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General Pharmacology

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General Pharmacology Neuromuscular Blocking Agents S. Habibian Dehkordi D.V.M Ph.D 73 84 * Neuromuscular blocking drugs Extract of vines (Strychnos toxifera; also ... – PowerPoint PPT presentation

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Title: General Pharmacology


1

General Pharmacology
Neuromuscular Blocking Agents
S. Habibian Dehkordi D.V.M Ph.D
2
Neuromuscular blocking drugs
0
  • Extract of vines (Strychnos toxifera also
    Chondrodendron species)
  • Used by indegenous peoples of Amazon basin in
    poison arrows (not orally active, so food is safe
    to eat)
  • Brought to Europe by Sir Walter Raleigh, others
  • Curare-type drugs Tubocurare (bamboo tubes),
    Gourd curare, Pot curare
  • Brody (1811) showed curare is not lethal is
    animal is ventilated
  • Harley (1850) used curare for tetanus and
    strychnine poisoning
  • Harold King (1935) isolates d-tubocurarine from a
    museum sample determines structure.

3
Neuromuscular blocking drugs
0
  • Block synaptic transmission at the neuromuscular
    junction
  • Affect synaptic transmission only at skeletal
    muscle
  • Does not affect nerve transmission, action
    potential generation
  • Act at nicotinic acetylcholine receptor NII

4
Neuromuscular blocking drugs
0
(CH3)3N-(CH2)6-N(CH3)3 Hexamethonium (ganglionic
)
(CH3)3N-(CH2)10-N(CH3)3 Decamethonium (motor
endplate)
5
Neuromuscular blocking drugs
0
  • Acetylcholine is released from motor neurons in
    discrete quanta
  • Causes all-or-none rapid opening of Na/K
    channels (duration 1 msec)
  • Development of miniature end-plate potentials
    (mEPP)
  • Summate to form EPP and muscle action potential
    results in muscle contraction
  • ACh is rapidly hydrolyzed by acetylcholinesterase
    no rebinding to receptor occurs unless AChE
    inhibitor is present

6
Neuromuscular Blocking Agents
These Drugs prevent interaction between Ach and
Nicotinic receptors in the skeletal muscles
Final results Temporary Paralysis of skeletal
muscles and muscle relaxation
Clinical uses
In the general anesthesia, they are used to a)
facilitate Tracheal intubation, b) induce muscle
relaxation, c) make orthopedic surgery easy, d)
reduce the dose of anesthetics
Mechanism of action
1- Some occupy the receptors and prevent Ach
action competitively
2- Some which are so-called depolarizing agents
block receptors
7
Classification of Muscle Relaxants According to
Mechanism of Action
Depolarizing , Non competitive,
agonist. Succinylcholine
Non depolarizing, Competitive,
antagonist. Tubocurarine
8
Depolarizing Agents
  • Prototype of depolarizing agent is
    succinylcholine (only depolarizing drug in
    clinical use).
  • Mechanism of Action Similar action to ACh, but
    longer acting.
  • Phase 1 Membrane is depolarized by opening
    AChR channels causing brief period of muscle
    fasciculation.
  • Phase II End-plate eventually repolarizes, but
    because succinycholine is not metabolized like
    ACh it continues to occupy the AChRs to
    desensitize the end-plate.
  • Because of the mechanism of action of depolazing
    drugs is similar to ACh, their blocking effects
    are augmented by AChE inhibitors.

9
Depolarizing Neuromuscular blocking drugs
0
  • Succinylcholine, decamethonium
  • Bind to motor end-plate and cause immediate and
    persistent depolarization
  • Initial contraction, fasciculations
  • Muscle is then in a depolarized, refractory state
  • Desensitization of Ach receptors
  • Insensitive to K, electrical stimulation
  • Paralyzes skeletal more than respiratory muscles

10
Depolarizing Agents
  • Therapeutic Use Adjuvant drugs in surgical
    anesthesia
  • Pharmacology Duration of action is short
    (several minutes) because it is rapidly broken
    down by plasma cholinesterases (must be
    administered by continuous infusion)
  • Adverse Effects When administered with halothane
    some genetically susceptible people (inherited
    autosomal dominant condition) experience
    malignant hyperthermia. Treatment rapid cooling
    of the body and dantrolene

11
Non-depolarizing (competitive).
  • Prototype of Non-depolarizing is tubocurarine
    (new generation pancuronium and gallamine).
  • Mechanism of Action In small clinical doses they
    act the predominantly at the nicotinic receptor
    site to block ACh.
  • At higher does they can block prejunctional Na
    channels thereby decreasing ACh release.
  • Because of the competitive nature of the
    postsynaptic blockade, transient relief of the
    block can be achieved by increasing ACh levels
    at the synaptic cleft (i.e. use cholinesterase
    inhibitors).

12
Non-depolarizing Neuromuscular blocking drugs
0
  • Competetive antagonist of the nicotinic 2
    receptor
  • Blocks ACh from acting at motor end-plate
  • Reduction to 70 of initial EPP needed to prevent
    muscle action potential
  • Muscle is insensitive to added Ach, but reactive
    to K or electrical current
  • AChE inhibitors increase presence of ACh,
    shifting equilibrium to favor displacing the
    antagonist from motor end-plate

13
Nondepolarizing drugs Metabolism
0
  • Important in patients with impaired organ
    clearance or plasmacholinesterase deficiency
  • Hepatic metabolism and renal excretion (most
    common)
  • Atracurium, cis-atracurium nonenzymatic (Hoffman
    elimination)
  • Mivacurium plasma cholinesterase

14
Nondepolarizing Agents
  • Therapeutic Use Adjuvant drugs in surgical
    anesthesia
  • Pharmacology Must be given by injection because
    they are poorly absorbed orally. Do not cross
    the BBB. Generally excreted unchanged (i.e. not
    metabolized).
  • Adverse Effects Tubocurarine causes release of
    histamine from mast cells decrease in blood
    pressure, bronchospasms, skin wheals. Newer
    generation dont.

15
  • Drug Interactions
  • Cholinesterase Inhibitors decrease the
    effectiveness of nondepolarizing agents
  • Aminoglycoside antibiotics (e.g. streptomycin)
    decrease ACh release by competing with Ca2
    increase action of nondepolarizing drugs
  • Calcium channel blockers increase the actions of
    nondepolarizing drugs by decreasing the amount of
    ACh released (i.e. increase action of
    nondepolarizing drugs)
  • Halogenated carbon anesthetics (e.g. Isoflurane)
    enhance neuromuscular blockade by 1) decreasing
    excitability of motoneurons, 2) increasing muscle
    blood flow, and 3) decreased kinetics of AChRs
    (increase action of nondepolarizing drugs)

16
Classification of Muscle Relaxants According to
Mechanism of Action
Ultra-Short Short Intermediate
Long Succinylcholine Mivacurium Vecuroni
um Pancuronium Atracurium Rocuronium Cis-
atracurium
17
Factors that affect their duration of action
  • 1-PH changes metabolic acidosis and to a lesser
    extent respiratory acidosis extend the blockage
    duration
  • 2-body temperature Hypothermia potentiate the
    blockage duration.
  • 3-age Older patients have prolonged effect also.
  • 4-electrolytes changes Decrease in serum
    potassium conc. potentiate the blockageDecrease
    in ionized calcium conc. also potentiate the
    blockage
  • Note
  • Concomitant administration of potent inhalational
    agents potentiate the duration of blockage esp.
    with isoflurane, enflurane and sevoflurane.

18
Classification based on chemical structures
1- drugs Molecoles are large, balk and
nonflexible. They arecompetitive blocking drugs
D-tubocurarine, Dimethyl (or Trimethyl)
tubocurarine, Gallamine and Pancuronium
2- Drugs molecules are small, rod shape and
flexible. They are depolarizing agents
Succinylcholine, Decamethonium
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Pharmacologic Consideration
19
Skeletal Muscle
Comparative neuromuscular blocking agents
Depolarizing neuromuscular blocking agents
CNS
They have no effect on CNS
Autonomic effects
Nicotinic receptors in the autonomic ganglia are
less sensitive than in the somatic ganglia
Effects of neuromuscular blocking agents on
Muscaranic receptors are very small
Histamine Release
Neuromuscular blocking agents cause histamine
releasing
20
Factors Prolonging the neuromuscular blocakde
  • Neonates
  • Old age
  • Obesity
  • Hepatic disease (both depolarizer NMDR)
  • Renal disease ( only NDMR)
  • Inhalational agents Prolong the block by both
    depolarizers NDMR. Inhalational agents decrease
    the requirement of relaxant .The maximum
    relaxation is by ether followed by desflurane
  • Antibiotics Both depolarizers NMDR
  • Aminoglycosides.
  • Tetracyclines.

21
  • Local Anaesthetics Except procaine local
    anaesthetics prolong the action by stabilizing
    post synaptic membrane.
  • Hypothermia Decreases metabolism of muscle
    relaxants.
  • Hypocalcemia Calcium is required for producing
    action potential. Action of NDMR is enhanced.
  • Hypokalemia NMDR block is enhanced.
  • Acid base imbalances especially acidosis.
  • Calcium channel blockers
  • Dantrolene
  • Neuromuscular disease
  • Hypermagnesemia.

22
Drugs which antagonise Neuromuscular Blockade
  • They reverse the block by NDMR only
  • Phenytoin
  • Carbamazepine
  • Calcium
  • Cholinesterase inhibitors
  • Azathioprine
  • Steroids.

23
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