Neuromuscular Blocking Agents (Week 3, Mod 7)

What are 4 situations where we would use muscle relaxants clinically?

1) To offset muscle hypertonicity with ketamine

• BZPs (benzodiazepines)

• Alpha-2 agonists

2) To relieve muscle spasms

• BZPs

3) To facilitate smooth induction of anesthesia in large animals 

4) To improve surgical conditions 

• Deep general anesthesia

• Local anesthesia 

• Centrally acting muscle relaxants

• Neuromuscular blocking drugs (muscle relaxants or NMBs)

What kind of muscle do NMBs target? Smooth, skeletal, or cardiac?

SKELETAL muscle ONLY… targets the somatic (voluntary) nervous system

What do NMBs target SPECIFICALLY?

Target nicotinic acetylcholine receptors at the synaptic cleft in a muscle cell

• Are nicotinic receptor ANTAGONISTS

Describe the structure of the nicotinic ACh receptor… how does its conformation change in response to ACh exposure?

Has 5 subunits, each has an alpha helices in the middle 

• Helices act as a gate, undergo a conformational change when receiving acetylcholine at the two alpha subunits (open)

• Allows influx of sodium into the cell to generate an action potential

Describe the general structure of a neuromuscular blocking drug.  How does its structure affect its mechanism of action?

NMBs are rigid, bulky molecules with quaternary N (nitrogen with 4 side chains → positively charged)

• Can’t diffuse through cell membranes, so has to inhibit receptor extracellularly 

• Need to block at least 80% of receptors present… only need about 1% of receptors to activate to generate a muscle contraction

What are the effects of NMBs? What kinds of muscles are more susceptible to these effects, and which are less susceptible?

Causes flaccid motor paralysis ONLY of the skeletal muscle; has no analgesic or anesthetic effects

• UNETHICAL to perform surgery with only NMBs… patient would be conscious while paralyzed 

Muscles that are capable of fast, short contractions will be the first to go (eye muscles, swallowing)

RESPIRATORY muscles are the last to be effected and the first to recover

What are 2 main unwanted side effects of using NMBs? Describe why these happen in detail.

1) Fall in blood pressure - due to GANGLION BLOCK and HISTAMINE RELEASE 

• Ganglions are highly dependent on nicotinic receptors to receive information, and are found all throughout the body; so could see a decrease in the input to the adrenal medulla, who’s products help to regulate blood pressure 

• Histamine release can also cause a drop in blood pressure 

2) Tachycardia 

• Tachycardia is a result of the drop in blood pressure; pumps faster in response

  • PNS is also somewhat blocked by neuromuscular blockers (PNS has MUSCARINIC receptors, which are very similar to nicotinic); PNS acts to slow the heart down, and if this action is blocked, can lead to tachycardia 

Describe the pharmacokinetics of NMBs… how does it need to be administered due to its chemical conformation?  Describe the rate of onset and duration, as well as how its excreted (very general)

NMBs are a quaternary ammonium compound… means it has a positive charge, so can’t diffuse like normal 

• As a result of this, MUST be administered IV

• Equilibriates with extracellular fluid, allowing the drug to move between cells to target the nicotinic receptors of skeletal muscle cells 

• Rate of onset and duration vary

• Generally metabolised by the liver or excreted uncharged by the kidney

• Small Volume of Distribution

  • Do not cross into “protected” organs eg CNS or placenta

How are muscle relaxants used practically?  What are some things you need to consider while using them?

• Are only administered IV

• Will induce apnoea, so patient must be mechanically ventilated

• are only administered to anaesthetised patients

• have no anaesthetic or analgesic effects

• can be ‘topped up’ or given by IV infusion for as long as required

What in particular do you need to consider while recovering a patient from surgery?  Think of what muscles are the first to recover as the NMBs wear off…

Though respiratory muscles are the first to recover after surgery, the muscles that control the airway are actually very sensitive to NMBs

• Therefore, though the patient is capable of breathing independently, they are unable to maintain a patent airway 

  • This is why you keep a patient intubated until they start swallowing

What 4 practical procedures  would require a neuromuscular blocking drug?

• to facilitate endotracheal intubation 

• to relax skeletal muscle for easier surgical access

• to control ventilation during anaesthesia

• ophthalmic surgery

Describe the recovery process from NMBs… whats one way we can speed up this process?

Will occur SPONTANEOUSLY

• As plasma concentration of relaxant declines, drug will move down its concentration gradient from the neuromuscular junction (NMJ) into plasma

• Eventually, sufficient relaxant will have left to restore NM transmission

• However, muscle relaxants are competitive antagonists

  • ACh is broken down by acetylcholinesterase, so if this enzyme is inhibited, ACh levels will increase

  • If ACh concentrations increase to a sufficient level at the NMJ, transmission will be restored

Therefore, can quicken the process of recovery with ANTICHOLINESTERASES

• Inhibits acetylcholinesterase enzyme, keeping it from breaking down ACh as the patient recovers 

What effects are commonly seen after using an anti cholinesterase drug?  Which nervous system are these symptoms from, and what receptor is responsible?

Can cause:

• Bradycardia

• Salivation 

• Bronchoconstricton 

• Urination and defecation 

All stimulated by the PNS… Though antichollinesterases help to increase ACh concentrations at neuromuscular junctions, they also work on EVERY acetylcholinesterase at every synapse in the body… even if its not needed. 

• Happens at MUSCARINIC receptors 

Because of the side effects anticholinesterases cause, what kind of drug is used in conjunction with them?  What is this combination usually called?

An antiMUSCARINIC drug 

This combo is called anticholinergic drugs… IMPORTANT to know the differences between anticholinergic and anticholinesterases 

What is Sugammadex?

An NMB CHEMICAL ANTAGONIST

• Interacts chemically with the NMB itself, rendering it inactive 

• No antimuscarinic needed 

• Is very expensive, so not commonly used 

What are two main factors that could affect the effectiveness of NMBs? Give examples for each.

1) Other drugs

• General anesthetics

• Antibiotics

• Anticholinesterases

2) Pathophysiological conditions

• hepatic / renal impairment

• age

• temperature

• acid base balance

• electrolyte disturbances

• myasthenia gravis - autoimmune disease; destroys nicotinic receptors 

What are the two main centrally-acting muscle relaxants??

Benzodiazepines

• diazepam; midazolam

Guaifenesin  (glycerol gualacolate, “Gee-Gee”)

• blocks impulse transmission at internuncial neurones within spinal cord and brain-stem

• relaxes limb > respiratory muscle

• mild sedation, no analgesia