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
