Muscle Relaxants

PPT from Kristen

Principle physiologic effect

Interrupt nerve transmission of nerve impulses at the neuromuscular junction (NMJ), resulting in muscle relaxation.

Depolarizing muscle relaxants do what?

Mimics acetylcholine

Non-depolarizing muscle relaxants do what?

Interferes w/ acetylcholine (blocks binding)

Effect of action potential depolarizing into the nerve terminal

• Influx of Ca++ ions

• Cause vesicles carrying Ach to fuse w/ terminal membrane

• Ach released via exocytosis into synaptic cleft

Effect of Ach release into the synaptic cleft

If both α subunits are bound w/ Ach then ligand gated ion channel opens

Neuromuscular Transmission

• Depolarization of motor end plate

• Na channels open, releasing Ca from Sarcoplasmic reticulum

• Actin & myosin interact causing muscle contraction

Contractile proteins:

• Actin

• Myosin

Acetylcholine (Ach) is rapidly hydrolyzed by what?

• in the NMby Aceytlcholinesterase breaking it into

  • Acetate

  • Choline

How is Ach built?

By Choline acetyltransferase (CHAT)

• Acetyl Coa + choline = Acetylcholine

Therapeutic uses of muscle relaxants

• allows for less anesthesia

• minimizes cardiovascular depression

• provides surgical relaxation

Clinical uses of neuromuscular blockade (NMB)

• Provide skeletal muscle relaxation

• Facilitate intubation

• Improve surgical conditions

• Mechanical ventilation in ICU

Pharmacokinetic characteristics

• Quaternary amoniums (

• Highly ionized (Polar)

• Highly Water soluble

• Limited volume of distribution (Vd) similar to ECF

  • Do not distribute to adipose tissue so use IBW instead

• Cannot cross BBB (no CNS effects)

• Not highly plasma protein bound

Quaternary Ammoniums

Positiviely charged polyatomic ion where a Central nitrogen is bonded to four carbon based groups

Depolarizing Neuromuscular Blocking Agents examples

Succinylcholine

Non-depolarizing Neuromuscular Blocking Agents Examples

• Rocuronium

• Vecuronium

• Cisatracurium

• Pancuronium

Succinylcholine characteristics

• Only depolarizing NMBA currently used

• Agonist at the NMJ (2 Ach molecules fused)

• Non-reversible

• Depolarizing effect occurs 20-40s after administration

• Fasciculations are a classic Side effect

• Flaccid paralysis after ~6-7 minutes (intended goal by anesthesia)

What are fasciculations?

• Brief, spontaneous & involuntary contractions of a single muscle motor unit

• Appear as visible skin twitches or “rippling” under the skin

• classic side effect of succinylcholine

Succinylcholine binding

• is Di-acetylcholine

• Binds to and activates Ach receptor mimicking Ach (Depolarizing agonist)

Succinylcholine metabolism

• Pseudocholinesterase

  • not located in synaptic cleft

  • synthesized by the liver and freely circulates in the plasma

  • cannot be broken down by Ach esterase so NMB only ends when Sch diffuses away from NMJ

Side effects of Sch

• Sinus bradycardia/sinus arrest

• Malignant hyperthermia trigger

• Myalgia

• INC’d intracranial pressure (ICP)

• INC'‘d intraocular pressure (IOP)

• INC’d K+

Non-depolarizing NMB characteristics

• bind to one or both Ach receptors

• Competitive agonists to Ach

• No conformational in Ach receptor

• Long acting

• reversible

Pancuronium characteristics

• Steroid ring w/ 2 modified Ach molecules

• Metabolized by Liver P450

• Tachycardia side effect

Duration of Pancuronium

• Full paralysis in 2-4 minutes

• Long acting effect ~ 100 minutes

• ½ life = 2 hrs

Vecuronium characteristics

• steroid ring

• Metabolized in the liver, Kidney and biliary excretion

Duration of Vecuronium

• Full paralysis in 45-60 seconds

• Intermediate acting ~ 45 minutes

• ½ life = 65-75 min

Cisatracurium characteristics

• Benzylisoquinoline

• Organ independent metabolism

  • Hoffman elimination

  • Ester hydrolysis

Duration of Cisatracurium

• Full paralysis in 2-3 minutes

• Intermediate acting ~ 40 minutes

• ½ life = 22-29 min

Rocuronium characteristics

• Steroid ring with 1 modified Ach molecule

• Metabolism by liver and biliary excretion

Duration of Rocuronium

• Full paralysis in 1-2 minutes

• Intermediate acting 30-60 minutes

• ½ life = 1.5 to 2.5 hrs

Standard intubation dose of rocuronium

0.6 mg/kg

Rapid sequence intubation dose of Rocuronium

1.2 mg/kg

Standard intubation dose of Vecuronium

0.08 to 0.1 mg/kg

Rapid sequence intubation dose of Vecuronium

0.1 to 0.2 mg/kg

Maintenance dose of rocuronium

0.1 to 0.2 mg/kg

Standard intubation dose of pancuronium

0.1 mg/kg

Standard intubation dose of Cisatracurium

0.15 to 0.2 mg/kg

Maintenance dose of Cisatracurium

0.02 mg/kg

Maintenance dose of pancuronium

0.02 mg/kg

Reversal agents

• Anticholinesterase

  • competitive at Ach receptor

  • Makes more Ach available by blocking the breakdown of Ach

Anticholinesterase characteristics

• Inc available Ach at NMJ (more chance for muscle contraction as more chance for Ach to bind)

• Bind and temporarily disable acetylcholinesterase

Anticholinesterase examples

• Neostigmine

• Pyridostigmine

side effects of excess Ach

• Salivation

• Lacrimation

• Urination

• Defecation

• GI upset

• Emesis (vomiting)

  • Bradycardia

  • Bronchospasm

Anticholinergics

Used in conjunction w/ anticholinesterase to prevent Ach from acting at other sites

(helpful because anticholinesterase causes excess Ach to build up, prevents side effects by preventing excess Ach from binding so it just circulates in the NMJ)

Anticholinergic examples

• Atropine

• Glycopyrrolate