Neuromuscular blocking drugs

Question 1

Neuromuscular blocking drugs

What do they do?

What does they result in?

Potentially what issue?

Answer 1

• NMBDs interrupt transmission of nerve impulses at the neuromuscular junction
• Results in complete paralysis of striated muscles while consciousness is retained, there is no analgesia, and spontaneous respiration ceases
• Potentially an animal welfare issue

Question 2

4 indications for NMBDs?

Answer 2

• Position the eyeball centrally without traction
  
  • Aids for intraocular or corneal surgeries
  • Most common indication in vet med
• Relax resp. muscles to allow mechanical ventilation (rare indication)
  
  • Sometimes in small animal ICU
• Relax the muscles for neurological or orthopedic surgeries (rare indication)
• Aid intubation (humans)

Question 3

What are the 3 minimum requirements for NMBD’s regarding ventilation and monitoring?

Answer 3

• Use mechanical ventilation (cuffed tube, etc.)
• Monitor cardiovascular, resiratory systems, and oxygenation
  
  • Eye position, pupillary reflex, etc. will not be available
  • Tachycardia and high blood pressure is the only sign they can show in response to noxious stimuli
• Monitoring end tidal agent (e.g. ISO) is useful but not mandatory
  
  • If not available, use high fresh gas flow and keep ISO vaporizer around 1%

Question 4

Contraindications for NMBDs?

Answer 4

• If there is no possibility to ventilate and monitor the patient
• If animal remains conscious
  
  • Conscious experience of complete muscle paralysis is EXTREMELY DISTRESSING even without pain
• If there is insufficient analgesia during surgery
  
  • NMBDs should not be used to “cover” the lack of analgesia
• If the personnel in charge does not have a complete understanding of the use of NMBDs
• It cannot be overemphasized that NMBDs MUST NOT be used as a sole agent for any kind of procedure (painful or nonpainful)
• Nevertheless, they MUST NOT be used as a sole agent for euthanasia

Question 5

Neuromuscular junction

Consists of?

Function (5 steps)?

Answer 5

• NMJ consists of a prejunctional motor nerve ending a highly folded postjunctional membrane of the skeletal muscle and a synaptic cleft between them
• Function
  
  • An impulse arrives at the motor terminal (Ca2+ influx)
  • Release of acetylcholine neurotransmitter
  • ACh binds to nicotinic cholinergic receptors on the postjunctional membranes (opening K+ and Na+ channels)
  • The resulting ion influx triggers an action potential that leads to muscle contraction
  • ACh is rapidly metabolized by the enzyme acetylcholinesterase in the synaptic cleft

Question 6

Mechanism of action: depolarizing and non-depolarizing NMBDs

Answer 6

• Depolarizing NMBDs act as an agonist on the nicotinic ACh receptors, thus causing muscle membrane depolarization
• Non-depolarizing NMBDs act as a competitive antagonist on the nicotinic ACh receptors, thus stabilizing muscle membranes

Question 7

Order of muscle relaxation

Answer 7

• Ocular muscles are the most sensitive and will be paralyzed first even at low doses
• Diaphragm is the most resistant–last to complete blockade and first to recover
• All other muscles are between
• Typical order of onset:
  
  • Eyes > larynx > diaphragm

Question 8

Drugs that potentiate NMBD effect?

Answer 8

• Inhalational anesthetics
• Aminoglycoside antibiotics
• Local anesthetics
• Cardiac antiarrhythmic drugs
• Diuretics
• Magnesium

Question 9

What are some other factors that influence the depth of NMBD effect?

Answer 9

• Hypothermia
• Electrolyte abnormalities
• Acid-base disorders
• Age
• Thermal burn

Question 10

NMBD chemical properties

Answer 10

• Water-soluble drugs
• Do not cross lipid barriers easily
• Therefore less likely to:
  
  • Cross BBB or placental barrier
  • Adsorb from GI tract

Question 11

Histamine release:

Occurs when?

Which NMBDs are more likely to cause it?

May cause what?

Treatment?

Answer 11

• Rare complication; mostly at high doses
• More likely to cause it:
  
  • Atracurium
  • Succinylcholine
• Histamine may cause
  
  • Bronchoconstriction
  • CV: vasodilation, (-) inotropy, tachycardia
• Treatment: e.g. low dose epinephrine

Question 12

What are the side effects of NMBDs at the ANS?

Answer 12

• Nicotinic ACh receptors are also found in the ANS
• Interactions with older NMBDs (e.b. pancuronium) are possible; those may have side effects related to ANS function
• Unlikely with modern NMBDs

Question 13

Classification/examples of NMBDs

Answer 13

• Depolarizing
  
  • Succinylcholine
• Non-depolarizing
  
  • Long-acting (>30 min): pancuronium
  • Imtermediate acting (10-30 min): atracurium, cisatracurium, rocuronium, vecuronium
  • Short-acting: rapacuronium

Question 14

Succinylcholine (SCh): general

Answer 14

• Cause sustained membrane depolarization on the end plate
• This will initially lead to muscle fasciculation, then the postjunctional Na channels close and remain closed until SCh is present
• This mechanism prevents neuromuscular transmission
  
  • Called the phase-1 block
• After prolonged or high dose SCh administration another type of block (phase-2) may develop which is similar to the non-depolarizing blockade

Question 15

Adverse effects of Succinylcholase?

Answer 15

• Cardiac arrhythmias (bradycardia, sinus arrest)
• Hyperkalemia
• Fasciculation, myalgia, myoglobinuria
• Elevated intra-ocular and intra-gastric pressures
• May trigger malignant hyperthermia
• Not a preferred NMBD in vet med

Question 16

Intermediate-acting non-depolarizing NMBDs: general

Answer 16

• Non-depolarizing NMBDs have less adverse effects than SCh
• Preferred for vet med: atracurium, cisatracurium, rocuronium, vecuronium
• Cumulative effects are less likely and recovery is rapid
• Little or no cardiovascular effects

Question 17

Atracurium

Answer 17

• Mixture of 10 stereoisomers
• Eliminated via
  
  • Plasma esterase enzyme
  • Spontaneous degradation (Hofmann elimination)–this depends on plasma pH and temperature
• Laudanosine is the major metabolite and it decreases the seizure threshold
• May cause histamine release at high doses

Question 18

Cisatracurium

Answer 18

• 1 of the 10 isomers of atracurium (represents ~15%)
• Elimination is mostly organ dependent (80% by Hofmann elimination)
• Laudanosine production is less
• Kind of a better but more expensive version of atracurium

Question 19

Rocuronium

Answer 19

• Excellent NMBD
• No. 1 choice in the vet med Uni. Vienna
• Can be antagonized with Sugammadex
• Mostly eliminated by the liver, partially by the kidneys
• Recovery is fast
• Antagonist is normally not needed

Question 20

Monitoring the effects of NMBDs

Answer 20

• Residual postoperative neuromuscular blockage may be assoc. with significant impairment of respiratory and pharyngeal muscle fx and increased risk for postoperative pulmonary complications
• It is impossible to be sure that residual blocking effects are not present only by examining the clinical signs
• Sustained ability to hold the head or stand may indicate that the patient recovered enough to protect the airway
• Monitoring the neuromuscular function with peripheral nerve stimulators is necessary
• Acceptable neuromuscular recovery is a TOF ratio >/= 0.9