Intro to Agents that Act on the NMJ Flashcards
What are the NTs involved in the peripheral nervous system?
AcH, acting on nicotinic R
What are the steps involved in NMJ neurotransmission?
1)Axonal conduction
2)Junctional transmission (cholinergic) (process is prototype for neurotransmission)
1) Synthesis of acetylcholine (ACh)
2) Storage of ACh
3) Release of ACh
4) Destruction of ACh
3)ACh signaling
4)Muscle contraction
What is involved with junctional transmission at the NMJ?
1) ACh synthesis - AcCoA + choline, via ChAT
2) ACh storage - via transporter into vesicle
3) ACh release - via interaction with vesicular VAMPS and membrane SNAPS
4) ACh destruction - via AChesterase on target cell membrane, or auto-downregulation
What are the characteristics of neuromuscular blockers of skeletal muscle relaxants?
- Lack CNS activity
- Interfere with transmission at the neuromuscular end plate
- Used as adjuncts during anesthesia
- No known effects on pain threshold or consciousness
What are the characteristics of the spasmolytic agents that are skeletal mm relaxants?
- Often called centrally acting muscle relaxants
- Used to reduce spasticity in a variety of neurologic conditions (chronic back pain, fibromyalgia, muscle spasms)
How can neuromuscular blocking agents (NMBAs) be classified?
Can be classified in three ways:
- Type of blockade (mechanism of action) - Depolarizing, Nondepolarizing
- Pharmacokinetic properties - Time of onset, duration of action, mode of elimination
- Chemical structure - Most bear resemblance to ACh
What is the MOA for nondepolarizing blockade neuromuscular blocking agents?
- Prevent access of ACh to the nACh receptor (competitive antagonism) and block depolarization
- Prototype: d-tubocurarine
What is the MOA for depolarizing blockade neuromuscular blocking agents?
- Neuromuscular blockade that results from excess of a depolarizing agonist (receptor desensitization)
- Prototype: succinylcholine
What is curare?
•Curare is a common name for various dart poisons originating from dozens of plants found in Central and South America
- prototypical non-depolarizing NMBA
What is the MOA for curare?
•MOA: competitive antagonists at both pre- and post-junctional nACh receptors
Interferes with ACh mobilization at the nerve ending
Prevents membrane depolarization and muscle contraction
What is the general rule for nondepolarizing NMBAs?
General Rule: larger muscles are more resistant to blockade and recover more rapidly
Clearance, duration of action, and time to onset/potency varies within this class of drugs
What is the clinically useful depolarizing NMBA?
succinylcholine
What is the duration of action for succinylcholine?
- Ultra-short duration of action is due to rapid hydrolysis and inactivation by butyrylcholinesterase (aka, pseudocholinesterase or plasma cholinesterase)
- Not effectively metabolized at the NMJ by acetylcholinesterase
What is the MOA for succinylcholine?
- Phase 1 depolarizing block
- Phase 2 desensitizing block
What is a phase I: depolarizing block?
- Mimics the effects of endogenous ACh, but duration of action is longer
- Depolarized membranes remain depolarized and unresponsive to subsequent impulses
- Fasciculations may occur due to depolarization spread to adjacent myocytes
- Flaccid paralysis results due to lack of repolarization
- Enhanced by cholinesterase inhibitors
What is phase 2: desensitizing block?
- Membrane becomes repolarized
- Desensitized receptors cannot be depolarized again
- nAChR behaves as if in a prolonged closed state (similar behavior to nondepolarizing block)
- Antagonized by AChE inhibitors
What is an important distinguishing property of NMBAs?
How are they administered?
Do they penetrate the CNS?
Time of onset is an important distinguishing property
Limited CNS penetration
Parenteral administration
What are the ultrashort acting NMBAs? What is the time of onset and duration of action?
succinylcholine
onset: 1-1.8 min., duration 5-8 min
What are the intermediate acting NMBAs? What is the time of onset and duration of action?
atracurium: 2-3 min onset, 20-35 min duration
cisatracurium: 2-3 min onset, 24-45 min duration
rocuronium: 1-2 min onset, 20-35 min duration
vecuronium: 2-4 min onset, 20-35 min duration
What are the lopng acting NMBAs? What is the time of onset and duration of action?
doxacurium: 4-8 min onset, 90-120 min duration
pancuronium: 3-4 min onset, 60-100 min duration
pipecuronium: 2-6 min onset, 30-90 min duration
What are the clinical indications for NMBAs?
- Surgical relaxation
- Endotracheal intubation
- Control of ventilation
What dictates choice of NMBA agent?
- Pharmacokinetics dictate choice of agent:
- Rapid time of onset for rapid sequence intubation
- Succinylcholine, rocuronium, vecuronium
- Longer duration of action for surgical muscle relaxation
- Pancuronium, atracurium, cisatracurium
- Hepatic and/or renal insufficiency
- Atracurium, cisatracurium
What are the ADRs of nondepolarizing NMBAs?
- Stimulation of histamine release
- Bronchospasm, hypotension, bronchial and salivary secretion
- Can be alleviated by premedication with antihistamines
- Steroids cause the least histamine release; also minimal release with atracurium and cisatracurium
- Cardiovascular effects
- Profound hypotension and tachycardia
- Effects are variable within the class
- d-Tubocurarine is not used clinically due to severe AEs and long duration of action
What are the ADRs of succinylcholine?
- Hyperkalemia
- Most common AE, severe in patients with burns, nerve damage or neuromuscular damage, head trauma, or other injuries
- Cardiovascular effects - negative inotropic and chronotropic
- Increased intraocular pressure
- Increased gastric pressure
- Muscle pain
What are the CIs to succinylcholine?
- Personal or familial history of malignant hyperthermia
- Skeletal myopathies
- Acute phase of injury following major burns
- Cardiac arrest risk in apparently healthy children subsequently found to have undiagnosed skeletal muscle myopathy
What are some clinical interactions to consider with NMBAs?
- Aging: renal and hepatic function
- Disease - Myasthenia gravis, severe burns and other neurologic injuries
What are some drug-drug interactions to consider with NMBAs?
- Drug-drug interactions
- Some agents enhance the neuromuscular blocking effects
- Aminoglycosides, inhaled general anesthetics, local anesthetics
- Other agents diminish the neuromuscular blocking effects
- Loop diuretics (high doses), phenytoin
How is a neuromuscular blockade reversed?
•Theoretically, administration of an agonist would work
- Examples: ACh, succinylcholine
- Rapidly degraded; succinylcholine ultimately induces paralysis
•In practice, cholinesterase inhibitors are used
•Examples: neostigmine, pyridostigmine, edrophonium
MOA: antagonize nondepolarizing blockade by increasing amount of ACh at NMJ
In addition to AChE inhibitors, what other drugs are used to reverse a neuromuscular blockade?
- Antimuscarinics are often used as adjuncts to AChE Inhibitors
- Examples: atropine, glycopyrrolate
- MOA: block peripheral effects of ACh saturation at parasympathetic synapses (salivation, bradycardia, bronchoconstriction, nausea, vomiting mediated by muscarinic ACh recptors)
What are the limitations of cholinesterase inhibitors?
- Ineffective in reversing deep neuromuscular blockade
- Slow onset of action
- Unpredictable efficacy
- Residual blockade in large number of patients
What is the MOA for sugammadex? ADRs?
sugammadex - Bridion
- MOA: binds rocuronium and vecuronium in plasma, creating a concentration gradient away from the NMJ
- FDA approved in December 2015 for reversal of neuromuscular blockade induced by rocuronium or vecuronium
- Adverse effects include rare, but potentially dangerous hypersensitivity reactions
- May reduce the efficacy or oral and non-oral progestin-containing contraceptives
What are some non-centrally acting spasmolytic agents? How effective are current spasmolytics?
•Current spasmolytics provide relief from the discomfort and pain of muscle spasms but infrequently allow a return to normalcy
Dantrolene
Botulinum toxin
What is the MOA of dantrolene? Clinical uses?
Dantrolene
- MOA: inhibits ryanodine receptors in the sarcoplamic reticulum and blocks release of Ca2+
- Used in treatment of malignant hyperthermia
What is the MOA of botulinum toxin? What are the clinical uses?
Botulinum toxin
- MOA: cleaves the SNARE complex and blocks docking/fusion to the presynaptic membrane, inhibiting ACh release
- Useful for generalized spastic disorders
What do cholinomimetics do?
Mimic the actions of ACh on nicotinic and muscarinic ACh receptors
Where are muscarinic ACh receptors?
nerves
heart and smooth mm
glands and endothelium
Where are nicotinic ACh receptors?
neuromuscular end plate, skeletal mm
autonomic ganglion cells
How is ACh recycled?
- Acetylcholinesterase (AChE): enzyme that cleaves ACh into choline and acetate
- Choline is recycled back into the motor neuron via the choline transporter
- Endocytosis occurs at the nerve terminal to replenish the number of available vesicles
What is the fxn of cholinesterases?
•Function: split ACh into acetic acid and choline
What are the 2 types of cholinesterases?
butyrylcholinesterase
acetylcholinesterase
What is butyrylcholinesterase?
- Butyrylcholinesterase (pseudocholinesterase, BuChE)
- Plasma and liver
- Succinylcholine and mivacurium
What is acetylcholinesterase? What is it targeted by?
- Acetylcholinesterase (AChE)
- Found in cholinergic synapses and neurons
- Primary target for AChE inhibitors
- Inhibition of AChE causes diffuse effects throughout the body
What are the chemical classes of AChE inhibitors?
- Three chemical groups
- Alcohols – charged, reversible
- Carbamates – charged or uncharged, reversible
- Organophosphates – mostly uncharged, irreversible, highly lipid soluble
What is the chemical grouping of AChE inhibitors important?
- Chemistry dictates PK profile
- Charged vs. uncharged
- Lipid soluble or insoluble
- Reversible or irreversible binding
What is an alcohol AChE inhibitor? What is its lipid solubility? Charged or uncharged?
Edrophonium
duration: 5-15 min
lipid solubility - low
charged
What are the properties of charged AChE inhibitors?
- Insoluble in lipids
- Do not cross the blood-brain barrier
- Poor PO absorption
What are some carbamate AChE inhibitors? What is the lipid solubility? Charged or uncharged?
neostigmine: duration 0.5 - 2 hours, low lipid solubility, charged
pyridostigmine: duration 3-6 hours, low lipid solubility, charged
physostigmine: duration 0.5 - 2 hours, high lipid solubility, uncharged
What are the characteristics of uncharged AChE inhibitors?
- Lipid soluble
- Cross the BBB
- Readily absorbed
What is an organophosphate AChE inhibitor? What is its lipid solubility? Charged or uncharged?
echothiophate: 100 hr duration, low lipid solubility, charged
*Echotiophate is an unusual organophosphate. Most organophosphates are uncharged and highly lipid soluble, making them easy to absorb via multiple routes and also extremely toxic. Echotiophate is the only clinically useful organophosphate.
What are the uses of AChE inhibitors?
- Myasthenia gravis
- Reversal of neuromuscular blockade during anesthesia
- Dementia associated with Alzheimer or Parkinson disease
- Antidote for anticholinergic poisoning - Symptoms reflect sympathetic nervous system activation (fight or flight)
- Poisoning due to organophosphate pesticide exposure
- Pretreatment of Soman nerve gas exposure
- High concentrations of long-acting agents are used as chemical warfare (e.g., soman gas)
What are the pharmacodynamics of AChE inhibitors?
- Bind to AChE (also BuChE) and block its enzymatic activity
- Increase the concentration of ACh at the NMJ
- Stimulates both nAChRs and mAChRs
- Consequences can be therapeutic or deadly (organophosphates, others at high concentrations)
What are the pharmacodynamics affecting AChE inhibitors?
Cholinesterase inhibitors have the potential to produce the following effects dependent on their distribution (and other factors):
- Stimulation of mAChRs at autonomic effector organs (smooth muscle)
- Stimulation, followed by depression or paralysis, of all autonomic ganglia (NNAChRs) and skeletal muscle (NMAChRs)
- Stimulation, with occasional subsequent depression, of cholinergic receptor sites in the CNS (NNAChRs)
What is the end-organ effect of AChE inhibitors on the CNS?
- Therapeutic concentrations
- Diffuse activation of electroencephalogram
- Subjective altering response
- Toxic concentrations
- Hyperstimulation of neurons
- General convulsions
- Coma
- Respiratory arrest
What are the end-organ effects of AChE inhibitors on the NMJ?
- Increased strength of contraction at low concentrations
- Paralysis at high concentrations (succinylcholine-like)
What is the effect of AChE inhibitors in the periphery?
mAChR stimulation:
eye:
sphincter mm of iris - contraction (miosis)
ciliary mm - contraction for near vision
lung:
bronchial mm - contraction/bronchoconstriction
bronchial glands - stimulation
GI tract
increased motility, relaxed sphincters, stimulated secretion
urinary bladder:
detrussor mm - contraction
trigone and sphincter mm - relaxation
Glands:
increased secretion from sweat, salivary, lacrimal, nasopharyngeal
What are the CV system effects of AChE inhibitors?
- Increase in the activity of both sympathetic and parasympathetic ganglia (nAChRs)
- Parasympathetic tone dominates at tissue level (M2 AChRs)
- Cardiac output falls
- Bradycardia
- Decreased atrial contractility
- Reduction in ventricular contractility
- Toxic concentrations
- Marked bradycardia
- Hypotension
What are the signs of acute AChE inhibitors toxicity? How does route matter?
- Acute intoxication (parasympathetic effects): SLUDGE
- Salivation, Lacrimation, Urination, Defecation, Gastrointestinal, Emesis
- Ingestion: GI symptoms occur first
- Percutaneous absorption: localized sweating and muscle fasciculations
- Lipid-soluble agents: CNS involvement follows rapidly
What are some consequences of parasym tone?
- Cholinergic
- Salivation, lacrimation
- Pupil constriction (myosis)
- Decrease in HR
- Increased secretion and motility
- Urination, defecation
What are some consequences of sympathetic tone?
- Adrenergic (anticholinergic)
- Cutaneous vasodilation
- Pupil dilation (mydriasis)
- Increase in HR
- Decreased secretion and motility
- Reduction/elimination of the desire to urinate
What effects are generally seen from SNS/PNS tone?
Effects are generally, but not always, opposite
ØRest and digest
ØSmooth muscle contraction
ØBlocked by atropine
- versus -
ØFight or flight
ØSmooth muscle relaxation
ØReversed by acetylcholinesterase inhibitors
How is AChE inhibitor poisoning treated and diagnosed?
- Use history of exposure and characteristic symptoms
- Measurement of AChE activity in erythrocytes and plasma
- Treatment includes the following:
- Atropine: antidote for cholinergic poisoning (mAChR antagonist)
- Maintenance of vital signs (particularly respiration)
- Decontamination
•What about nAChR stimulation?
What is the MOA for cholinesterase regeneratoris? Prototype?
- MOA: Re-activate inactive AChE by removing the phosphorous group from the active site
- Can restore active enzyme within minutes
- Must give before aging occurs
- Prototype: pralidoxime
What is the current antidote for organophosphate exposure?
- Parenteral atropine
- Oxime (pralidoxime)
- Benzodiazepine to alleviate convulsions
