Sweatman - NMB's Flashcards
1
Q
Where is the nicotinic M receptor found?
A
- Found on skeletal muscle
- Site of action of paralytic agents
- NOTE: nicotinic N receptors are found on autonomic ganglia
2
Q
Briefly describe the Ach receptor.
A
- Multimeric, ligand-gated ion channel
- Gates for Na+ influx into the cell, leading to depolarization
- Needs 2 Ach molecules to bind to the EC domain of its alpha subunits
1. Binding is short-lived, and terminated via the AchE enzyme
3
Q
What is the difference between the actions of the non-depolarizing and depolarizing agents?
A
- Non-depolarizing (e.g., rocuronium): prevents the opening of the channel when it binds
-
Depolarizing (e.g., succinylcholine): occupies the receptor AND blocks the channel
1. Normal closure of the gate prevented, and blocker may move rapidly in and out of pore
2. Desensitizes end plate by occupying receptor and causing persistent depolarization -> prevents repolarization, leading to flaccid paralysis - NOTE: effect of normal agonist, Ach, on the receptor is shown in figures A and B
4
Q
What are the effects of succinylcholine on the muscle?
A
- Rapid depolarization after drug application, shown by instant INC in muscle tone (blue line)
- Muscle cells depolarize (red), and membrane stays in depolarized state while sodium channels stay open b/c closure is a prerequisite for repolarization to begin
- Na+ channels eventually close, and normal process or repolarization can occur -> resting muscle tone begins to return
5
Q
What is the peripheral nerve stimulator?
A
- Device programmed to deliver 4 sequential stimuli at 2 Hz, causing a release of Ach from synaptic vesicles
- If 70-85% of neuromuscular (NM) receptors are blocked, b/t 2 and 4 twitches are visible -> dosing of NMB’s titrated to goal of 2-3 of 4 twitches visible
- ICU use reduces amount of drug used and shortens recovery of NM func and spontaneous ventilation
-
Posttetanic potentiation: Ca+-dep activation of PKC, increasing the # of released vesicles
1. INC Ach competes successfully, but temporarily w/NMB’s (only in phase 2 for succinylcholine)
6
Q
How is the effect of succinylcholine different in phase I vs. phase II in regards to…?
- End plate potential
- Onset
- Dose dependence
- Recovery
- TOF and tetanic stimulation
- AchE inhibition
- Muscle response
A
- Depol to -55 mV vs. transition to -80 mV
- Immediate vs. slow transition
- Lower vs. higher, or following prolonged infusion
- Rapid vs. more prolonged
- No fade vs. fade (followed by post-tetanic potentiation)
- Augments vs. reverses or antagonizes
- Fasciculations (muscle twitching), then flaccid paralysis vs. flaccid paralysis
7
Q
What is the metabolic fate of the non-depolarizing NMB’s?
A
- Rapid initial distribution, but slower elimination
- Highly ionized; poor protein binding
- Duration of action correlates closely with half-life, so binding kinetics to nicotinic receptor short-lived, and effects are dependent on local tissue concentration
- Hepatic (faster) and renal elim -> steroids metabolized to less potent 3-OH metabolites
- Atracurium (intermediate-acting): hepatic metabolism + Hofmann elim -> main product, laudanosine, causally related to seizures (non-enzymatic chem rxn)
-
Cisatracurium < dependence on hepatic inactivation, so produces < laudanosine and releases < histamine
1. Benefits of Atra w/fewer side effects, so it has largely replaced Atra in clinical use
8
Q
What is the metabolic fate of succinylcholine?
A
- Very short duration of action (5-10 min)
- Rapid hydrolysis by butyrylcholinesterase (liver) and high capacity pseudocholinesterase (plasma)
-
NM junction: sees small % of IV dose
1. Action terminated by diffusion from cleft, and plasma cholinesterase strongly impacts durability -
Genetic variants (many) of plasma cholinesterase
1. INC risk for abnormally long duration of effect
2. Dibucaine test via colorimetric assay -> INH normal enzyme by 80%; abnormal by only 20% - INC durability of action also seen w/ester-type local anesthetic agents
9
Q
Briefly compare the elim route, duration, and potency of the NMB’s (chart).
A
- Some of the steroidal drugs are significantly more potent
- Durability of action of succinylcholine much shorter than that of the other agents -> clinical utility for procedures where short effect is required, i.e., rapid sequence intubation (RSI)
10
Q
How do the NMB’s differ in their off-target actions?
A
- Nicotinic N receptor in autonomic ganglia, so stimulation can produce dysregulation of ANS activity and balance
1. Succinylcholine - Activation of the M2 receptor in the heart is important for closing Ca+ channels to reduce force and rate of contraction -> activation can lead to DEC CV capability
1. Succinylcholine - Potential for release of histamine from mast cells, which could lead to loss of vascular vol to the periphery and hypotension
1. Succinylcholine and Atracarium
11
Q
What AE’s are associated with succinylcholine?
A
- Hemodynamic changes: brady/tachycardia, ventricular arrhythmias, HTN
-
Hyperkalemia in certain conditions: up-regulation of AchR’s spreading throughout the muscle membrane, w/expression of 2 new isoforms of AchR’s (K efflux)
1. Lg burn injuries, trauma/massive crush injuries, upper/lower motor neuron lesions, muscular dystrophies, prolonged immobilization - Prolonged neuromuscular blockade: phase II blockade, atypical pseudocholinesterase
- INC in intraocular/intracranial pressure: unclear cause
- Muscle pain: from fasciculations
- Myoglobinuria
- Malignant hyperthermia
- Anaphylaxis
12
Q
What is malignant hyperthermia? Tx?
A
- Genetically determined (auto dom) AE produced by some drugs that cause uncontrolled release of Ca+ from the sarcoplasmic reticulum (pharmacogenomic)
1. Ca+ stimulates cell to produce symptoms shown in the attached image - Seen w/succinylcholine and all volatile anesthetic agents (desflurance, sevoflurane)
1. Safe drugs: N2O, local anesthetics, barbiturates, narcotics, tranquilizers, catecholamines, new muscle relaxants (e.g., atracurium) - Tx: dantrolene, stop giving trigger agent, hypervent w/O2, avoid CCB’s, correct hyperK and acidosis, cool core temp
13
Q
What are some drugs known to interact with NM function?
A
- Volatile anesthetics: isoflurane > sevoflurane, desflurane, and halothane > N2O (malignant hyperthermia -> give dantrolene)
- AB’s (e.g., aminoglycosides): enhancement of blockade (pre-junc p-type Ca+ channels), leading to depressed Ach release (similar to that caused by Mg+)
- Local anesthetics: can depress via pre-junc neural effect; block NM transmission in large doses
- Other NMB’s: depolarizing effect of succinylcholine can be antagonized by admin of small dose of non-depolarizing drug
14
Q
How can we terminate NMB?
A
- Two mechs (see attached image):
1. INC levels of Ach by preventing its metabolism by AchE -> INC Ach can then out-compete the paralytic and restore muscle activity
2. Suggamadex (only used for the steroidal agents -> not approved in the US yet)
15
Q
What are the 3 AchE inhibitors and their recommended anticholinergic agents?
A
- AchE inhibitors have variability in time to onset and durability
- Used in conjunction w/antimuscarinic agent to reduce consequences of off-target activation
- Note: atropine has greater effect on tachycardia, and glycopyrrolate is the only agent that does not cause sedation
17
Q
What is Sugammadex?
A
- Rapidly encapsulates steroids like rocuronium and vecuronium -> pore structure into which NMB inserts, preventing blocker from accessing binding site on Ach nicotinic receptor
- Reversal of any depth of NMB, incl. profound blockade
- Inactive against non-steroidal NMB’s, like cisatracurium or succinylcholine
- Not approved in the US yet
