4. Neuromuscular blocking & anti-cholinesterases Flashcards
Rocuronium
Type ED 95 Intubating dose Time to 95% depression TOF Time to recovery of 1st TOF
Reversed by what (& group)
Solubility water / fat
Excretion
Mtabolite
aminosteroid
develop
What is ED 95
What is the ED 95 of common NMB
Most potent
Roc, sux, vec, mivac, citrac pan
Dose required to depress the twitch height by 95%
The ED95 (mg/kg) of the commonly used neuromuscular blocking agents are:
vecuronium: 0.04 (0.1 mg/kg induction, 2.5x the ED95)
cisatracurium: 0.04 (0.2 mg/kg induction, 5x the ED95)
Pancuronium: 0.07 (0.1 mg/kg induction, 1.4x the ED95)
mivacurium: 0.08 (0.15 mg/kg induction, 2x the ED95)
suxamethonium: 0.27 (1mg/kg induction, 3-4x the ED95)
rocuronium: 0.31 (0.6-1 mg/kg induction, 1.9 to 3.2x the ED95)
Prolong non depol
delete and put into 1 card
Suxamethonium side effects
- myalgia ranges from 1.5 - 85%
- female
- ambulatory surgery
- like DOMS
no corel to fasiculations
- Transiet pottasium rise
- dangerous burns
- high SC injury
safe <48h from injury - Prolong block
- phase 2
genetic / acquired deficiency plas cholinesterase - Sux apneoa 1:1800
- Anaphylaxis
1: 1000. - MH
1: 45000 -100000
Adequate reversal
Ability to hold the head off the pillow for five seconds
Generation of tidal volumes of 15 ml/kg
Four equal twitches on train of four count
T4:T1 ratio of 0.9
PTC
used when too deep to see TOF
stimulation at 50Hz 5s mobilise enough presynaptic acetylcholine allow assessment deep block
ost-tetanic count of >15 approximates two twitches on the train-of-four count
Organophosphate poisoning
Pesticides and ‘chemical nerve agents’
Irreversibly bind to acetylcholinesterase (AChE) in the synaptic clefts of nerve termin
Form Covalent bond serine site
prevents bdown of Ach
Overstimulation of muscarinic and nicotinic ACh receptors in the autonomic nervous system
Overstimulation of ACh receptors in the central nervous system
Overstimulation of ACh receptors at the neuromuscular junction.
NDMR
How work
Where
Classified & ex
Non-depolarising muscle relaxants (NDMRs) inhibit the actions of acetylcholine at the neuromuscular junction by binding competitively to the α-subunit of the nicotinic acetylcholine receptor on the post-junctional membrane.
They also have effects on prejunctional receptors that serve to modulate acetyl choline release. Blockade of the receptors are thought to be responsible for fade during tetanic stimululi or train of four.
Aminosteroid
vecuronium, rocuronium and pancuronium.
benzylquinolinium:
atracurium, mivacurium and tubocurarine.
trac metabolic pathway
Temp + pH
pathway and undergoes ester hydrolysis accounting for 60% of its metabolism, and Hofmann elimination, which is temperature and pH dependent.
As pH and temperature decrease, Hofmann elimination also decreases and the reverse applies to and increase in temperature and pH.
Hyoscine
Properties
BBB - hydrobromide v butylbromide
S/E
Use
Repeat dosing
The antimuscarinic drug hyoscine (scopolamine) is a naturally occurring belladonna alkaloid with smooth muscle relaxant (antispasmodic) and antisecretory properties.
Hyoscine hydrobromide does cross the blood-brain barrier and so may cause sedation or drowsiness (hyoscine butylbromide does not cross the BBB) and it has a central antiemetic action (useful in motion sickness).
Repeated administration of hyoscine hydrobromide leads to accumulation, which occasionally can paradoxically result in an agitated delirium.
The central anticholinergic syndrome (excitement, ataxia, hallucinations, behavioural abnormalities and drowsiness) is a side effect of its use.
Pupillary dilatation is a feature, but a tachycardia (heart rate >100/minute) is rarely seen.
Atracurium
whats it made up of
tube dose
metab
affect how
metabolites
problems
benzylisoquinolinium
10 stereoisomer
4 chiral
intub dose 0.5mg kg - moderate duration
Body temp <40% hoffman -> Laudenosine - neuro side effects
Inc w/ inc temp & temp
Remainder - ester hydrolysis
reduced by alkalosis and enhanced by acidosis
both metabolisms yield laudonise
His release - reflex tachy
Stored at 2-8° (RT - activity sml % per month)
Elimination of a hypothetitical NMB w/ 3 quaterny n & Hep extraction ratio .25
Likely fitered kidny & not reabsorbed
Would be polarised - Low Vd
Unlikely ester - not tfer tissues
Mivacurium
Metabolism
Mivacurium with plasma cholinesterase deficiency
Heterozygous - 50% prolongation has been shown.
Homozygous - extend to 2 hours
Prolong / potentiate NDMR
Hypokalaemia Hypocalcaemia Hypermagnesaemia Metabolic alkalosis Respiratory acidosis and Hypothermia. enzyme activity decreased
drugs
Antibiotics such as streptomycin, polymyxin and neomycin
Cocaine, procaine and lidocaine and
Lithium due to its hypokalaemic effect.
Amitryptilline ; TCA - closed channel block
Verapamil - open channel
Vecuronium
Aminosteroid
10 mg of powder in mannitol and sodium hydroxide
unstable soln
Monoquaternary aminosteroid
Competitive inhibitor @ alpha subunit Nic AchR
Intubating dose 0.1 mg/kg - in 120 seconds.
(
Most CVstable
Least rel His
Lowest anaphylaxis
3, 3-17 and 17 dihydroxyvecuronium. 3 hydroxyvecuronium is an active metabolite
accumulate in renal failure.
Sim structure Roc ; Panc
more lip sol vs panc)
(panc releases norepi)
Suxamethonium
a dicholine ester which is equivalent to two acetylcholine molecules joined together
side effects include:
Bradyarrhythmias nodal brady secondary to direct nodal musc stim Myalgia Hyperkalaemia Raised intraocular pressure Anaphylaxis Malignant hyperthermia.
Doesnt cause increased reflux - increases tone of LOesSph
plasma cholinesterase (pseudo-cholinesterase) and only 20% of the administered dose reaches the neuromuscular junction.
A large total dose or repeated dosages of suxamethonium can cause a phase II block.
Sugammadex
Sugammadex is licensed for immediate reversal of rocuronium-induced neuromuscular blockade at a dose of 16 mg/kg.
modified gamma-cyclodextrin
encapsulate aminosteroid
A concentration gradient then forms which pulls the NMB molecules from the neuromuscular junction in the tissues back into the bloodstream.
Though it is most effective in reversing rocuronium, it will also reverse vecuronium. It has been shown also to bind weakly to pancuronium.
Neostigmine -
what is it
use
Action
direct or indirect
Type of molecule
motion in body
Onset + duration
Excretion
Neostigmine is an acetylcholinesterase inhibitor which is used to reverse a non-depolarising block and is used in the management of myasthenia gravis.
Inhibition of the acetylcholinesterase enzyme increases the concentration of acetylcholine at the neuromuscular junction. It also directly stimulates acetylcholine receptors in skeletal muscle and may cause a depolarising block in overdosage (not non-depolarising block).
It is a quaternary ammonium compound and poorly crosses the blood-brain barrier and has few central nervous system side effects.
When given intravenously it is active within one minute and lasts 20 - 30 minutes.
It is excreted renally and is mostly unchanged and has an elimination half life of 50 - 90 minutes.
Suggamadex is a
Recommended for us with
in what patient group
How does it work
Sugammadex (Bridion), a modified gamma-cyclodextrin,
Rocuronium- or vecuronium-induced moderate or deep muscle relaxation in adult (including elderly) patients and reversal of rocuronium-induced moderate muscle relaxation in paediatric patients.
Mechanism of action of sugammadex is to encapsulate rocuronium to provide for a rapid reversal of residual neuromuscular blockade.
Resistance to NDMR
a/w
x4
1 Burns
2 Antiepileptic drugs
3 Intracranial lesions
4 Hemiplegia (when neuromuscular function is monitored on the affected side).
Long term phenytoin therapy shortens the duration of action of long acting muscle relaxants by 50%. Burn victims and patients suffering from stroke may be resistant to non-depolarizing NMBDs (likely due to extrajunctional receptors).
Hypothermia is associated with prolongation (not resistance) of neuromuscular blockade.
Patients with myasthenia gravis are extremely sensitive to non-depolarising neuromuscular blockade.
Atracurium
Type compound
MOA
Cross placenta?
Why
Release
Metbolism
Atracurium is a benzyl isoquinolinium ester compound. It is a competitive antagonist at the neuromuscular junction preventing acetylcholine from binding.
Like all non-depolarising muscular blockers it is a highly charged quaternary compound. It is therefore unable to cross the placenta easily.
Atracurium can cause histamine release. This is reduced by using the enantiopure cis-atracurium.
About 60-90% of atracurium is metabolised by ester hydrolysis by non-specific esterases.
It also undergoes non-enzymatic breakdown (Hofmann elimination). The atracurium molecule combines with a base which catalyses a reaction to produce the metabolites, quaternary monoacrylate and laudanosine.
The Hofmann elimination is pH and temperature dependent.
Gantacurium
Class
Dose
Onset
Recovery TOF
Releax w/ suggamadex?
Broken down
by
Reversed with
The newest benzylisoquinolinium non-depolarising muscle relaxant is gantacurium, which is currently undergoing phase III trials in the U.S. When given as a dose of 1.8-4 ED95 it has a rapid onset of action of 90 seconds with spontaneous recovery of the train-of-four (TOF) ratio to 0.9 in approximately 10-14 min (intermediate duration).
Steroidal neuromuscular blocking relaxants are most likely to be reversed with sugammadex (rocuronium, vecuronium and pancuronium).
Gantacurium is broken down non-enzymatically to inactive metabolites by the endogenous amino acid, L-cysteine, in plasma. This amino acid conjugates with the central double-bond carbons in gantacurium causing alkaline hydrolysis. The exogenous administration of L-cysteine immediately reverses the effects of a dose of gantacurium.
It has been developed as a possible replacement for suxamethonium.
Features organophosphate poison
Rx of organophosphate
This leads to excess cholinergic activity and features that include:
Vomiting Diarrhoea Rhinorrhoea Salivation Constricted pupils Convulsions Muscle fasciculation Muscle paralysis (including respiratory) Apnoea Death.
Treatment consists of atropine to antagonise the cholinergic effects, and oxime (pralidoxime) to limit the inhibition of cholinesterase and diazepam to prevent seizures.
Trac metabolites
elim how
Hoffman degradation - 30-70% non-enzymatic spontaneous process which is temperature and pH dependent. Reduced at low temperature and pH conditions.
Ester hydrolysis - catalysis by non-specific plasma esterases.
principal metabolites are
laudanosine,
tetrahydropapaverine and
a monoquaternary alcohol metabolite
NDMR
Where& what do they act
specifically
What does blockade cause
inhibit the actions of acetylcholine
Neuromuscular junction
binding competitively
α-subunit
nicotinic acetylcholine receptor
post-junctional membrane.
They also have effects on prejunctional receptors that modulate acetyl choline release.
Fade during tetanic stimululi or train of four
What is the NMJ
Connection motor neuron & skeletal muscle fibre - NT ACh
Terminal axon - fas Aalpha motr neurone lies in groobe in middle surface m,uslce fibre it innervates
Most muscles - single terminal axon innervates a single muscle fibre
Some - intra ocular, intrsic laryngeal & some facial muslce - fibre innervation - multiple slower Ay motor fibres
Post synaptic membrane - folded - form peak & trough - on surface
Membrane over peak - ach recpt
trough contrain achesterase
AP arrives - depol influx ca
Ca - combine protein faciltate fusion vesicle - containing ach in presynamptic membrane
Central ion chanel of receptor opens- allow movement Ions across membrane
Movement of these ions allows generation of a min end plate potential
Summation of several end plate potentials continue until threshold potential reached
at this point voltage gate Na channel open rapid depol cell memnbrane
Depol - spreads thru fibre - reaches SR cause Ca release * contraction
How is Ach broken down
Acteylchonilestarse in torugh of post synaptic membrane
bind to either ester group Ach molecule or the quaternary ammonium group
choline removed
recycle - acetalyed enz hydrolysed to acetic acid
Classify drugs
Prevent synthesis
Prevent release
Deplete stores
Block receptoor
How is ach formed
Combineation choline & acteyl coa - catlysed by enz choline acetyl transferase
Syhtsises in acoplasm of motor nuerone 0 tprot to terminal axon - stored vesicle
Choline derive diet - recycle breakdown other acteylchol molecu
Hemicholinum
Prevent acetylcholinse synthesis
Synthetic compound
prevent uptake choline into nerve ending - reduce synth
Mg & aminoglycoside
Inhib ca entry in synaptic terminal
prevent release AcH
Botox
Binds irreversibly -> nicotnic nerve terminals to prevent ach release
Tetanus toxin
Depletes stores - rendering paralsyed
Depolarising muscle blockade
Sux what is it
phsyical prop
Suxamethonium
2 ach molecules join by ester link
Rapid profound muscle releax
facil intub trach
praylsis short procedure
modify effect sz - ect
Colourless soln cl salt 50mg.ml
store 4C prevent det
destroyed alkaline pH - not mix thio
Sux MOA
Metab/bbreakdown
MOA bind revs to ach recept on post synaptic - cause depol membrane
Mechaism breakdown - depol prolong create& create membrane potential not allow generation urther potent - relax
Broken down bytylucholinesterase - plasma but not NMJ
Lack plasma chol NMJ - explain prolong duration action
Hydrolysis sux by plasma cholinseterase - produce weak active metab - succinylmonocholine & choline - further hydrolsed by pl cholinest
succinic acid +; choline
Admin dose sux - 20% reach NMJ
rapid metab 2-10% excrete urine
Non depol MR
Competitive antago at NMJ - bind a subunit of nictonic receptor on post junctional membrane
