NMJ Pharm Flashcards
Skeletal Muscle Relaxants- drug list
Neuromuscular blocking drugs
- Nondepolarizing:
Isoquinoline derivatives: cisatracurium, tubocurarine
Steroid derivatives: pancuronium, rocuronium, vecuronium
- Depolarizing:
Succinylcholine
Spasmolytics (non-centrally acting)
Dantrolene
Acetylcholinesterase inhibitors
- drug list
Echothiophate Edrophonium Neostigmine Physostigmine Pyridostigmine
Antimuscarinic compounds- drug list
Atropine
Cholinesterase reactivator- drug list
Pralidoxime
Steps Involved in NMJ Neurotransmission
Axonal conduction
Junctional transmission (cholinergic)
- Synthesis of acetylcholine (ACh)
- Storage of ACh
- Release of ACh
- Destruction of ACh
ACh signaling
Muscle contraction
Neuromuscular Blockers
in general
Lack CNS activity
Interfere with transmission at the neuromuscular end plate
Used as adjuncts during anesthesia
No known effects on pain threshold or consciousness
Spasmolytic Agents
in general
Often called centrally acting muscle relaxants
Used to reduce spasticity in a variety of neurologic conditions (chronic back pain, fibromyalgia, muscle spasms)
Neuroscience II system course
Neuromuscular Blocking Agents (NMBAs)- ways to classify
- 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
NMBAs: Mechanisms of Action
Nondepolarizing blockade:
Prevent access of ACh to the nACh receptor (competitive antagonism) and block depolarization
Prototype: d-tubocurarine
Depolarizing blockade:
Neuromuscular blockade that results from excess of a depolarizing agonist (receptor desensitization)
Prototype: succinylcholine
Depolarizing NMBAs (Succinylcholine)
Interesting chemical structure
The only clinically useful depolarizing blocker
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
MOA:
Phase 1 depolarizing block
Phase 2 desensitizing block
succinylcholine: 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
succinylcholine: Phase 2: Desensitizing Block
Membrane becomes repolarized
Desensitized receptors are not responsive to agonist
nAChR behaves as if in a prolonged closed state (similar behavior to nondepolarizing block)
Antagonized by AChE inhibitors
Nondepolarizing NMBAs
Curare is a common name for various dart poisons originating from dozens of plants found in Central and South America
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
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
NMBAs: Pharmacokinetic Properties
ultrashort: succinylcholine
short: mivacurium
intermediate action: altracurium, cisatacurium, rocoronium, vecuronium
long action: doxacurium, pancuronium, pipecuronium
Time of onset is an important distinguishing property
Limited CNS penetration
Parenteral administration
NMBAs: Clinical Indications
Surgical relaxation
Endotracheal intubation
Muscle relaxation during mechanical ventilation in the ICU
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)
Adverse Effects of Nondepolarizing Agents
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
Succinylcholine: Adverse Effects
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
Succinylcholine: Contraindications
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
NMBAs: Interactions to Consider
Clinical interactions
- Aging: renal and hepatic function
- Disease (Myasthenia gravis, Severe burns and other neurologic injuries)
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)
Reversal of Neuromuscular Blockade
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
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)
Limitations of Cholinesterase Inhibitors
Ineffective in reversing deep neuromuscular blockade
Slow onset of action
Unpredictable efficacy
Residual blockade in large number of patients
Spasmolytic Agents: Non-centrally Acting
MOAs
Current spasmolytics provide relief from the discomfort and pain of muscle spasms but infrequently allow a return to normalcy
Dantrolene
MOA: inhibits ryanodine receptors in the sarcoplamic reticulum and blocks release of Ca2+
Used in treatment of malignant hyperthermia
Botulinum toxin
MOA: cleaves the SNARE complex and blocks docking/fusion to the presynaptic membrane, inhibiting ACh release
Useful for generalized spastic disorders
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
Two Types of Cholinesterases
Function: split ACh into acetic acid and choline
Butyrylcholinesterase (pseudocholinesterase, BuChE)
- Plasma and liver
- Succinylcholine and mivacurium
Acetylcholinesterase (AChE)
- Found in cholinergic synapses and neurons
- Primary target for AChE inhibitors
Inhibition of AChE causes diffuse effects throughout the body
Chemical Classes of AChE Inhibitors
Three chemical groups
Alcohols – charged, reversible
Carbamates – charged or uncharged, reversible
Organophosphates – mostly uncharged, irreversible, highly lipid soluble
Chemistry dictates PK profile
Charged vs. uncharged
Lipid soluble or insoluble
Reversible or irreversible binding
Properties of AChE Inhibitors- Charged agents
Insoluble in lipids
Do not cross the blood-brain barrier
Poor PO absorption
Edrophonium, neostigmine, pyridostigmine, echothiophate
Properties of AChE Inhibitors - Uncharged agents
Lipid soluble
Cross the BBB
Readily absorbed
Physostigmine
AChE Inhibitor Clinical (and other) Uses
Myasthenia gravis
Reversal of neuromuscular blockade during anesthesia
Dementia associated with Alzheimer or Parkinson disease
- Donepezil, rivastigmine, galantamine
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)
AChE Inhibitor Pharmacodynamics
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)
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)
AChE Inhibitors: End Organ Effects
CNS: Therapeutic concentrations - Diffuse activation of electroencephalogram - Subjective altering response Toxic concentrations - Hyperstimulation of neurons - General convulsions - Coma - Respiratory arrest
NMJ:
Increased strength of contraction at low concentrations
Paralysis at high concentrations (succinylcholine-like)
Cardiovascular System Effects of ACHE
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
AChE Inhibitor Toxicity
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
Parasympathetic
tone
Cholinergic Salivation, lacrimation Pupil constriction (myosis) Decrease in HR Increased secretion and motility Urination, defecation
Rest and digest
Smooth muscle contraction
Blocked by atropine
Sympathetic tone
Adrenergic (anticholinergic) Cutaneous vasodilation Pupil dilation (mydriasis) Increase in HR Decreased secretion and motility Reduction/elimination of the desire to urinate
Fight or flight
Smooth muscle relaxation
Reversed by acetylcholinesterase inhibitors
Dx/Tx of AChE Inhibitor Poisoning (Mild)
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?
Cholinesterase Regenerators
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
Current antidote for organophosphate exposure:
- Parenteral atropine
- Oxime (pralidoxime)
- Benzodiazepine to alleviate convulsions
