Muscle Relaxants Flashcards
Suxamethonium
- Two molecules of acetylcholine linked by their acetyl groups
- Stored at 4oC for stability
- ED95 0.5mg/kg
- Sch mimics action of Ach, binds AchR -> membrane depolarisation -> slow hydrolysis Sch (plasma cholinesterase not present at NMJ) -> sustained opening of receptor ion channel -> sustain depolarisation of post junctional membrane (inactivation h gate remains closed so propagation of AP inhibited) -> depolarised post junctional membrane cannot respond to sustained released of Ach -> phase I block
- Recovery - diffusion away from NMJ into plasma down a concentration gradient -> hydrolysis by plasma cholinesterase
- Onset 30-60s, duration 3-12mins
- D - protein binding 30%, VD 0.25L/kg, only 25% of IV dose reaches the NMJ before being hydrolysed
- M = Succinylcholine -> succinyl-mono-choline + choline (catalysed by plasma cholinesterase - pseudocholinesterase/ butyrylcholinesterase)
- Succinyl-mono-choline -> succinic acid + choline (catalysed by plasma cholinesterase as above)
=> Succinyl-mono-choline is weakly active - 90% metabolised prior to reaching NMJ
- E - Ester hydrolysis; Less than 10% excreted in the urine (rapid metabolism); T1/2B = 5mins (normal plasma cholinesterase), 90mins (complete absence of plasma cholinesterase)
S/E
- CNS - incr IOP + ICP
- CVS - bradycardia, arrhythmias
- RS - sux apnoea
- GI - incr intragastric pressure, incr salivation and gastric secretions
- Met/Endo - inch K+ 0.5mmol/L
- MSK - fasciculations, masseter spasm, myalgia
- Other - MH, anaphylaxis, phase II block
NDMR MoA
- Competitive antagonists at AChR
- Antagonist only needs to bind one AChR -> no conformational change, prevent access of Ach to receptor
- Binding is dynamic with repeated association and dissociation
- Higher concentration of Ach can displace the antagonist from the receptor
Intubation dose ID = 2-3x ED95
ED50
Median effective dose
- dose a drug that is required to produce a specific effect in 50% of the population
ED95
Corresponds to 95% twitch depression at adductor pollicis in half of the population
(ED50 of 95% twitch reduction)
Intubation dose = 2-3x ED95
AChE
Two functional sites of importance
Anionic site
- Negatively charged site that attracts the positively charge quaternary amide head of the ACh molecule
Esteratic site
- Ach molecule is broken at the ester bond to form choline, while the acetyl group is transferred to the esteratic site of the enzyme
- The enzyme undergoes rapid spontaneous hydrolysis to release the acetyl group, and go back to its original functional state
Phase II block
- Occurs when AChR continuously exposed to depolarising agents
- NMJ is depolarised by the initial exposure to the depolarising agent. Membrane potential gradually recovers even though the NMJ is still exposed to the agent
- Characteristic similar to non-depolarising block
- Proposed mechanisms
=> Pre-junctional block
=> Post-junctional receptor desensitisation - Antagonism with anticholinesterases - unpredictable response
Phase I (depolarising block)
- Caused by sux
- Characterised by - initial fasciculations with no fade or post-tetanic facilitation. With high or repeated doses, or in the absence of functional pseudocholinesterase -> phase II block
- Augmented by anticholinesterases
Desensitisation block
- Desensitised AChR are in conformational state where they cannot be activated to open their channel, even when bound by agonist
- State may be induced by high concentrations of agonists or other drugs
- Proposed mechanism - phosphorylation of receptor
- Safety mechanism to prevent over-excitation at NMJ
- Can be induced by - volatiles, barbiturates, verapamil, phenothiazines, alcohols
Sux apnoea
- Reduced pseudocholinesterase activity may exhibit prolonged paralysis
=> Initial block - absence of fade + post-tetanic potentiation
=> Prolonged block/ pseudocholinesterase deficiency demonstrated fade similar to NDMR - Giving anti cholinesterase inhibitor unlikely to be effective as also inhibits butyrylcholinesterase slowing metabolism
- Develop phase II block
- Can be due to:
Genetic variability
- Normal pseudocholinesterase = usual (Eu)
- Atypical (Ea) or ‘Dibucaine resistant’, Ea:Ea 1:3000, 4-8hrs
- Silent = Hetero - mild prolongation, homo - 3-4hrs but up to 24hrs
- Fluoride resistant (Ef) - homo very rare 1:150,000, mod sensitive to sux
- 96% homozygous for normal gene Eu:Eu
- Dibucaine number - identifies atypical genotype for butyrylcholinesterase
=> Test blood with benzoyl choline
=> Cholinesterase by spectrophotometry with dibucaine inhibition
=> Dibucaine inhibits normal butyrylcholinesterase activity more than it does abnormal enzyme - inhibits normal butyrylcholinesterase by about 80%, 20% inhibition if homozygous for atypical variant, 50% inhibit of heterozygous for atypical variant
Acquired deficiency
- Pregnancy/ post partum
- Liver disease
- Renal failure
- Cardiac failure
- Thyrotoxicosis
- Cancer
- Drugs
Rocuronium
- Aminosteroid compound
- Longer carbon side chain on quaternary amide than vec -> 6x less potent
- Monoquaternary amino steroid at physiologic pH
- Incompatible with thio, diaz, vanc, dex
- ED95 = 0.3mg/kg
- ID = 0.6-1mg/kg
- Mild vagolytic effect - incr HR and BP
- Highest anaphylaxis rate of all NDMR (1:2500)
- Pain on injection
- D - 30% plasma protein bound, VD 0.27L/kg
- M - Minimal metabolism, primarily hepatobiliary excretion with <1% metabolised. No active metabolites.
=> Liver failure - increased VD and reduced Cl
=> Age - Cl significantly reduced - E - Mainly excreted unchanged in bile and to a lesser extent in urine. T1/2 = 70mins, Cl = 3.7ml/kg
Vecuronium
- Aminosteroid compound (2-desmethyl derivative of pancuronium) - incr lipid solubility and alters degree of metabolism
- Monoquaternary (no vagolytic effect, reduced potency, incr lipid solubility, reduced stability in solution- white lyophilised powder)
- ED95 = 0.05mg/kg (potent), ID = 0.1mg/kg
- Min HD side effects (mild incr CO, rare bradycardia), anaphylaxis, pts with burns may have resistance to NDMR
- Onset 2-3mins, offset 40mins
- D - 60-90% plasm protein bound, VD 0.27L/kg, does not cross BBB or placenta
- M - Primarily eliminated unchanged in urine and bile. 30% deacetylated in liver
=> 3-hydroxy-vecuronium - 60% as potent, very short T1/2, renal excreted
=> 17-hydroxy-vecuronium
=> 3,17-di-hydroxy-vecuronium - E - Hepatic and renal clearance, T1/2 60mins
Pancuronium
- Bisquaternary aminosteroid
- ID 0.1mg/kg, ED95 0.07mg/kg
- Onset 3-5mins, duration 60mins
- Tachycardia (20%), incr MAP (20%) - indirect sympathomimetic action (decr NA reuptake), vagolytic effects - blocks cardiac muscarinic
- D - <50% protein bound, VD 0.25L/kg, VD incr in liver disease
- M - 30% metabolised by hepatic de-acetylation
=> 3-hydroxy-pancuronium - 50% as potnet
=> 17-hydroxy-pancuronium
=> 3-17-dihydroxy-pancuronium - E - Unchanged drug excreted mainly in urine (70%), metabolites excreted in bile
Atracurium
- Bisquaternary ammonium benzylisoquinolinium
- 10 stereoisomeric forms (4 chiral centres)
- Solution for injection - besylate (adjusts pH to 4, provides water solubility), stored at 4C
- ID 0.5mg/kg, ED95 0.25mg/kg
- Onset 3-5mins, duration 30mins
- Histamine release with rapid IV, large doses => hypotension and bradycardia
- D - VD increase in patients with hepatic failure
- M - organ independent metabolism
=> Hofmann elimination (40%) - spent base catalysed non-enzymatic chemical degradation, pH and temp dependent process (incr pH/ temp -> incr metab). Forms laudanosine and monoacrylates
=> Ester hydrolysis (60%) - non-specific plasma esterases, metabolites laudanosine (major metabolite, can cause seizures, excreted in urine), and acrylates (capable of damaging cells in vitro, clinical significance unknown). acidosis accelerates process - E - some direct renal elimination of unchanged drug. Laudanosine excreted via bile (70%) and urine (30%). T1/2 20mins, Cl 5ml/kg/min
Cisatracurium
- Bisquaternary ammonium benzylisoquinlinium
- One of the 10 stereoisomers of atracurium
=> Least adverse effects of atracurium isomers - ID 0.15mg/kg, ED95 0.05mg/kg
- Onset 3-5mins, offset 30mins
- No histamine release
- M - Hofmann elimination (predominant metabolic pathway) 80% clearance, higher potency - less laudanosine produced (cleared by liver)
=> No ester hydrolysis by plasma esterases - E - 95% excreted in urine mostly conjugated metabolites, 10-15% excreted unchanged in urine, T/12 20mins
- 3-4x more potent than atracurium - less molecules administered, less laudanosine and acrylates
Mivacurium
- Benzylisoquinolinium
- Mixture of 3 stereoisomers]
=> Cis-trans + trans-trans >90% total, T1/2B 2mins
=> Cis-cis <10% total, 10% potency, not metabolised enzymatically, T1/2B 30mins - ID 0.2mg/kg, ED95 0.1mg/kg
- Onset 2-4mins, duration 15mins
- Larger doses can cause hypotension and tachycardia due to HA release
- M - metabolised by plasma cholinesterase’s - butyrylcholinesterase to quaternary amino alcohols and quaternary monoesters (80% rate of sux)
- E - metabolites excreted in urine with T1/2 90mins. T1/2 3mins
Neostigmine
- Carbamate ester with quaternary amine group
- Covalent bonds at esteratic site of AchE, carbamylated enzyme unable to interact with Ach
- Inhibits plasma cholinesterase (prolongs duration of sux)
- Dose 0.05mg/kg (TOF 2-3), ceiling effect reached at 0.07mg/kg
- Incr Ach at all cholinergic receptors - muscarinic effects at low dose, nicotinic effects at high dose
- Also inhibits PChE -> augments sux
- Uses - reverse NDMR, myasthenia gravis, bladder atonia, glaucoma
- A - PO bioavailability 1-2%
- D - 2 compartment model, highly ionised and does not cross BBB (can cross placenta), 10% protein bound, VD 1L/kg
- M - Metabolised by plasma esterases to a quaternary alcohol, and some hepatic metabolism
- E - 50% renal elimination; T1/2 60-120mins, Cl 10ml/kg/min
- Duration of action related to time dissociation from esteratic site
Effects
=> Vagal effects - bradycardia, prolonged QT, asystole
=> Bronchospasm
=> Incr secretions + salivation
=> Miosis
=> Incr intestinal motility, N+V, diarrhoea
=> Incr ureteric and detrusor motility - urination
=> Anticholinergic used to antagonise these effects - glycopyrrolate antagonises muscarinic receptors without effecting nicotinic. Incr risk of tachyarrythmias, urinary retention, constipation, blurred vision, dry eyes/skin, insomnia
- Secondary muscle blockade - administration to fully recovered NMJ can cause weakness secondary to desensitisation and open channel blockade
- Neostigmine and glyco have similar times to onset and duration, whereas atropine has faster onset and shorter duration -> early tachy then late brady
Nicotinic effects
- Muscle - ↑[ACh] -> ↑Na+ influx > K+ efflux = Ca2+ influx -> end plate potential +/- AP -> contraction
=> Displaces and reverse NDMR
=> Augment and prolong depolarising muscle relaxant (↑Act at NMJ and inhibit PChE)
=> Weakness if high dose (ceiling 0.07mg/kg)
- Neuronal - autonomic ganglia (a3B4) - stimulation then depression.
=> Brain (a4B2) - nil, quaternary amine doesn’t cross BBB
Muscarinic effects
- PSNS post ganglionic
=> M1, 3, 5 - Gq GPCR (↑IP3/↑Ca2+, ↑DAG)
=> M2, 4 - Gi GPCR (↓cAMP)
=> Clinical effects - ↓HR, AV block,↓CO, constriction of airway SM -> obstruction, ↑tracheobronchial secretion, ↑salivation, ↑lacrimation, ↑ureteric peristalsis -> urination, ↑GIT peristalsis.
- SNS post ganglionic - ↑sweating, ↑skin vasodilation, ↑skeletal muscle vasodilation
Edrophonium
- Phenolic quaternary amine
- Electrostatic bonds at anionic site of AChE
- Hydrogen bonds at esteratic site
- Prevents ACh from interacting with enzyme
- Used to diagnose myasthenia gravis - rapid improvement in symptoms
- Onset 1-2mins, duration 60mins
- Atropine matches onset and duration profile
Pyridostigmine
- Carbamate ester with quaternary amine group
- Treatment of myasthenia gravis
- Slower onset
- Longer duration
- Less muscarinic effects
Physostigmine
- Carbamate ester with a tertiary amine group
- Lipid soluble as tertiary amine not charge -> crosses BBB (only anti cholinesterase to do so)
- Interaction with AChE similar to neostigmine
- Tx of central anticholinergic syndrome
- Initial excitation -> seizures
- Followed by depression -> unconsciousness and resp depression
Organophosphates
- Form stable enzyme complex (irreversible)
- Highly toxic
- Highly lipid soluble (rapidly absorbed through skin and crosses BBB)
- E.g insecticides, nerve gases (sarin), echothiophate eye drops (glaucoma tx)
- Phosphorylation of esteratic site of AChE (covalent bonds) -> formation of very stable complex
- Also inhibit plasma cholinesterase
- Nicotinic and muscarininc effect
- Autonomic stability
- Early CNS excitation followed by later CNS depression
- Tx - atropine, pralidoxime (AChE reactivator)
Sugammadex
- Modified gamma cyclodextrin
- Hydrophobic cavity and hydrophilic exterior due to polar hydroxyl groups (donut shaped)
- Dose 2mg/kg when TOF 2, 4mg/kg for deeper levels of block, 16mg/kg for rapid reversal when RSI dose of roc used (TBW for obese)
- Chlelates NDMR in plasma by directly binds aminosteroid relaxants and renders them inactive. Binds steroid portion with hydrophobic centre (roc > vec»_space;pan), forms tight 1:1 complex which is excreted in urine, established conc gradient between NMJ and plasma
- Bradycardia, bad taste, possible recurrence after suboptimal dose, potential for binding to other compounds (e.g OCP - equivalent to missing one daily dose, factor Xa)
- No muscarinic effects (no anticholinergic needed, much greater CVS and autonomic stability)
- Onset rapid, full reversal in 2mins
- D - does not bind plasma proteins, VD 12L
- M/E - no metabolism, up to 95% excreted unchanged via urine, T1/2 2hrs
- 24hr delay recommended prior to use of aminosteroid NMB again, if requiring re-blockade to use sux or benzylisoquinolinium.
- Drug interactions - fluclox, fusidic acid may displace roc from sugammadex - also binds OCP
Anticholinergic effects
E.g atropine, glyco, hyoscine
CNS (glyco does not cross BBB)
- Excitatory effects - restless, agitated, disorientated, hyperthermia
- Mild sedation
- Extrapyramidal sx
- Eyes - mydriasis, cycloplegia, incr IOP
CVS
- Incr HR (block cardiac muscarinic AChR)
RS
- Bronchodilation
GI/ GU
- Decr motility
- Urinary retention
- Dry mouth, skin, hyperthermia (inhibition of salivary, lacrimal, bronchial and sweat glands, reduced sweating)
Dantrolene
- Vials
- 20mg dantrolene, 3g mannitol, orange powder
- Reconstituted in 60mL sterile water
- Indications = MH, NMS
- Dose 2.5mg/kg IV every 10-15mins (up to 10mg/kg), after crisis 1mg/kg IV every 4-6hrs for 24hrs
- MoA - binds to RYR1 -> prevents release of Ca2+ from SR -> uncouples excitation/ contraction process
- No effect on muscle AP
- Protein binding 85%
- Hepatic metabolism - 5-hydroxy-dantrolene (30-50% effective)
- T1/2B = 3-12hrs, renal excretion
PD
CVS - nil direct
- Fluid overload and CHF (potentially due to rapid fluid shifts due to mannitol present in dantrolene), or excessive fluid administered
CNS - sedation, dizziness, confusion
Resp - resp muscle failure
GIT - N+V/ diarrhoea, hepatic dysfunction
Renal - diuresis (3g mannitol)
Uteroplacental - post-partum uterine atony, floppy childe
MSK - generalised muscle weakness
Other - phlebitis and tissue necrosis with extravasation due to alkalinity
- Anaphylaxis
Interactions - cannot be given with CCB (risk of accentuating hyperkalaemia + precipitating cardiac arrest).
- Potentiate NDMR
Malignant Hyperthermia
- Autosomal dominant
- Incidence 1:5000-50,000
- Ryanodine receptor mutation on chromosome 19
- Triggers - sux, volatiles
- Hypermetabolic reaction, 80% mortality untreated
Ryanodine receptors
- Located on SR
- Mediate release of Ca2+ from SR
- Three isoforms
- RYR1
=> Primarily skeletal muscle
=> Abnormal RYR1 + trigger -> excessive efflux of Ca2+ -> generalised muscle rigidity -> ↑ATP consumption to return CA2+ into SR -> ↑CO2, heat + lactate produced -> cell lysis -> myoglobinaemia, ↑K+, acidosis
- RYR2 - in myocardium
- RYR 3 - predominantly in brain
Early features
- ↑HR (earliest)
- Masseter spasm after sux
- ↑etCO2
- Cardiac arrhythmia
Developing
- Rapid ↑temp
- Sweating
- Progressive metabolic + resp acidosis
- ↑K+
- Generalised muscle rigidity
Late
- Myoglobinuria
- ↑CK
- Coagulopathy
- Cardiac arrest
Management
- Stop trigger, help, high FGF + FiO2 100%, TIVA
- Give dantrolene ASAP (2.5mg/kg)
- Tx life threatening complications
=> ↑K+ - hyperventilate, CaCl2, insulin + dextrose
=> ↑Temp - cooling
=> Arrhythmias - amiodarone, lignocaine
=> Renal protection - IVF, maintain UO
- Admit ICU
- Early ix - ABG, FBC, UEC, CK, coags, myoglobin
- Late ix - refer to MH clinic, in vitro caffeine and halothane contracture test, DNA analysis
Factors affecting neuromuscular blockade
Patient factors
- Hepatic disease - prolong amino steroids + sux
- Pseudocholinesterase deficiency - prolong sux
- Age - incr sensitivity in neonates
- Hypokalaemia - potentiate depolarising, reduce NDMR
- Hypermagnesaemia - potentiates
- Hypocalcaemia - potentiates
- Hypothermia - potentiase
- Hypovolaemia - slows onset + enhances duration
- MG - incr sensitivity to NDMR
- Eaton-Lambert - incr sensitivity to all
Drug
- Fruse - potentiates at low, reduces at high
- Inhalational - potentiates
- Aminoglycosides - potentiate
- LA - potentiate
- AChE - reduces
- OCP - potentiates depolarising
- CCB - potentiates
- Li - potentiates