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Chapter 12 Neuromuscular blocking drugs
Terms in this set (31)
Most common offender for hypersensitivity Rxn?
SCh is the most common offender. Even though it does not release histamine, rocuronium was identified as producing an increased risk
for hypersensitivity reactions in France and Norway, with no confirmation from other countries. There may be cross-sensitivity between all NMBDs because of the presence of a common antigenic component, the quaternary ammonium group.
Mechanism of Sch?
Attaches to the alpha monomers of the penta-peptide receptor complex.
Why is SCh c/i in burn victims/denervation injuries/ICU pts, and how does this explain tolerance to NMBD? Can it be given in renal failure w/ uremia?
Prolonged inactivity, sepsis, and denervation or trauma (burn injury) to skeletal muscles may be associated with a proliferation of extrajunctional receptors. When activated, extrajunctional receptors stay open longer
and permit more ions to flow, which in part explains the exaggerated hyperkalemic response when SCh is administered to patients with denervation or burn injury (Administration of SCh to apparently healthy boys with unrecognized muscular dystrophy has resulted in acute hyperkalemia and cardiac arrest). In addition, extrajunctional receptors and hyperkalemia will develop in any patientwho is immobile (critical care patients) for several days. Proliferation of these receptors also accounts for the resistance or tolerance to nondepolarizing NMBDs, as can occur with burns or prolonged
Even though they may have increased potassium levels, patients with renal failure are not susceptible to exaggerated release of potassium, and SCh can be safely administered to these patients, assuming that they do not have uremic neuropathy.
What are the two classes of non-depolarizing blockers?
Nondepolarizing NMBDs are either aminosteroid compounds (pancuronium, vecuronium, rocuronium) or benzylisoquinolinium
compounds (atracurium, cisatracurium, mivacurium).
Dose and rate of onset SCh, main use?
Typically, doses of 0.5 to 1.5 mg/kg intravenously are administered and produce a rapid onset of skeletal muscle paralysis (30 to 60 seconds)
that lasts 5 to 10 minutes because of its unique breakdown. Intubation.
Dose generally used for intubation and what should you use if unsuccessful w/ SCh?
Although an intravenous dose of 0.5 mg/kg may be adequate, 1.0 to 1.5 mg/kg is commonly administered to facilitate tracheal intubation. If a subparalyzing dose of a nondepolarizing NMBD (pretreatment with 5% to 10% of its 95%effective dose [ED95]) is administered 2 to 4 minutes
before injection of SCh to blunt fasciculations, the dose of SCh should be increased by about 70%.
Explain the difference between phase 1 and phase 2 blockade?
Phase 1 blockage is defined when postjunctional membrane and inactivated sodium channels cannot respond to subsequent release of ACh, clinically resulting as fascitculations and flaccid paralysis. (depolarizing block)
Phase 2 blockade is occurs onec the membrane potential repolarizes due to ATPase despite chronically opened Na/K channels (leads to hyperkalemia), at this point the receptor is desensitized to ACh ligand and has a block mechanism similar to curares, clinically you see the fade of TOF. (non-depolarizing block). >3-5mg/kg IV
How is SCh degraded
Pseudocholinesterase in the plasma produced by the liver. Only exreme endstage liver Dz causes noticable changes in SCh half life.
What is the dobicaine number?
Atypical plasma cholinesterase lacks the ability to hydrolyze ester bonds in drugs such as SCh and mivacurium.The dibucaine number reflects the quality of plasma cholinesterase (ability to metabolize SCh and mivacurium) and not the quantity of enzyme that is circulating in plasma. For example, decreases in plasma cholinesterase activity because of liver disease or anticholinesterases are often associated with a normal dibucaine number. Dibucaine is an amide local anesthetic that inhibits normal plasma activity by about 80%, whereas the activity of atypical enzyme is inhibited by about 20%
Explain cardiac sequalae of SCh.
If you were to give increased ACh to the nodal tissue, you'd potentially creat heart block, the same concept exists w/ SCh which can cause sinus arrest. IV administration of atropine 1-3 minutes prior to SCh can decrease this liklihood. (This is when you consider the phase 1 mechanism of this drug)
May also increase BP/SVR due to ganglionic stimulation.
Explain the mechanism of SCh induced myalgia, and how it is tx?
Unsynchronized contractions of skeletal muscle fibers (fasciculations) associated with generalized depolarization lead to myalgia. Prevention of fasciculations by prior administration of subparalyzing doses of a nondepolarizing NMBD (pretreatment) or lidocaine will decrease the incidence but not totally prevent myalgia.11 Magnesium will prevent fasciculations, but not myalgia. Nonsteroidal anti-inflammatory drugs
are effective in treating the myalgia.
Opthalmic considerations of SCh? What other pressures are increased?
There is an unknown mechanism of increased IO pressure 2-4 mins after administration. It is common practice not to use SCh in open eye injuries due to concern of extrusion of intraocular contents, however this is theoretical, however still considered a C/I.
Increased intracranial pressure, intragastric pressure as well (not clinicaly impt).
One reason why SCh is C/I in children?
Trismus esp w/ halothane.
What is sugammadex?
Sugammadex is a reversal agent used for reversal of aminosteriod neuromuscular blockade, however only vecurarium and rocurarium can be reversed w/ this drug.
Why do non-depolarizing NMBD not go into the CNS?
The quatinary ammonium amine of these compounds prevents BBB crossing. Therefore, nondepolarizing NMBDs do not produce central nervous system effects, renal tubular reabsorption is minimal, oral administration is ineffective, and maternal administration does not adversely affect the fetus.
What contraindications do non-DP blockers share w/ SCh
Increased resistance w/ myopathies, burn victims, and muscles affected by CVA due to endplate prolifferation causing scavenging of drug.
Cardiovascular sequelae of non-DP blockers?
Hypotension induced from acute histamine release, esp. w/ mepivicaine and atracurium.
Pancuronium is a bisquaternary aminosteroid nondepolarizing
NMBD with an ED95 of 70 mg/kg; onset of action of 3 to 5 minutes and a duration of action of 60 to 90 minutes (LONG ACTING), 80% of a single dose of pancuronium is eliminated unchanged in urine. With ARF 30% to
50%, thus resulting in a prolonged duration of action. 10-40% Hepatically cleared.
Also increased HR 10-15%, MAP, and CO. No histamine release w/ this NMBD. Drug has 1 active metabolite which is 50% as active at NMJ.
Intermediate acting characteristics of NMBD: 1) compare pan to roc 2) Duration of action? 3) Recovery profile? 4) Cardiovascular sequelae? What can be used to reverse this class?
When compared with pancuronium, these drugs have (1) a similar onset of maximum neuromuscular blockade, with the exception of rocuronium, which is unique because of its rapid onset, which can (with large doses)
parallel that of SCh; (2) approximately one third the duration of action (hence the designation intermediate acting); (3) a 30% to 50% more rapid rate of recovery; and (4) minimal to absent cardiovascular effects except for atracurium. Neostigmine or sugammadex antagonism of the neuromuscular blockade produced by intermediateacting nondepolarizing NMBDs is facilitated by the concomitant spontaneous recovery that occurs after rapid clearance of the drug.
Vecuronium is a monoquaternary aminosteroid nondepolarizing
NMBD with an ED95 of 50 mg/kg that produces
an onset of action of 3 to 5 minutes and a duration of
action of 20 to 35 minutes w/ both hepatic and renal excretion. 1 active metabolite 50% as powerful at NMJ. Has almost no vagolytic properties, not significantly affected by ARF, lipo-philicity makes it possible to secreted in bile.
Rocuronium is a monoquaternary aminosteroid nondepolarizing
NMBD with an ED95 of 0.3 mg/kg that has an onset of action of 1 to 2 minutes and a duration of action of 20 to 35 minutes. Conceptually, when a large number of molecules are administered, the result is a larger number of molecules that are available to diffuse to the NMJ. Thus, a rapid onset of action is more likely to be achieved with a less potent drug such as rocuronium. 3-4x ED95 has a similar onset of action as SCh (however this will produce a duration similar to pancuronium). Renal excretion makes this a questionable choice in ARF.
Atracurium is a bisquaternary benzylisoquinolinium nondepolarizing NMBD (mixture of 10 stereoisomers) with an ED95 of 0.2 mg/kg that produces an onset of action of 3 to 5 minutes and a duration of action of 20 to 35 minutes. Clearance is via spontaneous nonenzymatic degradation at normal body temperature and pH known as Hofmann elimination) and a biologic mechanism (ester hydrolysis by nonspecific plasma esterases, thus liver/renal dz does not affect.
benzylisoquinolinium nondepolarizing NMBD with an ED95 of 50 mg/kg that has an onset of action of 3 to 5 minutes and a duration of action of 20 to 35 minutes Structurally, cisatracurium is an isolated form of 1 of the 10 stereoisomers of atracurium. This drug principally undergoes degradation
by Hofmann elimination Cisatracurium, in contrast to atracurium, is devoid of histamine-releasing effects, so cardiovascular changes do not accompany the rapid intravenous administration of even large doses of cisatracurium. Clearance is via spontaneous nonenzymatic degradation t normal body temperature and pH known as Hofmann elimination but not ester hydrolysis. Optimal paralytic for renal transplant.
Mivacurium is a benzylisoquinolinium nondepolarizing NMBD with an ED95 of 80 mg/kg that has an onset of action of 2 to 3 minutes and a duration of action of 12 to 20 minutes. As such, the duration of action of mivacurium is approximately twice that of SCh and 30% to 40% that of the intermediate-
acting nondepolarizing NMBDs. Mivacurium consists of three stereoisomers, with the two most active isomers undergoing hydrolysis by plasma cholinesterase at a rate equivalent to 88% that of SCh. Hydrolysis of these two isomers is responsible for the short duration of action of mivacurium. As with SCh, hydrolysis of mivacurium is decreased and its duration of action increased in patients with atypical plasma cholinesterase.
What is the definition of the ED95?
The amount of NMBD needed to cause depression of twitch response in 95% of patients.
Explain how to use TOF stimulation to control NMBD.
Depression of the twitch response greater than 90% or elimination of two to three twitches of the TOF correlates with acceptable skeletal muscle relaxation for performance of intra-abdominal surgery in the presence of an adequate concentration of volatile anesthetic. If all twitches from TOF stimulation are absent, more NMBD should not be given until some twitch is present. If some of the twitches from TOF stimulation are present, antagonism is likely to be successful.
What are the recommended doses of anticholinesterase at a gvien TOF?
<2 --> .07 mg/kg of tof neostigmine
3-4 --> .04 mg/kg of tof neostigmine
4 --> .5-.25 mg/kg of edrophonium less if TOF has less fade.
Explain the tropism of neostigmine and why other drugs must be administered in its presence.
Neostigmine has a quaternary ammonia group which prevents diffusion into the CNS. Given the fact that it does have cardiac sequeale it must be co-administered either w/ atropine or glycopyrrolate.
Max dose of neostigmine?
Explain the TOF ratio?
TOF ratio is the ratio between the initial twitch relative the final twich. A TOF of greater than .7 indicates almost no no blockade. W/ SCh a TOF the ratio is usually 1 because the height of the intiatal spike is similar to the final one in phase 1 blockade. Phase 2 is indicated by TOF fo .3.
A) shows the effects of a non-depolarizing NMBD or a phase 2 response.
B) shows the effects of a phase 1 SCh blockade.
What other tests may be better than TOF .7 evaluation?
Head lift / leg lift test for 5 seconds is more accurate, these values are accurate because a TOF may show adequate recovery for some muscle groups but it does not necessarily reflect recovery for pharyngeal musculature.
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