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Primary Pharmacology > Neuromuscular Blockers > Flashcards

Neuromuscular Blockers Flashcards

1
Q

Substances causing depolarising neuromuscular blockade

A

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

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2
Q

Mechanism of depolarising block
Pharmacological characteristics

A

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

Competative, Reversible

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3
Q

What would be the results of neuromuscular testing on a patient with depolarising block

A

Reduced single twitch hight
Reduced TOF hight but no fade
No tetanus fade
No post tetanic facilitation

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4
Q

Risk factors for post depolarising block muscle pain
How long can they last
What can reduce it

A

Young, male, early ambulating
Several days
Pretreatment with benzos, lidocaine or small dose non depolarising agent? Dantrolene

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5
Q

What breaks down sux?
All names

A

Plasma cholinesterase also known as butyrylcholinesterase or pseudocholinesterase

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6
Q

Structure of plasma cholinesterase
Synthesis and location

A

Lipoprotein with four polypeptide chains
Made in liver
Found in liver, kidneys, pancreas, brain and plasma NOT in erythrocytes

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7
Q

Structure of sux
How is it metabolised

A

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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8
Q

Normal plasma conc of plasma cholinesterase

A

4000-12000. IU/L

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9
Q

What else can metabolise sux slowly

A

Acetylcholinesterase

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10
Q

What can cause low plasma cholinesterase activity?

A

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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11
Q

When do plasma cholinesterases change in pregnancy
By how much

A

Third trimester and 7 days post partum
Drop to 75% when pregnant and 67% of normal post partum

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12
Q

How can plasma cholinesterase genetic configuration be assessed

A

Dibucaine number
Fluoride number

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13
Q

What is the genetic control of plasma cholinesterase synthesis

A

Pair of autosomal recessive genes

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14
Q

What is a dibucaine number

A

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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15
Q

Possible genotypes for plasma cholinesterase
Dibucaine numbers and duration of apnoea

A

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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16
Q

Significance of u, a, s and f in dibucaine numbers
Dibucaine numbers of the heterozygous and homozygous abnormalities

A

U normal - 80 homozygous
A atypical - 60, 20
S silent - 80, 0
F fluoride resistance 75, 65

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17
Q

Strength of dibucaine used in dibucaine testing

A

10^-5 molar

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18
Q

What can cause excess plasma cholinesterase

A

Alcohol
Obesity
Genetic variant

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19
Q

Other than sux what muscle relaxant is metabolised by plasma cholinesterase

A

Mivacurium

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20
Q

Properties of ideal muscle relaxant

A

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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21
Q

Characteristics of phase 1 sux block

A

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

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22
Q

Characteristics of sux phase 2 block

A

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

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23
Q

How does a phase 2 sux block occur

A

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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24
Q

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

A

75%

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25
Q

What group do all non depolarising muscle relaxants have

A

Quaternary ammonium group

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26
Q

How do non depolarising muscle relaxants impact blood pressure

A

Decreased muscle contraction thus decreased skeletal muscle pump thus decreased venous return and thus decreased cardiac output and Bp

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27
Q

Twitcher findings post non depolarising block

A

Reduced single twitch height
Reduced TOF with fade
Tetanic Fade
Post tetanic facilitation

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28
Q

Compare monitoring phase 1 block with non depolarising block

A

Single twitch - both reduced
TOF - all reduced vs fade
Tetany - no fade vs fade
Post tetanic facilitation - absent vs present

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29
Q

Types of non depolarising muscle relaxants
Characteristics of groups

A

Amino steroids - steroid nucleus with ach type fragment. Minimal histamine release. Slow metabolism
Benzolisoquinoliums - histamine release, rapid degredation

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30
Q

Why are benzylisquinolium nmbs rapidly degraded

A

Ester link easily broken

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31
Q

Where are most non depolarising nmbs metabolised

A

Liver

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32
Q

What potentiates non depolarising nmbs

A

Sux
IV and voletile anaesthetics
Opioids
Aminoglycosides
Tetracyclines
Metronidazole
Lincosamdes
Polymixins
Magnesium
Verapamil
Nifedipine
Protamine
Diuretics
Catecholamines

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33
Q

How many ach need to bind to channel to open it

A

2

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34
Q

How do anticholinesterases work

A

Competative binding to acetylcholinesterase increasing ach outcompeting nmb

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35
Q

Examples of reversible anticholinesterases

A

Neostigmine
Distigmine
Edrophonium
Pyridostigmine

36
Q

How do acetylcholinesterase work physiologically

A

ACh acety ester binds to esteric site and quaternary amine binds to anionic site
It is then hydrolysed

37
Q

How do the reversible antichoinesterases bind to acetylcholinesterase

A

Carbamyl ester that binds covalently to the serine amino acid on the esteratic site
Quaternary amine group attracted to anionic site providing stability

38
Q

Bioavailability of neostigmine orally
Why

A

30 fold lower than iV (15mg vs 500mcg dose) due to quaternary amine

39
Q

What else do anticholinesterases do

A

Some direct cholinergic agonism

40
Q

Use of edrophonium
Special clinical feature

A

Diagnosing myasthenia gravis
Only lasts 5 minutes

41
Q

Side effects of neostigmine

A

Bradycardia
Decreased vasomotor tone
Decreased Bp
Bronchoconstriction
Increased secretions
Increased gi tone
Depolarising neuromuscular blockade in excess
Miosis
Blurred vision

42
Q

How do organophosphates bind to acetylcholinesterase

A

Covalently and irreversibly to the esteratic site

43
Q

Can organophosphates enter the CNS

A

Yes, they are very lipid soluble

44
Q

Organophosphate in clinical use
What for
Issue in anaesthetics

A

Ecothiopate
Tx of glaucoma
Prolongs sux and mivacurium

45
Q

What is suggamadex
How does it work
What does it work on

A

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

46
Q

Why is the half life of suggamadex relatively short

A

Very water soluble so excreted rapidly in the urine

47
Q

Atricurium dose
Duration of action of initial dose

A

0.3-0.6mg/kg
30mins

48
Q

Dose of cisatricurium

A

0.15mg/kg

49
Q

Structure of atricurium

A

Bisquaternary benzylisoquinoliuim diester

50
Q

T1/2 of common muscle relaxants

A

Atricurium 20mins
Pancuronium 115mins
Rocuronium 131 mins
Suxamethonium 3.5mins
Mivacurium variable based on Isomer 2-52mins

51
Q

CNS effects of atricurium

A

No increase in IOP or ICP
Metabolite laudanosine can increase convulsions

52
Q

CVS and RS effects of atricurium

A

Histamine release can lower SVR and cause Bronchospasm

53
Q

Placental transfer of atricurium

A

Insignificant

54
Q

Protein binding of atracurium

A

82%

55
Q

Elimination of atracurium

A

Hofmann elimination (spontaneous fragmentation) producing inactive laudanosine and quaternary mono activate
Ester hydrolysis producing quaternary alcohol and quaternary acid
60% by other methods!

56
Q

Excretion of atracurium

A

Metabolites
55 bile
35 urine

57
Q

Side effects of atracurium

A

Histamine release with bronchospam, hypotension erythema, weals

58
Q

What is cis atracurium
Clinical relevance

A

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

59
Q

Structure of mivacurium

A

Bisquateranry benzylisoquinolinium

60
Q

What sterioisomers does mivacurium contain
Proportions
Differences?

A

Trans trans (57%) t1/2 2-3mins
cis trans (36%) t1/2 2-3 mins
Cis cis (6%) t1/2 34-52 mins

61
Q

CNS rs and cvs effects of miviacurium (except paralysis)

A

Nil

62
Q

Placental transfer of mivacurium

A

Minimal

63
Q

Elimination of mivacurium

A

Tt and ct by plasma cholinesterases
Cc in the liver

64
Q

Structure of pancuronium

A

Bisquaternary amino steroid

65
Q

CVS effect of pancuronium

A

Tachycardia
Increased cardiac output
Increased blood pressure

66
Q

Rs effects of pancuronium except paralysis

A

Bronchodilation

67
Q

GI effects of pancuronium

A

Increased lower oesophageal sphincter tone

68
Q

Elimination of pancuronium

A

50% excreted unchanged mainly in urine
40% deacetylated in liver with metabolites laminated in bile
1 metabolite has some nmb activity

69
Q

Structure of neostigmine

A

Quaternary amine with alkylcabamic acid ester

70
Q

Duration of action of neostigmine

A

40mins

71
Q

Elimination of neostigmine

A

Hydrolysis by the acetylcholinesterase it is blocking and by plasma cholinesterases
Some hepatic metabolism with biliary excretion

72
Q

Duration of initial bolus dose of rocuronim
T1/2

A

38-150mins
131mins

73
Q

CVS effect of rocuronium

A

Increased heart rate, cardiac output and blood pressure due to vagal blocaked

74
Q

Elimination of rocuronium

A

Hepatic with some renal

75
Q

Effect of hepatic or renal failure on rocuronium

A

Prolongation of block

76
Q

T1/2 suggamadex

A

120mins

77
Q

Structure of sux

A

Dicholine ester of acetylcholine

78
Q

What happens to sux if stored out of the fridge

A

Spontaneous hydrolysis

79
Q

Effect of sux on CNS

A

Small ICP increase
IOP increase

80
Q

Effect of sux on cvs

A

Increased Bp and bradycardia

81
Q

Effect of sux on gi

A

Low oesophageal sphincter pressure and increased intragastric pressure, overall barrier pressure increased
Increased gastric secretions

82
Q

Side effects of sux

A

Muscle pain
Hyperkalaemia
MH
Histamine release

83
Q

Structure of vecuronium

A

Monoquaternary aminosteroid, becoming Bisquaternary at ph 7.4

84
Q

Elimination of vecuronium

A

Spontaneous deacetylation and hepatic
25% in urine rest in bile

85
Q

Effect of hepatic and renal failure on vecuronium

A

Renal - no effect, safe to use with absent renal function
Hepatic - prolonged effect

86
Q

Drugs that reduce vecuronium efficiency

A

Phenytoin

87
Q

What happens iwht acidosis and vecuronium

A

More stable in acid conditions so potentiated

Primary Pharmacology (18 decks)

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