Neuromuscular Blockers Pharmacology

-paralyzing agent

-causes respiratory arrest

-pt must be ventilated

What are the warnings with neuromuscular blockers?

central nervous system

-brain and spinal cord

-integrative control centre

peripheral nervous system

-peripheral nerves (cranial and spine)

-communication between CNS and body

sensory (afferent) division

-composed of sensory neurons

-conducts signals from receptors to CNS

motor (efferent) division

-composed of motor neurons

-conducts signals from CNS to effectors

autonomic nervous system

controls involuntary responses

somatic nervous system

controls voluntary movement

sympathetic division

-mobilizes body systems

-flight or fight responses

parasympathetic division

-conserves energy

-rest and digest responeses

ACh

binds to ligand gated nicotinic receptors on muscle fibers (nAChR)

neuromuscular blocking agents

-induce muscle paralysis during surgical procedures and in the ICU

-surgical relaxation

-facilitate endotracheal intubation

-control ventilation

respiratory depression

What would be the worst thing it could happen if a patient is mistakenly administered a NM blocker?

rapidly

Larger muscles (eg, abdominal, trunk, paraspinous, diaphragm)are more resistant to neuromuscular blockade and recover more __________ than smaller muscles (eg, facial, foot, hand).

diapharygm

is usually the last muscle to be paralyzed and the first to recover from NM blockers

administration of the wrong drug

What is the most common type of error with NM blockers?

by preventing nACh receptor signaling

1) non-depolarizing/antagonists

2) depolarizing blocker

How can we block muscle contraction?

non-depolarizing NMBA intermediate acting

-Cisatracurium

-Vecuronium

-Rocuronium

non-depolarizing NMBA long acting

-Pancuronium

-Tubocurarine

Depolarizing NMBA

Succinylcholine

-AChE inhibitors: Neostigmine, Pyridostigmine, Edrophonium

-Sugammadex

What drugs reverse the neuromuscular blockade?

MOA of Non-depolarizing NM blockers

Competitive AChR antagonist-compete for nAChR binding at muscle membrane in NMJ end plate

tubocurarine

Nondepolarizing neuromuscular blocking agent prototype: competitive nicotinic blocker

PK of non-depolarizing NM Blockers

-Highly ionized (polar), do not easily cross any cell membranes

• No CNS penetration

• Not absorbed in GI tract → only parenteral administration

• DoA strongly correlates with elimination t1/2 (little/no active metabolites)

0.8-1.4 mins

What is the onset of action for Succinylcholine?

6-11 mins

What is the duration of Succinylcholine?

hydrolysis by plasma cholinesterases

How is succinylcholine eleminated?

2-3 mins

What is the onset of Vecuronium?

25-40 mins

What is the duration of Vecuronium?

hepatic and renal elimination

What is the mode of elimination of Vecuronium?

0.5-2 mins

What is the onset of action of Rocuronium?

36-73

What is the duration of action of Rocuronium?

hepatic elimination

What is the mode of elimination of Rocuronium?

2-8 mins

What is the onset of action of Cisatracurium?

45-90 mins

What is the duration of action of Cistracurium?

hofmann reaction

What is the mode of elimination of Cisatracurium?

6 mins

What is the onset of action of d-Tubocurrarine?

80 mins

What is the duration of action of d-Tubocurrarine?

renal and hepatic elimination.

What is the mode of elimination of d-Tubocurrarine?

3-4 mins

What is the onset of action of Pancuronium?

85-100 mins

What is the duration of action of Pancuronium?

renal and hepatic elimination

What is the mode of elimination of Pancuronium?

intermediate acting NM blockers

more commonly used than long acting

Rocuronium

is the least potent but most rapid onset

Atracurium

-rarely used bc of AEs but cheaper

-active, toxic metabolite of laudanosine

Cisatracurium

-is a potent stereoisomer of atracurium

-Less laudanosine formation

-More advantages clinically, fewer AE

-One of the most common in use today

Tubocurarine

prototype (first described) no longer available

Pancuronium

-rarely used

-DOA > 1 hr

-steroidal

-moderately increased HR, BP, CO

-tachycardia mainly due to vagolytic action, but also NE release and block of NE reuptake

use acetylcholinesterase (AChE) inhibitors

Whats the first option to reverse non-depolarizing NM blockers?

Neostigmine; pyridostigmine

-inhibit AChE and also directly increase ACh release

-muscarinic effects

Edrophonium

-inhibits AChE activity; more rapid onset; less effective in presence of potent NM blockade

-muscarinic effects

Sugammadex (Bridion)

-can rapidly encapsulate and inactivate the steroidal agents

-Rocuronium and Vecuronium (only approved for these!) → complex excreted in urine

-faster reversal

-no muscarinic effects

AEs of Sugammadex

-Hypersensitivity reactions (nausea, pruritus, urticarial)

-May cause anaphylaxis

-Might also encapsulate progesterone

Succinylcholine

-depolarizing NM blocker

-Receptor opening once →depolarization; and then receptor stays desensitized

MOA of Succinylcholine

agonist at AChR

1. Depolarizes membrane by opening nAChR channel in the same way as ACh.

2. Spreads to adjacent membrane → transient contractions (fasciculations)

3. Succinylcholine persists longer at NMJ than ACh because of its resistance to degradation by AChE → prolonged depolarization

4. Persistent stimulation causes Na+ channels inactivation. Membrane remain depolarized, but unresponsive to subsequent impulses (channels do not open again until membrane is repolarized) → flaccid paralysis

5. If prolonged exposure (infusion or repeated boluses), membrane gradually repolarizes but neurotransmission remains blocked (receptor desensitization)

within 60 seconds

What is the onset of action of Succinylcholine?

DoA of Succinylcholine

-Very short! (5-10 min)

-Very favorable for short procedures, emergencies where immediate airway management is required

-Plasma cholinesterase has large capacity to metabolize, only fraction of initial dose reaches NMJ → Circulating plasma cholinesterase directly influences DoA

AEs of Succinylcholine

-Hyperkalemia; probably as result of fasciculations (K+ release from muscle cells), esp. in pts with burns, nerve damage, NM disease, closed head injury

-Muscle pain related to fasciculations

-Bradycardia; can stimulate SA node muscarinic receptors in some patients (children)

malignant hyperthermia

What is the interaction of Succinylcholine + volatile anesthetics (halothane)?

dantrolene

How do you treat the malignant hyperthermia caused by Succinylcholine + volatile anesthetics (halothane)?

malignant hyperthermia

Rare autosomal dominant disorder (mostly mutation in the ryanodine receptor type 1) that leads to a life-threatening hypercatabolic state

Dantrolene (Ryanodex®)

-interferes with release of intracellular Ca+2 → used IV to treat the muscle rigidity & hyperthermia

-requires fast admin (IV) to control acidosis and muscle contraction