Neuromuscular Junction/Ganglia Drugs Flashcards
Rocuronium
Intermediate-acting agent
Rapid onset and lower potency; an alternative to succinylcholine.
Uses: rapid induction anesthesia, relax laryngeal and jaw muscles to facilitate tracheal intubation.
No tachycardia
Hepatic elimination
Competitive blocker
D-tobucurarine
Natural alkaloid
Long duration, competitive.
No longer in USA-seldom used.
Renal and hepatic elimination.
Newer agents are used because of shorter duration of action, diminished frequency of side effects (ganglionic blockade, block of vagal responses, and histamine release).
Inability ot penetrate BBB.
Blockage at autonomic ganglia and muscarinic sites:
Fall in BP and tachycardia.
Reversed by anti-ChE agents
Partial blockade at autonomic ganglia and adrenal medulla.
Atracurium, vecuronium, doxacurium, mivacurium, rocuronium are more selective.
Prevents depolarization by ACh
Causes flaccid paralysis
Weak block of cardiac muscarinic ACh receptors.
Can cause histamine release with hypotension.
Pancuronium
No histamine release.
Long duration, competitive.
Blocks muscarinic receptors (vagal blockade and tachycardia).
Less ganglionic blockade at common clinical doses.
Renal and hepatic elimination
Vecuronium
Ammonio steroid.
No tachycardia
Intermediate duration, competitive.
Hepatic and renal elimination.
Metabolized in the liver.
Competitive antagonist at nACh receptors especially at NMJ.
No histamine release and minimal antimuscarinic effect.
Atracurium
Benzylisoquinolones
Intermediate duration, competitive.
No vagolytic and ganglionic blocking actions.
Some histamine release.
Degraded by 2 routes:
1. Hydrolysis of the ester by plasma esterases.
2. Spontaneous (Hofmann) degradation: N alkyl cleavage.
Routes remain functional renal failure.
Mivacurium
Benzylisoquinolones
Short duration, competitive
VERY sensitive to catalysis by cholinesterase or other plasma hydrolyses (explains short duration of action).
Slight histamine release.
Cisatracurium
Benzylisoquionolones 10 cis isomers Intermedia duration, competitive. Hofmann and renal elimination. Fewer adverse side effects then atracurium.
Competitive vs depolarizing agents
Competitive: Bulky, rigid molecules
-Block the binding of ACh, which diminishes the amplitude of the EPP and becomes insufficient to initiate muscle AP.
-Reduces the frequency of channel opening events, but does not effect conductance or duration of opening for a single channel.
One molecule of antagonist is sufficient block one receptor, but need simultaneous binding of two agonist modules for receptor activation.
Constant distance between quaternary groups.
Depolarizing: more flexible structures that enable bond rotation (succinylcholine).
-Initially, depolarize membrane by opening channels like ACh does.
-They persist longer at the NMJ because resistance to acetylcholinesterase.
-Brief period of repetitive excitation
-Transient muscle fasciculation
-Then, get NMJ block and flaccid paralysis, because ACh is binding to receptors that are already depolarized; -80 to -55 depolarization is resistance to more depolarization by ACh.
Sequence of repetitive excitation (fasciculations) followed by block influencing factors.
Anesthetic agent used concurrently.
With increasing concentrations…the black may convert from a depolarizing to a non depolarizing type (phase 1 to a phase 2 block).
Botulinum Toxin
Interferes with the synthesis and release of ACh.
Administer locally to muscles of the orbit.
Controls muscle spasms and facial muscle relaxation.
Can treat achalasia by injection into lower esophageal sphincter.
Dantrolene
Blocks Ca2+ release from SR.
Used in the treatment of MALIGNANT HYPERTHERMIA!!!
Sequence and characteristics of paralysis: competitive blocking agent
Intravenous injection
Motor weakness progresses to total flaccid paralysis.
First, the small rapid moving muscles like the eyes, jaw, and larynx relax.
Later, muscles of the limbs and trunk relax.
Recovery of muscles usually occurs in the reverse order of their paralysis.
Diaphragm is the first muscle to regain function.
Sequence and characteristics of paralysis: depolarizing agent (succinylcholine)
Intravenous injection
Muscle fasiculations over chest and abdomen occur briefly.
Relaxation occurs within 1 minute.
Becomes maximal within 2 minutes; transient apnea occurs.
Disappears as a rule within 5 minutes.
After infusion, effects of drug disappear rapidly.
Muscle soreness may follow.
Muscle relaxation of longer duration is achieved by continuous IV injection.
Succinylcholine
Rarely causes effects attributable to ganglionic blockade at doses producing neuromuscular relaxation.
CV effects observed due to successive stimulation: vagal ganglia manifested by bradycardia; sympathetic ganglia causing hypertension and tachycardia.
Histamine Release
-Direct action of muscle relaxant on mast cell; not IgE-mediated anaphylaxis.
Tubocurarine-injected intracutaneously or intra-arterially produces typical histamine-like raised reddened marks (wheals).
Clinical responses to neuromusscular blocking agents: bronchospasm, hypotension, excessive bronchial and salivary secretion: caused by the release of HISTAMINE.
Succinylcholine, mivacurium, atrcurium, doxacurium cause histamine release to a lesser extent unless administered rapidly.
Ammonio steroids, pancuronium, vecuronium, and rocuronium have less tendency to release histamine after intradermal or systemic injection.
Succinylcholine: Life Threatening Implications
Release K+ rapidly from intracellular sites
-May be a factor in production of apnea in patients in electrolyte imbalance.
Induced hyperkalemia:
Life threatening
Depolarizing blocking agents should be avoided in patients with predisposition to redistribution of K+ (congestive heart failure patients and burn victims).
Higher doses of a competitive blocking agent should be used instead.
Succinylcholine cautions:
-Patients with…
rhabdomyolysis
ocular lacerations
spinal cord injuries with paraplegia or quadriplegia
muscular dystrophies
Not for children 8 years old and younger EXCEPT when emergency intubation and securing an airway is necessary.
Toxicology of Neuromuscular Blocking agents
- Prolonged apnea
- CV collapse
- Responses resulting from histamine release
- Anaphylaxis rarely occurs
- Failure of adequate respiration in postop period: not always die directly to excessive muscle paralysis from drug.
- could be from airway obstruction or decreased PCO2 from hyperventialtion.
- directly related factors: body temperature, electrolyte imbalance, altered physiology and disease states.
Malignant Hyperthermia
Life threatening event
Triggered by administration of some anesthetics and neuromuscular blockers.
Due to uncontrolled release of Ca2+ from SR of skeletal muscle.
Clinical features: contracture, rigidity and heat production from skeletal muscle.
Hyperthermia (overheated), accelerated muscle metabolism, metabolic acidosis and tachycardia.
Susceptibility to malignant hyperthermia:
No clinical signs visible in the absence of anesthetic intervention.
Linkage between the contracture test on fresh biopsy of skeletal muscle and a mutation in the ryanodine receptor (on sarcoplasmic reticulum); others on L type Ca2+ channels.
Treatment: IV injection of DANTROLENE (limits the capacity of Ca2+ and calmodulin to activate Ryr-1).
Rapid cooling, inhalation of 100% oxygen and control of acidosis.
Phase 1 Neuromuscular blockade by succinylcholine
EPP: depolarized to -55
Immediate onset
Lower dose-dependence
Rapid recovery
Augments antichilinesterae inhibition.
Muscle response: Fasciculations-> flaccid paralysis.
Train of four and tetanic stimulation: no fade
Phase 2 Neuromuscular blockade by succinylcholine
EPP: Repolarization toward -80
Slow transition onset
Higher dose dependence or follows prolonged infusion
Prolonged recovery
Train of four and titanic stimulation: fade
Anticholinesterse inhibition: reverses or antagonizes
Muscle response: flaccid paralysis
Respiratory paralysis
Cause: adverse reaction or overdose of neuromuscular blocking agent
Treatment: positive-pressure artificial respiration with oxygen, maintenance of patient airway.
Hastening of treatment: Administration of neostigmine methyl sulfate or edrophonium IV (short half life so repeat is required).
Other toxic effects…
Use NEOSTIGMINE
- Antagonizes only the skeletal muscular blocking action of the competitive blocking agents,
- May aggravate side effects of hypotension or induce bronchospasm; sympathomimetic amines may be given to support BP.
- Atropine or glycopyrolate is administered to counteract muscarinic stimulation.
- Antihistamines definitely beneficial: counteract the responses that follow release of histamine, useful when administered before the neuromuscular blocking agent.
Therapeutic uses of Neuromuscular blocking agents
MAIN CLINICAL USE IS AS AN ADJUVANT IN SURGICAL ANESTHESIA TO OBTAIN RELAXATION OF SKELETAL MUSCLE, PARTICULARLY OF ABDOMINAL WALL, TO FACILITATE OPERATIVE MANIPULATIONS.
Reasons for use:
Much lighter levels of anesthesia can be used.
The risk of respiratory and CV depression if minimized,
Post anesthetic recovery is shortened,
Uses:
NMJ blocking agents be used to substitute for inadequate anesthesia depth; the risk of reflex responses to painful stimuli and conscious recall may occur.
Orthopedic procedures.
Facilitate intubation with an endotracheal tube and bronchoscopy and other procedures like this.
Used in combination with other anesthetic agents.
Administration:
Parenterally: nearly always IV,
Potentially hazardous drugs
Use to prevent trauma during electroshock therapy
The seizures induced by this treatment may cause dislocations or fractures.
Succinylcholine or mivacurium used because of the brevity of relaxation.
Use in the control of muscle spasms
Used to treat spasticity involving the alpha motor neuron with the objective of increasing the functional capacity and reliving discomfort.
Agents that act in the CNS: act at either higher centers or the spinal cord to block spasms.
BACLOFEN, BENZODIAZEPINES, TIZANDINE
Agents that act peripherally:
-Botulinum toxin A: produces flaccid paralysis of skeletal muscle, diminished activity of parasympathetic synapses, diminished activity of sympathetic cholinergic synapses, restoration of function requires nerve sprouting.
-Dantrolene: causes a generalized weakness; treatment of spasticity and hyperreflexia, should be reserved for non ambulatory patients with severe spasticity; hepatotoxicity reported with continued use.
