neuromuscular blocking

NEUROMUSCULAR NEUROMUSCULAR BLOCKING AGENTSBLOCKING AGENTS

Carlos Darcy Alves Bersot TSA.SBACarlos Darcy Alves Bersot TSA.SBA MD RESPONSÁVEL PELO CET H.F.LAGOAMD RESPONSÁVEL PELO CET H.F.LAGOA

Médico Anestesiologista do Hospital Federal da Lagoa-SUSMédico Anestesiologista do Hospital Federal da Lagoa-SUSMédico Anestesiologista do Hospital Pedro Ernesto-UERJMédico Anestesiologista do Hospital Pedro Ernesto-UERJ

•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

Key Concepts

•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.

History of neuromuscular blocking History of neuromuscular blocking agentsagents

• Early 1800’s – curare discovered in use by South American Indians as arrow poison

• 1932 – West employed curare in patients with tetanus and spastic disorders

• 1942 – curare used for muscular relaxation in general anesthesia

• 1949 – gallamine discovered as a substitute for curare

• 1964 – more potent drug pancuronium synthesized

Curares - Chondrodendron e Strychnos

Bloqueadores Não-despolarizantes

Strychnos toxiferaFarmacologia – Texto e atlas, 4ª ed., 2003.

West 1932West 1932

Milestones of Neuromuscular Milestones of Neuromuscular Blockade in AnesthesiaBlockade in Anesthesia

• 1942 introduction of dTc in anesthesia• 1949 Succinylcholine, gallamine metocurine introduced• 1958 Monitoring of NMF with nerve stimulators• 1968 Pancuronium• 1971 introduction of TOF• 1982 Vecuronium,Pipecurium,atracurium• 1992 Mivacurium• 1994 Rocuronium• 1996 Cisatracurium• 2000 Rapacurium introduced and removed

Aspectos Morfológicos e Funcionais

Aspectos Morfológicos e Funcionais

Imagem da junção neuromuscular em varredura

Sinapse neuromuscular imagem em microscopia eletrônica

Canais Voltagem Dependentes

2 (embrionário)

2 (maduro)

Only the two identical subunits are capable of binding ACh molecules

Neuromuscular Physiology

Acetylcholine receptor channelsExtrajunctional

Junctional

Anesthesia 5th ed p 740

Bloqueadores Não-despolarizanteMECANISMO DE AÇÃO

Potenciais de ação e potenciais de placa terminal na vigência de bloqueador não-despolarizante

Tubocurarine

Margem de Segurança da Transmissão Neuromuscular

Bloqueadores Não-despolarizante

Muscle AP

Nerve AP

Left Leg Muscle Stimulation

Right Leg Nerve Stimulation

Right Leg Muscle Stimulation

Site of Action of d-Tubocurarine

Bersot,CDA UFRJ

Non-depolarizing Block

succinilcolina

Bloqueadores Despolarizantes

Bersot,cda ufrj 2002

Farmacologia da Junção Neuromuscular

Bloqueadores Não-despolarizantes

COMPOSTOS SINTÉTICOS

Derivados Isoquinolínicos

Lee, (2003) Pharmacology & Therapeutics, 98:143-169


Bloqueadores Não-despolarizantesCOMPOSTOS SINTÉTICOS

Derivados Aminoesteróides


Paton & Zaimis, 1949 – Decametônio e Succinilcolina


Bloqueadores Despolarizantes


SuccinylcholineSuccinylcholine

“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.”

SuccinylcholineSuccinylcholine

Advantages Disadvantages

Rapid onset Hyperkalemia(burns,massive trauma,denervation.…)

Short Duration

I.M. injection Cardiac DysrhythmiasMasseter SpasmMalignant HyperthermiaMyalgiasProlonged effect

Succinylcholine: Succinylcholine: Hyperkalemic ResponseHyperkalemic 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)

Succinylcholine:Succinylcholine: Myalgias 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

Succinylcholine:Succinylcholine:increased intragastric pressureincreased intragastric pressure

– G-E junction opens at pressures > 28cm H20– transient increase up to 40 cm H20– Defasciculate, abolishes the rise

Succinylcholine:Succinylcholine:intraocular pressureintraocular 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

Succinylcholine:Succinylcholine:Prolonged Apnea after….Prolonged Apnea after….

• Etiology• Diagnosis• Management

Prolonged Apnea after SuccinylcholineProlonged Apnea after SuccinylcholineEtiologyEtiology

• Decreased Plasma Cholinesterase Activity– Physiologic Variation– Disease States– Iatrogenic– Genetic

Duration of Sux induced NM-block VS pChE activity


Plasma CholinesterasePlasma Cholinesterase(Prolonged Apnea after….)(Prolonged Apnea after….)

• Disease States– Hepatic Cirrhosis (reduced 50%)– renal disease (50%), returns to normal after renal transplant– malignancy (bronchogenic, GI)– Burns

Plasma CholinesterasePlasma Cholinesterase(Prolonged Apnea after(Prolonged Apnea after…)…)

• Iatrogenic– echthiophate– anticholinesterases– pancuronium– pheneizine (MAO inhibitor)– glucocorticoids (estrogens)– organophosphates (insecticides)– cytotoxic drugs (cyclophosphamide)

Malignant Hyperthermia Malignant Hyperthermia (Hyperpyrexia)(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

Muscle Relaxants:Muscle Relaxants:Physio-chemical PropertiesPhysio-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)

Muscle Relaxants:Muscle Relaxants:Physio-chemical PropertiesPhysio-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)

PancuroniumPancuronium

• Bis-quaternary Aminosteroid• High potency therefore slow onset• Long acting• No or slight increase on blood pressure• Vagolytic• Renal clearance

RocuroniumRocuronium

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

MivacuriumMivacurium

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)

Cis-AtracuriumCis-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

RapacuroniumRapacuronium 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).

HR CO

SVR MAP

Hemodynamic Effects of d-Tubocurarine and Pancuronium

Effect of Potency on Onset of NMB

Effect of Dose on Onset of NMB

Hepato-Biliary DiseaseHepato-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.

Percent of Dose DependantPercent of Dose Dependant on Renal Elimination on Renal Elimination

> 90% 60-90% 40-60% <25%

Gallamine (97) Pancuronium (80) d-TC (45) Succinylcholine

Pipecuronium (70) Vecuronium (20)

Doxacurium (70) Atracurium (NS)

Metocurine (60) Mivacurium (NS)

Rocuronium

Rationale Choice of Muscle Rationale Choice of Muscle Relaxant:Relaxant:

Cardiovascular EffectsCardiovascular Effects

Tachycardia

Bradycardia

Hypotension

Arrhythmias

Reversal of Neuromuscular Reversal of Neuromuscular BlockadeBlockade

How?• Anticholinesterases:

– Edrophonium– Neostigmine

• Cholinesterase

• Removal of blocking agents– Org 25969 (Cylcodextrin)

• Ring of sugars that soak up Rocuronium •

AnticholinesterasesAnticholinesterases

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)

Difficulty reversing blockDifficulty reversing block

• Right dose?• Intensity of block to be reversed?• Choice of relaxant?• Age of patient?• Acid-base and electrolyte status?• Temperature?• Other drugs?

Cold patients-longer durationsCold patients-longer durations


POSTOPERATIVE RESIDUAL POSTOPERATIVE RESIDUAL CURARIZATIONCURARIZATION

( ( PORCPORC))

• common after NDMRs• long acting > intermediate > short acting• Assoc with respir. morbidity

• not observed in children• monitoring decreases incidence

• 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)

Neuromuscular Transmission

Approximate Relationships of % Approximate Relationships of % receptor blockade, ST and TOF receptor blockade, ST and TOF

with NDMBwith NDMBTotal receptors

Blocked %

Single twitch, T1

% normal

Train of Four, T4

% Normal

T4/T1

100 0 0

90-95 0 0 T1 lost

85-90 10 0 T2 lost

20 0 T3 lost

80-85 25 0 T4 lost

80-90 48-58 0.6-0.7

95 69-79 0.7-0.75

75 100 75-100 0.75-1.0

100 100 0.9-1.0

50 100 100 1.0

25 100 100 1.0

Monitoring Neuromuscular Monitoring Neuromuscular FunctionFunction

• Visual/tactile assessment of evoked responses

• Measurement of evoked responses• Mechanomyography• Electromyography• Accelerometry


• Mechanomyography

– Gold standard


• Accelerometry

MonitoringMonitoring Neuromuscular Neuromuscular FunctionFunction

SUPRAMAXIMAL STIMULATION

– 10-20% above current output required to stimulate all nerve fibers

– Minimizes influence of :temp.skin resistance and changes in electrode conductance


• STIMULATION PATTERNS

• Single Impulse or Twitch (ST)• Train of Four (TOF)• Tetanus• Double Burst Simulation (DBS)• Post Tetantic Count (PTC)

STIMULATION STIMULATION PATTERNSPATTERNS

• SINGLE TWITCH

– Onset, dependency on frequency– Recovery

• Control required• May still have residual paralysis

STIMULATION STIMULATION PATTERNSPATTERNS

• TETANUS

– 50 Hz, fade with NDMR’s– 100 Hz, fade without NDMR’s– Sensitive indicator of residual block

SIMULATION PATTERNSSIMULATION 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 ????

STMULATION PATTERNSSTMULATION 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

STIMULATION PATTERNSSTIMULATION 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

neuromuscular blocking

Health & Medicine

transmisso neuromuscular

neuromuscular junction

succinylcholine administration

normal muscle

plasma cholinesterase

nondepolarizing agents

onset of action

site of action