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Primary Pharmacology > Muscle relaxants and autonomic pharm > Flashcards

Muscle relaxants and autonomic pharm Flashcards

1
Q

Sux

A
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2
Q

Roc

A
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3
Q

Vec

A
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4
Q

Pan

A
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5
Q

Atra

A
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6
Q

CisAtra

A
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7
Q

What class is suxamethonium

A

Dicholine ester - 2 ACh molecules combined

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8
Q

What class is rocuonium

A

Aminosteriod

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9
Q

Give 3 examples of an aminosteriod

A

Roc, Vec, Pancuronium

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10
Q

What class is atracurium

A

Benzylisoquinolinium

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11
Q

What drugs belong in the class Benzylisoquinoloinium

A

Atracurium and cisatracurium

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12
Q

What preparation does suxamethonium come in

A

50mg/ml in 2ml

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13
Q

What preparation does rocuonrium come in

A

10mg/ml in 5ml

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14
Q

What preparation does vecuonium come in

A

Freeze dried powder 10mg ampule

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15
Q

What preapration does pancuronium come in

A

2mg/ml in 5 or 10ml ampule

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16
Q

What preparation does atracurium come in

A

10mg/ml in 5ml/2.5ml/25ml ampule

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17
Q

What preparation does cisatracurium come in

A

2mg/ml in 5ml ampule

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18
Q

What is the dose of suxamethonium

A

1mg/kg (0.5 - 1.5)
ED 95 0.5mg/kg

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19
Q

What is the dose of rocuonium

A

0.3mg/kg ED 95
0.6 mg/kg intubation
1.2mg/kg RSI

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20
Q

What is the dose of vecuronium

A

0.05mg/kg ED 95
0.1mg/kg intubation

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21
Q

What is the dose of pancuronium

A

0.06mg/kg ED 95
0.1mg/kg intubation

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22
Q

What is the dose of atracurium

A

0.25mg/kg ED 95
0.5mg/kg intubation
top up dose 0.1-0.2mg/kg

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23
Q

What sit he dose of cistatracruium

A

0.05mg/kg ED95
0.15mg/kg intubation

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24
Q

Onset of suxamethonium

A

End of fasciculations
30-60 seconds

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25
Q

Onset of rocuonrium

A

90-120 seconds

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26
Q

Onset of vecuronium

A

2-3 minutes

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27
Q

Onset of pancuronium

A

3-6 minutes

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28
Q

set of atracurium

A

2-3 minutes

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29
Q

Onset of Cisatracurium

A

3-6 minutes

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30
Q

Duration of action of suxamethonium

A

5-10 minutes

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31
Q

Duration of action of Rocuonrium

A

35-50 minutes

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32
Q

Duration fo Vecuronium

A

30-40 minutes

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33
Q

Duration of action of pancuronium

A

70-120 minutes

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34
Q

Duration of action of atracurium

A

35-50 minutes - 95% recovery
Hypothermia doubles this

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35
Q

Duration of action of Cisatracurium

A

40-55 minutes

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36
Q

Volume of distribution of Suxamethonium? T1/2 beta

A

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

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37
Q

Distribution of rocuronium

A

180ml/kg *small!!

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38
Q

Volume of distirbution of vecuronium

A

200ml/kg

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39
Q

Volume of distribution of pancuronium

A

250ml/kg
Protein bidning <50%

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40
Q

Volume of distribution of atracurium

A

170ml/kg
Does not cross BBB
Does not cross placenta
82% protein bound

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41
Q

Volume of distribution of cisatracurium

A

200ml/kg

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42
Q

Metabolism of suxamethonium

A

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

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43
Q

Excretion of sexamethonium

A

<10% in urine

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44
Q

Suxamethonium reversal

A

nil

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45
Q

Suxamethonium adverse effects - 9 things

A

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)

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46
Q

Rocuronium metabolism

A

Minimal (hepatic)
no active metabolites

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47
Q

Rocuronium Excretion

A

unchanged in bile - 80%
20% in urine

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48
Q

Rocuronium reversal

A

Sugammadex
Neostigmine

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49
Q

Adverse effects of rocuonrium

A

High dose –> tachycardia
Pain on injection
Anaphylaxis

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50
Q

Vecuronium metabolism

A

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

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51
Q

Vecuronium excretion

A

Hepatic and renal clearance

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52
Q

Vecuronium reversal

A

Sugammadex
Neostigmine

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53
Q

Vecuronium Side effects

A

Minimal
Anaphylaxis rare

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54
Q

Pancuronium metabolism

A

30-40% hepatic - de-acetylation
Active metabolites - 3 hydroxypancuronium 50% as potency
70% however is excreted uncahnged, metabolites excreted in bile

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55
Q

Pancuronium excretion

A

70% however is excreted uncahnged, metabolites excreted in bile

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56
Q

Pancuronium reversal

A

Neostigmine

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57
Q

Pancuronium side effects

A

Tachycardia by 20%
Increased MAP by 20%
indirect sympathomimetic be reducing NA reuptake at post-ganglionic nerve ending and blocking cardiac muscurinic recepotors

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58
Q

Atracurium Metabolism

A

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

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59
Q

Excretion of atracurium

A

10-30% renal

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60
Q

Reversal of atracurium

A

neostigmine

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61
Q

Adverse effects of atracurium

A

histamine release
Laudanosine accumulation causes seizurese - after 6 days of infusion this risk occurs
Increases risk of critical illness myopathy

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62
Q

Cisatracurium Metabolism

A

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

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63
Q

Excretion of cistracurium

A

10-15% unchanged in urine
6ml/kg/min
Elimination half life 20 minutes
Unaltered clearance by renal or hepatic impairement

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64
Q

Cisatracurium reversal

A

Neostigmine

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65
Q

Cisatracurium adverse effects

A

No histamine release

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66
Q

Acetycholine is found where?

A

NMJ
Pregaglionic PSNS and SNS nerve fibres
Post ganglionic PSNS and SNS fibres (sweat glands

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67
Q

How is acetylcholine made?

A

Choline + Acetyl CoA under catalyst choline acetyltransferase

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68
Q

Where does choline come from?

A

Diet, liver synthesis, reuptake from synaptic cleft after breakdown of ACh

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69
Q

Where does Acetyl CoA come from

A

Produced in mitochondria from pyruvate and CoA by pyruvate dehydrogenase

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70
Q

Acetylcholinesterase is found where

A

Synaptic cleft
post synaptic folds

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71
Q

How does acetychloinesterase work

A

Hydrolyses acetylcholine to Choline and acetate

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72
Q

A non depolarising block has what 2 key characteristics

A

Competitive inhibition
No fasciculations

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73
Q

What effect does a non depolarising block have on tetanic stimulation and TOF? What about pot tetanic potentiation?

A

Fades with tetanic stimulation and TOF due to reduced ACh mobilisation

Post tetanic potentiation –> increased ACh syntheiss and release, increase calcium in synaptic terminal

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74
Q

Non depolarising muscle relaxants act on each muscle group equally true or false

A

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

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75
Q

Depolarising muscle relaxants act how at the acetylcholine receptor?

A

Non competitive
Prejunctional action fo ScH produces fasciculations
Depolarises the post junctional membrane

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76
Q

Does suxamethonium produce fade? Post tetanic potentiation?

A

No to either

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77
Q

What happens if anticholinesterase is given to someone with Suxamethonium

A

Augmented action

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78
Q

What is a phase 2 block in the context of muscle relaxants

A

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

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79
Q

What is a desensitisation block?

A

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

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80
Q

What are the ideal physicochemical properties of a NMJ blocking agent

A

Water soluble
Stable in solutino
Sterile without additives
Long shelf life
No refridgeration
Cheap
Compatible with othe drugs

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81
Q

Pharmacokinetic proerties of an ideal NMJ blocking agent

A

rapid onset
Short duration
Rapid metabolism
Inactive metbaolites
No transfer across BBB or placenta
Organ independent elimination

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82
Q

Pharmacodynamic properties of an ideal NMJ blocking agent

A

Non depolarising
Action confined ot NMJ
Availability of specific reversal agent
No locla or systemic effects
No histamine release
No trigger of MH

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83
Q

What is a long acting neuromuscular blocking agent

A

Pancuronium

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84
Q

What is the structure of suxamethonium or succinylcholine

A

two Acetylcholine molecules linked by the acetyl groups

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85
Q

MOA of succinylocholine

A

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

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86
Q

Non depolarising muscle relaxant MOA

A

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

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87
Q

ED95 is what?

A

95% twitch depression at adductor pollicus

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88
Q

INtubation dose relative ot ED95

A

2-3xx

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89
Q

ED50

A

median dose correpsonding to 50% twitch depression at adductor pollicus

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90
Q

Drug factors affecting onset fo action in NMB

A

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

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91
Q

Patients factors affecting onset of action of NMB

A

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

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92
Q

Which drugs potentiate the action of neuromuscular blockade

A

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

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93
Q

What factors other than other drugs can prolong neuromuscular blockade

A

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

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94
Q

What effect does a burn have on NMB

A

Receptor upregulation and resistance to non depolarising muscle relaxants

Decreased plasma cholinesterase activity

95
Q

Neuromuscular agents vs neuromuscular disease
- Parkinsone
- Myasthenia
- Eaton Lambet
- MS
- GBS
- MND
- Cerebral palsy
-Muscular dystrophy

A
96
Q

Pancuronium compound is

A

Bis-quaternary amino steriod

97
Q

Vecuonrium compound? How is it chemically different to pancuronium? How is this significant

A

Aminosteriod - mono quaternary analogue of pancuronium (loss of one methyl group) which reduces its ACh like properties, increases lipid solubility producing a shorter duration of action

98
Q

vecuonrium comes as a powder why?

A

Unstable in solution
Comes with mannitol and sodium hydroxide in the powder

99
Q

Rocuronium precipitates with which co-induction agent?

A

Thiopental

100
Q

Atracurium is what sort of compound? What chemically is it composed of?

A

Benzyl-iso-quinolinium compound
Mixture of 10 isomers - 4 chiral centres

101
Q

How does atricurium come? Any additives?

A

Solution fo injection
Besylate adjusts pH to 3.25 - 3.65 pH, water solubility
Stored at 4 degrees

102
Q

Cisatracurium has what relationship to atricurium

A

One of 10 sterioisomers
3-4x more potent than atracurium - less laudanosine and acrylates

103
Q

What is an example of an anticholinesterase

A

Neostigmine
Pyridostigmine
Physostigmine
Edrophonium

104
Q

Neostigmine chemically is what

A

QUaternary amine

105
Q

How does neostigmine work

A

Covalent bonds at esteric site of acetylcholinesterases inhibiting action

106
Q

Onset of neostigmine

A

3 minutes

107
Q

Duration of action of neostigmine

A

30-60 minutes

108
Q

Pharmacokinetics of neostigmine

A

low oral bioavailability
Low protein binding
Low Vd
Metabolised by plasma esterases in the liver
50% unchanged in the urine excretion
T1/2 beta 60-90 minutes

109
Q

Effects of neostigmine

A

3B’s 3Hs

Block reversal - Reversal of non depolarising block
Bronchospasm
bradycardia
Hypotension
Hypersalivation
Hypermotility - Increased intestinal motility and ureteric peristalsis

110
Q

Dose for reversal of block for neostigmine

A

50 microg/kg IV (ceiling of effect 70microg/kg)

111
Q

Physostigmine is what type of compound

A

tertiary amine crossing BBB

112
Q

Why is pyridostigmine not used in anaesthetics

A

Also a quarternary amine but slower onset, longer duration so more useful for myasthenia gravis

113
Q

Neostigmine and a partcular poison have a common MOA - which poison? How are they different?

A

Organophosphates
- form stable enzyme complexes leading to phosphorlyation fo the esteratic site of Acetylcholine causing a very stable complex that inhibits plasma cholinesterase as well. Leads to nicotinic and muscuriniuc effects and autonomic instability

Pralidoxime and atropine are used

114
Q

What chemically is suggamadex

A

Gamma cyclodextrin

115
Q

How does suggamadex work

A

Chelates NDMRs in plasma - encapsulates all 4 steriod rings of rocuronium leading to 1:1 excretion in the urine. Establishes concentration gradient between NMJ and plasma

116
Q

What is the order of affinity of suggamadex with NDMA

A

Roc > Vec > pan

117
Q

Sugammadex rate of reversal vs atropine

A

faster, dose dependent effect

118
Q

Why is suggamadex a cleaner MOA than neostigmine

A

anticholinergics not required for coadministration to avoid side ffects
greater cardiovascular stability

119
Q

Side effects of sugammadex

A

Bradycardia
Bad taste
Expensive
Suboptimal dosing can lead to recurrence of blockade
May bind to OCP

120
Q

Dose of suggamadex after 0.6mg/kg rocuronium

A

2-4mg/kg

121
Q

Dose of suggamadex for deeper levels of blockade

A

8-16mg/kg

122
Q

Which muscle relaxants are safe in malignant hyperthermia

A

Atricurium

123
Q

Atricurium does not mix with?

A

alkaline solutions e/.g. barbituates

124
Q

Atropine derived from where? Chemical structure?

A

Alkaloid from Atropa Belladona - a tertiary amine

125
Q

Atropine chemically prepared as?

A

Tertiary amine as the ester of tropic acid and tropine - comes as a racemic mixture of D and I hyoscyamine (I form active)

126
Q

MOA of atropine

A

An anticholinergic acting by competitive antagonism of acetylcholine at muscurinic receptors

Minimal action at nicotinic receptors except at high doses

127
Q

Atropine presentation

A

Clear colourless solution for injectino containing 0.5 or 0.6mg/mlatropine sulfate

Also as a tablet 0.6mg

128
Q

Routes of adminsitration fo atropine

A

IM, IV
Oral

129
Q

Dose of atropine in adults

A

0.015-0.02mg/kg in adults

3mg needed for complete vagal block in adults

130
Q

Atropine effects

A

Cardiovascular - low doses produces an initial bradycardia followed by tachycardia, little effect on BP. Decreases AV condution time and may produce arrhtyhmias.

Respiration - bronchodilation and increases dead space, reduces secretions, RR increased, reduced laryngospasm

CNS - either excitation or depression - if centrala nticholinergic syndrome somnolence, confusion, amnesia, hallucinations, ataxis, dysarthria

Antiemetic
Antiparkinsonian

Reduces salivations, gastric secetions and perisalsis. Antispasmodic. Reduces lower oesophageal tone

Cucloplegia, mydriasis and increased IOP

BMR increased and sweating inhibited
Suppresses ADH secretion

131
Q

Toxicity of atropine

A

Dry mouth
Anticholinergic syndrome
urnary retention
Gluacoma if ocular adminitration (not in IV or IM)

132
Q

Absorption of atropine

A

rapidly absorbed from gut, bioavailability 20%

133
Q

Distribution of atropine

A

50% protein bound
2-4L/kg Vd
Cross placenta and BBB

134
Q

Metabolism fo atorpine

A

Hydrlysed in liver and tissue to tropine and tropic acid

135
Q

Excretion fo atropine

A

94% in urine within 24 hours uncahnged, clearance 70L/hr and half life 2.5 hours

136
Q

Chemical structure of cisatracurium

A

benzyl-isoquinolinium ester - one fo the 10 stereoisomers of atracurium due to the presence of 4 chiral centres

137
Q

Cisatracurium comes as? storage

A

clear colourless pale yellow solution for injection in 5, 10, 20ml vials containing 6.7mg/mL of cisatracurium besilate equivalent ot cisatracurium 5mg/mL

Store at 2-8 degrees, no antimicrobial preservative an dpH 3.25 and 3.65

138
Q

Mode of action of cisatracurium

A

competitive antagonist of acetylcholine at the nicotinic N2 recepotrs at the post synaptic membrane of the neuromuscular junction

139
Q

Neuromuscular recovery time from cisatracurium dose is depednent on? What is the mean time to recovery after multiday infusions (5-6 days)

A

time only; not dose - once recovery has started the rate of recovery is independent of dose administered

50 minutes

140
Q

What is the IV infusion rate of cisatracurium

A

3microg/kg/min although wide variabiltiy in dose requireemmnts

T1 suppression 90-99%

Can be reduced to 1-2microg/kg/min

141
Q

Cisatracurium CVS and respiratory side effects? Toxicity? Other side effects?

A

Fewer than atracurium, no change in MAP or HR following rapid bolus but bradycardia and hypotension possible but rates <1%

Bronchospasm occasionally reported

Histamine release not seen with cisatracurium

Use associated with critical illness neuropathy or myopathy; no effect on ICP or IOP

142
Q

Distribution of cisatracurium

A

Vd 0.12-0.16L/kg

143
Q

Metabolism of cisatracurium

A

Major: Hoffman elimination/degredation with cleavage of link between quaternary nitrogen ion and central chain to laudanosine and quatarnary monoacrylate

Laudanosine cleared by the liver

Minor degredative pathway is via hydrolysis by non specific esterases in the blood to quaternary alcohol and quaternary acid

Metabolites inisignificant activity

144
Q

What is Hoffman elimination

A

Spontnaeous degredation of the link between quaternary nitrogen ion and central chain - seen in cisatracurium and atracurium degredation

145
Q

Excretion of cisatracurium

A

Cleearance 5ml/kg/min
Eliminiation half life 22-29 minutes
Minimal alteration by renal or hepatic impairment with no dosing change required

95% of dose excretion in the urine as metabolites, 4% faeces ; 10-15% unchanged in urine

146
Q

Factors prolonging duration of cisatracurium action

A

Hypokalaemia, hypocalcaemia, hypermagnesaemia, hypoproteinaemia, dehydration,. acidosis, hypercapnoea

Voltailes, ketamine, non depolarising NMB agents, diuretics (acetazolamide, furosemide), CaB, propanolol, lidocaine, aminoglycoside

147
Q

What is dantrolene used in

A

Malignant hyperthermia and NMS
Heat stroke
Muscule spaciity
Tetanus adjunct

148
Q

Dantrolene chemically

A

Phenyl hydantoin derivative

149
Q

Mode of action of dantrolene

A

acts within skeletal muscle fibres to inhibit calciumr elease through the inhibition of ryanodine receptors in the sarcoplasmic reticulum to cause a reduction in muscular contraction to a given electrical stimulus. Part of its action may be due to marked GABA-ergic effect

150
Q

Routes of administraton of dantrolene and doses

A

1-10mg/kg IV an average of 2.5mg/kg is required

Oral dose 25-100mg 6 hourly

Therapeutic effects seen within 15 minutes

151
Q

Effects of dantrolene

A

CVS - no consistent effect, may have anti-arrhtyhmic effects. Improves beta adrenergic responsiveness in failing myocardium

Resp negligible
CNS - central GABA ergic effects, sedtion
GU - increases effectivenss of voiding
Metabolic - decreases force of electrically induced muscle twitches whilst having no effect on action potentional

152
Q

Toxicity and side effects of dantrolene

A

high irritating if extravasating

Chronic use can illicit muscle wekness, drowsiness, GI disturbances

Hepatic dysfunction reversible

153
Q

Dantrolene kinetics

A

20-70% of oral dose absorbed
Distribution - 80-90% protein bound, Vd 0.6L/kg
Metabolism - liver by hydroxylation and acetylation
Excretion - 25% urine as metabolite primarily, clearance 2.3ml/kg/min, eleminiation half life 3-12 hours

154
Q

Glycopyrronium or glycopyrrolate chemical

A

quaternary amine

155
Q

Presentation of glycopyrronium

A

vial containing 0.2mg/ml as a clear solution

Powder for topical applications

Fixed dose combination of 0.5mg with 2.5mg of neostigmine

156
Q

Main actions and mode of action of glycopyrrolate

A

Anticholinergic - profound anti-secretory action

Competitie antagonism of acetylcholine at peripheral muscarinic receptors

157
Q

Dose of glycopyrrolate

A

0.2-0.4mg IV and IM dose

Paediatric dose 4-10mcg/kg

Peak effects 3 minutes after IV injection

158
Q

Peak effect timing of glycopyrollate

A

3 minutes post injection

159
Q

Cardiovascular effect sof glycopyrrolate

A

Less dysrhythmias than atropine

Tachycardia when the drug is administered IV in doses >0.2mg

Protective against bradycardias due to the oculocardiac reflex or Suxx

Vagolytic effects last 2-3 hours

160
Q

Respiratory effects and CNS effects of glycopyrrolate

A

Resp - long lasting bronchgodialtor, increased in physiological dead space

CNS - unabel to cross the BBB, headache and drowsiness not uncommon. Post anaesthetic recovery faster with glycopyrolate compared to atropine . No effect on pupil size

161
Q

Abdominal and metabolic effects of glycorpyrollate

A

powerful antisialogogue for 8 hours after IV dose 0 5x more potent than atoprine

Reduces gastric volume for 90% for 4 hours after administration and reduces antral motility. Reduces lower oesophageal tone

INhibits sweat gland activity but little effect on body temperature

162
Q

Side effects of glycopyrollate

A

Anticholinergic - dry mouth, difficulty with urination, inhibition of sweating

Headache

163
Q

Drug kinetics for glycopyrrolate

A

Absorption - oral absorption poor and errratic, bioavailability 5% . IM and IV similar absorption

Distribution very fast redistribution 95% gone form the plasma in 5 minutes, crosses the palcenta. Vd 0.2L/kg

164
Q

Metabolism of glycopyrrolate

A

Very little

165
Q

Excretion of glycopyrrolate

A

urine 85%
Bile 15%
80% unchanged
Clearance is 0.9L/min
Eliminiation half life is 0.6-1.1 hours

166
Q

Ropivocaine and Bupivocaine pKa and protein binding?

A

8.1
95%

167
Q

Potency of Ropivocaine and Bupivacaine in comparisone to lignocaine

A

Ropivocaine 3x potency
Bupivocaine 4x potency

(lignocaine is 2x more potent than the base procaine that is used for comparison)

168
Q

Vd of suxamethonium?

A

0.2L/kg

169
Q

Vd of pancruonium

A

0.2L/kg

170
Q

Vd of rocuonrium

A

0.2L/kg

171
Q

Atricurium Vd

A

0.2L/kg

172
Q

Which muscle relaxant has the longest duration of action? WHy?

A

Pancruonium

10% hepatic metabolism
80% renal clearance

173
Q

How is pancuronium cleared form the body? How is it metabolised? How important is metabolism to its clerance?

A

10% hepatic metabolism
80% renal clearance unchanged

174
Q

Rocuronium clearance? Degree of metabolisM?

A

Hepatic 15%
50% unchnaged - 40% bile, 10% renal

175
Q

Vecuronium metabolisma nd clearance

A

60% hepatically metabolised
20% renally unchanged
20% biliary unchanged

176
Q

What is acetycholinesterase and where is it found? How does it act?

A
  • Acetylcholinesterase (AChE) is an enzyme that hydrolyse acetylcholine (ACh) into choline & acetate AChE is found in synaptic clefts and is responsible for the termination of synaptic transmission
177
Q

What varieties of cholinesterase are found

A

Achesterase - nerve endings & in RBCs
2. Non-specific or pseudocholinesterases - destroy other esters - tissues & plasma

178
Q

What are the binding sites on acetylcholinesterase?

A
  • Acetylcholinesterase has 2 binding sites - anionic and esteratic
    ◦ ANionic site binds quaternary amine group of ACh
    ◦ Esteratic site binds ester group of ACh
    ◦ Binding –> hydrolysis and breakdown into choline and Acetyl CoA
179
Q

What are the classes of drugs affecting acetylcholinesterase

A

◦ (1) Reversible antagonist via electrostatic binding – e.g. edrophonium
‣ causes electrostatic attachment to the anionic site of the enzyme -> stabilising the H+ bond at the esteratic site -> edrophonium-AchE complex prevents Ach from binding
◦ (2) Reversible antagonist via covalent bonding – e.g. neostigmine
‣ [Formation of carbamyl esters (carbamates)] - ie. neostigmine, physostigmine & pyridostigmine
‣ antagonise AchE enzyme by being competitive substrate for Ach -> forms a carbamyl-ester complex at the esteratic site of enzyme. - longer lasting bond (15-30min)
◦ (3) Irreversible antagonist via covalent bonding – e.g. organophosphates
‣ combine with Ach at the esteraic site to form a stable covalent bond -> does not undergo hydrolysis. - synthesis of a new AchE is required.

180
Q

How does Edrophonium act on acetylcholinestase?

A

◦ (1) Reversible antagonist via electrostatic binding – e.g. edrophonium
‣ causes electrostatic attachment to the anionic site of the enzyme -> stabilising the H+ bond at the esteratic site -> edrophonium-AchE complex prevents Ach from binding

181
Q

How does neostigmine act on acetylcholinestase

A

◦ (2) Reversible antagonist via covalent bonding – e.g. neostigmine
‣ [Formation of carbamyl esters (carbamates)] - ie. neostigmine, physostigmine & pyridostigmine
‣ antagonise AchE enzyme by being competitive substrate for Ach -> forms a carbamyl-ester complex at the esteratic site of enzyme. - longer lasting bond (15-30min)

182
Q

How do organophosphates act on acetylcholinestase

A

◦ (3) Irreversible antagonist via covalent bonding – e.g. organophosphates
‣ combine with Ach at the esteraic site to form a stable covalent bond -> does not undergo hydrolysis. - synthesis of a new AchE is required.

183
Q

What are muscurinic effects of activation

A
  • Muscarinic effects
    ◦ occur at lower doses than nicotinic effects
    ◦ CVS – bradycardia ± hypotension
    ◦ RESP – bronchoconstriction ± bronchospasm
    ◦ CNS – miosis, cholinergic syndrome – confusion, agitation, nausea/vomiting
    ◦ GIT – hypersalivation, ↑GIT motility, nausea/vomiting, diarrhoea
    ◦ GUT – urination, incontinence
    ◦ OTHER – lacrimation, diaphoresis
    ‣ Mnemonic SLUDGE-BM: Salivation/Sweating, Lacrimation, Urination, Diaphoresis/Diarrhoea, GI upset, Emesis, Bradycardia/bronchospasm, Miosis
184
Q

What are consequences of nicotonic receptor activation

A

◦ Reversal of non-depolarising neuromuscular blockers
◦ Prolongs effect of suxamethonium (depolarising NMB)
◦ Anticholinesterase overdose → excess synaptic ACh → depolarisation block ± fasciculation

185
Q

What are the clinical uses of acetylcholinestases?

A

Reversal of NDMR
Diagnosis and Tx of Myasthenia
Treatment of cognitive impairment in Alzhemiers
Gluacoma
Anticholinergic syndrome

186
Q

Explain which drug is used in treatment of myasthenia gravis and MOA

A

‣ Mechanism – anticholinesterase drugs ↑ synaptic ACh → competes with myasthenia auto-antibodies for post-synaptic nAChR → ↑muscle strength
* Drugs – e.g. edrophonium for diagnosis, pyridostigmine for maintenance

187
Q

WHy is acetylcholinestase implicated in the treatment of dementia? What types of dementia? What drugs?

A

Treatment of cognitive impairment in neurodegenerative diseases (e.g. Alzheimer’s disease, Lewy body dementia, etc) Mechanism – ↑ synaptic ACh in CNS → ↑ cholinergic transmission
‣ Drugs – e.g. rivastigmine, galantamine, donepezil

188
Q

Acetylcholinestases are used in the treatment of glaucoma - explain MOA

A

‣ Mechanism – constriction of sphincter pupillae and ciliary muscles → miosis → facilitate outflow of aqueous humor → IOP decreases Drugs – e.g. echothiophate eye drops, physostigmine

189
Q

What is anticholinergic syndrome?

A

‣ Anticholinergic syndrome caused by: anti-histamines, anti-parkinsonians, atropine, antispasmodics, mydriatics, skeletal muscle relaxants, plants
‣ CLINICAL FEATURES: delirium, tachycardia, dry and flushed skin, dilated pupils, myoclonus, hyperthermia, urinary retention, bowel sounds, seizures, dysrhythmias(tachy)
‣ Mechanism – increase synaptic ACh Drugs – e.g. physostigmine (tertiary amine + lipophilic → readily crosses BBB)

190
Q

How are the acetylcholinestases functionally different?

A
  • Duration of action
    ◦ Edrophonium short
    ◦ Neostigmine medium
    ◦ Organophosphate long
  • Reversible
    ◦ Edorphonium and neostigmine
    ◦ Irreversible organophosphate
191
Q

Describe key pharmacodynamics and pharmacokinetics of edrophonium

A

◦ Quaternary amine
◦ Clear solution 10mg/ml
◦ Onset 1-2 minutes
◦ Lasts 10 minutes
◦ 0.1mg/kg for reversal of NDMR blockade or 2-10mg for Tensilontest
◦ Does not cross BBB
◦ Same SE as neostigmine
◦ Vd 1L/kg
◦ Metabolised by liver glucoronidation
◦ 35% as biliary metabolites and 65% renally unchanged

192
Q

Describe key pharmacological characteritysics fo pyridostigmine

A

◦ Analogue of neostigmine
◦ ¼ potency
◦ MoA Neostigmine
◦ Slower onset 16mins (so not used to reverse NDMR)
◦ DoA 6hrs (used for MG)

193
Q

Organophosphate pharmacology

A

◦ Irreversible
◦ Covalent binding wtih ACHe and therefore new acetylcholinesterase synthesis required
◦ Leads to muscle weakness and fasciculations
◦ Excitation, seizures and respirtory depression along with
‣ Bradycardia
‣ Bronchoconstriction
‣ Brain - confusion, agitation
‣ Hypotension
‣ Hypersecretion - incontinence, diarrhoea, respiratory secretions, vomiting, lacrimation
◦ Lipid soluble, transcutaneous absorption
◦ Large Vd
◦ Long excretion time

194
Q

Pharmaceutics of suxamethonium

A

Dicholine ester with 2 ACh molecules
50mg/ml in 2ml ampoule
Kept in the fridge 2-8 degrees, shelf life 2 months
pKa 13, pH 3.5
$2 per vial (CHEAP)

195
Q

Can you use suxamethonium in an infusion?

A

no

196
Q

What is the prescribed offset of Neuromuscular blockade defined as?

A

TOF 0.9

197
Q

Methods of administering suxamethonium

A

IM/IV

198
Q

How would you describe the efficacy of the metabolism of suxamethonium

A

High capacity and high efficacy
20% reaches NMJ before hydrolysis

199
Q

What factors might cause a more prolonged blockade specifically in suxamethonium

A

Liver failure, renal failure
Malignancy, pregnancy
Malnutrition
Drugs - MAOI, neostigmine, OCP< metaclopramide, cocaine, organophosphates
Extracorpereal

200
Q

Rocuronium pharmaceutics

A

Aminosteriod
10mg/ml in 5ml amoule
Unstable in solution requiring mannitol and NaOH
pH 3.5 pKa 8
2/12 shelf lfie
kept in the fridge
Clear and colourless
Good water solubility

201
Q

Rocuronium onset at 4x ED 95

A

45 sec to 1 minute

202
Q

Mechanism of metabolism of rocuronium

A

De-acetylation <10% of total clearance

203
Q

How is rocuronium cleared

A

80% liver (<10% of this is metabolism)
20% urine

204
Q

Protein binding of rocuronium

A

50%

205
Q

T1/2 beta after rocuronium infusion

A

70 minutes

206
Q

Interactions of rocuronium

A

Thiopentone precipitates

207
Q

Side effects of rocuronium

A

Tachycardia - vagolytic
Pain on injection
Anaphylaxis 6:100000 or 1:3500 (associated with use of pholcodine)

208
Q

Protein binding of Vecuronium

A

77%

209
Q

Succinylcholine apnoea can be reversed with

A

FFP

210
Q

What is phase 1 block

A

Reduced block amplitude, TOF >0.7, no post tetanic potentiation and giving acetylcholinesterases will potentiate block

The first phase of depolarising muscle relaxant block

211
Q

Phase 2 block

A

Seen with higher doses of in those with deficiency in metabolic process

SImilar to non depolarising blockade, TFO <0.3, fade during tetany, post tetanic facilitation, antagonism, by ACHe (so can be used to reverse)

Due to post junctional receptor desensitisation, presynaptic blockade or activation of Na/K ATPase by initial depolarisation

212
Q

Explain the concept of fade

A

Progressive reduction in twitch height with high frequency stimulation

Non depolarising drugs only

Degree of fade is proiportional to block

Due to blockade of presynatpic alpha3beta2 receptors reducing reserve release of ACh (positive feedback downregulated)

213
Q

Cisatricuronium pKa

A

19

214
Q

Cisatricurium storage

A

Refridgerate 2-8 degrees, lasts 3 months
Water soluble so no need for reconstitution

215
Q

Do you get anaphylaxis with Atricurium?

A

4 / 100 000

216
Q

Protein binding of atricurium

A

80%

217
Q

Protein binding of cisatricurium

A

15-40%

218
Q

What proportion of atricurium activity is due to cisatricurium?

A

50%

219
Q

What impact does temperature have on Benzylisoquinolonium metabolism?

A

Reduction in temperature delays both ester and Hoffman elimination

Reduction in pH reduces Hoffman
Increase in pH reduces ester action

220
Q

How does Laudanosine act

A

Gluycine receptor antagonist leading to seizures

221
Q

SE of suggamadex

A

0.3% anaphylaxis
bradycardia
Coagulopathy for 1 hour post

222
Q

What relationship does ED95 have to potency?

A

Increased ED95 reduces potency

223
Q

What is onset time of muscle relaxants defined as

A

Time to twitch height reduction by 95% (single twitch)

224
Q

Depth of muscle relaxtion

A

Post tetanic count

225
Q

Offset time of muscle relaxant

A

TOF 0.9

226
Q

Duration of muscle relaxant determined by what aftcors other than potency factors

A

Decreased temperature decreases Hoffman and ester hydrolysis

pH - decreases affects Hoffman, increases effects Ester

Liver and renal failure
Drugs - roc action shortened by Succ

227
Q

What baseline characteristics of patients determine duration of NMB?

A

Neonates immature NMJ so prolonged blockade
Increased muscle mass = reduced block (affecting genders)
Muscle type and location - blood flow

228
Q

Factors which reduce potency of NMB

A
  1. ACh release increased - hyperkalaemia
  2. Pathology - critical illness myopathy, burns, malignant hyperthermia
  3. Tetanus toxin
  4. Neostigmine
229
Q

Factors which increase potency of NMB

A
  1. ACh release reduced by acidsosis, hypokalaemia, hypermagnesaemia
  2. Path - myashtenia, lambert eaton
  3. Toxins - botox, tetradotoxin
  4. Presynpatic drugs reducing ACh release - volatiles, furosemide, LA< CaB, Mg, Aminoglycosides
  5. Postynatpic
    - Volatiles, aminoglycosides, barbituates, hyponatraemia, LA
230
Q

General adverse effecs from muscle relaxant use

A
231
Q

Benzylisoquinolonium SE

A
232
Q

Aminosteriod adverse events

A
233
Q
A

Primary Pharmacology (11 decks)

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