M2 L4: neuromuscular blockers

Question 1

what is the somatic nervous sys

Answer 1

• part of the efferent (motor) division
• contains somatic (skeletal muscle)
• no ganglia, neurons go straight to the neuron
  operates under conscious control
• Voluntary control over skeletal muscles
• Act at neuromuscular junction:
  
  • Synapse between: synaptic terminal of a neuron and motor end plate of a skeletal muscle fiber
• Neurotransmitter is acetylcholine (Ach): acts on nicotinic receptors (Nm) -> muscle contraction

Question 2

neuromuscular blocking drugs

Answer 2

What happens to the muscle when it is blocked: they relax, they will not contract because you inhibited the stimulation, if this continued for a while they become paralyzed

Block neuromuscular transmission at the NMJ
Paralysis of affected skeletal muscles
Act on post-synaptic cholinergic Nm receptors

2 classes: non-depolarizing ( turning off treadmill), depolarizing ( continued to run on treadmill until can’t)

Question 3

non-depolarizing neuromuscular blockers

Answer 3

How can you overcome this problem: increase acetylcholine
Reversible

Competitive antagonists to Ach
Block nicotinic Nm receptors at NMJ
Prevent muscle depolarization and action potential
Muscle cannot contract -> muscle paralysis
Effect can be overcome by using AChE inhibitors
Ex: neostigmine

Question 4

tubocurarine

Answer 4

prototypical drug
natural alkaloid - of plant origin
historically known for its use of arrow poison
onset of action: 4 minutes
duration of action: 45-60 min
Derived from a plant

Used to line the tops of arrows with in war
Will induce paralysis of the respiratory muscles
Now we use this to relax the respiratory system for surgeries so there is no resistance - you want the chest to be relaxed for minimal damage

No longer in use
Other related drugs are safer to use: pancuronium, atracurium

Question 5

depolarizing neuromuscular blockers

Answer 5

Ach agonists
Activate nicotinic Nm receptors at NMJ
Muscle contraction (initially)
Not inhibited by acetylcholinesterase enzyme (AChE)
Continuous and prolonged activation of Nm receptors
Persistent muscle depolarization
No time allowed for repolarization and relaxation
Muscle exhaustion and paralysis

Work with acetylcholine to stimulate muscle contraction, muscle keeps contracting until tired until muscles become paralyzed
Now you reach a status of repolarization

Question 6

succinylchoine

Answer 6

Only drug clinically used right now
Very short acting
Stays for 10 min max
Relatively safe
Doesn’t last long whatever happens
Onset: 30 sec
Duration of action: 5-10 min
Short duration bc it is metabolized by plasma cholinesterase enzyme ( called cholinesterase 2)

Question 7

phases of depolarizing block

Answer 7

Depolarizing phase: (initial)
- Disorganized depolarization of muscle fibers
- Fasciculation (twitching)
- Unable to repolarize
Desensitizing phase:
- After prolonged exposure to the drug
- Muscle repolarize and no longer responsive to Ach
- Flaccid paralysis
- Muscle becomes desensitized
- Paralysis is prolonged by using AChE inhibitors
Then continuous contraction is occurring
Once muscle stops responding doesn’t matter what you add in

Depolarizing phase- induce muscle contraction - initial effect
Failure of repolarization
Failure of relaxation until muscles get tired
Now no more depolarization because the muscle respond
Eventually becomes paralyzed

Question 8

non-depolarizing neuromuscular blockers

Answer 8

• Act like antagonists
  
  • Block Nm receptors
  • Competitive inhibitors of Ach
  • Prevent muscle depolarization and action potential -> inhibition of muscle contraction -> muscle paralysis
    Can be overcome by using AChE inhibitors

Question 9

depolarizing neuromuscular blockers

Answer 9

• Act like agonists
  
  • Activate Nm receptors
  • Mimics Ach activation
    1. Initial depolarization and muscle contraction 2. desensitization and muscle paralysis
    Paralysis is prolonged by using AChE inhibitors

Question 10

Clinical indications

Answer 10

1. Surgeries
   a. Induce skeletal muscle relaxation
   b. Ex: intra-abdominal an intra-thoracic procedures
   
   2. Endotracheal intubation
      a. Relaxation of tracheal and pharyngeal muscles
      b. Facilitates insertion of endotracheal tube
   3. Assisting ventilation
      a. Elim chest wall resistance
      Allow the ventilator to maintain respiration

Question 11

adverse effects

Answer 11

• Paralysis of the diaphragm - respiratory failure
  
  • Hyperkalemia: may cause dysrhythmia - cardiac arrest
  • Muscle pain
  • Malignant hyperthermia (rare)
    Last 3 depolarizing blockers

Question 12

Dose adjustment

Answer 12

Increased dose: burns, UMNL
Decreased dose: old age, myasthenia gravis