Muscle Relaxants, NMBA (L&J Chp 14) Flashcards
Succinylcholine dose - dogs
0.3-0.4mgkg
Succinylcholine dose - cats
0.2mgkg
Succinylcholine dose - horses
0.12-0.15mgkg
Pancuronium dose - dogs
0.07-0.1mgkg
Pancuronium dose - cats
0.06-0.1mgkg
Pancuronium dose - horse
0.12mgkg
Atracurium dose - dogs
0.1-0.2mgkg
Atracurium dose - cats
0.1-0.25mgkg
Atracurium dose - horses
0.07-0.15mgkg
Vecuronium dose - dogs
0.1mgkg
Vecuronium dose - cats
0.025-0.1mgkg
Vecuronium dose - horses
0.1mgkg
Pipecuronium dose - cats
0.003mgkg
Pipecuronium dose - dogs
0.05mgkg
Cisatracurium dose - dogs
0.075-0.3mgkg
Cisatracurium dose - cats
0.05-0.3mgkg
Mivacurium dose - dogs
0.01-0.05mgkg
Mivacurium dose - cats
0.08mgkg
Rocuronium dose - dogs
0.1-0.6mgkg
Rocuronium dose - cats
0.1-0.6mgkg
Doxacurium dose - dogs
0.002-0.005mgkg
Gantacurium (GW280430A) dose - dogs
0.06mgkg
Gentacurium (GW280430A) dose - cats
0.06mgkg
Rocuronium dose - horses
0.3-0.6mgkg
Pancuronium
- Non-depol (competitive) NMBA
- Steroid molecule-based structure
- Dose-dependent onset ~5’
- Repeated doses = cumulative effect –> infusion not common
- Duration of action 40-60’
- Mostly renal excretion with some hepatic metabolism –> prolonged duration of action in patients with renal insufficiency
Pancuronium and CV effects
- Blocks cardiac muscarinic R, increasing HR
- Effect varies among species - usually not a clinical concern
- Muscarinic blocking effect, associated tachycardia appear to be due to second positive charge on steroid ring
Difference btw pancuronium and vecuronium
Pancuronium - single methyl group (and thus positive charge) = vecuronium –> no CV effects
Atracurium
- Short-acting, non-depolarizing (competitive) NBMA
- Benzolisoquinoline structure similar to that of d-tubocurarine
- Dose-dependent onset approx 5’
- Dose-dependent duration in dogs approx 30’
- Repeated doses do not tend to be cumulative so longer term maintenance of NMB via infusion is viable
Atracurium elimination
- Almost half of drug degraded by Hoffmann elimination, nonspecific ester hydrolysis
- Remaining fraction of the drug degraded by undefined routes –> no evidence of prolonged action in humans with renal or hepatic insufficiency
- Can be safely given to patients with hepatic or renal insufficiency without an increase in duration of action
Atracurium: Hoffman elimination…
Does not require enzymatic activity
Is not a biologic proces
Storage of atracurium
Drug should be refrigerated
Supplied at pH 3.25-3.65 to slow degradation
What happens when atracurium injected IV…
- When injected at physiologic pH/temperature, spontaneously decomposes into laudanosine and quaternary monoacrylate
Laudanosine
- Byproduct of atracurium, cis-atracurium metabolism
- has potential to induce seizures
- Dependent on hepatic clearance –> plasma concentrations may be elevated in patients with hepatic insufficiency
Are the theoretical concerns of laudanosine clinical concerns as well?
-Laudanosine-induced CNS stimulation/resultant seizures unlikely in clinical patients unless drug used for prolonged periods of time as might occur in intensive care settings
What will increase duration of NMB using atracurium/decrease CRI rate?
- Hypothermia
- Hofmann elimination is pH/temperature dependent so hypothermia will increase duration of NMB and decrease infusion rate necessary to maintain NMB
Esterhydrolysis of atracurium
- Accomplished by several plasma esterases not related to plasma cholinesterase
- Duration of action not prolonged in the presence of cholinesterase inhibitors (in contrast to depolarizing NMBA succinylcholine)
NMBA with benzylisoquinolone structure
-Associated with histamine release –> varying degree of resultant hypotension
d-Tubocurarine
- Prototypical benzylisoquinolone NMBA
- Most potent histamine-releasing NMBA
What is true about the newer NMBA (atracurium, cisatracurium) having the benzylisoquinolone structure?
- Require several times the ED95 dose required for NMB before appreciable amounts of histamine are released
- Hypotension, tachycardia not usually observed in clinical cases
Atracurium Composition
-racemic mixture of ten optical isomers
Cisatracurium
- 1R-cis, 1R’-cis isomer
- Comprises approximately 15% of racemic atracurium –> approx 4x potency, reduced potential for histamine release
Cisatracurium onset, duration of action
-Similar to atracurium
Elimination of cisatracurium
- Hofmann elimination responsible for greater than half administered dose of cisatracurium
- No ester hydrolysis
Production of laudanosine with cisatracurium metabolism
- Hofmann elimination –> laudanosine production
- Since 4x as potent as atracurium, can give lower dose so have less laudanosine production
Where do NMBA exert their effects?
- NMJ
- Motor end plate
NMJ
-Forms interface btw large myelinated motor nerve and muscle supplied by the nerve
Parts of NMJ
- Prejunctional motor nerve ending
- Synaptic cleft
- Postjunctional membrane of the skeletal muscle fiber
What type of receptor is present on the pre junctional area of the NMJ?
Nicotinic R
What type of receptor is present on the postjunctional area of the NMJ?
Nicotinic R
Nicotinic R
- Receptor type on the pre/post junctional area of the NMJ
- Bind/respond to ACh or another suitable ligand
Prejunctional receptor
Thought to be important in the synthesis and mobilization of ACh stores but not in its release
Two types of post junctional receptors
- Junctional
- Extrajunctional
Junctional post junctional receptors
- Found on the motor endplates of normal adult animals
- Responsible for binding with released ACh –> effecting muscle ctx –> therefore responsible for relaxant effect when NMBA administered
Extrajunctional post junctional receptors
- Not normally present in muscles of typical adults
- Present in neonates
Why are extrajunctional post junctional receptors important?
- Synthesized by muscles receiving less than normal degree of motor nerve stimulation
- Produced by muscles following spinal cord or peripheral nerve injury or after period of disuse as when limb is casted
Where are extrajunctional post junctional receptors located?
Not restricted to the motor endplate
May be located over the entire muscle surface
What is true about extrajunctional post junctional receptors and NMBA?
- Appear to be more sensitive to depolarizing NMBA, less sensitive to non depolarizing NMBA
- If the degree of neural deficit is severe, extrajunctional receptors may be numerous and widely distributed over the muscle membrane
- Such patients may very different responses to actions of depolarizing NMBA and thus profound release of intracellular K+ with concomitant adverse cardiac effects may result if succinylcholine is administered to these patients
-Binding of ligands to the receptor is what kind of process?
Competitive
Whichever suitable ligand is present in highest concentrations in the vicinity of the receptor will win the competition and affect the outcome
What advantage does an antagonist have over an agonist related to binding on the alpha subunits?
- Two molecules of ACh required to bind to each of the alpha subunits on the R
- Antagonists: need only to bind to one of the subunits to present normal NM transmission
- Ctx of the muscle does not occur in response to motor nerve depolarization and paralysis results
Interaction of ACh and NMBA at the post junctional receptors
Dynamic process of binding and release
Depends on the sheer number of receptors present (10-20,000/micrometer^2)
So: success or failure of NM transmission in the presence of NMBA is determined by the concentration of NMBA vs concentration of ACh
What determines the success/failure of NM transmission in presence of NMBA?
success or failure of NM transmission in the presence of NMBA is determined by the concentration of NMBA vs concentration of ACh
High % of R binding ACh…
Favoring of muscle contraction
High % of R binding NMBA…
Favoring paralysis
Mechanism of reversing paralysis induced by NMBA
- Increasing concentration of ACh compared with concentration of NMBA will increase probability that ACh will win competition for R and restore normal NM transmission
- Clinically: accomplished by administration of AChE inhibitors
What happens when anticholinesterase drug administered?
- eg neostigmine
- Available ACh not degraded immediately but persists within the synapse
- Able to repeatedly interact with receptors –> tips competitive balance in favor of ACh –> more R participate in current flow, global muscle strength increases
- Interaction also seen as the activity of a NMBA wanes due to drug elimination
Rocuronium
- Derivative of vecuronium
- Approximately 1/8th potency
Rocuronium vs vecuronium
-Similar molecular weights but rocuronium has a lower potency so larger injected dose of rocuronium places greater number of molecules near NMJ –> more rapid onset of blockade
Rocuronium clinical uses
- Similar duration of atracurium, vecuronium
- More rapid onset but cannot provide optimal conditions for human intubation as quickly as succinylcholine
- Virtually no CV effects
- No histamine release
Rocuronium elimination
Primary route - hepatic clearance
Small fraction eliminated by the kidney
Rocuronium reversal
Administration of suggammadex
Suggammadex
Used for reversal of rocuronium, vecuronium
Chelating agent that preferentially binds to, physically removes the NMBA from the motor end plate
Pipercuronium
Steroid relaxant derived from pancuronium
Differences btw pipercuronium and pancuronium
- Manipulation of the steroid structure –> greatly reduced antimuscarinic effects
- Piper = free of tachycardic effects while retaining long duration of action
- Can cause hypotension in dogs
Pipercuronium elimination
-Eliminated primarily by renal route with smaller fraction undergoing biliary excretion
Vecuronium
-First NMBA devoid of CV effects
