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Pharmacology (Dustin, Ben) > A13-14: Central + NMJ Skeletal Muscle Relaxants > Flashcards

A13-14: Central + NMJ Skeletal Muscle Relaxants Flashcards

1
Q

Describe the nAChR …

types, ligand binding, effects etc.

A

A cation-selective (Na / K) ion channel

  • NN neuronal type (α and β subunits); NM muscular type (α2βγδ pentamer)
  • 2-5 ACh molecules can bind (depending on subunit structure)
  • Continuous stimulation results in depolarization blockade (after a few seconds)
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2
Q

What are the two main target regions / systems for pharmacological relaxation of skeletal muscles?

How is the general effect different between these targets?

In one of these regions, what are two subcategories of areas that can be targeted?

A
  1. Centrally (CNS) muscle relaxants - decreases tone of muscle (“spasmolytic” effect)
  2. Peripheral (NMJ) muscle relaxants - paralyzes muscle (“total relaxation” effect)
    • Presynaptic drugs - botulinum, conotoxin
    • Postsynaptic drugs - curares, etc.
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3
Q

List some indications for peripheral muscle relaxants.

( 7, from slide)

A
  1. Surgery - muscle relaxation during narcosis
  2. Artifical Respiration - relaxing muscles of pts on AR (ex: severe COPD)
  3. Electroshock
  4. Intubation
  5. Tetanus
  6. Epileptic Seizure - if unresp. to antiepileptics
  7. Overdose - amphetamine, theophylline

May help memory to break them up into uses in medical procedures (1-4) and treatment of conditions (5-7).

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4
Q

What are the 3 categories of postsynaptically-acting peripheral muscle relaxants?

A
  1. Curare derivatives - tubocurarine + isoquinolones + steroids
  2. Depolarizing muscle relaxants - succinylcholine, etc.
  3. Ryanodine antagonists - dantrolene, etc.
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5
Q

In general, what is the mechanism of curare derivatives?

Structure?

Route of admin?

A
  • competitive antagonism of the muscular type nAChR (NM)
  • basic structure is a bisquaternary ammonium base … presence of quaternary nitrogens results in lipid insolubility > no BBB entry
  • given via IV administration
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6
Q

What is the time range in which full paralysis is induced by curare derivatives?

(Probably less important: in what order are various sets of muscles in the body paralyzed?)

A
  • 2-6 minutes
  • (Extrinsic eye muscles > facial mm. > pharyngeal mm. > extremities > trunk > diaphragm)
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7
Q

What are the 2 structural classifications of curare derivatives?

And the members of each classification?

(5 in one, 4 in the other)

A
  • Isoquinolones: end in “-curium”
    1. D-tubocurarine
    2. doxacurium
    3. atracurium
    4. cisatracurium
    5. mivacurium
  • Steroids: end in “-curonium”
    1. pancuronium
    2. pipecuronium
    3. vecuronium
    4. rocuronium
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8
Q

Which of the curare derivatives are long acting?

Intermediate acting?

Short acting?

A
  • Long (60-180 min): doxacurium, pancuronium, pipecuronium
  • Intermediate (20-40 min): vecuronium, rocuronium, atracurium + cisatracurium
  • Short (10-15 min): mivacurium

(Katzung: generally curare derivatives excreted by kidney have longer half-life/action; those eliminated by liver have shorter)

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9
Q

What special form of elimination occurs to some curare derivatives? Which ones?

(What does it produce + what is the significance of this?)

A
  • Hofmann Elimination - a spontaneous breakdown reaction that happens to atracurium and cisatracurium
  • (Creates laudanosine which has no NMJ blocking effect, but crosses BBB + may cause seizures and interfere with anesthesia)
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10
Q

Which of the curare derivatives undergo elimination primarily by the…

kidney?

liver?

Hofmann elimination?

a serum enzyme? (which enzyme?)

A
  • Kidney: pipecuronium, pancuronium
  • Liver: vecuronium, rocuronium
  • Hofmann: atracurium, cisatracurium
  • Pseudocholinesterase: mivacurium

(Remember, as mentioned before, those eliminated in kidney tend to have longer half-life than liver-metabolized curares. It also seems like the reason for mivacurium’s especially short half-life is this plasma enzyme breakdown.)

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11
Q

What are 6 adverse effects of curare derivatives?

Which drugs tend to cause which ones?

A
  1. “Recurarization“ - recurrent muscle weakness after discontinuation of drug (unknown reason)
  2. Ganglion blockade - ↓ BP + ↑ HR (d-tubocurarine + pancuronium)
  3. Histamine Release - itching, bronchospasm + hypotension (atra-/mivacurium)
  4. M2 Blockade - tachycardia (pancuronium)
  5. NE Release/Reuptake Inhib. - ↑ HR (pan-)
  6. Laudanosin Accum. - Hofmann elim. metabolite > spasms/convulsions (atra-/cisatra-)
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12
Q

What are 2 pharmacological methods for terminating the effects of curare derivatives?

A
  1. ACh-ase Inhibitors - neostigmine/distigmine ↑ levels of ACh at NMJ to overcome competitive inhibition by curares; (atropine is co-admin’d with them to block muscarinic overstimulation)
  2. Sugammadex - binds + neutralizes steroid curare derivatives
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13
Q

What factors enhance (4) and attenuate (2) the effects of curare derivatives at the NMJ?

A
  • Enhanced Effects
    1. General anesthetics - inhaled fluranes also relax muscle
    2. Antibiotics - aminoglycosides/tetracyclines (via blocking prejunctional Ca++ channels)
    3. Local Anesthetics - Na+ channel interference
    4. Myasthenia Gravis - nAChR blocked by Ab
  • Attenuated Effects
    1. ​​ACh-ase Inhibitors
    2. Motoneuron Lesions
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14
Q

What is the clinically relevant drug in the category of depolarizing muscle relaxants?

(1 drug w/ 2 names)

Its indications?

A

Succinylcholine / Suxamethonium

  • short surgeries
  • short invasive diagnostics (bronchoscopy)
  • intubation
  • electroshock
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15
Q

What is the duration of action of succinylcholine?

(In what order does it paralyze different muscle groups?)

A
  • 5-10 minutes DOA after IV admin
  • arms > neck > legs > diaphragm > facial mm. > pharyngeal mm.
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16
Q

There are two phases to succinylcholine’s action at the NMJ…

what phenomenon characterizes phase I?

Describe it.

A

Phase I - Depolarization

  • Succinylcholine binds nAChR and produces a depolarization much like ACh would, resulting initially in muscle twitching
  • Because it is not metabolized by ACh-ase, SCh continues to activate the nAChR > membrane remains depolarized + nearby Na+ channels enter an inactive state
  • (Excitation-contraction coupling requires repolarization + repetitive NMJ firing to maintain muscle tension, so all this > flaccid paralysis.)
17
Q

There are two phases to succinylcholine’s action at the NMJ…

what phenomenon characterizes phase II ?

Describe it.

A

Phase II - Desensitization

  • With prolonged SCh exposure, depolarization fades + membrane repolarizes but is desensitized + can’t easily be repolarized again
  • (Mechanism for this is unclear, but may be due to channels being physically blocked or receptors being occupied by SCh)
18
Q

How do ACh-ase inhibitors affect succinylcholine’s effects in…

phase I (depolarization)?

phase II (desensitization)?

(This is extra from Katzung but I think helps with understanding of what is happening in these phases.)

A
  • Phase I - they augment the flaccid paralysis by the action of extra ACh helping to maintain the depolarized/unresponsive state of the muscle membrane
  • Phase II - they can be used to overcome the paralysis, as in phase II the repolarized, but desensitized membrane can be stimulated again with a sufficient dose of ACh
19
Q

What are 6 adverse effects of succinylcholine?

A
  1. Myalgia - due to initial uncoordinated twitching; worse in ambulatory/muscular patients than in bed-ridden
  2. Arrhythmia - cholinergic stim via SCh can ↑/↓ HR + force; mostly bradycardia occurs
  3. Hyperkalemia - K+ flows thru nAChR out of cell
  4. Vomiting - spasms ↑ gastric P
  5. Intraocular P ↑ - via myofibril contraction or ocular vessel dilation
  6. Malignant Hyperthermia - details on next card
20
Q

What is malignant hyperthermia?

What triggers it + what clinical conditions / signs does it cause?

A
  • A genetic disorder of ryanodine receptors (RyR1) resulting in continous outflow of Ca++ from the SR causing continuous shivering resulting in hyperthermia
  • Succinylcholine triggers it (uknown reason)
  • Leads to lactic acidosis, myoglobinemia/-uria and acute renal failure
21
Q

What drug can be used to treat malignant hyperthermia?

Mechanism?

What is its main side effect?

(How are the complications of MH treated?)

A

Dantrolene - a hydantoin derivative

  • Binds + antagonizes RyR1 (Doesn’t affect cardiac / SM RyR2)
  • Main side effect: hepatotoxicity (1-2% of cases, but 20-30% lethal in those)
  • (Bicarb for acidosis, physical cooling for hyperthermia)
22
Q

What is the general purpose of centrally-acting skeletal muscle relaxants?

How does their action differ from peripherally-acting ones? (generally, not including molecular targets)

A

They relieve pathologically increased muscle tone (spasticity) without inhibiting voluntary muscle movement.

23
Q

There are 3 general categories of centrally-acting muscle relaxants based on their g**eneral indications…

what are they?

(this is a very general distinction made in the slides, so don’t overthink it)

A
  1. Drugs for Spasticity Only - baclofen
  2. For Acute Spasms Only - mephenesine, guaiphenesin, chlorzoxazone
  3. For both Acute Spasms and Spasticity - diazepam, tizanidine, tolperisone, carisoprodol

Note that in this conext “spasticity” is a chronic conditon of increased tendon reflexes, hypertonia and paralysis in skeletal muscle via lost inhibition of motor neurons.

24
Q

Which centrally-acting drug is used for spasticity only (not for acute spasms)?

What is its mechanism? Side effect?

(there was very little on these centrally-acting drugs in the slides, so anything in small text in the following cards is extra)

A

Baclofen

  • GABAB agonist (blocks mono + polysynaptic reflexes by acting as an inhibitory neurotransmitter)
  • is highly sedative; discontinuation causes similar withdrawal sx to benzodiazapenes + alcohol; overdose causes respiratory depression, hyporeflexia, bradycardia etc.
25
Q

Which 3 centrally-acting drugs are used for acute muscle spasms only (not spasticity)?

A
  1. Mephenesin + Guaiphenesin - unknown mechanisms; may be NMDA-R antagonists; meph no longer used, guaiph used mostly as an expectorant
  2. Chlorzoxazone - unknown mechanism, but does cause general CNS depression
26
Q

Which 4 centrally-acting muscle relaxers are used for both acute spasms and spasticity?

Mechanisms? Toxicity?

A
  1. Diazepam - a benzodiazepene; allosteric modulation of GABAA receptor to increase GABA binding
  2. Tizanidine - an α-2 agonist; related to clonidine
  3. Tolperisone - unknown mechanism; Wiki says blocks VGSCs and VDCCs in reticular formation
  4. Carisoprodol - a prodrug, its metabolite meprobamate is hepatotoxic (and activates GABAA receptors); has abuse potential
27
Q

What drug blocks the presynaptic release of acetylcholine?

What is the effect?

A

Botulinum toxin (Botox)

Cleaves SNARE proteins, preventing release of Ach-containing vesicle

Effect: local flaccid paralysis when injected into a muscle, systemic paralysis if absorbed systemically. Dangerous for respiratory muscle paralysis.

Injected into facial muscles to reduce wrinkles, or clinically can be used to treat some spastic muscle disorders/dystonia

Pharmacology (Dustin, Ben) (17 decks)

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