Pharmacology 9

NMB's

depolarising

bis-quarternary
- suxamethonium
  - 8 SE's
    - muscle pain
    - arrythmias
      - bradycardia most common
        
        stimulation of muscarinic receptors at SAN
    - hyperkalaemia
      - 0.5mmol/L
      - more in BURNS (ok in first 24 hours and after 18 months) and DENERVATING INJURIES
        
        e.g. muscular dystrophy
    - increased intra-ocular pressure
      - 10-15mmHg (100%) for several minutes
    - increased gastric pressure (compensated by increased sphincter pressure)
      - 10cmH20
    - anaphylaxis
    - MH
      - ryanodine receptor (RYR1)
      - chromosome 19
      - autosomal dominant
      - 1:200,000
      - Tx: stop drug, 100% O2 in new circuit, ABC, dantrolene 1-3mg/kg IV, cooling
        
        orange powder
        
        20mg dantrolene
        
        3g mannitol
        
        mixed w. 60mL water
        
        pH 9.5
        
        ‘REMEMBER 3 x 20 = 60’
        
        only works on skeletal muscle - NOT smooth
      - caffeine-halothane test to confirm
    - sux apnoea
      - causes
        
        genetic: chromosome 3
        
        acquired: cardiac/renal/liver failure, pregnancy, thyrotoxicosis, burns, malnutrition
      - dibucaine number
        
        80 = normal (Eu:Eu, 96% of population)
        
        40-60 = carrier
        
        <20 = homo (Ea:Ea or Es:Ea)
        
        0 = silent homo (Es:Es - no cholinesterase to inhibit)
        
        dibucaine breaks down normal cholinesterases much more than abnormal, the number is the proportion broken down
        
        can also use fluoride or scolione number
      - ‘still sux his thumb at 3’
  - PK
    - met. pseudocholinesterase
      - 90% before reaching NMJ
      - pseudocholinesterase is in plasma, kidneys, brain, pancreas, placenta (NOT NMJ)
    - effect potentiated by anticholinesterases

non-depolarising

aminosteroids
- mono-quarternary
  - rocuronium
    - higher risk of anaphylactoid reactions
    - met: mostly in bile as lipophyllic, 17-desacetyl is 20x less potent (not important)
  - vecuronium
    - powder with mannitol and sodium hydroxide
    - met: 3-desacetyl is 80% as potent
  - rapacuronium
    - removed due to high risk of bronchospasm
  - points about mono-quaternary structures
    - less potent
    - in acidic conditions, the tertiary amine can become charged, making them more potent
- bis-quarternary
  - pancuronium
    - long acting
    - met: 60% unchanged in urine, 3-hydroxy is half as potent
    - sympathomimetic and vagolytic
benzylisoquinoliniums
- mono-quarternary
  - tubocurarine
- BIS-QUARTERNARY
  - atracurium
    - mixture of 10 stereo and geoisomers
    - PK
      - PB 15%
    - metabolism
      - 45% plasma esterases (accelerated by acidosis (although unlikely within clinical range
        
        to a monoquarternary alcohol derivative
      - 45% Hoffman (slowed by hypothermia and acidosis)
    - issues
      - histamine release
      - both pathways produce laudanosine
        
        glycine antagonist
        
        may be epileptogenic
        
        excreted in urine
  - cis-atracurium
    - more potent (4x)
    - more Hoffman (77%)
    - less histamine
  - mivacurium
    - short acting
    - mixture of 3 isomers
    - met: plasma esterases
    - issues
      - lots of histamine release, give slowly
      - when plasma esterases are low
        
        pregnancy
        
        cardiac/liver/renal failure
        
        thyrotoxicosis
        
        cancer

NMBs Contd....

interactions

prolong block
- mechanisms
  - prevent Ach synthesis
    - hemicholinium
  - prevent Ach release
    - botox
      - binds irreversibly to nicotinic receptors
      - ‘you release from you buttocks’
  - deplete Ach stores
    - tetanus
      - block release of inhibitory neurotransmitters
  - block Ach receptor
    - NMB’s
- drugs (MTV CALF)
  - magnesium + metoclopramide
  - tetracyclines
  - volatiles
  - Ca channel blockers/acute phenytoin
  - aminoglycosides
  - local anaesthetics/lithium
  - furosemide
- electrolytes
  - hypokalaemia
    - think Nernst!
  - hypermagnesaemia
shorten block
- enzyme inducers: (?chronic) phenytoin, carbamazepine
- sugammadex
  - selective relaxant binding agent
  - modified gamma-cyclodextrin
  - hydrophilic exterior, lipophilic core
  - encapsulates amino steroid and excretes it in urine (not metabolised)
  - dose
    - 2mg/kg
      - 2 twitches with TOF
    - 4mg/kg
      - 2 post-tetanic twitches
    - 16mg/kg
      - after RSI dose
  - preparation
    - 200mg or 500mg
  - pros
    - rapid
    - anytime
    - no muscarinic side effects
  - cons
    - expensive
    - fluclox or fusidic acid may displace roc
    - not recommended in renal failure
    - may decrease progesterone levels when on OCP
    - dysgeusia
acetylcholinesterase inhibitors
- competitive
  - quaternary amine
    - edrophonium
      - myasthenia gravis test
      - quaternary amine binds to anionic site, hydroxyl group binds to esteratic site
      - does not cross BBB or to placenta (as QA)
- through carbamylated enzyme complex
  - quaternary amines
    - neostigmine
      - cationic part binds to anionic site and the terminal carbon binds to the esteratic site, then the phenol breaks away
      - T1/2 60 mins
    - pyridostigmine
      - myasthenia gravis treatment
      - T1/2 4 hours
  - tertiary amine
    - physostigmine
      - Tx for glaucoma and BZ poisoning
- irreversible
  - organophosphates
    - phosphorylate esteratic site
    - Tx: ABC, atropine, pralidoxime (promotes hydrolysis of the phosphorylated enzyme)