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
What effect does a burn have on NMB
Receptor upregulation and resistance to non depolarising muscle relaxants
Decreased plasma cholinesterase activity
Neuromuscular agents vs neuromuscular disease
- Parkinsone
- Myasthenia
- Eaton Lambet
- MS
- GBS
- MND
- Cerebral palsy
-Muscular dystrophy
Pancuronium compound is
Bis-quaternary amino steriod
Vecuonrium compound? How is it chemically different to pancuronium? How is this significant
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
vecuonrium comes as a powder why?
Unstable in solution
Comes with mannitol and sodium hydroxide in the powder
Rocuronium precipitates with which co-induction agent?
Thiopental
Atracurium is what sort of compound? What chemically is it composed of?
Benzyl-iso-quinolinium compound
Mixture of 10 isomers - 4 chiral centres
How does atricurium come? Any additives?
Solution fo injection
Besylate adjusts pH to 3.25 - 3.65 pH, water solubility
Stored at 4 degrees
Cisatracurium has what relationship to atricurium
One of 10 sterioisomers
3-4x more potent than atracurium - less laudanosine and acrylates
What is an example of an anticholinesterase
Neostigmine
Pyridostigmine
Physostigmine
Edrophonium
Neostigmine chemically is what
QUaternary amine
How does neostigmine work
Covalent bonds at esteric site of acetylcholinesterases inhibiting action
Onset of neostigmine
3 minutes
Duration of action of neostigmine
30-60 minutes
Pharmacokinetics of neostigmine
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
Effects of neostigmine
3B’s 3Hs
Block reversal - Reversal of non depolarising block
Bronchospasm
bradycardia
Hypotension
Hypersalivation
Hypermotility - Increased intestinal motility and ureteric peristalsis
Dose for reversal of block for neostigmine
50 microg/kg IV (ceiling of effect 70microg/kg)
Physostigmine is what type of compound
tertiary amine crossing BBB
Why is pyridostigmine not used in anaesthetics
Also a quarternary amine but slower onset, longer duration so more useful for myasthenia gravis
Neostigmine and a partcular poison have a common MOA - which poison? How are they different?
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
What chemically is suggamadex
Gamma cyclodextrin
How does suggamadex work
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
What is the order of affinity of suggamadex with NDMA
Roc > Vec > pan
Sugammadex rate of reversal vs atropine
faster, dose dependent effect
Why is suggamadex a cleaner MOA than neostigmine
anticholinergics not required for coadministration to avoid side ffects
greater cardiovascular stability
Side effects of sugammadex
Bradycardia
Bad taste
Expensive
Suboptimal dosing can lead to recurrence of blockade
May bind to OCP
Dose of suggamadex after 0.6mg/kg rocuronium
2-4mg/kg
Dose of suggamadex for deeper levels of blockade
8-16mg/kg
Which muscle relaxants are safe in malignant hyperthermia
Atricurium
Atricurium does not mix with?
alkaline solutions e/.g. barbituates
Atropine derived from where? Chemical structure?
Alkaloid from Atropa Belladona - a tertiary amine
Atropine chemically prepared as?
Tertiary amine as the ester of tropic acid and tropine - comes as a racemic mixture of D and I hyoscyamine (I form active)
MOA of atropine
An anticholinergic acting by competitive antagonism of acetylcholine at muscurinic receptors
Minimal action at nicotinic receptors except at high doses
Atropine presentation
Clear colourless solution for injectino containing 0.5 or 0.6mg/mlatropine sulfate
Also as a tablet 0.6mg
Routes of adminsitration fo atropine
IM, IV
Oral
Dose of atropine in adults
0.015-0.02mg/kg in adults
3mg needed for complete vagal block in adults
Atropine effects
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
Toxicity of atropine
Dry mouth
Anticholinergic syndrome
urnary retention
Gluacoma if ocular adminitration (not in IV or IM)
Absorption of atropine
rapidly absorbed from gut, bioavailability 20%
Distribution of atropine
50% protein bound
2-4L/kg Vd
Cross placenta and BBB
Metabolism fo atorpine
Hydrlysed in liver and tissue to tropine and tropic acid
Excretion fo atropine
94% in urine within 24 hours uncahnged, clearance 70L/hr and half life 2.5 hours
Chemical structure of cisatracurium
benzyl-isoquinolinium ester - one fo the 10 stereoisomers of atracurium due to the presence of 4 chiral centres
Cisatracurium comes as? storage
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
Mode of action of cisatracurium
competitive antagonist of acetylcholine at the nicotinic N2 recepotrs at the post synaptic membrane of the neuromuscular junction
Neuromuscular recovery time from cisatracurium dose is depednent on? What is the mean time to recovery after multiday infusions (5-6 days)
time only; not dose - once recovery has started the rate of recovery is independent of dose administered
50 minutes
What is the IV infusion rate of cisatracurium
3microg/kg/min although wide variabiltiy in dose requireemmnts
T1 suppression 90-99%
Can be reduced to 1-2microg/kg/min
Cisatracurium CVS and respiratory side effects? Toxicity? Other side effects?
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
Distribution of cisatracurium
Vd 0.12-0.16L/kg
Metabolism of cisatracurium
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
What is Hoffman elimination
Spontnaeous degredation of the link between quaternary nitrogen ion and central chain - seen in cisatracurium and atracurium degredation
Excretion of cisatracurium
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
Factors prolonging duration of cisatracurium action
Hypokalaemia, hypocalcaemia, hypermagnesaemia, hypoproteinaemia, dehydration,. acidosis, hypercapnoea
Voltailes, ketamine, non depolarising NMB agents, diuretics (acetazolamide, furosemide), CaB, propanolol, lidocaine, aminoglycoside
What is dantrolene used in
Malignant hyperthermia and NMS
Heat stroke
Muscule spaciity
Tetanus adjunct
Dantrolene chemically
Phenyl hydantoin derivative
Mode of action of dantrolene
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
Routes of administraton of dantrolene and doses
1-10mg/kg IV an average of 2.5mg/kg is required
Oral dose 25-100mg 6 hourly
Therapeutic effects seen within 15 minutes
Effects of dantrolene
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
Toxicity and side effects of dantrolene
high irritating if extravasating
Chronic use can illicit muscle wekness, drowsiness, GI disturbances
Hepatic dysfunction reversible
Dantrolene kinetics
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
Glycopyrronium or glycopyrrolate chemical
quaternary amine
Presentation of glycopyrronium
vial containing 0.2mg/ml as a clear solution
Powder for topical applications
Fixed dose combination of 0.5mg with 2.5mg of neostigmine
Main actions and mode of action of glycopyrrolate
Anticholinergic - profound anti-secretory action
Competitie antagonism of acetylcholine at peripheral muscarinic receptors
Dose of glycopyrrolate
0.2-0.4mg IV and IM dose
Paediatric dose 4-10mcg/kg
Peak effects 3 minutes after IV injection
Peak effect timing of glycopyrollate
3 minutes post injection
Cardiovascular effect sof glycopyrrolate
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
Respiratory effects and CNS effects of glycopyrrolate
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
Abdominal and metabolic effects of glycorpyrollate
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
Side effects of glycopyrollate
Anticholinergic - dry mouth, difficulty with urination, inhibition of sweating
Headache
Drug kinetics for glycopyrrolate
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
Metabolism of glycopyrrolate
Very little
Excretion of glycopyrrolate
urine 85%
Bile 15%
80% unchanged
Clearance is 0.9L/min
Eliminiation half life is 0.6-1.1 hours
Ropivocaine and Bupivocaine pKa and protein binding?
8.1
95%
Potency of Ropivocaine and Bupivacaine in comparisone to lignocaine
Ropivocaine 3x potency
Bupivocaine 4x potency
(lignocaine is 2x more potent than the base procaine that is used for comparison)
Vd of suxamethonium?
0.2L/kg
Vd of pancruonium
0.2L/kg
Vd of rocuonrium
0.2L/kg
Atricurium Vd
0.2L/kg
Which muscle relaxant has the longest duration of action? WHy?
Pancruonium
10% hepatic metabolism
80% renal clearance
How is pancuronium cleared form the body? How is it metabolised? How important is metabolism to its clerance?
10% hepatic metabolism
80% renal clearance unchanged
Rocuronium clearance? Degree of metabolisM?
Hepatic 15%
50% unchnaged - 40% bile, 10% renal
Vecuronium metabolisma nd clearance
60% hepatically metabolised
20% renally unchanged
20% biliary unchanged
What is acetycholinesterase and where is it found? How does it act?
- 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
What varieties of cholinesterase are found
Achesterase - nerve endings & in RBCs
2. Non-specific or pseudocholinesterases - destroy other esters - tissues & plasma
What are the binding sites on acetylcholinesterase?
- 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
What are the classes of drugs affecting acetylcholinesterase
◦ (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.
How does Edrophonium act on acetylcholinestase?
◦ (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
How does neostigmine act on acetylcholinestase
◦ (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)
How do organophosphates act on acetylcholinestase
◦ (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.
What are muscurinic effects of activation
- 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
What are consequences of nicotonic receptor activation
◦ Reversal of non-depolarising neuromuscular blockers
◦ Prolongs effect of suxamethonium (depolarising NMB)
◦ Anticholinesterase overdose → excess synaptic ACh → depolarisation block ± fasciculation
What are the clinical uses of acetylcholinestases?
Reversal of NDMR
Diagnosis and Tx of Myasthenia
Treatment of cognitive impairment in Alzhemiers
Gluacoma
Anticholinergic syndrome
Explain which drug is used in treatment of myasthenia gravis and MOA
‣ 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
WHy is acetylcholinestase implicated in the treatment of dementia? What types of dementia? What drugs?
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
Acetylcholinestases are used in the treatment of glaucoma - explain MOA
‣ Mechanism – constriction of sphincter pupillae and ciliary muscles → miosis → facilitate outflow of aqueous humor → IOP decreases Drugs – e.g. echothiophate eye drops, physostigmine
What is anticholinergic syndrome?
‣ 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)
How are the acetylcholinestases functionally different?
- Duration of action
◦ Edrophonium short
◦ Neostigmine medium
◦ Organophosphate long - Reversible
◦ Edorphonium and neostigmine
◦ Irreversible organophosphate
Describe key pharmacodynamics and pharmacokinetics of edrophonium
◦ 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
Describe key pharmacological characteritysics fo pyridostigmine
◦ Analogue of neostigmine
◦ ¼ potency
◦ MoA Neostigmine
◦ Slower onset 16mins (so not used to reverse NDMR)
◦ DoA 6hrs (used for MG)
Organophosphate pharmacology
◦ 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
Pharmaceutics of suxamethonium
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)
Can you use suxamethonium in an infusion?
no
What is the prescribed offset of Neuromuscular blockade defined as?
TOF 0.9
Methods of administering suxamethonium
IM/IV
How would you describe the efficacy of the metabolism of suxamethonium
High capacity and high efficacy
20% reaches NMJ before hydrolysis
What factors might cause a more prolonged blockade specifically in suxamethonium
Liver failure, renal failure
Malignancy, pregnancy
Malnutrition
Drugs - MAOI, neostigmine, OCP< metaclopramide, cocaine, organophosphates
Extracorpereal
Rocuronium pharmaceutics
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
Rocuronium onset at 4x ED 95
45 sec to 1 minute
Mechanism of metabolism of rocuronium
De-acetylation <10% of total clearance
How is rocuronium cleared
80% liver (<10% of this is metabolism)
20% urine
Protein binding of rocuronium
50%
T1/2 beta after rocuronium infusion
70 minutes
Interactions of rocuronium
Thiopentone precipitates
Side effects of rocuronium
Tachycardia - vagolytic
Pain on injection
Anaphylaxis 6:100000 or 1:3500 (associated with use of pholcodine)
Protein binding of Vecuronium
77%
Succinylcholine apnoea can be reversed with
FFP
What is phase 1 block
Reduced block amplitude, TOF >0.7, no post tetanic potentiation and giving acetylcholinesterases will potentiate block
The first phase of depolarising muscle relaxant block
Phase 2 block
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
Explain the concept of fade
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)
Cisatricuronium pKa
19
Cisatricurium storage
Refridgerate 2-8 degrees, lasts 3 months
Water soluble so no need for reconstitution
Do you get anaphylaxis with Atricurium?
4 / 100 000
Protein binding of atricurium
80%
Protein binding of cisatricurium
15-40%
What proportion of atricurium activity is due to cisatricurium?
50%
What impact does temperature have on Benzylisoquinolonium metabolism?
Reduction in temperature delays both ester and Hoffman elimination
Reduction in pH reduces Hoffman
Increase in pH reduces ester action
How does Laudanosine act
Gluycine receptor antagonist leading to seizures
SE of suggamadex
0.3% anaphylaxis
bradycardia
Coagulopathy for 1 hour post
What relationship does ED95 have to potency?
Increased ED95 reduces potency
What is onset time of muscle relaxants defined as
Time to twitch height reduction by 95% (single twitch)
Depth of muscle relaxtion
Post tetanic count
Offset time of muscle relaxant
TOF 0.9
Duration of muscle relaxant determined by what aftcors other than potency factors
Decreased temperature decreases Hoffman and ester hydrolysis
pH - decreases affects Hoffman, increases effects Ester
Liver and renal failure
Drugs - roc action shortened by Succ
What baseline characteristics of patients determine duration of NMB?
Neonates immature NMJ so prolonged blockade
Increased muscle mass = reduced block (affecting genders)
Muscle type and location - blood flow
Factors which reduce potency of NMB
- ACh release increased - hyperkalaemia
- Pathology - critical illness myopathy, burns, malignant hyperthermia
- Tetanus toxin
- Neostigmine
Factors which increase potency of NMB
- ACh release reduced by acidsosis, hypokalaemia, hypermagnesaemia
- Path - myashtenia, lambert eaton
- Toxins - botox, tetradotoxin
- Presynpatic drugs reducing ACh release - volatiles, furosemide, LA< CaB, Mg, Aminoglycosides
- Postynatpic
- Volatiles, aminoglycosides, barbituates, hyponatraemia, LA
General adverse effecs from muscle relaxant use
Benzylisoquinolonium SE
Aminosteriod adverse events
