Neuromuscular Physiology and Pharmacology Flashcards
Where do motor neurons to skeletal muscle originate?
anterior (ventral) horn of the spinal cord (DAVE— ventral efferent)
The sensory neurons from the skeletal muscle carry action potentials to the spinal cord via the _______ _______.
dorsal horn (DAVE— dorsal afferent)
The motor and sensory nerves of the skeletal muscle are ______ nerves.
somatic
Explain the role of calcium in the pre-synaptic junction?
when an action potential is generated and reaches the pre-synaptic junction–> stimulates Ca channel to open–> Ca causes vesicles to open–> release AcH into synaptic cleft–> pre-synaptic nicotinic receptor response to AcH–> produce more and release more AcH
What is the positive feedback system that is associated with AcH?
the pre-synaptic nicotinic receptor responds to AcH by increasing the synthesis and release of AcH… this is a positive feedback system that prevents depletion of AcH at the NMJ.
Explain the events that occur when AcH leaves the pre-synaptic membrane.
AcH diffuses down concentration gradient from pre-synaptic membrane to motor end plate of postsynaptic membrane–> combines with nicotinic receptors of protein channel–> when BOTH alpha subunits of nicotinic receptor channel are occupied by AcH, the channel snaps open= Na and Ca into the cell, K ions diffuse out into extracellular space–> contraction of muscle cell
How is the neurotransmitter action impulse at the neuromuscular junction terminated?
acetylcholinesterase, aka true cholinesterase, breaks down acetylcholine into choline and acetate–> as AcH is metabolized, the motor end plate repolarizes and the muscle cell becomes ready for another squirt of AcH from the nerve terminal–> choline is transported back into the nerve terminal where it is used to re-synthesize AcH
Acetylcholinesterase breaks acetylcholine down into _____ and ______.
choline (reabsorbed by nerve terminal to re-synthesize AcH) and acetate
The release of the neurotransmitter (AcH) from all nerve terminals, including the motor nerve terminals, depends on the entry into the terminal of ______ ions.
calcium ions; calcium comes in, neurotransmitter goes out
How does calcium relate to hyporeflexia and hyper-reflexia?
hypocalcemia is associated with a decrease in amount of neurotransmitter released (hyporeflexia), and hypercalcemia is associated with an increase in amount released (hyperreflexia)
Magnesium will be the OPPOSITE of calcium
Calcium and magnesium are ______ (agonists or antagonists) at nerve terminals (pre-synaptically).
antagonistic
The channel operated by the nicotinic receptor has _____ subunits. _____ AcH molecules are needed to open each nicotinic AcH receptor channel.
5 subunits (2 are identical– 40k); 2 AcH molecules are needed
It takes ___ (#) acetylcholine molecules to open the ______-gated channel of the skeletal muscle motor end plate.
2; acetylcholine gated channels
Non-depolarizers are _______ (competitive or non-competitive).
competitive inhibitors; when non-depolarizers bind to either AcH binding site on a nicotinic receptor, AcH CANNOT attach to that receptor, so the channel CANNOT open.
Succinylcholine binds to the nicotinic receptors and _____ (opens or closes) the channels. ________ is maintained for an extended amount of time because Sux is not metabolized by true acetylcholinesterase.
opens; depolarization
What neuromuscular blocking agent mimics acetylcholine at the NMJ?
Succinylcholine; results in opening of the channel and remains open d\t slower metabolism by plasma cholinesterase—> depolarization is prolonged
What type of neuromuscular blocking agent produces the following effect: IV administration–> diffuses from vascular department into synaptic cleft of NMJ–> combines with nicotinic receptors of motor end plate–> exerts no direct effect on the channel–> channels stay closed, the post-synaptic membrane remains polarized.
Non-depolarizing NMB’s
What NMB agent is associated with the following: action potentials cannot be initiated in skeletal muscle until the cell repolarizes because the Na channels are in the inactivated state.
depolarizing neuromuscular blocker
How is succinylcholine metabolized?
by an enzyme in the plasma called plasma cholinesterase… also called pseudocholinesterase and butyrocholinesterase; as circulating Sux is metabolized, a gradient is created for Sux to diffuse from the skeletal muscle motor end plate back into the plasma to be quickly metabolized
How is succinylcholine terminated?
by diffusion
At the NMJ, does the pre-synaptic action of Sux enhance or antagonize its postsynaptic action?
Sux, by stimulating the presynaptic nicotinic receptor, augments the release of AcH–> since the released AcH opens channels and depolarizes the motor end-plate like Sux, the presynaptic action of Sux enhances its post-synaptic action.
What are some of the physiological properties of neuromuscular relaxants?
1- 100% ionized at physiologic pH
2- very highly protein bound
3- do not cross the BBB (ions do not cross lipid bilayers)
4- do not cross the placental barrier (same reason)
5- trapped in renal tubule after filtration because of high degree of ionization (all muscle relaxants can be excreted by the kidney if other routes are unavailable)
What is the trade name for succinylcholine?
Anectine (very short)
What is the trade name for vecuronium?
Norcuron (intermediate)
What is the trade name for rocuronium?
Zemuron (intermediate)
What is the trade name for pancuronium?
Pavulon (LONG)
What is the trade name for cisatracurium?
Nimbex (intermediate)
What is the trade name for mivacurium?
Mivacron (short)
What is the trade name for atracurium?
Tracrium (intermediate)
_________ is the primary route of elimination for succinylcholine, atracurium, cisatracurium, and mivavurium.
metabolism
_________ excretion is the primary route of elimination for vecuronium and rocuronium.
biliary excretion
_________ excretion is the primary route of elimination for d-tubocurarine, metocurarine, pancuronium, gallamine, doxacurium, and pipecuronium.
renal excretion
What two NMBs are metabolized by plasma cholinesterase?
succinylcholine and mivacurium
What two NMBs are metabolized by Hoffman elimination?
atracurium (but also by ester hydrolysis) and cisatracurium
What two NMBs are metabolized primarily by biliary excretion?
vecuronium and rocuronium (both are secondary by renal excretion)
What is the difference in metabolism of cisatracurium and atracurium?
Nimbex is ONLY metabolized by Hoffman elimination, whereas Atracurium (tracrium) is eliminated by ester hydrolysis (non-specific esterases) and Hoffman (pH and temperature dependent degradation)
Which NMBs elicit the release of histamine?
succinylcholine, mivacurium, atracurium, d-tubocurarine, metocurarine
Why does succinylcholine have the potential to produce bradycardia?
mimics the action of acetylcholine and directly stimulates muscarinic receptors in the SA node
Which NMBs can produce significant hypotension?
succinylcholine, d-tubocurarine, and metocurarine
Which NMBs can produce significant hypertension?
pancuronium and gallamine
What is the main cause related to administration of Mivavurium for hypotension and reflex tachycardia?
seen with rapid administration of high doses (>0.25mg/kg)
Which of the commonly used NMBs DO NOT have histamine release?
cisatracurium, vecuronium, rocuronium, pancuronium
Why is mild hypertension sometimes noted with the administration of pancuronium?
from an increase in HR d\t moderate antagonism of acetylcholine at the SA node
How much can K levels rise after administration of Succinylcholine to a patient? to a burn patient?
plasma K+ concentration may increase by 0.5 mEq/liter in normal patients; 5-10 mEq/liter in burn, trauma, or head injury patients
What conditions are associated with proliferation of extrajunctional postsynaptic cholinergic nicotinic receptors?
This occurs when nerve action potentials to skeletal muscle are interrupted–> post synaptic nicotinic receptors up-regulate and spread from the NMJ to the entire muscle fiber–> K exits the cells when the nicotinic receptor is stimulated
burns, paraplegia or hemiplegia, skeletal muscle trauma, upper motor neuron injury (head injury, CVA, parkinson’s)
If a nerve stimulator is used on the right wrist of a patient with right sided hemiplegia, will the twitch be , or same as left?
it will be greater than the left d\t the upregulation of nicotinic receptors
What are some of the criteria for the diagnosing of malignant hyperthermia?
unexplained signs of pyrexia (fever), tachycardia, cyanosis, rigidity 75%, or failure of the masseter muscle to relax (trismus) 50%
What are the serum composition changes that can be seen with malignant hyperthermia?
increased H+, K+, Ca+, and CO2; decreased O2
What is the defect in malignant hyperthermia?
failure of the sarcoplasmic reticulum to sequester calcium, so sustained contractions with increased metabolism result
What is the treatment for malignant hyperthermia?
dantrolene–> acts on the sarcoplasmic reticulum to decrease the release of calcium to contractile proteins
What is one of the earliest and most sensitive signs of malignant hyperthermia?
unexplained doubling or tripling in end-expiratory CO2; sympathetic hyperactivity manifested by increased HR is also an early sign of increased metabolism
What agents can trigger malignant hyperthermia?
Succinylcholine and halogenated inhalational agents (isoflurane, desflurane, halothane, enflurane, sevoflurane)
What effect does local anesthetics have on NMBs?
amides can increase block; reduce dose by 1/3 to 1/2
What effect does volatile inhalational agents have on NDMBs?
block increased; reduce dose by one third to one half in presence of halogenated inhalational agent
Is NDM blockade affected by Myasthenia Gravis?
block increased
What is the effect of age when considering NDMBs?
block increased d\t organs of elimination less effective
What effect does a thermal (burn) injury have on NDMBs?
block DECREASED; manifests 10 days after injury; peaks at 40 days; and declines after 60 days
What effect does antibiotics have on NMBs?
block increased: gentamycin, neomycin, streptomycin, tatracycline
block unchanged: PCN, chloramphenicol, cephalosporins
What effect does anticholinesterase agents have on succinylcholine?
block increased by cholinesterase inhibitors (edrophonium, neostigmine, physostigmine, echothiophate) as well as other drugs that depress this enzyme (like ester local anesthetics such as procaine and phenothiazines such as chlorpromazine)
What effect does lithium and CCBs have on NMBs?
block increased
What is the appropriate level of blockade for abdominal surgery?
90% blockade; 1 of 4 twitches
While it is NOT an indicator of recovery, tidal volume returns to normal (>5ml/kg) when approx ______ % of receptors are occupied by NMBs.
75-80%
If a patient has 4/4 twitches, how many receptors can still be blocked?
70-75% blockade can still remain
What are some indicators that approx 50% or less receptors are occupied by NMBs?
pass inspiratory pressure test at least -40cm; head lift for 5 seconds; sustained strong hand grip; sustained bite, very reliable indicator of recovery
Data suggests that conditions for intubation are appropriate when approx ____ % of receptors are blocked.
95% (diaphragm moves… no twitch with TOF)
% blockade that is present with TOF 1/4.
90%– good for abdominal procedures
% blockade that is present with TOF 4/4.
70-75%
What is a phase 1 block?
depolarizing (phase 1) neuromuscular block— succinylcholine; amplitude of single twitch contractions decreases in proportion to the severity of the block
When can a phase 2 block occur with Sux?
higher doses or prolonged exposure of the motor end plate to Sux leads to development of phase II, or desensitization block–> ion channels of the motor end plate close for reasons that are unknown, and the motor end plate repolarizes–> has characteristics of nondepolarizing block (mimics NDMBs)
Ganglionic blockade is a side effect produced by which two NDMBs?
D-tubocurarine and metocurarine (ANS BLOCKADE)
Which two NDMBs has antimuscarinic actions?
pancuronium and gallamine
It is best to reverse a patient when ____ twitches are observed, but acceptable if only _____ is present.
2-3; 1
Is the ventral horn located anteriorly or posteriorly?
ANTERIOR, but is EFFERENT
What type of muscle fiber are motor neurons?
A alpha–> largest, most myelinated–> fastest conduction velocity
Are nicotinic receptors found presynaptically or postsynaptically?
BOTH
Explain the steps involved in neuromuscular impulse transmission; including the role of the presynaptic nicotinic receptor vs the postsynaptic receptor.
action potential travels motor nerve axon to the presynaptic nerve terminal-> depolarizes presynaptic terminal–> voltage gated calcium channels open–> Ca+ diffuses into terminal causing vesicles to release AcH (quantal release) into the synaptic cleft (exocytosis)–> presynaptic nicotinic receptor responds to the increased ACh in the synaptic cleft by increasing the synthesis and mobilization of ACh (positive feedback)–> ACh traverses the synaptic cleft to reach the postsynaptic nicotinic receptor of the motor end plate–> ACh binds to BOTH alpha subunits and opens the ion channel–> Na, Ca diffuse in, K diffuses out–> depolarization–> contraction (excitation-contraction coupling)–> acetylcholinesterase (aka true, specific, genuine, or type 1 cholinesterase) breaks down ACh into choline and acetate (by hydrolysis)–> choline is transported back into the nerve terminal where it is used to re-synthesize ACh
What is the explanation for the phenomenon of fade seen with NDMB’s and with the phase II block seen with Sux?
the positive feedback system seen with the presynaptic nicotinic receptor–> causes increase in synthesis and mobilization of ACh containing vesicles (storage pools)
What is the potential reason that larger initial doses of muscle relaxants are normally given compared to maintenance doses?
b\c the initial release of ACh is approx 125 quanta, each containing 10,000 ACh molecules–> this is a transient release and subsequent releases are much less… requiring less muscle relaxant doses
What does the release of neurotransmitters from any nerve terminal (including motor nerve terminal DUH!) depend on?
the entry of Ca+ ions into the nerve terminal; “calcium comes in, neurotransmitter goes out”
side note: so…. hypocalcemia results in a decrease in the neurotransmitter release, and hypercalcemia causes an increase in the neurotransmitter release
magnesium concentration has the OPPOSITE effect
Name what things acetylcholinesterase is responsible for degrading.
ACh, ester local anesthetics, neostigmine, edrophonium, remifentanil, and esmolol
In regards to Sux… how common are fasciculations? how is it metabolized?
60-90% and myalgia within 24-48 hours after; not metabolized by true acetylcholinesterase, instead by plasma cholinesterase
Name 5 common characteristics of nondepolarizing blocks (phase II):
1) MOA is competitive inhibition
2) fade follows high frequency stimulation (>0.1Hz)
3) exhibits post-tetanic facilitation
4) antagonized by anticholinesterases
5) no fasciculations
What are 2 other names for Sux?
anectine, diacetylcholine; composed of two acetylcholine molecules linked together
What are some other names for plasma cholinesterase?
pseudo-, butyro-, benzoyl-, false, non-specific, and type II cholinesterase
Name 6 common characteristics of depolarizing blocks (phase I):
1) decreased single twitch height
2) response to high frequency stimulation is maintained
3) minimal or no fade after TOF
4) antagonized by nondepolarizers
5) potentiated by anticholinesterase
6) muscle fasciculations precede block
Name 5 common properties of neuromuscular relaxants:
1) 100% ionized at physiologic pH
2) very highly protein bound
3) DO NOT cross BBB (ions do not cross lipid bilayers)
4) DO NOT cross placenta
5) trapped in renal tubule after filtration because high degree of ionization (all NMBs can be excreted by the kidney if other routes are unavailable)
What response is seen in serum K level change after giving succinylcholine?
increase by 0.5 meQ/liter in normal pt and 5-10 meQ/liter in burn, trauma, or head injury pt
Why is bradycardia seen with succinylcholine?
b\c of increased K+, especially after repeated dosing
What effect can succinylcholine have on intraocular pressure?
increase by 5-15mmHg
The termination of a drug and the elimination are two different actions. What NMB’s are terminated by redistribution?
R-VRAC
redistribution–> vecuronium, rocuronium, atracurium, cisatracurium
If you use a nerve stimulator on the right wrist of a patient with right sided hemiplegia, will the twitch be less than, the same as, or greater than the twitch on the left?
GREATER than d\t upregulation of extrajunctional receptors (nicotinic receptors)
When nerve action potentials to skeletal muscle are interrupted, postsynaptic nicotinic receptors up-regulate and spread from the neuromuscular junction to the entire muscle fiber…. K+ exits when the receptor is stimulated… risk for hyperkalemia…. What are 5 primary conditions that this can occur with?
1) thermal trauma (burns)
2) spinal cord transection (para or hemiplegia)
3) skeletal muscle trauma
4) upper motor neuron injury (head injury, CVA, parkinsons)
5) prolonged immobility
What are some common signs of MH?
unexplained signs of increased ETCO2, pyrexia (fever), tachycardia, cyanosis, rigidity, trismus (masseter muscle spasm)
What are changes in serum composition seen with MH?
increased H+, K+, Ca++, and CO2; decreased O2
What is the primary defect involved in MH?
mutation of the RyR1 (ryanodine receptor), which is embedded in the sarcoplasmic reticulum of skeletal muscle–> causes constant calcium release from the SaRet–> sustained contractions with increased metabolism
What is the role of Dantrolene in the treatment of MH?
acts on the sarcoplasmic reticulum to decrease the release of calcium to contractile proteins
How often is trismus (masseter muscle spasm) seen with MH?
50%
How often is whole body rigidity seen in patients with MH?
75%
What is the earliest and second earliest signs of MH?
elevation of ET CO2, followed by tachycardia in response to increased metabolism (sympathetic hyperactivity)
What are the primary agents that can trigger MH?
succinylcholine and halogenated inhalational agents (isoflurane, desflurane, halothane, enflurane, sevoflurane)
Why isn’t cardiac muscle directly involved in malignant hyperthermia?
cardiac myocytes (muscle fibers) express the RyR2 isoform of the ryanodine receptor
What are two other ways of saying the the “block” was increased?
potentiated=prolonged=increased=augmented
What effect does local anesthetics and volatile anesthetic agents have on the degree of nondepolarizing neuromuscular blockade?
LA- block is increased by amides–> dose of NDMB can be reduced by 1/3 to 1/2
VA- block increased–> dose can be reduced 1/3 to 1/2 in presence of halogenated agent
**block unchanged in Sux administration with VA’s
What is the effect of K+ on the degree of blockade in regards to a depolarizing block vs a nondepolarizing block?
NDMB- in presence of decreased K, block increased
DMB- in presence of hyperkalemia, block increased
What antibiotics can increase the degree of NMB’s?
neomycin, streptomycin, tobramycin, dihydrostreptomycin, kanamycin, gentamicin, polymyxin B, colistin, linomycin, tetracyline
**unchanged by: PCN, chloramphenicol, cephalosporins, erythromycin
What is the % of receptors occupied for the following? : complete paralysis (0/4 TOF)
99-100%
What is the % of receptors occupied for the following? : diaphragm moves (0/4 TOF)
95%
What is the % of receptors occupied for the following? :
head lift >5 sec, sustained hand grip, sustained bite
50%
What is the % of receptors occupied for the following? :
sustained tetanus at 50Hz for 5 sec; VC at least 20ml/kg
70%
What is the % of receptors occupied for the following? :
no palpable fade in double burst stimulation, more sensitive than TOF as indicator
60-70%
What is the % of receptors occupied for the following? :
abdominal relaxation is adequate for most intra-abdominal procedures (1/4 TOF)
90%
What is the % of receptors occupied for the following? :
tidal volume returns to normal (>5ml/kg), single twitch as strong as baseline (not an indicator of recovery)
75-80%
What is the % of receptors occupied for the following? :
No palpable fade in TOF, useful as a gauge of recovery
70-75%
What is the effect of cholinesterase inhibitors on the level of blockade of a NDMB vs a DMB?
NDMB- block is antagonized by agents that inhibit true acetylcholinesterase (edrophonium, neostigmine, pyridostigmine)
DMB- block is enhanced (augmented) by cholinesterase inhibitors (edrophonium, neostigmine, pyridostigmine)
Does fade occur with a depolarizing muscle blockade?
No… only with NDMB’s… also no post tetanic facilitation (post-tetanic potentiation) will be present with DMB’s
What is the difference in a phase I and phase II blockade?
Phase I is a depolarizing blockade
Phase II is a densensitization blockade
What is a phase II block in regards to succinylcholine administration?
typically Sux will cause a phase I block… however prolonged exposure of the motor end-plate to Sux leads to a phase II (desensitization) blockade… will show characteristics of NDMB like fade and post-tetanic facilitation
