08.2 pharmacology of neuromuscular transmission
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Neuromuscular Junction Blocking
Agents(1 Hr.)
Lecturer: Dr. M. Gossell-Williams
Contact: Dept. of Basic Medical Sciences,
Pharmacology section
Email: maxine.gossell@uwimona.edu.jm
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Objectives
Students are expected to already have an
understanding of transmission of the action
potential at the NMJ and how this action potential
translates into muscle contraction.
Understanding NMJ transmission involves
knowledge of channels, transmitters and receptors
involved.
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Objectives
This lecture covers
1. Understanding how this transmission
process may be interfered with by
i. inhibiting neurotransmitter synthesis and
release
ii. inhibiting the action of a neurotransmitterat the receptor level
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2. Be able to compare and contrast the blockade
produced by antagonist drugs and depolarizing
drugs
3. Be able to apply this knowledge in the
assessment of the clinical application of drugs
which interfere with this site.
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NEUOMUSCULAR JUNCTON BLOCKING DRUGS
5. If EPP is large enough then AP(action potential) is developed in
the membrane, stimulating
voltage sensitive Na+ channels.
6. This results in Ca+ ion influx and
contracture of muscle.
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MORE DETAILED NMJ
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Stimulus
Depolarization of the sarcolemmaAction potential initiated and propagated along the T-
tubules
Calcium released from SR system
Calcium ions diffuse and attach to the binding sites on
troponin C
Inhibitory effect of troponin I on the interaction of actinand myosin is removed
thin filaments slide along thick filaments shortening the
sarcomere.
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POINTS TO NOTE
Structure of the Nicotinic Receptor:5 subunits,2E, F, K,H, Two binding sites for Ach.
(different from ganglionic nicotinic receptor:
2E, 3F ).
.
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POINTS TO NOTE
Characteristics of voltage sensitive Na+
channels:exist in three states controlled by gating
system
RESTING, ACTIVATED and INACTIVATED.
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POINTS TO NOTE
Once channels are activated , then inactivated, they will
never assume resting state until the membrane is
repolarized.
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POINTS TO NOTE
PERSISTENT depolarization at the motor end plate, ie
prolonged opening of nicotinic Na+ channels, causes
inactivation of the immediate surrounding muscle
membrane.
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The Drugs
NMJ blockade may be obtained by:
1. Inhibition of Ach synthesis and storage:
HEMICHOLINIUM- blocks choline uptake
TRIETHYLCHOLINE- false transmitter
VESAMICOL- blocks Ach uptake by vesicle
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2. Inhibition of Ach release:
AMINOGYCOSIDES, MAGNESIUM
BOTULIN TOXIN, FBUNGAROTOXIN
SAXITOXIN,TETRODOTOXIN, CIGUATOXIN
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PROPRANONOL, DANTROLENE
Non-Depolarizing Depolarizing
NonSteriodal Steriodal
d-TUBOCURARINE PANCURONIUM SUCCINYLCHOLINE
GALLAMINE VECURONIUM (DECAMETHONIUM)
ATRACURIUM ALCURONIUM
MIVACURIUM RAPACURONIUM
3. Interfering with the postsynaptic action of Ach:
A
B
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Non-Depolarizing
d-TUBOCURARINE PANCURONIUM
GALLAMINE VECURONIUM
ATRACURIUM ALCURONIUM
MIVACURIUM
3. Interfering with the postsynaptic action of Ach:
A
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Depolarizing
SUCCINYLCHOLINE
3. Interfering with the postsynaptic action of Ach:
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PHARMACODYNAMICS
MOA
Agonist of Nicotinic receptors
not metabolised by acetylcholinesterase.
persistent depolarization of the nicotinic sodium
channels blockade of voltage-gated sodium channel
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PHARMACODYNAMICS
ORDER OF BLOCKADE
EYE>
MASTICATION>
LIMBS>
ABDOMINAL>
RESPIRATORY
OVERALL EFFECT
Skeletal muscle paralysis
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PHARMACOKINETICS
ROUTE: IMorIV
Usually 0-3- 1mg/kg BWbyIV
ONSET: < 5 MINS
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PHARMACOKINETICS
SHORT ACTING (5-15MINS): SUCCINYLCHOLINE,
MIVACURIUM
MEDIUMACTING (15-30 MINS):ATRACURIUM,
VECURONIUM,ALCURONIUM
LONGACTING (30-120 MINS): d-TUBOCURARINE,
PANCURONIUM,
GALLAMINE
Grouping based on Duration of action
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PHARMACOKINETICS-ELIMINATION
1ST
PHASE: REMOVAL FROM SITE2ND PHASE:
BLOOD
a.
PSEUDOCHOLINESTE-
RASE
Succinylcholine
Mivacuriumb. SPONTANEOUS
Atracurium
(= laudanosine)
RENAL (MAIN)
Pancuronium
Gallamine
Tubocurarine
HEPATIC (Main)
Alcuronium
Vecuronium (bile)
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OTHER EFFECTS/SIDE EFFECTS
GANGLIONIC
M2MUSCARINIC RECEPTOR BLOCKADE
HISTAMINE RELEASE
MALIGNANT HYPERTHERMIA
INCREASEIOP
POST-OPERATIVE PAIN
Increase K+ release-HYPERKALEMIA
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CLINICAL APPLICATIONS
MUSCLE RELAXANT
WITHGENERAL ANAESTHESICS
DURINGENDOTRACHEAL INTUBATION
DURINGORTHOPEDICMANIPULATION
TOALLEVIATE THE PERIPHERAL SYMPTOMSOFCONVULSION
TO PROVIDECONTROLLED VENTILATION (OBSTRUCTIVE
AIRWAYDISEASE)
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Comparision of Non-depolarise and Depolarising agents
D-TC Ch
I itial
c tracti
Re ersal f
l c a e
Effect fM asthe ia
Gra is
te c
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