Paralytics

Question 1

NMJ Blockers

Overview

Answer 1

• Act by antagonizing action of ACh at NMJ via muscle-form of nAChR
• Completely paralyzes skeletal muscle
• Predominant use as adjuncts during surgical and orthopedic procedures
• Some may also block nAChRs elsewhere, such as the autonomic ganglia
• Two of drugs also act at muscarinic receptors

Question 2

Nicotinic Receptors

Answer 2

Question 3

Nicotinic Receptor

Blockade

Answer 3

Question 4

Blockade Susceptibility

Answer 4

Susceptibility to blockade varies across the musculature

Appears to be a function of muscle fiber diameter and speed

Question 5

Order of Paralysis

Answer 5

• Rapid orbital muscles of the eye ⇒ extremities ⇒ trunk muscles ⇒ intercostals muscles ⇒ diaphragm
• Last muscle to be paralyzed is the diaphragm ⇒ relatively slow muscle with large diameter fibers
• Patient should be intubated and undergoing ventilation before complete paralysis is in place
• Recovery occurs in reverse order
• Diaphragm & respiration recovers first, before the patient is ready or even able to get up

Question 6

Succinylcholine

Overview

Answer 6

• Only therapeutically useful NMJ blocker that acts as a depolarizing agent
• Effectively a more stable agonist than ACh
• Undergoes slow inactivation
• Poorly metabolized by the plasma cholinesterase
• Much more prolonged duration of action than ACh

Question 7

Succinylcholine

MOA

Answer 7

• Phase I
  
  • Initial activation ⇒ persistent depolarization of muscle end plate (synaptic target) ⇒ Na⁺ channel inactivation ⇒ receptor blockade
  • Causes fasciculations
    
    • Can be prevented by pre-treatment with a small dose of nondepolarizing blocker
    • Requires adjusting dose of succinylcholine
  • Maintained depolarization ⇒ ⊗ ability of ACh to trigger muscle action potentials
  • Effects enhanced by cholinesterase inhibitors
• Phase II
  
  • Later, nicotinic receptors will inactivate
  • Continuous exposure ⇒ desensitization of muscle nicotinic receptors ⇒ muscle repolarization but the end plate remains blocked
  • Most likely due to succinylcholine blocking the ion channel of the muscle nicotinic receptor
  • Sometimes called ‘desensitization block’
  • Effects reversed by cholinestearse inhibitors

Question 8

Succinylcholine

Adverse Reactions

Answer 8

• Apnea (major adverse rxn)
  
  • May extend into the postoperative period
• Hyperkalemia ⇒ cardiac arrest
  
  • D/t release of K⁺ from muscle via nAChRs
  • Most often when nAChRs upregulated
    
    • Following nerve injury or denervation, e.g. massive muscle nerve damage; burn victims
    • Nerve activity regulates # of nAChRs on the muscle, normally @ high density only at the synapse
  • Succinylcholine not used in children d/t possibility of undiagnosed skeletal myopathies
• Transient increased intraocular pressure (esp. if the eyeball has been injured)
  
  • Contraindicated w/ orbital injuries and glaucoma
• Increased gastric or intracranial pressure (variable)
• Malignant hyperthermia
  
  • Esp. when used together w/ inhaled anesthetics like halothane
  • Autosomal dominant polymorphism, most often in the ryanodine receptor (~1/50k)
• Myalgias
  
  • Esp. in heavily muscles pts
  • May be 2/2 development of fasciculations
  • May be relieved by giving a defasciculating dose
    
    • 10% of intubating dose of non-depolarizing blocker

Question 9

Succinylcholine

Cross Reactions

Answer 9

• Activates automonic ganglia ⇒ tachycardia short term
• Slight stimulation of histamine release ⇒ can cause bradycardia
• Activates mAChR on cardiac muscle ⇒ tachycardia

Question 10

Non-Depolarizing Drugs

Answer 10

Remaining neuromuscular blockers all act as basic competitive blockers for ACh at the muscle nicotinic receptors.

Drugs have varying additional effects.

Question 11

NMJ Blocker

Use

Answer 11

Succinylcholine and mivacurium used initially for rapid induction of paralysis

Long acting NMJ blocker is used to maintain paralysis

Question 12

Basic Pharmacokinetics

Answer 12

All NMJ blockers delivered IV

Quaternary amines ⇒ poorly absorbed orally

Elimination varies based on drugs:

• Hydrolyzed by plasma esterase ⇒ short acting (minutes)
  
  • Plasma esterase variants w/ poor hydrolysis activity ⇒ prolonged half-life
• Eliminated by the liver ⇒ intermediate acting (tens of minutes)
  
  • Half-lives will be prolonged in individuals with liver disease
• Spontaneous hydrolysis ⇒ intermediate acting
• Renal elimination (metabolism and/or excretion) ⇒ long acting (hours)
  
  • Half-lives even longer in pts w/ renal insufficiency

Question 13

Short Acting

NMJ Blockers

Answer 13

Mivacurium

• Fastest onset short-acting blocker
• High concentrations needed for intubation ⇒ sign. histamine release ⇒ bronchoconstriction
• No longer available in the US
• Ester bond cleaved by plasma esterase and inactivated

Question 14

Intermediate Acting

NMJ Blockers

Answer 14

• Vecuronium
  
  • Liver > renal breakdown
• Atracurium
  
  • Mostly spontaneous hydrolysis ⇒ Hoffman elimination
  • Small amount of hepatic breakdown → laudanosine
    
    • Product has longer T ½ and can cross BBB
    • High blood conc. can cause seizures
• Cisatracurium
  
  • Isomer of Atracurium
  • Causes less histamine release ⇒ used more often
  • Lesser degree of hepatic breakdown ⇒ produces less laudanosine ⇒ less likely to cause seizures
  • Can be used in pts w/ hepatic and renal disease
• Rocuromium
  
  • Most rapid onset of intermediate drugs (~ 1 min)
  • Good adverse profile

Question 15

Long Acting

NMJ Blockers

Answer 15

• Tubocurarine
  
  • Active component of curare
  • Also blocks nAChR @ autonomic ganglia & causes sign. Histamine release
  • Only available for research
• Pancuronium
  
  • Causes moderate block of mAChR @ heart ⇒ tachycardia ⇒ called “vagolytic” effect
• Pipercuronium & Doxacurium
  
  • Long acting blockers w/ minimal side effects

Question 16

Assessment of NMJ Block

Answer 16

Peripheral nerve stimulation ⇒ muscle stimulation ⇒ assessment of NMJ block ⇒ dose adjustment

Train-of-four stimuli response proportional to % of receptors blocked.

• Most useful when abnormal pharmacokinetic or pharmacodynamic response suspected
  
  • Severe renal or hepatic disease
  • Neuromuscular disease
  • Severe pulmonary disease ⇒ concern postoperatively
• Other drugs can decrease the requirement for neuromuscular blockade
  
  • Volatile anesthetics
  • Aminoglycoside abx
  • Lithium

Question 17

Non-depolarizing Blocker

Assessment

Answer 17

Train-of-four stimuli ⇒ “fade” in resulting muscle twitches

• # of surviving twitches ∝ proportion of nicotinic receptors blocked
• Involves blockade of presynaptic nicotinic receptors @ nerve ending itself
  
  • Receptors usu. increase ACh release during times of increased demand

Question 18

Depolarizing Blocker (Succinylcholine)

Assessment

Answer 18

Train-of-four stimuli ⇒

• Phase I block
  
  • Level of muscle twitches diminished but constant ⇒ no fade
  • Due to inactivation of channels at the muscle
• Phase II block
  
  • Succinylcholine may block the nicotinic receptor
  • Response is similar to the non-depolarizing blockers ⇒ there is fade

Question 19

Clinical Assessment

Answer 19

Question 20

NMJ Blocker

Reversal

Answer 20

• For all blockers except succinylcholine (and mivacurium):
  
  • Reversal may be accelerated w/ a cholinesterase inhibitor (e.g. neostigmine)
    
    • ↑ ACh @ NMJ will compete away the blocker
  • To prevent concomitant ACh excess at muscarinic sites Atropine or glycopyrrolate (another antimuscarinic) may be given ⇒ “preventing overshoot”
• Suggamadex is a specific reversal agent for vecuronium and rocuronium
• Succinylcholine and mivacurium given first & usually eliminated before reversal initiated with neostigmine
  
  • Cholinesterase inhibitor will not reverse mivacurium b/c agent dependent on pseudocholinesterase for inactivation & inhibitor does not block this enzyme
  • Cholinesterase inhibiter can reverse phase II of succinylcholine

Question 21

Key Drugs

Answer 21