

  • ** most common: hyperkalemia
  • CV effects
  • increased intraocular pressure
  • increased gastric pressure
  • mm. pain
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7
Q

dantrolene

A

spasmolytic agent (non-centrally acting)

  • MOA: directly binds to and inhibits skeletal mm. ryanodine receptors in the sarcoplamic reticulum and blocks release of Ca2+
  • **Used in treatment of malignant hyperthermia

Also approved for management of spasticity associated with motor neuron disorders (multiple sclerosis, cerebral palsy, spinal cord injury, stroke)

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8
Q

Echothiophate

A

AChE inhibitor, organophosphate
* charged, won’t penetrate CHS

** very long acting, 100 hours!

USE:

  • Myasthenia gravis
  • Reversal of neuromuscular blockade during anesthesia
  • Nerve gas and organophosphate pesticide exposure
  • Antidote for anticholinergic poisoning (i.e. histamine OD)
  • Symptoms reflect sympathetic nervous system activation (fight or flight)
  • Dementia associated with Alzheimer or Parkinson disease
  • High concentrations of long-acting agents are used as chemical warfare
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9
Q

Edrophonium

A

AChE inhibitor, alcohol
** charged, won’t penetrate CNS

** shortest acting, 5-15 mins

USE:

  • Myasthenia gravis
  • Reversal of neuromuscular blockade during anesthesia
  • Nerve gas and organophosphate pesticide exposure
  • Antidote for anticholinergic poisoning (i.e. histamine OD)
  • Symptoms reflect sympathetic nervous system activation (fight or flight)
  • Dementia associated with Alzheimer or Parkinson disease
  • High concentrations of long-acting agents are used as chemical warfare
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10
Q

Neostigmine

A

AChE inhibitor, carbamate
** charged, won’t penetrate CNS

USE:

  • Myasthenia gravis
  • Reversal of neuromuscular blockade during anesthesia
  • Nerve gas and organophosphate pesticide exposure
  • Antidote for anticholinergic poisoning (i.e. histamine OD)
  • Symptoms reflect sympathetic nervous system activation (fight or flight)
  • Dementia associated with Alzheimer or Parkinson disease
  • High concentrations of long-acting agents are used as chemical warfare
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11
Q

Physostigmine

A

AChE inhibitor, carbamate
* uncharged, will enter CNS, has high lipid solubility

USE:

  • Myasthenia gravis
  • Reversal of neuromuscular blockade during anesthesia
  • Nerve gas and organophosphate pesticide exposure
  • Antidote for anticholinergic poisoning (i.e. histamine OD)
  • Symptoms reflect sympathetic nervous system activation (fight or flight)
  • Dementia associated with Alzheimer or Parkinson disease
  • High concentrations of long-acting agents are used as chemical warfare
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12
Q

Pyridostigmine

A

AChE inhibitor, carbamate
* charged, won’t penetrate CNS

USE:

  • Myasthenia gravis
  • Reversal of neuromuscular blockade during anesthesia
  • Nerve gas and organophosphate pesticide exposure
  • Antidote for anticholinergic poisoning (i.e. histamine OD)
  • Symptoms reflect sympathetic nervous system activation (fight or flight)
  • Dementia associated with Alzheimer or Parkinson disease
  • High concentrations of long-acting agents are used as chemical warfare
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13
Q

Atropine

A

Antimuscarinic compound: inhibits parasympathetics

used as an adjunct along with AChE inhibitors to avoid excess PS activation d/t ACh.

MOA: block peripheral effects of ACh saturation at parasympathetic synapses (salivation, bradycardia, bronchoconstriction, nausea, vomiting mediated by muscarinic ACh recptors)

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14
Q

Pralidoxime

A

Cholinesterase reactivator

MOA: Re-activate inactive AChE by removing the phosphorous group from the active site (pulls off organophosphate)

  • Can restore active enzyme within minutes
  • Must give before aging occurs

= Current antidote for organophosphate exposure:
1. Parenteral atropine
2. (pralidoxime)
3. Benzodiazepine to alleviate convulsions
(carried by military soldiers)

only used in AChE poisoning!!!

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15
Q

neuromuscular blockers

A

= adjuncts during anesthesia: result in mm. paralysis during surgery

  • Lack CNS activity
  • Interfere with transmission at the neuromuscular end plate
  • Used as adjuncts during anesthesia
  • No known effects on pain threshold or consciousness

ex: Cisatracurium, tubocurarine, pancuronium, rocuronium, vecuronium, succinylcholine

Two classes:

  1. nondepolarizing blockade:
    - Prevent access of ACh to the nACh receptor (competitive antagonism) and block depolarization
    - ex: tubocurarine
  2. depolarizing blockade:
    - Neuromuscular blockade that results from excess of a depolarizing agonist (receptor desensitization)
    - ex: succinylcholine
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16
Q

spasmolytic agents

A

ex: Dantrolene, Botulinum toxin
Often called centrally acting muscle relaxants

Used to reduce spasticity in a variety of neurologic conditions (chronic back pain, fibromyalgia, muscle spasms)

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17
Q

fastest onset? shortest acting NMBA?

A

succinylcholine - useful for intubation!

18
Q

long duration of action NMBA?

A

pancuronium: 1-2 hours - useful in longer surgeries! \

cisatracurium

19
Q

intermediate duration of action?

A

rococuonium, vecuronium - useful in longer surgeries!

20
Q

AE’s of nondepolarizing agents?

A
  • seen in tuborurarine, but less common in the newer drugs: cisatracurium, pancuronium, rocuronium, vecuronium
  1. stimulation of histamine release:
    - Bronchospasm, hypotension, bronchial and salivary secretion
    - Steroids cause the least histamine release; also minimal release with atracurium and cisatracurium
  2. Cardiovascular effects: profound hypotension and tachycardia
21
Q

which NMBA to not use in hepatic/renal insufficiency?

A

cisatracurium, atracurium

22
Q

which NMBA have most rapid onset? used for intubation?

A

succinylcholine
rococuronium
vecucuronium

23
Q

how to reverse neuromuscular blockade?

A

theoretically agonists would work, i.e. ACh or succinylcholine (but these won’t work b/c they are rapidly degraded and utlimately induce paralysis if large)

** in practice use cholinesterase inhibitors: Neostigmine, pyridostigmine, physostigmine (all don’t cross the brain barrier)

** antimuscarinics are often used as adjuncts to AChE inhibitors (like atropine, glycopyrrolate) - this is b/c ACh will be increased everywhere and can cause (PS , has mACh) - need to inhibit the PS effects like bradycardia, salivation, nausea, vomiting.

24
Q

most common AE of succinylcholine?

A

hyperkalemia - severe in patients with burns, nn. damage or NM damage, head trauma or injuries

25
Q

CI’s for succinylcholine?

A
  • malignant hyperthermia
  • skeletal myopathies
  • acute phase of injury following major burns
  • cardiac arrest risk in healthy children w/ un ddx skeletal mm. myopathy
26
Q

botulinum toxin

A

non-centrally acting spasmolytic agent

MOA: cleaves the SNARE complex and blocks docking/fusion to the presynaptic membrane, inhibiting ACh release

**Useful for generalized spastic disorder

27
Q

AChE inhibitors

A

increased ACh in the entire body! so will affect PS, sympathetic along with NMJ

three chemical groups:

  • aclohols: charged, reversible
  • Carbamates – charged or uncharged, reversible
  • Organophosphates – mostly uncharged, irreversible, highly lipid soluble
  • Note: charged molecules CANT enter the CNS.

MOA: Bind to AChE (also BuChE) and block its enzymatic activity
- Increase the concentration of ACh at the NMJ
Stimulates both nAChRs and mAChRs
- Consequences can be therapeutic or deadly (organophosphates, others at high concentrations)

Sites of action:

  1. CNS: can cause hyperstimulation of neurons if overused, coma, resp. arrest
  2. NMJ: increased strength of contraction, or paralysis at high concnetrations
  3. PS stimulation: CO decreased, bradychardia, hypotension

USE:

  • Myasthenia gravis
  • Reversal of neuromuscular blockade during anesthesia
  • Nerve gas and organophosphate pesticide exposure
  • Antidote for anticholinergic poisoning (i.e. histamine OD)
  • Symptoms reflect sympathetic nervous system activation (fight or flight)
  • Dementia associated with Alzheimer or Parkinson disease
  • High concentrations of long-acting agents are used as chemical warfare (e.g., sarin gas)
28
Q

AChE inhibitor toxicity?

A

= parasympathetic effects!

SLUDGE - Salivation, Lacrimation, Urination, Defecation, Gastrointestinal, Emesis

Ingestion: GI symptoms occur first

Percutaneous absorption: localized sweating and muscle fasciculations

Lipid-soluble agents: CNS involvement follows rapidly

NOTE:
- mild AChE inhibitor:

29
Q

PS vs SYMP in eyes?

A

PS = pupil constriction (myosis)
** blocked by atropine

SYMP = pupil dilation (mydriasis)
** reversed by AChE inhibitors

30
Q

tx of AChE poisoning?

A

give atropine to block the muscarinic effects

use pralidoximine to regenerate the cholinesterase for the nicotinic receptors (if organophosphate has bound, causing the)

31
Q

nicotinic AChR’s

A

THE AChR at the NMJ

Ligand-gated ion channels

Activation allows ions to pass through the open channel pore (ionotropic)

Two basic subtypes in mammals (NN and NM, with a variety of subunit isoform combinations)

NM = only found in NMJ
NN =  found in CNS, autonomic ganglia and adrenal medulla
32
Q

Muscarinic AChR’s

A

Not found at NMJs

G protein-coupled receptors (GPCRs)

Activation leads to a series of intracellular events triggered by second messengers (metabotropic)

Five subtypes in mammals (M1-M5)

33
Q

myasthenia graivs

A

Muscle disease caused by immune-mediated loss of nAChRs

Circulating antibodies to the nAChR are present in nearly all cases

A diminished motor response is noted

Nerve conduction and sensory and autonomic functions are normal

Weakness begins with extraocular muscles (ptosis, diplopia)

Generalized weakness is common

tx:
- Pyridostigmine, neostigmine, and ambenonium are used in the symptomatic treatment of MG

34
Q

aminoglycoside toxicity?

A

nephrotoxicity, ototoxicity and…..

    • Neuromuscular blockade: rare but serous AE
    • MG is an absolute contraindication to use!!!
35
Q

Thymoma

A

comorbid condition seen in MG - associated with AI disorders (Grave’s, PA, Cushing, hypogammaglob.)

36
Q

test to support ddx of MG?

A

Edrophonium = “Tensilon test”
* AChE inhibitor (will reverse ptosis)

AE: watch out for bradychardia! (stimulation of mACHR –> decreased CO)

CI: asthma (see increase in mACHR –> smooth mm. contraction)

37
Q

MG med that causes hallucinations and seizures at high amounts?

A

Physostigmine (lipid and uncharged) - can cross the BBB and are inapprpriate d/t CNS AE’s

Hyperstimulation of neurons, general convulsions, coma, respiratory arrest at toxic concentrations

38
Q

AE of pyridostigmine? Which drug may be used to help

A

SLUDGE - salivation, lacrimation, urination, diarrhea, GI upset, eye mm. contraction (miosis), bronchoconstriction

use Atropine or clygopyrrolate : mACHR antagonists (“antimuscarinic compounds”)

39
Q

unconscious, with nonreactive, pinpoint-sized pupils, massive oral foaming, and muscle fasciculations. \ 12 year history of depression. tx?

A

ddx: organophosphate exposure (insecticide OD)
== AChE inhibitor

tx:
- cholinesterase reactivator: pralidoxime
- muscarinic AChR antagonist: atropine

MOA of pralidoxime:
- Re-activate inactive AChE by removing the phosphorous group from the active site

40
Q

neuromuscular blocking agent that produces mm. fasciculations upon administration?

A

succinylcholine- depolarizing agent

41
Q

malignant hyperthermia

A

Pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases and depolarizing muscle relaxants

  • Anesthetics: halothane, isoflurane, sevoflurane, desflurane
  • Depolarizing muscle relaxants: succinylcholine

Sx: hypermetabolic

  • rapid onset
  • Hyperthermia, tachycardia, tachypnea
  • Increased CO2 production, acidosis
  • Increased O2 consumption
  • Muscle rigidity
  • ATP depletion leads to compromised muscle membrane integrity, causing hyperkalemia and rhabdomyolysis

tx: dantrolene

42
Q

molecular mechanisms of MH?

A

The majority of currently described MH-associated mutations occur in ion channels (channelopathies )

The ryanodine receptor gene (RYR1) found on chromosome 19q13.1

CACNL1A3: alpha-1 subunit of the dihydropyridine-sensitive L-type calcium channel

The precise reasons why these RYR1 or CACNL1A3 (or other channel) mutations result in sensitivity to inhalation anesthetics and muscle relaxants and precipitate MH is unknown

MSK II: Test 1 (7 decks)

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