Muscle Pharmacology

Question 1

Depolarizing muscle relaxant

Answer 1

Succinylcholine

Question 2

Nondepolarizing muscle relaxants

Answer 2

Aminosteroid- vecuronium

Benzylisoquinolone- cis-atracurium

Question 3

Acetylcholinesterase inhibitors

Answer 3

Edrophonium
Neostigmine
Physostigmine

Question 4

Acetylcholinesterase regenerators

Answer 4

Pralidoxime chloride (2-PAM)

Question 5

Anti-spasmodic; Rx for malignant hyperthermia

Answer 5

Dantrolene

Question 6

Binding sites for Ach and NMBA’s

Mechanism of each

Answer 6

Extra cellular alpha subunits
both alpha sites must be occupied by Ach in order to propagate a muscle cell depolarization: then the receptor opens a central channel and permits transit of Na, K, Ca ions while blocking others.
When nondepolarizing NMBAs bind to EITHER alpha subunit(only need 1), the channel cannot open, and a NM blockage occurs, competitively

Question 7

Synthesis of acetylcholine

Answer 7

Acetyl-coenzyme A and choline; catalyze by choline acetyltransferase and stored in synaptic vesicles

Question 8

Presynaptic Ach receptors

Answer 8

Different strains of only alpha and beta units
Feedback for Ach mobilization and release during high frequency activation (>2Hz)- Ach feeds back and causes release of Ach
Blocked by non-depolarizing NMBAs (fade)- because they only need to bind to one alpha subunit to work.

Question 9

Extra junctional receptors

Answer 9

When nerve activity is reduced (trauma, burns, skeletal muscle denervation), immature receptors proliferate rapidly and spread over entire post junctional membrane.
Degraded soon after neural influence returns
Highly sensitive to agonists; resistant to nondepolarizers
Massive activation with succinylcholine can produce fatal hyperkalemia

Question 10

Short acting nondepolarizing agent

Answer 10

Mivacurium

Question 11

Intermediate acting non depolarizing agents

Answer 11

Atracurium
Cis-atracurium
Vecuronium
Rocuronium

Question 12

Long acting non depolarizing agents

Answer 12

Doxacurium
Pancuronium
Pipecuronium

Question 13

MOA of succinylcholine

Answer 13

Similar action to Ach, but longer acting
Membrane is depolarized by opening AchR channels causing brief period of muscle fasciculation
End plate potential eventually repolarizes, but because SC is not metabolized like Ach, it continues to occupy the AchR’s to ‘desensitize’ the end plate.
Blocking effects are augmented by AchE inhibitors
SC is metabolized by plasma pseudocholinesterases

Question 14

MOA of competitive non-depolarizers

Answer 14

Bind to one or both alpha units of AchRs and competes with Ach. Channel remains closed
Dynamic binding (repeated assoc/dissoc)- competition
Presynaptic receptors blocked at higher doses
Reversal of block can be achieved by increasing Ach levels in synaptic cleft (AChE Inhibitors)

Question 15

The aminosteroid non-depol agents

Answer 15

Pancuronium
Vecuronium
Rocuronium

Question 16

Benzylisoquinolones non depolarizing agents

Answer 16

D-tubocurarine

Cis-atracurium

Question 17

How is cis-atracurium metabolized?

Answer 17

Hepatic metabolism and Hoffman elimination- degradation at physiologic temp and pH

Question 18

How are steroidal non-depolarizers metabolized?

Answer 18

Liver and excreted by kidneys

Question 19

Train of four in absence vs. presence of drug

Determining if adequate blocking:

Answer 19

Absence- a sustained muscle contraction observed: tetany
Nondepolarizing- fade 1–>4 or 1/2–>4. Or nothing if all receptors are bound. As it wears off, first twitch is very strong, then fades.
Depolarizing- phase 1 is constant but diminished. phase 2 is fade (TOF<0.3). All or nothing response.

TOF ratio= 4/1 in a fade. TOF of 0.15-0.25 indicates adequate surgical relaxation
TOF>0.9 needed for safe exhumation and recovery after surgery

Question 20

Full reversal of NMBA’s depend on

AchE Inhibitors MOA

Answer 20

Diffusion, redistribution, metabolism and excretion of NMBA
Only effective for competitive block, increase Ach at nicotinic and muscarinic receptors to antagonize NMBA.

Must be accompanied by anticholinergic medication- gylcopyrrolate or atropine.

Question 21

Sugammadex (Bridion)

Answer 21

Modified gamma-cyclodexrin
Encapsulates and electrostatically binds rocuronium and vecuronium within the molecule’s core
Renally eliminated
Effect can occur within 2 minutes- rapid reversal of NMBAs

Question 22

first clinical sign of malignant hyperthermia reaction to a depolarizing agent

Answer 22

Rise in end-tidal CO2

Question 23

ICU-acquired weakness

Answer 23

NMBA usage= Syndrome of neuromuscular dysfunction characterized by diffuse, symmetric weakness, often sparing cranial nerves.
Other causes of weakness have been excluded
Alert patient who can follow simple commands and participate in NM exam; feels pain
Weakness may be profound and quadriplegic

Question 24

Risk factors for ICU-acquired weakness
Treatment
Cautions*
Classification

Answer 24

Sepsis, multiple organ failure, mechanical ventilation, hyperglycemia, exposure to pharmacological agents like glucocorticoids and NMBAs

Rehabilitation and supportive care- slow recovery
*May have a hyperkalemic response to succinylcholine because of spread of extra-junctional Ach receptors

Critical illness myopathy-CIM
Critical illness polyneuromyopathy-CINM
Critical illness polyneuropathy-CIP
Neuromuscular junction- NMJ

Question 25

Classification of nerve gases

Answer 25

GA- tabun
GB- sarin
GD- soman IV
GF- cyclosarin 
VX

OP- organophosphates

Question 26

Sarin MOA and effects

Answer 26

Covalently binds AchE, blocking its activity

Autonomic- BBB= bradycardia, bronchorrhea, bronchospasm
Muscarinic- SLUDGE= salivation, lacrimation, urination, diaphoresis, GI distress (diarrhea), emesis
Nicotinic- MTWThF=mydriasis, tachycardia, weakness, hyperTHermia, fasciculation (paralysis)

Question 27

Nerve gas therapy

Answer 27

Atropine
Diazepam
Pralidoximine Cl (2-PAM): regenerates AchE by removing inhibitor
Pyridostigmine (pre-treatment): reversibly binds to and inhibits AchE, making it unable for binding to nerve gas agent.