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MSK II Exam I > NMJ Pharm > Flashcards

NMJ Pharm Flashcards

1
Q

Skeletal Muscle Relaxants- drug list

A

Neuromuscular blocking drugs
- Nondepolarizing:
Isoquinoline derivatives: cisatracurium, tubocurarine
Steroid derivatives: pancuronium, rocuronium, vecuronium

  • Depolarizing:
    Succinylcholine

Spasmolytics (non-centrally acting)
Dantrolene

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2
Q

Acetylcholinesterase inhibitors

- drug list

A 
Echothiophate 
Edrophonium 
Neostigmine 
Physostigmine 
Pyridostigmine
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3
Q

Antimuscarinic compounds- drug list

A

Atropine

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4
Q

Cholinesterase reactivator- drug list

A

Pralidoxime

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5
Q

Steps Involved in NMJ Neurotransmission

A

Axonal conduction

Junctional transmission (cholinergic)

  1. Synthesis of acetylcholine (ACh)
  2. Storage of ACh
  3. Release of ACh
  4. Destruction of ACh

ACh signaling

Muscle contraction

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6
Q

Neuromuscular Blockers

in general

A

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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7
Q

Spasmolytic Agents

in general

A

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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8
Q

Neuromuscular Blocking Agents (NMBAs)- ways to classify

A
  1. Type of blockade (mechanism of action)
    Depolarizing
    Nondepolarizing
  2. Pharmacokinetic properties
    Time of onset
    Duration of action
    Mode of elimination
  3. Chemical structure
    Most bear resemblance to ACh
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9
Q

NMBAs: Mechanisms of Action

A

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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10
Q

Depolarizing NMBAs (Succinylcholine)

A

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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11
Q

succinylcholine: Phase I: Depolarizing Block

A

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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12
Q

succinylcholine: Phase 2: Desensitizing Block

A

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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13
Q

Nondepolarizing NMBAs

A

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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14
Q

NMBAs: Pharmacokinetic Properties

A

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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15
Q

NMBAs: Clinical Indications

A

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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16
Q

Adverse Effects of Nondepolarizing Agents

A

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

17
Q

Succinylcholine: Adverse Effects

A

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

18
Q

Succinylcholine: Contraindications

A

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

19
Q

NMBAs: Interactions to Consider

A

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)
20
Q

Reversal of Neuromuscular Blockade

A

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)
21
Q

Limitations of Cholinesterase Inhibitors

A

Ineffective in reversing deep neuromuscular blockade
Slow onset of action
Unpredictable efficacy
Residual blockade in large number of patients

22
Q

Spasmolytic Agents: Non-centrally Acting

MOAs

A

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

23
Q

Acetylcholinesterase (AChE):

A

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

24
Q

Two Types of Cholinesterases

A

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

25
Q

Chemical Classes of AChE Inhibitors

A

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

26
Q

Properties of AChE Inhibitors- Charged agents

A

Insoluble in lipids
Do not cross the blood-brain barrier
Poor PO absorption

Edrophonium, neostigmine, pyridostigmine, echothiophate

27
Q

Properties of AChE Inhibitors - Uncharged agents

A

Lipid soluble
Cross the BBB
Readily absorbed

Physostigmine

28
Q

AChE Inhibitor Clinical (and other) Uses

A

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)

29
Q

AChE Inhibitor Pharmacodynamics

A

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)

30
Q

Cholinesterase inhibitors have the potential to produce the following effects dependent on their distribution (and other factors):

A

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)

31
Q

AChE Inhibitors: End Organ Effects

A 
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)

32
Q

Cardiovascular System Effects of ACHE

A

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
33
Q

AChE Inhibitor Toxicity

A 
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

34
Q

Parasympathetic

tone

A 
Cholinergic
Salivation, lacrimation
Pupil constriction (myosis)
Decrease in HR
Increased secretion and motility 
Urination, defecation

Rest and digest
Smooth muscle contraction
Blocked by atropine

35
Q

Sympathetic tone

A 
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

36
Q

Dx/Tx of AChE Inhibitor Poisoning (Mild)

A

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?

37
Q

Cholinesterase Regenerators

A

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

MSK II Exam I (16 decks)

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