Neuromuscular Blockers Flashcards
Substances causing depolarising neuromuscular blockade
Sux
Decamethonium
Any agonist that is not cleared eg ach in presence of excessive anticholinesterase
Mechanism of depolarising block
Pharmacological characteristics
Agent binds to receptor causing depolarisation
Persists at the receptor preventing repolarisation
Competative, Reversible
What would be the results of neuromuscular testing on a patient with depolarising block
Reduced single twitch hight
Reduced TOF hight but no fade
No tetanus fade
No post tetanic facilitation
Risk factors for post depolarising block muscle pain
How long can they last
What can reduce it
Young, male, early ambulating
Several days
Pretreatment with benzos, lidocaine or small dose non depolarising agent? Dantrolene
What breaks down sux?
All names
Plasma cholinesterase also known as butyrylcholinesterase or pseudocholinesterase
Structure of plasma cholinesterase
Synthesis and location
Lipoprotein with four polypeptide chains
Made in liver
Found in liver, kidneys, pancreas, brain and plasma NOT in erythrocytes
Structure of sux
How is it metabolised
Succinic acid with two choline moieties at either end
Plasma cholinesterase hydrolyses the 2 ester links holding the choline moieties to the succinic acid, first choline removed quickly, second slowly
Normal plasma conc of plasma cholinesterase
4000-12000. IU/L
What else can metabolise sux slowly
Acetylcholinesterase
What can cause low plasma cholinesterase activity?
Enzyme deficiency - pregnancy, collagen disorder, carcinomatosis, MI, liver disease, hypothyroidism, blood dyscrasias, ketamine, pancuronium, anticholinesterase, ocp, propranolol, cytotoxics, ecothiopate eye drops.
Abnormality of enzyme - inherited disease
When do plasma cholinesterases change in pregnancy
By how much
Third trimester and 7 days post partum
Drop to 75% when pregnant and 67% of normal post partum
How can plasma cholinesterase genetic configuration be assessed
Dibucaine number
Fluoride number
What is the genetic control of plasma cholinesterase synthesis
Pair of autosomal recessive genes
What is a dibucaine number
Patients plasma cholinesterase breaks down benzoyl choline
Add dibucaine (a local anaesthetic) to the solution and it variably inhibits the plasma cholinesterase based on its geneotype. The amount of inhibition is recorded as the dibucaine number (e.g if all benzoyl choline was remaining dibucaine number would be 0, if non of it was it would be 100).
Possible genotypes for plasma cholinesterase
Dibucaine numbers and duration of apnoea
EuEu - normal homozygous - dn80 - 1-5minutes
EuEa, EuEs, EuEf - dn60-80 (or 30-65 depending on source) - 10 minutes
EaEa, EsEs, EfEf - dn0-65 (or 20 depending on source) - 2 hours
Significance of u, a, s and f in dibucaine numbers
Dibucaine numbers of the heterozygous and homozygous abnormalities
U normal - 80 homozygous
A atypical - 60, 20
S silent - 80, 0
F fluoride resistance 75, 65
Strength of dibucaine used in dibucaine testing
10^-5 molar
What can cause excess plasma cholinesterase
Alcohol
Obesity
Genetic variant
Other than sux what muscle relaxant is metabolised by plasma cholinesterase
Mivacurium
Properties of ideal muscle relaxant
Non depolarising
Rapid onset
Short duration
Non-cumulative
No side effects
Spontaneous predictable reversal
High potency
Inactive metabolites
Unaffected by renal or hepatic failure
Characteristics of phase 1 sux block
Well sustained response to tetanic stimulation
No post tetanic fasciulations
TOF >0.7
Potentiate by anticholinesterases
Characteristics of sux phase 2 block
Tetanic fade
Post tetanic fascilitation
TOF <0.3
Tachyphylaxis
Antagonised by anticholinesterases
How does a phase 2 sux block occur
Large, repeated or infusion of sux
Depolarises, remains depolarised, increased NaKATPase activity, membrane potential resets however, receptor still doesn’t respond appropriately to ach as blocked
How many ach receptors must be blocked by a nondepolasrising agent before contraction fails
75%
What group do all non depolarising muscle relaxants have
Quaternary ammonium group
How do non depolarising muscle relaxants impact blood pressure
Decreased muscle contraction thus decreased skeletal muscle pump thus decreased venous return and thus decreased cardiac output and Bp
Twitcher findings post non depolarising block
Reduced single twitch height
Reduced TOF with fade
Tetanic Fade
Post tetanic facilitation
Compare monitoring phase 1 block with non depolarising block
Single twitch - both reduced
TOF - all reduced vs fade
Tetany - no fade vs fade
Post tetanic facilitation - absent vs present
Types of non depolarising muscle relaxants
Characteristics of groups
Amino steroids - steroid nucleus with ach type fragment. Minimal histamine release. Slow metabolism
Benzolisoquinoliums - histamine release, rapid degredation
Why are benzylisquinolium nmbs rapidly degraded
Ester link easily broken
Where are most non depolarising nmbs metabolised
Liver
What potentiates non depolarising nmbs
Sux
IV and voletile anaesthetics
Opioids
Aminoglycosides
Tetracyclines
Metronidazole
Lincosamdes
Polymixins
Magnesium
Verapamil
Nifedipine
Protamine
Diuretics
Catecholamines
How many ach need to bind to channel to open it
2
How do anticholinesterases work
Competative binding to acetylcholinesterase increasing ach outcompeting nmb
Examples of reversible anticholinesterases
Neostigmine
Distigmine
Edrophonium
Pyridostigmine
How do acetylcholinesterase work physiologically
ACh acety ester binds to esteric site and quaternary amine binds to anionic site
It is then hydrolysed
How do the reversible antichoinesterases bind to acetylcholinesterase
Carbamyl ester that binds covalently to the serine amino acid on the esteratic site
Quaternary amine group attracted to anionic site providing stability
Bioavailability of neostigmine orally
Why
30 fold lower than iV (15mg vs 500mcg dose) due to quaternary amine
What else do anticholinesterases do
Some direct cholinergic agonism
Use of edrophonium
Special clinical feature
Diagnosing myasthenia gravis
Only lasts 5 minutes
Side effects of neostigmine
Bradycardia
Decreased vasomotor tone
Decreased Bp
Bronchoconstriction
Increased secretions
Increased gi tone
Depolarising neuromuscular blockade in excess
Miosis
Blurred vision
How do organophosphates bind to acetylcholinesterase
Covalently and irreversibly to the esteratic site
Can organophosphates enter the CNS
Yes, they are very lipid soluble
Organophosphate in clinical use
What for
Issue in anaesthetics
Ecothiopate
Tx of glaucoma
Prolongs sux and mivacurium
What is suggamadex
How does it work
What does it work on
Synthetic gamma cyclodextrin (an oligosaccharide)
Forms a tube which a single amino steroid fits into, encapsulating it and removing it rapidly reducing its unbound active concentration
Roc and vecuronium
Why is the half life of suggamadex relatively short
Very water soluble so excreted rapidly in the urine
Atricurium dose
Duration of action of initial dose
0.3-0.6mg/kg
30mins
Dose of cisatricurium
0.15mg/kg
Structure of atricurium
Bisquaternary benzylisoquinoliuim diester
T1/2 of common muscle relaxants
Atricurium 20mins
Pancuronium 115mins
Rocuronium 131 mins
Suxamethonium 3.5mins
Mivacurium variable based on Isomer 2-52mins
CNS effects of atricurium
No increase in IOP or ICP
Metabolite laudanosine can increase convulsions
CVS and RS effects of atricurium
Histamine release can lower SVR and cause Bronchospasm
Placental transfer of atricurium
Insignificant
Protein binding of atracurium
82%
Elimination of atracurium
Hofmann elimination (spontaneous fragmentation) producing inactive laudanosine and quaternary mono activate
Ester hydrolysis producing quaternary alcohol and quaternary acid
60% by other methods!
Excretion of atracurium
Metabolites
55 bile
35 urine
Side effects of atracurium
Histamine release with bronchospam, hypotension erythema, weals
What is cis atracurium
Clinical relevance
Atracurium consists of 10 isomers
Cisatracurium just consists of cis-cis atracurium
Lower histamine release and lower iV bolus dose but otherwise similar to atracurium
Structure of mivacurium
Bisquateranry benzylisoquinolinium
What sterioisomers does mivacurium contain
Proportions
Differences?
Trans trans (57%) t1/2 2-3mins
cis trans (36%) t1/2 2-3 mins
Cis cis (6%) t1/2 34-52 mins
CNS rs and cvs effects of miviacurium (except paralysis)
Nil
Placental transfer of mivacurium
Minimal
Elimination of mivacurium
Tt and ct by plasma cholinesterases
Cc in the liver
Structure of pancuronium
Bisquaternary amino steroid
CVS effect of pancuronium
Tachycardia
Increased cardiac output
Increased blood pressure
Rs effects of pancuronium except paralysis
Bronchodilation
GI effects of pancuronium
Increased lower oesophageal sphincter tone
Elimination of pancuronium
50% excreted unchanged mainly in urine
40% deacetylated in liver with metabolites laminated in bile
1 metabolite has some nmb activity
Structure of neostigmine
Quaternary amine with alkylcabamic acid ester
Duration of action of neostigmine
40mins
Elimination of neostigmine
Hydrolysis by the acetylcholinesterase it is blocking and by plasma cholinesterases
Some hepatic metabolism with biliary excretion
Duration of initial bolus dose of rocuronim
T1/2
38-150mins
131mins
CVS effect of rocuronium
Increased heart rate, cardiac output and blood pressure due to vagal blocaked
Elimination of rocuronium
Hepatic with some renal
Effect of hepatic or renal failure on rocuronium
Prolongation of block
T1/2 suggamadex
120mins
Structure of sux
Dicholine ester of acetylcholine
What happens to sux if stored out of the fridge
Spontaneous hydrolysis
Effect of sux on CNS
Small ICP increase
IOP increase
Effect of sux on cvs
Increased Bp and bradycardia
Effect of sux on gi
Low oesophageal sphincter pressure and increased intragastric pressure, overall barrier pressure increased
Increased gastric secretions
Side effects of sux
Muscle pain
Hyperkalaemia
MH
Histamine release
Structure of vecuronium
Monoquaternary aminosteroid, becoming Bisquaternary at ph 7.4
Elimination of vecuronium
Spontaneous deacetylation and hepatic
25% in urine rest in bile
Effect of hepatic and renal failure on vecuronium
Renal - no effect, safe to use with absent renal function
Hepatic - prolonged effect
Drugs that reduce vecuronium efficiency
Phenytoin
What happens iwht acidosis and vecuronium
More stable in acid conditions so potentiated
