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Neuromuscular blocking
1. NEUROMUSCULAR
BLOCKING AGENTS
Carlos Darcy Alves Bersot TSA.SBA
MD RESPONSÁVEL PELO CET H.F.LAGOA
Médico Anestesiologista do Hospital Federal da Lagoa-SUS
Médico Anestesiologista do Hospital Pedro Ernesto-UERJ
2. Key Concepts
•Muscle relaxation does not ensure unconsciousness, amnesia, or analgesia
•Neuromuscular blocking agents are used to improve conditions for tracheal intubation, to provide
immobility during surgery, and to facilitate mechanical ventilation.
•Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists, whereas
nondepolarizing muscle relaxants function as competitive antagonists.
•Depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away
from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme,
pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or
butyrylcholinesterase).
•With the exception of mivacurium, nondepolarizing agents are not significantly metabolized by
either acetylcholinesterase or pseudocholinesterase. Reversal of their blockade depends on
redistribution, gradual metabolism, and excretion of the relaxant by the body, or administration of
specific reversal agents (eg, cholinesterase inhibitors) that inhibit acetylcholinesterase enzyme
activity.
•Compared with patients with low enzyme levels or heterozygous atypical enzyme in whom
blockade duration is doubled or tripled, patients with homozygous atypical enzyme will have a
very long blockade (eg, 4–6 h) following succinylcholine administration.
•Succinylcholine is considered contraindicated in the routine management of children and
adolescents because of the risk of hyperkalemia, rhabdomyolysis, and cardiac arrest in children with
undiagnosed myopathies
3. •Normal muscle releases enough potassium during succinylcholine-induced depolarization to raise
serum potassium by 0.5 mEq/L. Although this is usually insignificant in patients with normal baseline
potassium levels, a life-threatening potassium elevation is possible in patients with burn injury,
massive trauma, neurological disorders, and several other conditions
•Doxacurium, pancuronium, vecuronium, and pipecuronium are partially excreted by the kidneys, and
their action is prolonged in patients with renal failure.
•Atracurium and cisatracurium undergo degradation in plasma at physiological pH and temperature
by organ-independent Hofmann elimination. The resulting metabolites (a monoquaternary acrylate
and laudanosine) have no intrinsic neuromuscular blocking effects
•Hypertension and tachycardia may occur in patients given pancuronium. These cardiovascular
effects are caused by the combination of vagal blockade and catecholamine release from adrenergic
nerve endings
•Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged
neuromuscular blockade (up to several days), possibly from accumulation of its active 3-hydroxy
metabolite, changing drug clearance, or the development of a polyneuropathy
•Rocuronium (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.
4.
5.
6. History of neuromuscular blocking
agents
• Early 1800’s – curare • 1942 – curare used for
discovered in use by muscular relaxation in
South American general anesthesia
Indians as arrow • 1949 – gallamine
poison discovered as a
• 1932 – West substitute for curare
employed curare in • 1964 – more potent
patients with tetanus drug pancuronium
and spastic disorders synthesized
26. Bloqueadores Não-despolarizante
MECANISMO DE AÇÃO
Tubocurarine
Potenciais de ação e potenciais de placa terminal na
vigência de bloqueador não-despolarizante
37. Succinylcholine
“Except when used for emergency tracheal
intubation or in instances in clinical practice
where immediate securing of the airway is
necessary, succinylcholine is contraindicated in
children and adolescent patients.”
39. Succinylcholine:
Hyperkalemic Response
Major burns, Massive trauma, Denervation injuries
prolonged immobility, sepsis.
– normal response; approx. 0.5 mEq/L
– not attenuated by defasciculation
– increased extrajunctional receptors (few days to form)
40.
41. Succinylcholine:
Myalgias
• mechanism-speculative
• incidence: 0.2-89%
• young, female, early ambulation
• severity not related to intensity of fasciculations
• Pre-treatment with NDMR prevents fasciculations
and may decrease myalgias
43. Succinylcholine:
intraocular pressure
– Prevention: defasciculate, benzodiazepam,
lidocaine,acetazolamide, deep anesth. at laryngoscopy
– Drug of Choice? for the “Glaucoma” and “full stomach”
– Recommendations: SUX if possible, priorize, Airway first.
– If SUX is used: sedate and defasciculate
– transient increase of 8mm Hg ; peaks at 2-4 min
– due to contraction of extra-ocular muscles
• See Vachon C. Succinylcholine and the open globe: Tracing the
Teaching Anesthesiol 99: 220-223, 2003
49. Malignant Hyperthermia
(Hyperpyrexia)
• Condition caused by a defect in the molecule
linking muscle membrane t-tubules to the
sarcoplasmic reticulum (ryanodine receptor).
• Uncontrolled Ca++ release from the S.R. leads to
contracture and a rise in body core temperature.
• Succinylcholine can precipitate an attack even in
the absence of halothane like anesthetics.
• Dantrolene blocks this inappropriate response of
the ryanodine receptor and prevents Ca++ loss
50. Muscle Relaxants:
Physio-chemical Properties
Highly Ionized at Physiol. pH
– + charged quaternary N attracted to
- charged cholinergic receptor
– most contain 2 + charges (biquaternary) separated by
varying sizes of lipophilic bridge (potency)
– quaternary ammonium (like Ach)
51. Muscle Relaxants:
Physio-chemical Properties
Highly Water Soluble/ Relatively Hydrophilic
– easily excreted in urine
– do not cross lipid membranes (most cells, BBB,
placenta)
– small volume of distribution
– not actively metabolized by the liver
(cytochrome P-450 enzyme system requires lipophilic
substrates)
52. Pancuronium
• Bis-quaternary Aminosteroid
• High potency therefore slow onset
• Long acting
• No or slight increase on blood pressure
• Vagolytic
• Renal clearance
53. Rocuronium
Mono-quaternary aminosteroid
– potency, approx 1/6 that of Vecuronium
– fast onset (< I min with 0.8 mg/kg)
– intermediate duration (44 min with 0.8 mg/kg)
– minimal CV side effects
– onset and duration prolonged in elderly
– slight decrease in elimination in RF
54. Mivacurium
Bisquaternary benzylisoquinoline
– potency, 1/3 that of atracurium
– relatively slow onset 1.5 min with 0.25 mg/kg
– short duration 12-18 min with 0.25 mg/kg
– histamine release with doses 3-4X ED95
– hydrolyzed by pChE, recovery may be prolonged in
some populations (e.g. atypical pChE)
55. Cis-Atracurium
one of the stereo isomers of atracurium (15%)
– 3 X more potent than atracurium
– slow onset, intermediate duration
– eliminated by Hoffman degradation
– Laudanosine as a metabolite
– non-organ elimination
– doses of 5 X ED95 (0.05mg/kg)
• no histamine release
• CV stability
56. Rapacuronium
monoquaternary aminosteroid, analogue of
Vecuronium
– low potency, fast onset, short to intermediate
duration
– 1.5-2.0 mg/kg doses give good intubating conditions
at 60 sec
– duration of action, dependent on dosage and age of
patient
– 20 % decrease in aBP observed with 2-3 mg/kg
doses
– principle route of elimination may be liver as 22% is
renal excretion.
– introduced in 2000 in US and removed, after
paediatric deaths (bronchospasm).
61. Hepato-Biliary Disease
Pancuronium (20% metabolized to active metabolite)
increased Vd
decreased plasma clearance
prolonged elimination T1/2
A large initial dose is required to prod the same plasma conc. but
the block will be prolonged
Vecuronium (20-30%metabolized to active metabolite)
initial studies yielded similar results to pancuronium
later studies show effect only with large doses
Rocuronium is excreted unchanged in the urine and bile. Biliary
excretion (2/3) appears to the predominant route. In cirrhotic
patients, rocuronium pharmacodynamics and elimination kinetics
are not changed much. The prolonged onset and slightly
prolonged recovery is explained by the larger Vd in these
patients.
64. Reversal of Neuromuscular
Blockade
How?
• Anticholinesterases:
– Edrophonium
– Neostigmine
• Cholinesterase
• Removal of blocking agents
– Org 25969 (Cylcodextrin)
• Ring of sugars that soak up Rocuronium
•
65. Anticholinesterases
Unwanted side effects
– Autonomic
– Nausea and vomiting
• Neostigmine > Edrophonium ?
• Edrophonium (0.5-1.0 mg/kg) with Atropine ( 7-15
ug/kg)
• Neostigmine (40-70 ug/kg) with Glycopyrolate
(0.7-1.0mg)
66. Difficulty reversing block
• Right dose?
• Intensity of block to be reversed?
• Choice of relaxant?
• Age of patient?
• Acid-base and electrolyte status?
• Temperature?
• Other drugs?
68. POSTOPERATIVE RESIDUAL CURARIZATION
( PORC)
• common after NDMRs
• long acting > intermediate > short acting
• Assoc with respir. morbidity
• not observed in children
• monitoring decreases incidence
69. • Ventilatory response to hypoxia is impaired and does
not return to normal until TOF > 0.9
(Ericksson et al, Anesthesiology 78: 693-699 1993)
• Reduced Pharyngeal muscle coordination with TOF
0.6-.08
(Ericksson et al, Anesthesiology 87: 1035-43 1997)
77. Monitoring Neuromuscular
Function
SUPRAMAXIMAL STIMULATION
– 10-20% above current output required to stimulate all nerve
fibers
– Minimizes influence of :temp.skin resistance and changes in
electrode conductance
78. Monitoring Neuromuscular
Function
• STIMULATION PATTERNS
• Single Impulse or Twitch (ST)
• Train of Four (TOF)
• Tetanus
• Double Burst Simulation (DBS)
• Post Tetantic Count (PTC)
79. STIMULATION
PATTERNS
• SINGLE TWITCH
– Onset, dependency on frequency
– Recovery
• Control required
• May still have residual paralysis
80. STIMULATION
PATTERNS
• TETANUS
– 50 Hz, fade with NDMR’s
– 100 Hz, fade without NDMR’s
– Sensitive indicator of residual block
81. SIMULATION PATTERNS
• TRAIN OF FOUR (TOF)
– Measures continued relaxation
– Identifies phase II block
– No control required
– Tolerable in awake patients
– measurement O.7 of o.9 or
1 ????
82. STMULATION PATTERNS
• DOUBLE BURST STIMULATION
– Two bursts of 50Hz stimulation, separated by
750msec
– Measured fade correlates with TOF
– Tactile and visual evaluation of response superior to
TOF
83. STIMULATION PATTERNS
• POST TETANIC COUNT
– 50 Hz for 5 sec, followed in 3 sec by ST@ 1 Hz
– Shouldn’t be repeated more than 6 mins
– Used to monitor intense block
– Predicts optimal time to reversal
Notas do Editor
As principais substâncias que promovem o bloqueio pós-juncional por competição são os alcalóides do curare, provenientes de plantas do gênero Chondrodendron e Strychnos. Esses compostos apresentam grande valor histórico, pois o curare são e foram compostos utilizados pelos índios para a captura de suas prezas, sendo extraídos dessas plantas e utilizados nas pontas de flechas. Como apresentavam ação paralizante da presa, o interesse por cientistas da época foi grande. E
A margem de segurança da transmissão neuromuscular nos permite avaliar o quanto a transmissão neuromuscular esta comprometida, no gráfico acima temos nas ordenadas a força de contração do músculo, sendo todas relativas ao registro inicial; nas abscissas encontra-se a fração de receptores bloqueados. Logo quanto maior a concentração do bloqueador competitivo, maior será a fração de receptores bloqueados, até chegar a um ponto em que a transmissão neuromuscular começa a ficar compromotida, no exemplo acima temos vários tipos de preparações e pode-se notar que a partir de 75% de bloqueio a preparações começam a apresentar o comprometimento da transmissão. Isso é muito importante no processo cirúrgico, pois o paciente pode apresentar certo grau de bloqueio mesmo sem apresentar comprometimento da transmissão, consequentemente uma dose adicional inadequada pode promover sérios efeitos (como bloqueio prolongado).
Temos também o outro grupo de bloquedores neuromusculares, que são os bloqueadores despolarizantes. Esses foram descobertos por Burns e Paton em 1951, sendo o primeiro o Decametônio; esses compostos apresentam estrutura semelhante a acetilcolina e apresentam uma ação de agonista estável, ou seja são capazes de interagir com o receptor (pois apresentam afinidade), no entanto, possuem pouca atividade.
Five years ago, a letter from Burroughs Wellcome containing this statement was sent to all anesthesiologists in Canada and the US. This was followed by a deluge of protest, so great that the company replaced the “contraindication” with a warning of the rare possibility of inducing life-threatening hyperkalemia in infants and children with undiagnosed myopathies. No other drug used in anesthesia is associated with such a high incidence of complications yet continues to be used 54 yrs after its introduction. The second is an anonymous quote but heard quite often
Complications assoc with Succ which present or persist into the PACU: Muscle pains Myoglobinaemia Myoglobinuria Hyperkalemia Phase II block Reduced pChE Malignant hyperthermia Anaphylaxis Often asked question: What are the contraindications to succinylcholine?
Vulnerable periods for Sux induced hyperkalemia: Spinal cord injuries: 24hrs to 6 months Burns:7days to 1 year
mechanism: reversible damage to muscle fibers caused by shearing stresses from the uncoordinated activation of individual muscle fibers is one possible explanation many suggestions to reduce or prevent fasciculations, myalgias and muscle damage: Pretreat with an NDMR, a “taming dose of Succ,benzodiazepine, lidocaine,fentanyl, MgSo4, dantrolene, Vitamin C, and Ca gluconate. Defasciculation. is probably the most reliable.-but watch out for the sensitive patient! One recent doubled blinded, randomised control study showed no difference in the incidence of myalgias comparing sux (after defasciculation with dTC) and mivacurium.
We would expect a blocking agent to possess a positive charge with an affinity for the complementary negative charge on the Ach receptor. It is a fact that all clinically useful NM blocking agents bear a positively charged N. At least one quaternary N is necessary to achieve high potency, by confirming the drug within a very restrictive volume of distribution An increase in the size of the N substituents leads to a decrease in depolarizing activity and generally some decrease in potency.
Mivacurium: Advantages: 1) short cases,2) facility with infusion Disadvantages: 1) slow onset ( can be shortened with priming) 2) hypotension with large doses, or when given quickly (less than 30 sec), 3) prolonged duration in susceptible population.
It still has landanosine as one of its bi-products of spontaneous degradation but because it is more potent
This is a series of aminosteriods with different potencies. Agents with low potencies <100 ug/kg have feaster onsets. The asymtope is at approx 90-100 sec. So even with less potent agents we may not do any better than 90-100 sec
Onset of NM block can be increased by administering a larger dose. The typical intubating dose is about 2.5 -3 X the ED 95 of that particular agent. By using an even larger dose onset time can be further reduced but this has an expense and that is a longer duration of action.
In renal failure patients, the elimination kinetics were slightly decreased for Rocuronium
Edrophonium and neostigmine are both Quaternary Ammonium cpds\\ Edrophonium: Predominant site of action is presynaptic. Does have mild muscarinic effects. Because of its short duration of action in small doses (e.g. 1 mg) useful in Dx of Myasthenia Crisis vs Cholinergic crisis.Dosing requirements same for children and adults but higher doses needed for elderly Neostigmine: Predominant effect is post-synaptic. Renal clearance is 50% Hepatic clearance 50%, Inactive metabolites. Time course of onset and duration produced by an equipotent does of neostigmine similar in adults and children but dose is less for children
It is going to be difficult to reverse a block induced with Doxacurium in “cold”and hypokalemic 80 year old on an aminoglycoside with barely one twitch with O.3 mg/kg of Edrophonium Factors prolonging NMB: Deficiency or atypical pseudocholinesterase, Hypermagnesemia,Hypothermia,Respiratory acidosis, Hypokalemia, Antibiotics
POST OPERATIVE RESIDUAL CURIZATION OR PARALYSIS Is a common problem especially with long acting agents Until recently the standard was TOF > 0.7 . This value was derived from “awake unanesthetized volunteers who had sign. decreases in measured FVC and max inspiratory pressures. It now appears that a TOF of >0.9 is needed to assure complete recovery from NMB, since we now know that even small degrees of block may modify respiratory response to hypoxia and predispose to aspiration!
Erickson in 1993 showed decreased hypoxic drive in subjects given vecuronium to reduce the TOF to <0.7 but had a normal response when TOF > 0.9 Again Erickson in 1997 demonstrated in volunteers impaired swallowing and aspiration with TOF as high as0.9
Sensitive to variations in current,temperature and tension preload Cannot distinguish between non-depolarizing and depolarizing block Presence of full twitch does not guarantee full recovery
100 Hz not physiological
Four supramaximal stimuli given every 0.5 sec May be repeated to more than every 10-12 sec Each stimuli after the first causes contraction, with fade giving basis for evaluation Provides useful correlation of fade and clinical NM block. Fade can be visualized, felt or measured. But it is difficult to assess fade visually or by tactile means. Cannot monitor deep NM block
In non-paralyzed muscle, response is two short contractions of equal strength. In partly paralyzed muscle the second response is weaker
Potentiation of facilitation of contractions is seen after tetanic simulation when muscle relaxants are onboard. There is more Ach competing for receptor sites with the neuromuscular blocker. This is seen with NDMR’s but can also be observed in Phase II block induced with succinylcholine. Magnitude is a function of the depth of block.
