Pharm: Agents that act on NMJ Flashcards
cistracurium
- nondepolarizing nACHR antagonist : isoquinolone derivative
- intermediate duration of action 20- 45 mins
tubocurarine
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!
pancuronium
- nondepolarizing nACHR antagonist : steroid derivative
** long acting: 1-2 hours
rocuronium
- nondepolarizing nACHR antagonist : steroid derivative
- intermediate duration of action 20- 45 mins, very fast onset!
vecuronium
- nondepolarizing nACHR antagonist : steroid derivative
- intermediate duration of action 20- 45 mins, very fast onset!
succynylcholine
-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
dantrolene
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)
Echothiophate
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
Edrophonium
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
Neostigmine
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
Physostigmine
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
Pyridostigmine
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
Atropine
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)
Pralidoxime
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!!!
neuromuscular blockers
= 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:
- nondepolarizing blockade:
- Prevent access of ACh to the nACh receptor (competitive antagonism) and block depolarization
- ex: tubocurarine - depolarizing blockade:
- Neuromuscular blockade that results from excess of a depolarizing agonist (receptor desensitization)
- ex: succinylcholine
spasmolytic agents
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)
fastest onset? shortest acting NMBA?
succinylcholine - useful for intubation!
long duration of action NMBA?
pancuronium: 1-2 hours - useful in longer surgeries! \
cisatracurium
intermediate duration of action?
rococuonium, vecuronium - useful in longer surgeries!
AE’s of nondepolarizing agents?
- seen in tuborurarine, but less common in the newer drugs: cisatracurium, pancuronium, rocuronium, vecuronium
- stimulation of histamine release:
- Bronchospasm, hypotension, bronchial and salivary secretion
- Steroids cause the least histamine release; also minimal release with atracurium and cisatracurium - Cardiovascular effects: profound hypotension and tachycardia
which NMBA to not use in hepatic/renal insufficiency?
cisatracurium, atracurium
which NMBA have most rapid onset? used for intubation?
succinylcholine
rococuronium
vecucuronium
how to reverse neuromuscular blockade?
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.
most common AE of succinylcholine?
hyperkalemia - severe in patients with burns, nn. damage or NM damage, head trauma or injuries
CI’s for succinylcholine?
- malignant hyperthermia
- skeletal myopathies
- acute phase of injury following major burns
- cardiac arrest risk in healthy children w/ un ddx skeletal mm. myopathy
botulinum toxin
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
AChE inhibitors
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:
- CNS: can cause hyperstimulation of neurons if overused, coma, resp. arrest
- NMJ: increased strength of contraction, or paralysis at high concnetrations
- 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)
AChE inhibitor toxicity?
= 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:
PS vs SYMP in eyes?
PS = pupil constriction (myosis)
** blocked by atropine
SYMP = pupil dilation (mydriasis)
** reversed by AChE inhibitors
tx of AChE poisoning?
give atropine to block the muscarinic effects
use pralidoximine to regenerate the cholinesterase for the nicotinic receptors (if organophosphate has bound, causing the)
nicotinic AChR’s
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
Muscarinic AChR’s
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)
myasthenia graivs
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
aminoglycoside toxicity?
nephrotoxicity, ototoxicity and…..
- Neuromuscular blockade: rare but serous AE
- MG is an absolute contraindication to use!!!
Thymoma
comorbid condition seen in MG - associated with AI disorders (Grave’s, PA, Cushing, hypogammaglob.)
test to support ddx of MG?
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)
MG med that causes hallucinations and seizures at high amounts?
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
AE of pyridostigmine? Which drug may be used to help
SLUDGE - salivation, lacrimation, urination, diarrhea, GI upset, eye mm. contraction (miosis), bronchoconstriction
use Atropine or clygopyrrolate : mACHR antagonists (“antimuscarinic compounds”)
unconscious, with nonreactive, pinpoint-sized pupils, massive oral foaming, and muscle fasciculations. \ 12 year history of depression. tx?
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
neuromuscular blocking agent that produces mm. fasciculations upon administration?
succinylcholine- depolarizing agent
malignant hyperthermia
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
molecular mechanisms of MH?
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
