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Pharmacology test 3
Roussel- Neuromuscular blockers
29
Science
Professional
10/16/2012

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Term

Neuromuscular Blockers

(2)

Definition
  • Neuromuscular blockers cause skeletal muscle relaxation by interfering with signal transmission at the neuromuscular junction.
  • They are used as adjuncts to anesthesia, to facilitate endotracheal intubation and mechanical ventilation, and in the intensive care units for patients requiring paralysis.

 

Term

Extra-junctionalAchR Proliferation

Causes

(3)

Definition

 

Burn Injury

 

Prolonged Immobility

 

Neuromuscular Disease

 

Term

 

Succinylcholine
(6)

 

Definition
  • The only depolarizing agent in clinical use in the US
  • Metabolized by pseudocholinesterase
  • Rapid Onset/Short Duration
  • Malignant Hyperthermia Trigger
  • Hyperkalemia Risk
  • Succinylcholine should be avoided in patients susceptible to malignant hyperthermia (e.g. family or personal history), patients at risk for hyperkalemia
    (e.g. renal failure, burn trauma, bed ridden, muscular dystrophy, upper motor neuron disease), and patients with known or suspected pseudocholinesterase
    abnormality or deficiency.

 

Term

 

Atracurium
(6)

 

Definition
  • Non-Enzymatic degradation in the plasma by Hofmann Elimination
  • Laudanosine Breakdown Product that may accumulate with excessively large doses or liver failure; causes CNS excitation and seizures
  • Histamine Release
  • An intermediate duration benzyl isoquinolone derivative that undergoes nonenzymatic breakdown in the plasma by Hofmann elimination.
  • Atracurium does not rely on the hepatic or renal systems for termination of effects. Its administration is associated with histamine release.
  • Laudanosine is a breakdown product that, under circumstances of hepatic failure or extremely high atracurium doses, could cause central nervous system excitation or seizures.

 

Term

 

Cisatracurium
(6)

 

Definition
  • Hofmann Elimination
  • Laudanosine Breakdown Product
  • NO Histamine Release
  • An intermediate duration benzyl isoquinolone derivative that,like atracurium, undergoes Hofmann elimination with laudanosine as a breakdown product.
  • Cisatracurium also does not rely on the hepatic or renal systems for termination of effects.
  • Unlike atracurium, cisatracurium is not associated with histamine release.

 

Term

 

Pancuronium
(4)

 

Definition
  • Long acting
  • Vagolytic and Catecholamine releasing side effects
  • Renal Elimination
  • A long acting steroid derivative associated with significant vagolytic effects and catecholamine release.

 

Term

 

Rocuronium
(3)

 

Definition
  • Rapid Onset suitable for Rapid Sequence Intubation
  • An intermediate duration steroid derivative with rapid onset suitable for rapid sequence induction;
  • it has less vagolytic effects than pancuronium.

 

Term

 

Vecuronium

 

Definition
  • Active 3-OH metabolite that may cause prolonged paralysis after prolonged administration
  • An intermediate duration steroid derivative with no vagolytic effects; its active 3-hydroxy metabolite is associated with prolonged neuromuscular blockade and polyneuropathy after long-term administration to patients in intensive care units.

 

Term

General Points

(5)

Definition
  • NMBs cause PARALYSIS(i.e. patients will stop breathing!)
  • NMBs have NO Intrinsic Anesthetic Properties
  • NMB’s are used to facilitate intubation and mechanical ventilation, to provide immobility during surgical procedures,and as adjuncts in the ICU.
  • Succinylcholine may cause hyperkalemia
  • Succinylcholine is a Malignant Hyperthermia trigger

 

Term

Neuromuscular blockers

(3)

Definition
  • Neuromuscular blockers cause skeletal muscle relaxation by interfering with signal transmission at the neuromuscular junction;
  • they are used as adjuncts to anesthesia, to facilitate endotracheal intubation and mechanical ventilation, and in intensive care units to cause skeletal muscle paralysis.
  • Development of neuromuscular blocking agents is aimed at improving specificity for the nicotinic receptors at the neuromuscular junction, decreasing onset time, and eliminating cumulative dosing effects.
Term

Neuromuscular signal transmission

 

Mechanism

(7)

Definition
  • Neuromuscular signal transmission at the neuromuscular junction begins with arrival of an impulse at the motor nerve terminal which results in calcium influx and subsequent release of acetylcholine into the synaptic cleft.
  • Motor end plate depolarization results from binding of two acetylcholine molecules to the nicotinic cholinergic receptor;
  • if the end plate depolarization is sufficient to cause adjacent muscle membrane depolarization, an action potential is propagated along the entire muscle fiber and excitation-contraction coupling causes muscle contraction.
  • Acetylcholine at the neuromuscular junction is either metabolized by acetylcholinesterase or diffuses away from the motor end plate.
  • In addition to the acetylcholine receptors at the end plate, there are two additional types of acetylcholine receptors involved in neuromuscular transmission:
    • prejunctional receptors that are involved in mobilization of additional acetylcholine vesicles for subsequent release of acetylcholine, and
    • extrajunctional/perijunctional receptors that may proliferate during periods of prolonged immobilization or after burn injury
Term
Types of
acetylcholine receptors involved in neuromuscular transmission
Definition
  • prejunctional receptors that are involved in mobilization of additional acetylcholine vesicles for subsequent release of acetylcholine, and
  • extrajunctional/perijunctional receptors that may proliferate during periods of prolonged immobilization or after burn injury
Term

Pharmacodynamics of Neuromuscular Blocking Agents

Structure-Activity Characteristics

Definition
  • All of the neuromuscular blocking agents bear a structural resemblance to acetylcholine
Term
Depolarizing Agents
Definition
  • Succinylcholine is two acetylcholine molecules linked together.
  • [image]
Term
Nondepolarizing Agents
Definition
  • In nondepolarizing neuromuscular blocking agents the double acetylcholine structure is concealed within either a benzyl isoquinolone or steroid ring system.
    • Benzyl isoquinolone agents have an “urium”
      ending. Steroid derivative agents have
      an “onium” ending.
  • Nondepolarizing agents also contain quaternary nitrogens that make them poorly lipid soluble.

Term

Mechanism of Action of Depolarizing Agents

(4)

Definition
  • Succinylcholine is the only depolarizing neuromuscular blocker in clinical use in the United States.
  • 2 phases:
    • Phase 1: Depolarizing
    • Phase 2: Desensitizing
Term

Mechanism of Action of Depolarizing Agents:

Phase I

(3)

Definition
  • PHASE I (DEPOLARIZING)
  • During Phase I block, succinylcholine reacts with the nicotinic receptor to open the ion channel and cause depolarization of the end plate and subsequent muscle fasciculations (i.e. disorganized contraction of muscle motor units).
  • Because succinylcholine is not metabolized effectively at the synapse, the depolarized membranes remain depolarized and unresponsive to additional impulses; a flaccid paralysis results.
Term

Mechanism of Action of Depolarizing Agents:

Phase II

(3)

Definition
  • PHASE II (DESENSITIZING)
  • Continued exposure to succinylcholine results in membrane repolarization and resistance to depolarization.
  • Although the mechanism is not clear, Phase II block clinically resembles a nondepolarizing block.
Term

Mechanism of Action of Nondipolarizing Agents

(3)

Definition
  • Nondepolarizing muscle relaxants act predominantly as competitive antagonists at the nicotinic receptor site;
  • at larger doses they may enter and block the pore of the ion channel.
  • Nondepolarizing agents may also antagonize prejunctional sodium channels.
Term
Response to Nerve Stimulation
Definition
  • Patient sensitivity to neuromuscular blockade is variable;
  • peripheral nerve stimulation is helpful in monitoring neuromuscular function during use of intermediate or long acting agents, during rapid-sequence inductions, and during continuous infusions of short-acting neuromuscular blockers.
  • Ulnar nerve stimulation of the adductor pollicis muscle and facial nerve stimulation of orbicularis oculi are the most commonly monitored sites.
Term

Reversal of Neuromuscular Blockade

Depolarizing Agents

Definition
  • Depolarizing neuromuscular blockade is terminated by diffusion of succinylcholine away from the neuromuscular junction and hydrolysis by pseudocholinesterase;
  • there is no specific agent available to reverse a depolarizing block.
Term

Reversal of Neuromuscular Blockade

Nondepolarizing Agent

(3)

Definition
  • In general, termination of nondepolarizing blockade depends on redistribution, metabolism, and excretion of the nondepolarizing agents;
  • neuromuscular blockade by nondepolarizing agents is also reversible with cholinesterase inhibitors (e.g. neostigmine, edrophonium).
  • To prevent muscarinic side effects of cholinesterase inhibitors (e.g. bradycardia, bronchoconstriction, peristalsis,glandular secretions), antimuscarinic anticholinergic agents (e.g. glycopyrrolate,atropine) are generally given with reversal agents.
Term
Pharmacokinetics
Definition
  • All of the neuromuscular blocking drugs are highly polar and require intravenous or intramuscular administration.
Term
Pharmacokinetics of Depolarizing Agents
Definition
  • Pseudocholinesterase rapidly hydrolyzes succinylcholine; thus, only a small fraction of the initial intravenous dose reaches the neuromuscular junction.
  • Succinylcholine’s very short duration of action is terminated by diffusion of succinylcholine away from the neuromuscular junction.

 

Term

Pharmacokinetics of Nondepolarizing Agents

(3)

Definition
  • Because neuromuscular blocking agents are highly polar and do not easily cross membranes, their volumes of distribution are small.
  • In general, renally excreted agents (e.g. pancuronium) tend to have longer half-lives than hepatically metabolized and eliminated agents (e.g. vecuronium).
  • Steroidal agents are to some degree hepatically metabolized to 3-hydroxy, 17-hydroxy, or 3,17-hydroxy products.
Term
Organ System Effects
Definition
  • In general, cardiovascular effects of neuromuscular blocking agents are related to vagolytic effects, histamine release,or blockade of autonomic ganglia.
  • Side effects specific to succinylcholine administration include triggering malignant hyperthermia in susceptible patients, hyperkalemia, increased intraocular pressure, increased intragastric pressure, and muscle pain.
  • Anesthetic agents, local anesthetics, and aminoglycoside antibiotics enhance neuromuscular blockade; whereas anticonvulsants cause resistance to non-depolarizing neuromuscular blockade.
Term

Clinical Uses

(3)

Definition
  • Neuromuscular blocking agents are used as adjuncts to anesthesia to produce skeletal muscle relaxation;
  • they do not cause unconsciousness, amnesia, or analgesia.
  • Neuromuscular blocking agents are also used to facilitate endotracheal intubation, improve effectiveness of controlled ventilation, and provide skeletal muscle relaxation for intensive care unit patients requiring paralysis.
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