Morgan & Mikhail Chap 11(NMBlocking Agents) Flashcards
Neuro Muscular Transmission
YOUTUBE MORE!!!
ACh is rapidly hydrolyzed into acetate and choline by the substrate-specific enzyme
acetylcholinesterase. This enzyme is embedded into the motor end-plate membrane
immediately adjacent to the ACh receptors. After unbinding ACh, the receptors’ ion channels close, permitting the end-plate to repolarize. Calcium is resequestered in the
sarcoplasmic reticulum, and the muscle cell relaxes.
Different Muscle Relaxants
Mechanism of Action
Similar to ACh, all neuromuscular blocking agents are quaternary ammonium compounds whose positively charged nitrogen imparts an affinity for nicotinic ACh receptors
Depolarizing muscle relaxants very closely resemble ACh and readily bind to ACh receptors, generating a muscle action potential. Unlike ACh, however, these drugs are
not metabolized by acetylcholinesterase, and their concentration in the synaptic cleft does not fall as rapidly, resulting in a prolonged depolarization of the muscle end-plate
Continuous end-plate depolarization causes muscle relaxation because the opening of perijunctional sodium channels is time limited (sodium channels rapidly “inactivate”
with continuing depolarization; Figure 11–3). After the initial excitation and opening (Figure 11–3B), these sodium channels inactivate (Figure 11–3C) and cannot reopen until the end-plate repolarizes. The end-plate cannot repolarize as long as the depolarizing muscle relaxant continues to bind to ACh receptors; this is called a phase I block. More prolonged end-plate depolarization can cause poorly understood changes
in the ACh receptor that result in a phase II block, which clinically resembles that of nondepolarizing muscle relaxants.
Nondepolarizing muscle relaxants bind ACh receptors but are incapable of inducing
the conformational change necessary for ion channel opening. Because ACh is
prevented from binding to its receptors, no end-plate potential develops. Neuromuscular blockade occurs even if only one α subunit is blocked.
Thus, depolarizing muscle relaxants act as ACh receptor agonists, whereas
nondepolarizing muscle relaxants function as competitive antagonists.
For example, conditions associated with a chronic decrease in ACh release (eg, muscle denervation injuries) stimulate a compensatory increase in the number of ACh receptors within muscle membranes. These states also promote the expression of the immature
(extrajunctional) isoform of the ACh receptor, which displays low channel conductance properties and prolonged open-channel time. This upregulation causes an exaggerated
response to depolarizing muscle relaxants (with more receptors being depolarized) but a resistance to nondepolarizing relaxants (more receptors that must be blocked). In contrast, conditions associated with fewer ACh receptors (eg, downregulation in
myasthenia gravis) demonstrate resistance to depolarizing relaxants and increased sensitivity to nondepolarizing relaxants.
Response to Peripheral Nerve Stimulation
GO BACK AND LOOK AT CHAPTER 6
Tetany—a sustained stimulus of 50 to 100 Hz, usually lasting 5 s
Single twitch—a single pulse 0.2 ms in duration
Train-of-four—a series of four twitches in 2 s (2-Hz frequency), each 0.2 ms long
Double-burst stimulation (DBS)—three short (0.2 ms) high-frequency stimulations
separated by a 20-ms interval (50 Hz) and followed 750 ms later by two (DBS3,2)
or three (DBS3,3) additional impulses
Succinylcholine
The only depolarizing muscle relaxant in clinical use today is succinylcholine.
Succinylcholine remains popular due to its rapid onset of action (30–60 s) and short
duration of action (typically less than 10 min). Its rapid onset of action relative to other neuromuscular blockers is largely due to the relative overdose that is usually administered.
Prolonged paralysis from succinylcholine caused
by abnormal pseudocholinesterase (atypical cholinesterase) should be treated with
continued mechanical ventilation and sedation until muscle function returns to
normal by clinical signs.
Drug Interactions
A. Cholinesterase Inhibitors
Although cholinesterase inhibitors reverse nondepolarizing paralysis, they markedly prolong a depolarizing phase I block by two mechanisms. By inhibiting acetylcholinesterase, they lead to a higher ACh concentration at the nerve terminal, which intensifies depolarization.
B. Nondepolarizing Relaxants
In general, small doses of nondepolarizing relaxants antagonize a depolarizing phase I
block. Because the drugs occupy some ACh receptors, depolarization by
succinylcholine is partially prevented. In the presence of a phase II block, a
nondepolarizer will potentiate succinylcholine paralysis.
Other Drugs Potential Effect on NMBs
Clinical Considerations: Succinylcholine (Cardio, Fasciculations, Hyperkalemia)
A. Cardiovascular
The cardiovascular actions
of succinylcholine are therefore very complex. Stimulation of nicotinic receptors in parasympathetic and sympathetic ganglia and muscarinic receptors in the sinoatrial node of the heart can increase or decrease blood pressure and heart rate. Low doses of
succinylcholine can produce negative chronotropic and inotropic effects, but higher
doses usually increase heart rate and contractility and elevate circulating catecholamine levels. In most patients, the hemodynamic consequences are inconsequential in
comparison to the effects of the induction agent and laryngoscopy.
B. Fasciculations
The onset of paralysis by succinylcholine is usually signaled by visible motor unit
contractions called fasciculations. These can be prevented by pretreatment with a small dose of nondepolarizing relaxant. Because this pretreatment usually antagonizes a
depolarizing block, a larger dose of succinylcholine is required (1.5 mg/kg).
Fasciculations are typically not observed in young children and older adult patients.
Clinical Considerations: Succinylcholine (Remainder…)
D. Muscle Pains
Patients who have received succinylcholine have an increased incidence of
postoperative myalgia. The efficacy of nondepolarizing pretreatment is controversial.
Administration of rocuronium (0.06–0.1 mg/kg) prior to succinylcholine has been
reported to be effective in preventing fasciculations and reducing postoperative
myalgias.
E. Intragastric Pressure Elevation
Abdominal wall muscle fasciculations increase intragastric pressure, which is offset by an increase in lower esophageal sphincter tone. Therefore, despite being much discussed, there is no evidence that the risk of gastric reflux or pulmonary aspiration is increased by succinylcholine.
F. Intraocular Pressure Elevation
Extraocular muscle differs from other striated muscle in that it has multiple motor endplates on each cell. Prolonged membrane depolarization and contraction of extraocular
muscles following administration of succinylcholine transiently raises intraocular pressure and theoretically could compromise an injured eye. However, there is no evidence that succinylcholine leads to a worsened outcome in patients with “open” eye
injuries. The elevation in intraocular pressure is not always prevented by pretreatment with a nondepolarizing agent.
Summary of Nondepolarizing Muscle Relaxants
A. Suitability for Intubation
None of the currently available nondepolarizing muscle relaxants equals
succinylcholine’s rapid onset of action or short duration. However, the onset of
nondepolarizing relaxants can be quickened by using either a larger dose or a priming
dose.
Although a larger
intubating dose speeds onset, it prolongs the duration of blockade.
B. Suitability for Preventing Fasciculations
To prevent fasciculations and myalgia, 10% to 15% of a nondepolarizer intubating dose can be administered 5 min before succinylcholine.
C. Maintenance Relaxation
There is great variability among patients in response to muscle relaxants. Monitoring
neuromuscular function with a nerve stimulator helps prevent over- and underdosing and reduces the likelihood of serious residual muscle paralysis in the recovery room.
Maintenance doses, whether by intermittent boluses or continuous infusion (Table 11–
6), should be guided by the nerve stimulator and clinical signs (eg, spontaneous
respiratory efforts or movement).
D. Potentiation by Inhalational Anesthetics
Volatile agents decrease nondepolarizer dosage requirements by at least 15%. The actual degree of this postsynaptic augmentation depends on the inhalational anesthetic (desflurane > sevoflurane > isoflurane > halothane > N2O/O2/narcotic > total intravenous anesthesia).
E. Potentiation by Other Nondepolarizers
Some combinations of different classes of nondepolarizers (eg, steroidal and benzylisoquinolinium) produce a greater than additive (synergistic) neuromuscular blockade.
F. Autonomic Side Effects
In clinical doses, the nondepolarizers differ in their relative effects on nicotinic and muscarinic cholinergic receptors.
G. Histamine Release
Histamine release from mast cells can result in bronchospasm, skin flushing, and hypotension from peripheral vasodilation. Atracurium and mivacurium are capable of triggering histamine release, particularly at higher doses.
H. Hepatic Clearance
Only pancuronium, vecuronium, and rocuronium are metabolized to varying degrees by the liver. Active metabolites likely contribute to their clinical effect. Vecuronium and rocuronium depend heavily on biliary excretion. Clinically, liver failure prolongs blockade
I. Renal Excretion
Pancuronium, vecuronium, and rocuronium are partially excreted by the kidneys.
The duration of action of pancuronium and vecuronium is prolonged in patients with
kidney failure. The elimination of atracurium and cisatracurium is independent of kidney function. The duration of action of rocuronium and mivacurium is not significantly affected by renal dysfunction.
Dosages of NMBs
General Pharmacological Characteristics
Additional Considerations for Special Populations
Atracurium
Look up in full text book (digis - page 343)
Cisatracurium
Like atracurium, cisatracurium undergoes degradation in plasma at physiological pH and temperature by organ-independent Hofmann elimination. The resulting
metabolites (a monoquaternary acrylate and laudanosine) have no neuromuscular blocking effects.
Rest look up in book (handbook page 92)
Mivacurium
Look up in full text book (digis - page 346)
Pancuronium
Look up in full text book (digis - page 346)
Vecuronium
After long-term
administration of vecuronium to patients in intensive care units, prolonged
neuromuscular blockade (up to several days) may be present after drug discontinuation,
possibly from accumulation of its active 3-hydroxy metabolite, changing drug clearance.
Rest look up in book (handbook page 92)
Rocuronium
Rocuronium (at a dose of 0.9–1.2 mg/kg) has an onset of action that approaches
succinylcholine (60–90 s), making it a suitable alternative for rapid-sequence inductions but at the cost of a much longer duration of action.
Rest look up in book (handbook page 93)
