Muscle relaxants and autonomic pharm Flashcards
Sux
Roc
Vec
Pan
Atra
CisAtra
What class is suxamethonium
Dicholine ester - 2 ACh molecules combined
What class is rocuonium
Aminosteriod
Give 3 examples of an aminosteriod
Roc, Vec, Pancuronium
What class is atracurium
Benzylisoquinolinium
What drugs belong in the class Benzylisoquinoloinium
Atracurium and cisatracurium
What preparation does suxamethonium come in
50mg/ml in 2ml
What preparation does rocuonrium come in
10mg/ml in 5ml
What preparation does vecuonium come in
Freeze dried powder 10mg ampule
What preapration does pancuronium come in
2mg/ml in 5 or 10ml ampule
What preparation does atracurium come in
10mg/ml in 5ml/2.5ml/25ml ampule
What preparation does cisatracurium come in
2mg/ml in 5ml ampule
What is the dose of suxamethonium
1mg/kg (0.5 - 1.5)
ED 95 0.5mg/kg
What is the dose of rocuonium
0.3mg/kg ED 95
0.6 mg/kg intubation
1.2mg/kg RSI
What is the dose of vecuronium
0.05mg/kg ED 95
0.1mg/kg intubation
What is the dose of pancuronium
0.06mg/kg ED 95
0.1mg/kg intubation
What is the dose of atracurium
0.25mg/kg ED 95
0.5mg/kg intubation
top up dose 0.1-0.2mg/kg
What sit he dose of cistatracruium
0.05mg/kg ED95
0.15mg/kg intubation
Onset of suxamethonium
End of fasciculations
30-60 seconds
Onset of rocuonrium
90-120 seconds
Onset of vecuronium
2-3 minutes
Onset of pancuronium
3-6 minutes
set of atracurium
2-3 minutes
Onset of Cisatracurium
3-6 minutes
Duration of action of suxamethonium
5-10 minutes
Duration of action of Rocuonrium
35-50 minutes
Duration fo Vecuronium
30-40 minutes
Duration of action of pancuronium
70-120 minutes
Duration of action of atracurium
35-50 minutes - 95% recovery
Hypothermia doubles this
Duration of action of Cisatracurium
40-55 minutes
Volume of distribution of Suxamethonium? T1/2 beta
0.25L/kg
Protein binding 30%
T 1/2 life beta 5 minutes if normal plasma cholinesterase and 90 minutes in compelte absence of palsma cholinesterase
Distribution of rocuronium
180ml/kg *small!!
Volume of distirbution of vecuronium
200ml/kg
Volume of distribution of pancuronium
250ml/kg
Protein bidning <50%
Volume of distribution of atracurium
170ml/kg
Does not cross BBB
Does not cross placenta
82% protein bound
Volume of distribution of cisatracurium
200ml/kg
Metabolism of suxamethonium
99% plasma cholinesterase. To Succinyl-monocholine and choline –> then succinylmonocholine (weakly active) to succinic acid and choline
Only 20% of IV dose reaches NMJ before being hdyrlysed
Excretion of sexamethonium
<10% in urine
Suxamethonium reversal
nil
Suxamethonium adverse effects - 9 things
3 A’s
3’Ms
3’s Hs
Apnoea - succ apnoea due to plasma cholinesterase
A - Arrhythmia - bradycardia repeat does, stimulation of muscurinic recepeotrs in sinus node. Jucntional arrhtyhmias, K mediated
A - Anaphylaxis - most common drug to cause it
M - malignant hyperthermia
M - myalgias - 50% incidence, muscle fibre damage during fasciculations, 24-72 hours, facial, neck, intercostal and abdominal muscles. Female, middle age more common
M - masseter spasm
H - hyperkalaemia - 0.5mmol - depolarisation involves efflux of K into CSF. Burns, UMN lesions and SC injury have proliferation of extrajunctional recepotrs
H - histamine release
H - High cavity pressure - intragastric, ICP, IOPincrease by up to 10mmHg (lower oesophageal spincter tone increases more)
Rocuronium metabolism
Minimal (hepatic)
no active metabolites
Rocuronium Excretion
unchanged in bile - 80%
20% in urine
Rocuronium reversal
Sugammadex
Neostigmine
Adverse effects of rocuonrium
High dose –> tachycardia
Pain on injection
Anaphylaxis
Vecuronium metabolism
30-40% hepatic - hepatic de-acetylation to 3 hydroxy vecuronium with a very short half life, 60% as potent and renally excreted
Active metabolites
Reanl clearance also
Vecuronium excretion
Hepatic and renal clearance
Vecuronium reversal
Sugammadex
Neostigmine
Vecuronium Side effects
Minimal
Anaphylaxis rare
Pancuronium metabolism
30-40% hepatic - de-acetylation
Active metabolites - 3 hydroxypancuronium 50% as potency
70% however is excreted uncahnged, metabolites excreted in bile
Pancuronium excretion
70% however is excreted uncahnged, metabolites excreted in bile
Pancuronium reversal
Neostigmine
Pancuronium side effects
Tachycardia by 20%
Increased MAP by 20%
indirect sympathomimetic be reducing NA reuptake at post-ganglionic nerve ending and blocking cardiac muscurinic recepotors
Atracurium Metabolism
2/3 –> ester hydrolysis by non specific plasma esterases –> laudanosine (excreted in urine) and acrylates. Acidosis accelerates this
1/3 Hoffman elimination - pH and temperature dependnet process (both increase metabolism) also producing the same metabolites
Excretion of atracurium
10-30% renal
Reversal of atracurium
neostigmine
Adverse effects of atracurium
histamine release
Laudanosine accumulation causes seizurese - after 6 days of infusion this risk occurs
Increases risk of critical illness myopathy
Cisatracurium Metabolism
80% hoffman elimination to laudanosine (cleared by liver)
Hoffman degradation is cleavage of the link betweent he quaternary nitrogen ion and the central chain
Minor pathway via hydrolysis by non specific esterases in the blood to quaternary alcohol and quaternary acid
Metabolites insignificant to NMB
Excretion of cistracurium
10-15% unchanged in urine
6ml/kg/min
Elimination half life 20 minutes
Unaltered clearance by renal or hepatic impairement
Cisatracurium reversal
Neostigmine
Cisatracurium adverse effects
No histamine release
Acetycholine is found where?
NMJ
Pregaglionic PSNS and SNS nerve fibres
Post ganglionic PSNS and SNS fibres (sweat glands
How is acetylcholine made?
Choline + Acetyl CoA under catalyst choline acetyltransferase
Where does choline come from?
Diet, liver synthesis, reuptake from synaptic cleft after breakdown of ACh
Where does Acetyl CoA come from
Produced in mitochondria from pyruvate and CoA by pyruvate dehydrogenase
Acetylcholinesterase is found where
Synaptic cleft
post synaptic folds
How does acetychloinesterase work
Hydrolyses acetylcholine to Choline and acetate
A non depolarising block has what 2 key characteristics
Competitive inhibition
No fasciculations
What effect does a non depolarising block have on tetanic stimulation and TOF? What about pot tetanic potentiation?
Fades with tetanic stimulation and TOF due to reduced ACh mobilisation
Post tetanic potentiation –> increased ACh syntheiss and release, increase calcium in synaptic terminal
Non depolarising muscle relaxants act on each muscle group equally true or false
false
Diaphragm and laryngeal adductors (vocal cords) - onset of action more rapid but less intense –> greater blood flow to centrally located muscles. They are somewhat resistant to effect of NDMRs as composed of faster fibres, more ACh recepotrs and therefore more receptors need to be occupied.
Recovery is fastest in the diaphragm –> laryngeal adductors –> adductor pollicus
Adductor policus slower onset of action, but sensitive. It is blocked more than respiratory muscles
Orbicularis oculi closely reflects laryngeal adductors
Depolarising muscle relaxants act how at the acetylcholine receptor?
Non competitive
Prejunctional action fo ScH produces fasciculations
Depolarises the post junctional membrane
Does suxamethonium produce fade? Post tetanic potentiation?
No to either
What happens if anticholinesterase is given to someone with Suxamethonium
Augmented action
What is a phase 2 block in the context of muscle relaxants
Seen in suxamethonium with reptitive or prolonged use
Proposed mechanism is a prejunctional block + post junctional desensitisation –> coincides with tachyphylaxis and produces a blocks imilar to rocuronium
Abruptly transitions from phase 1 block where the usual rapid onset and recovery does not accor
Unpredictable reversal with anticholinesterases
Risk factors - atypical cholinesterase, myasthenia, neonates
What is a desensitisation block?
Differs from phase 2
Nicotinic Ach receptors insensitive to channel opening effects of agonsits including ACh
Due to phosphoryltion fo the receptor
Safety mechanism to prevent overexcitation at the NMJ
What are the ideal physicochemical properties of a NMJ blocking agent
Water soluble
Stable in solutino
Sterile without additives
Long shelf life
No refridgeration
Cheap
Compatible with othe drugs
Pharmacokinetic proerties of an ideal NMJ blocking agent
rapid onset
Short duration
Rapid metabolism
Inactive metbaolites
No transfer across BBB or placenta
Organ independent elimination
Pharmacodynamic properties of an ideal NMJ blocking agent
Non depolarising
Action confined ot NMJ
Availability of specific reversal agent
No locla or systemic effects
No histamine release
No trigger of MH
What is a long acting neuromuscular blocking agent
Pancuronium
What is the structure of suxamethonium or succinylcholine
two Acetylcholine molecules linked by the acetyl groups
MOA of succinylocholine
Mimics action of ACh - one or both alpha units of nicotinic ACh receptor at NMJ simulated leading to membrane depolarisation. Slow hydrolysis of SCh (plasma cholinesterase not present at the NMJ)
Sustained opening of receptor ion channel, sustained depolarisation of post junctional membrane and depolarised post junctional membrane cannot respond
Recovery of recepotr due to diffusion away into plasma down a concentration gradient. Plasma cholinesterase metabolism
Non depolarising muscle relaxant MOA
competitive antagonsits of ACh at post synaptic nicotinic ACh receptors of the NMJ
Bind to one or both alpha subunits f the recepotr with no conformational change but prevent access of ACh to the recepotr. Binding is dynamic with repeat associationa nd dissociation. Higher concentration of ACh can displace
ED95 is what?
95% twitch depression at adductor pollicus
INtubation dose relative ot ED95
2-3xx
ED50
median dose correpsonding to 50% twitch depression at adductor pollicus
Drug factors affecting onset fo action in NMB
DPPI
Dose - increase faster onset
Potency - decreased potency –> more drug molecules adminsitered –> more recpeotrs occupied –> faster onset
Physicochemical
- Mollecular weight, ionisation, lipid solubility, protein binding, volume distribution
Drug interactions
Patients factors affecting onset of action of NMB
Cardiac output - high = faster onset
Skeletal muscle blood flow - diaphgram and laryngeal adductors more blood flow
Age - infants higher cardiac output and muscle floow
Site of ijection
Myasthenia - faster onset
Which drugs potentiate the action of neuromuscular blockade
Voltaile anaesthetics - depressed tone of skeletal muscles, increase blood flow
Aminoglycosides - decreased ACh release from prejunctional membrane
Lithium - sodium channel blockade
Diuretics - variable
Local anaesthetics 0 variable, sodium channel blockade can stabilise post junctional membrane decreased prejunctional release of ACh
Calcium channel anatagonsits prolong bloackde
What factors other than other drugs can prolong neuromuscular blockade
Drug - dose, type, use of anticholinetases
Electrolytes - H+, low K, (hgih K shortens), hypocalcium (high calcium increased ACh releas eand shortens blockade), hypermagneseamia prolongs blockade
Age - immature enzyme systems in neonates
Women - slonger duration of action, smaller ECG volume
Hypothermia
Pathology - mythasthenia increase sensitivtiy as reduced post huntional ACH receptors due to autoantimodies. Resistance to SCh