Neuromuscular Blockers Flashcards by ian rowley

Substances causing depolarising neuromuscular blockade

Sux
Decamethonium
Any agonist that is not cleared eg ach in presence of excessive anticholinesterase

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Mechanism of depolarising block
Pharmacological characteristics

Agent binds to receptor causing depolarisation
Persists at the receptor preventing repolarisation

Competative, Reversible

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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

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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

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What breaks down sux?
All names

Plasma cholinesterase also known as butyrylcholinesterase or pseudocholinesterase

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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

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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

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Normal plasma conc of plasma cholinesterase

4000-12000. IU/L

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What else can metabolise sux slowly

Acetylcholinesterase

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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

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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

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How can plasma cholinesterase genetic configuration be assessed

Dibucaine number
Fluoride number

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What is the genetic control of plasma cholinesterase synthesis

Pair of autosomal recessive genes

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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).

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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

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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

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Strength of dibucaine used in dibucaine testing

10^-5 molar

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What can cause excess plasma cholinesterase

Alcohol
Obesity
Genetic variant

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Other than sux what muscle relaxant is metabolised by plasma cholinesterase

Mivacurium

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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

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Characteristics of phase 1 sux block

Well sustained response to tetanic stimulation
No post tetanic fasciulations
TOF >0.7
Potentiate by anticholinesterases

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Characteristics of sux phase 2 block

Tetanic fade
Post tetanic fascilitation
TOF <0.3
Tachyphylaxis
Antagonised by anticholinesterases

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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

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How many ach receptors must be blocked by a nondepolasrising agent before contraction fails

75%

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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

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