Pharm NMBs (10)

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  1. Neuromuscular Blockers (NMBs)
    • drugs that block neural transmission at the neuromuscular junction causing relaxation of affected skeletal (NOT smooth) muscles → resulting in paralysis
    • also affect the respiratory system
    • all are structurally related to Ach & all useful NMBs contain one or two quaternary nitrogens
  2. Acetylcholine (ACh)
    • the neurotransmitter responsible for physiologic transmission of nerve impulses from
    • 1. pre- & post-ganglionic neurons of the cholinergic (parasympathetic) nervous system
    • 2. pre-ganglionic adrenergic (sympathetic) neurons
    • 3. multiple nerve endings in the central nervous system
    • 4. neuromuscular junction in skeletal muscles
  3. What are two types of ACh receptors?
    • 1. nicotinic (nAChR)
    • 2. muscarinic (mAChR)
  4. Muscle Activation
    1) motor neuron depolarization causes an action potential to travel down never fiber to the neuromuscular junction

    • 2) axon terminal depolarization causes an influx of Ca2+
    • 3) this triggers fusion of the synaptic vesicles & release of ACh from terminal button

    4) ACh diffuses across the synaptic cleft of the NMJ & binds to post-synaptic nAChR located on the muscle fiber at the motor end-plate

    {nAChR are pentamers in which two ACh must bind in a specific confirmation to produce agonistic action}

    5) binding of 2 ACh molecules to nAChR opens the channels causing an influx of Na+

    6) depolarization of the sarcolemma that travels down the t-tubules ultimately causes the release of Ca2+ from the sarcoplasmic reticulum

    7) this causes muscle contraction

    8) unbound ACh in the synaptic cleft defuses away or is hydrolyzed (inactivated) by acetylcholinesterase (AChase)
  5. What effect does ACh have on pre-synaptic NMJ nicotinic receptors?
    ACh acts on pre-junctional nicotinic receptors in a positive feedback manner to INCREASE its own release during high-frequency stimulation
  6. What are the two classes of Neuromuscular Blockers?
    • 1. Non-Depolarizing NMBs - Competitive
    • 2. Depolarizing NMBs
  7. Non-Depolarizing (Competitive) NMBs
    • drugs that competitively antagonize the action of ACh at post-synaptic nicotinic AChRs (found on motor end-plates)
    • if ACh isn't able to bind & cause muscle contraction, paralysis is the result
    • they reduce the frequency of channel-opening events but once a channel has been opened, they can't affect the magnitude, conductance, or duration of said event
    • only 1 NMB molecule is needed to block the nAChR
    • usually takes ≥70% blockade of nAChRs to see a paralytic response
    • b/c they're competitive blockers their effect is reversible
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  8. What effect do non-depolarizing NMBs have on ACh's binding to pre-synaptic NMJ nicotinic receptors?
    • non-depolarizing NMBs BLOCK pre-junctional receptors, meaning ACh cannot bind to them & induce its own release during high-frequency stimulation → ACh fails to mobilize
    • this manifests as “Fade Phenomenon”
  9. Fade Phenomenon
    • there is a reduction in twitch height with successive stimuli
    • “Fade” constitutes a key property of NON-depolarizing NMBs & is useful for monitoring purposes

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  10. How are NMB blockades monitored?
    • non-depolarizing NMBs can be monitored by transdermal stimulation (depolarizing NMBs can't)
    • monitoring aims to decrease unwanted effects of NMBs that can come about because of prolonged paralysis or delayed recovery
  11. Train-of-four (TOF)
    • a supramaximal stimulus is delivered by peripheral nerve stimulation & the number of contractions are observed at the nerve being stimulated
    • most commonly used technique for monitoring NMBs
    • delivered as a group of 0.2 millisecond pulses, spaced 500 milliseconds apart at a frequency of 2 Hz

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  12. What are the two types of Non-Depolarizing NMBs?
    • 1) Aminosteroid Derivatives
    • 2) Benzylisoquinoline Derivatives
  13. Aminosteroid Derivatives
    • Pancuronium (is active the longest)
    • Rocuronium (is active for a long time)
    • Vecuronium
    • [A PeRVe]
  14. Where are Aminosteroid derivatives metabolized?
    • in the liver
    • if a patient has a diseased liver an alternative NMB or drug dose might have to be used
    • ALL NMBs are filtered through renal system; something to keep in mind during dosage
  15. Benzylisoquinoline Derivatives
    • Atracurium
    • Cisatracurium
    • [BAC or CAB]
  16. How are Benzylisoquinoline derivatives metabolized?
    • by organ INDEPENDENT elimination
    • therefore they might be a better NMB choice (than aminosteroids) if a patient has liver or kidney failure
    • can further decide between cisatracurium (seems to last longer) or atracurium by looking at what side-effects each result in
    • eg. atracurium is less favorable because → laudanosine (seizures) & histamine release
  17. Laudanosine
    • a metabolite of the non-depolarizing NMB atracurium that produces tachycardia & potential seizure-like activity
    • atracurium is a benzylisoquinoline derivative
  18. What are some therapeutic uses of non-depolarizing NMBs?
    • skeletal muscle relaxation for surgical procedures or as an adjuvant to anesthesia
    • to maintain synchrony in mechanically ventilated patients
    • to prevent shivering during hypothermia protocols
  19. Non-depolarizing NMB Duration of Action
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  20. Adverse effects of Non-Depolarizing NMBs
    • 1. tachycardia & hypertension due to vagolytic + sympathomimetic properties (pancuronium, rocuronium)
    • 2. histamine release potentially leading to: hypotension, reflex tachycardia, flushing, urticaria, bronchospasm (atracurium)
    • 3. Acute Quadriplegic Myopathy Syndrome (AQMS)
  21. Acute Quadriplegic Myopathy Syndrome (AQMS)
    • preferential loss of the motor protein myosin & myosin-associated thick filament proteins in ICU patients characterized by severe muscle weakness & atrophy of spinal nerve innervated limb & trunk muscles that can go on for days or weeks
    • risk of getting AQMS from NMB use increases if steroids are also being taken
    • occurs more often in prolonged use (longer surgical procedures) or long ventilation times & can increase morbidity
  22. How can a non-depolarizing NMB blockade be reversed?
    • 1. by increasing the concentration of ACh: it will have a higher chance of occupying a nAChR site than the drug
    • 2. by giving AChase inhibitors (eg. neostigmine): decreasing ACh breakdown helps increase the amount of ACh in the synaptic cleft
    • #2 is not as effective for “deep blockade”; is more effective when 4/4 TOF twitches occur
  23. What is the main kind of Depolarizing NMB?
    • Succinylcholine - comprised of two ACh molecules
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  24. Phase I Block of Depolarizing NMBs
    • succinylcholine binds to a nAChR, opening of the receptor's channel, depolarizing the motor end-plate, & Ca2+ is released from the sarcoplasmic reticulum causing fasciculation
    • succinylcholine doesn't dissociate from the nAChR, maintaining the membrane potential above threshold preventing the muscle cell from repolarizing

    ACh cannot propagate an action potential on an already depolarized end-plate & succinylcholine is fairly resistant to degradation by AChase

    as the calcium is independently reuptaken by the sarcoplasmic reticulum, the muscle relaxes → paralysis
  25. fasciculation
    a small, local, involuntary muscle contraction, aka a "muscle twitch"
  26. Phase II Block of Depolarizing NMBs
    • the end-plate eventually repolarizes, but because succinylcholine is not metabolized like ACh, it continues to occupy the nAChRs
    • this “desensitize” the motor end-plate making it impossible to depolarized again
    • this phenomenon is rarely seen in clinical practice b/c it only occurs w/ prolonged or repeated use of succinylcholine, resulting in paralysis that can last 30 – 60 minutes
    • phase II is similar to how non-depolarizing NMBs act
  27. What is responsible for metabolizing succinylcholine?
    • butyrylcholinesterase
    • this enzyme is not readily availably in the NMJ synaptic cleft which explains why the more succinylcholine that's used, the longer it takes to degrade & the longer paralysis lasts
  28. What effect do depolarizing NMBs have on ACh's binding to pre-synaptic NMJ nicotinic receptors?
    • twitch height is reduced in a constant manner but no “fade phenomenon” is seen
    • this means the effect of succinylcholine can't be effectively monitored during paralysis
  29. What is succinylcholine mainly used for?
    • to facilitate endotracheal intubation
    • rocuronium (a non-depolarizing NMB) can also be used for this purpose
  30. Adverse effects of Depolarizing NMBs
    • Hyperkalemia
    • Masseter muscle rigidity
    • Bradycardia
    • Malignant hyperthermia
    • Muscle pain (usually the day after surgery)
    • Prolonged paralysis from butyrylcholinesterase deficiency
    • Anaphylaxis
    • Increased intragastric pressure
    • Increased intra-ocular pressure

    *why succinylcholine isn't used unless for rapid sequence intubation
  31. Malignant Hyperthermia
    • high fevers & rigidity that can quickly lead to death if untreated
    • can have a genetic predisposition to it
  32. Can succinylcholine (the depolarizing NMB) be reversed?
    • not readily because succinylcholine & ACh have essentially the same mechanism of action
    • in fact, their effect is augmented by AChase inhibitors (AChase is already not effective at breaking down succinylcholine, now with less enzyme available it would be even worse → longer lasting paralysis)
  33. General Sequence of Muscle Paralysis
    • small, rapid muscles (eye) > limbs, neck, trunk, masseter, & upper airway > intercostal muscles, larynx, & face > diaphragm
    • larger muscles (eg. diaphragm) are more resistant to block
    • paralysis fades in the REVERSE order → the diaphragm regains function 1st
    • the sequences = the same for both types of NMBs
  34. Characteristics of All NMBs
    • they don't alter level of consciousness or pain sensation
    • have poor oral absorption → must be given intravenously
    • they IONIZE & don't cross the BBB
    • their duration of action is the time from administration to the time when the evoked neuromuscular function of the thumb returns to 25% of baseline
  35. What effect do inhalation anesthetics have on a NMB blockade?
    they reduce postsynaptic receptor sensitivity to ACh & therefore decrease muscle contractility

    eg. desflurane > sevoflurane > isoflurane > halothane > nitrous oxide
  36. What effect do antibiotics have on a NMB blockade?
    • they decrease presynaptic ACh release
    • reduce postsynaptic nAChR sensitivity
    • impair ion channels
    • eg. Aminoglycosides, Colistin, Clindamycin, Tetracyclines
  37. What effect do calcium channel blockers & local anesthetics have on a NMB blockade?
    they reduce postsynaptic receptor sensitivity to ACh which leads to decreased muscle contractility
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Pharm NMBs (10)
2013-12-15 20:47:48
Exam 2
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