Chapter 2 Peripheral nervous system drugs - neuromuscular blockers (Nm antagonists)

Question 1

Nicotinic receptors on muscle end plate

Answer 1

1) Action potential reach presynaptic terminal => cause ca++ influx and cause vesicle to release Ach
2) Ach diffuse across cleft and bind to nicotinic receptors on muscle end plate
3) nicotinic receptors have 5 subunits (two which bind Ach)
4) when both occupied — ion channels open allow Na+ and Ca++ influx and K+ efflux
5) Simulataneous oepning of many channels l/t membrane depolarization and propgation of an action potential in the muscle cell
6) Inducing excitation-contraction coupling mechanism which causes muscle contraction

Question 2

Neuromuscular blockage

Answer 2

• nondepolarizing blockade
  1) pure antagonists compete for nicotinic receptors
  2) antagonists lack activity therefore no muscle contrraction (fascuclations)
  3) blockade overcome by high levles of agonist (Ach)
• depolarizing blockade
  1) when agonist binds to receptor (causing fasciculation) followed by SLOW dissociation of agonist from receptor
  2) during this bound time, other agonist molecules cannot stimulate the receptor

consequence?
* paralysis of all muscles + those for respiration
* intubationt and ventilation equipment must be prepared prior to injecting Nm blockers

Monitoring:
* peripheral nerve stimulator (delivers electrical impulses to nerves by way of electrodes placed on skin
* response to stimulus (muscle twitch) indicates level of Nm blockade
* Train of four
1) 1 twitch — sufficient relaxation w/ nitrous-narcotic
2) 3 twitches — sufficient relaxation w/ inhalation agents
3) 4 twitch >75% of 1st — patient rdy for extubation

reversing Nm blockade
* reversal of Nm blockade allows patient to use diaphragm and intercostal muscles to breathe
* essential that at least a single twitch is produced in response to stimulation before an attempt made to d/c artificial ventilation (purpose/timing)
* pre-reversal: atropine or glycopyrrolate (muscarinic antagonists) administered prior to reversing agents to prevent bradycardia, salivation and other muscarinic effects caused by administration of cholinesterase inhibitors
* reversal – cholinesterase inbhitors inhibit acetylcholine degradation ===> resulting inc’d Ach concentration competes with neuromuscular blockers, reversing blockade!

Question 3

sustained tetany and single stimulation

Answer 3

pt who respond to sustained (5 sec) 50 hz stimulant ready for extubation (pt will cough, inspire, and raise head)

failure to elicit >5% of normal twitch to a single 0.2 msec, 0.1 hz stimulation indicates that blockade is sufficient for intubation

Question 4

Doxacurium (nuromax)

competitive nondepolarizing

Answer 4

action – minimal cardiovascular effect

clinical use – adjunct to anesthesia in long surgery cases; facilitate mechanical ventilation

onset + duration — onset: 3-10 mins + duration 40-240 min

IV + cleared by liver

adverse effect:
transient hypotension and HTN

Order of paralysis
1. small muscles (fingers, eyes)
2. limbs, neck, trunk
3. intercostal muscles, diaphragm

Question 5

Rocuronium (zemuron)

competitive nondepolarizing

Answer 5

• minimal cardiovascular effect

clinical use – faciliate rapid sequence and routine intubation; facilitate mechnical venlation

onset + duration: 1-3 min, 15-60 min

IV – cleared by liver

adverse effect — transient hypotension and hypertension

Question 6

Pancuronium (pavulon)

competitive nondepolarizing

Answer 6

• competes with Ach at nicotinic receptors
• does not activate receptor; blockade can be overcome by high level of agonists
• has vagolytic actions (inc HR)

clinical uses –
* when elevated HR is desired
* adjunct to anesthesia
* facilitate mechanical ventilation and intubation

onset + duration – 1-3 min, 35-55 min

IV - depends on renal excretion (60-80%)
* renal or liver impairment requires dosage adjustments

adverse effects: vagolytic (inc hr)

order of paralysis
1. small muscles (fingers, eyes)
2. limbs, neck, trunk
3. intercostal muscles, diaphragm

histamine release rare

Question 7

cisatracurium

competitive nondepolarizing

Answer 7

• competes with Ach at nicotinic receptors
• does not activate receptor; blockade can be overcome by high level of agonists

clinical use – ideal for pt w/ kidney and liver failure! (metabolized in blood)

onset + duration 2-5 min, 20-60 min

IV – metabolism (hoffman degradation [breaks ester linkage] in bloodstream)

adverse effects – bradycardia + hypotension

order of paralysis
1. small muscles (fingers, eyes)
2. limbs, neck, trunk
3. intercostal muscles, diaphragm

Question 8

atracurium (tracrium)

competitive nondepolarizing

Answer 8

• competes with Ach at nicotinic receptors
• does not activate receptor; blockade can be overcome by high level of agonists

clinical use – ideal for pt w/ kidney and liver failure! (metabolized in blood)

onset + duration 3-5 min, 20-45 min

IV – metabolism (hoffman degradation [breaks ester linkage] in bloodstream)

adverse effect: moderate histamine release (vasodilation, hypotension) — mast cell activation

administer slowly to avoid massive histamine release

order of paralysis
1. small muscles (fingers, eyes)
2. limbs, neck, trunk
3. intercostal muscles, diaphragm

Question 9

vecuronium (norcuron)

competitive nondepolarizing

Answer 9

• competes with Ach at nicotinic receptors
• does not activate receptor; blockade can be overcome by high level of agonists

clinical use –
* adjunct to anethesia: following –>
* muscle relaxant
* eases intubation and ventilation
* eases orthopedic manipulation
* controls respiration during chest surgery

onset + duration: 3-5 min, 25-40 min

IV – little dependence onf kidney (<20%) for elimination
* dosage adjumsnet necessary for liver impairment

adverse effects:
* usually cardiac stable, but induces severe tachycardia, bradycardia, AV block or CHF complications in 1% of pts

order of paralysis
1. small muscles (fingers, eyes)
2. limbs, neck, trunk
3. intercostal muscles, diaphragm

very little histamine release

Question 10

succinylcholine

competitve depolarizing

Answer 10

• initial fasculations (depolarization) then PHASE 1 block (4 min block of voltage sensitive sodium channels)
• Phase 2 block (desensitize receptor, lasts 20 min)
• Parasympathetic stimulation (therapeutic dose)
• Sympathetic stimulation (high dose)

clinical use —
* ideal for intubation b/c of rapid onset and short duration
* adjunct to anesthesia and mechanical ventilation

onset + duration 30-60 sec (IV), 3-5 min

pharmcokinectics
* IM/IV
* diffuses way from endplate
* hydrolyzed by plasma pseudocholinersterase and acetylcholinesterase

adverse effects
* inc intraocular pressure (contraindicted in open eye wounds)
* inc gastric pressure (caution - reflux during intubation)
* dysrhythmias
* post-op muscle pain (myoglobin relase and hyperkalemia)
* May trigger malignant hyperthermia

Orders of paralysis
1) fasciculations in chest and abdomen
2) neck, arms, legs
3) facial, pharynx, larynx
4) respiratory muscle’

effects not reversed by acetylcholinesterase
Other contraindications:
* hyperkalemia
* burns
* digoxin
* myopathies
* pseudocholinesterase deficiency (Pseudocholinesterase is a serine hydrolase enzyme primarily produced in the liver that catalyzes the hydrolysis of choline esters, most prominently succinylcholine and mivacurium)
* glaucoma