NMJ Pharm Flashcards by Briana Tillman

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

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Acetylcholinesterase inhibitors

- drug list

Echothiophate 
Edrophonium 
Neostigmine 
Physostigmine 
Pyridostigmine

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Antimuscarinic compounds- drug list

Atropine

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Cholinesterase reactivator- drug list

Pralidoxime

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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: 1. Atropine: antidote for cholinergic poisoning (mAChR antagonist) 2. Maintenance of vital signs (particularly respiration) 3. 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: 1. Parenteral atropine 2. Oxime (pralidoxime) 3. Benzodiazepine to alleviate convulsions