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

 
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.
 
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 neurotransmitter

at the receptor level
 
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.
NEUOMUSCULAR JUNCTON TRANSMISSION
1. Arrival of action potential at motor
end plate.

2. Ach released from vesicles

diffusing into cleft.

3. Ach binds to receptors which

stimulates Nicotinic Na+
channels .

4. Influx of Na+ ions through channels

results in MEPP (miniature end
plate potentail) which summate to
give EPP (end plate potential).
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.
MORE DETAILED NMJ
 Stimulus
Depolarization of the sarcolemma
Action 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 actin and myosin is

removed

thin filaments slide along thick filaments shortening the sarcomere.

 POINTS TO NOTE

•Structure of the Nicotinic Receptor:

5 subunits,2, , ,, Two binding sites for Ach.
(different from ganglionic nicotinic receptor: 2, 3 ).

.
 POINTS TO NOTE

•Characteristics of voltage sensitive Na+ channels:

exist in three states controlled by gating system
RESTING, ACTIVATED and INACTIVATED.
 POINTS TO NOTE

•Once channels are activated , then inactivated, they will

never assume resting state until the membrane is
repolarized.
 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.
 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
2. Inhibition of Ach release:

AMINOGYCOSIDES, MAGNESIUM

BOTULIN TOXIN, BUNGAROTOXIN

SAXITOXIN,TETRODOTOXIN, CIGUATOXIN
3. Interfering with the postsynaptic action of Ach:

A Non-Depolarizing Depolarizing

Non Steriodal Steriodal

d-TUBOCURARINE PANCURONIUM SUCCINYLCHOLINE
GALLAMINE VECURONIUM (DECAMETHONIUM)
ATRACURIUM ALCURONIUM
MIVACURIUM RAPACURONIUM

PROPRANONOL, DANTROLENE
3. Interfering with the postsynaptic action of Ach:
Non-Depolarizing
A

d-TUBOCURARINE PANCURONIUM
GALLAMINE VECURONIUM
ATRACURIUM ALCURONIUM
MIVACURIUM
 PHARMACODYNAMICS

MOA
competitive antagonist of nicotinic receptors
3. Interfering with the postsynaptic action of Ach:

Depolarizing

SUCCINYLCHOLINE
 PHARMACODYNAMICS

MOA
• Agonist of Nicotinic receptors
• not metabolised by acetylcholinesterase.

• persistent depolarization of the nicotinic sodium

channels
• blockade of voltage-gated sodium channel
 CHEMISTRY

Non-depolarizing and depolarizing

•Charged N groups
•Similarity to Ach
• Very polar agents
 PHARMACODYNAMICS

OVERALL EFFECT
Skeletal muscle paralysis

ORDER OF BLOCKADE
EYE>
MASTICATION>
LIMBS>
ABDOMINAL>
RESPIRATORY
 PHARMACOKINETICS

ROUTE: IM or IV
Usually 0-3- 1mg/kg BW by IV

ONSET: < 5 MINS

 PHARMACOKINETICS
Grouping based on Duration of action
SHORT ACTING (5-15MINS): SUCCINYLCHOLINE,
MIVACURIUM

MEDIUM ACTING (15-30 MINS): ATRACURIUM,

VECURONIUM,ALCURONIUM

LONG ACTING (30-120 MINS): d-TUBOCURARINE,

PANCURONIUM,
GALLAMINE
 PHARMACOKINETICS-ELIMINATION
1ST PHASE: REMOVAL FROM SITE
2ND PHASE: RENAL (MAIN)
BLOOD
Pancuronium
a.
Gallamine
PSEUDOCHOLINESTE-
RASE Tubocurarine
Succinylcholine
Mivacurium
HEPATIC (Main)
b. SPONTANEOUS
Alcuronium
Atracurium
Vecuronium (bile)
(= laudanosine)
 OTHER EFFECTS/SIDE EFFECTS

•GANGLIONIC
•M2 MUSCARINIC RECEPTOR BLOCKADE
•HISTAMINE RELEASE
•MALIGNANT HYPERTHERMIA
•INCREASE IOP
•POST-OPERATIVE PAIN
•Increase K+ release-HYPERKALEMIA
 CLINICAL APPLICATIONS

MUSCLE RELAXANT
• WITH GENERAL ANAESTHESICS
• DURING ENDOTRACHEAL INTUBATION
• DURING ORTHOPEDIC MANIPULATION
• TO ALLEVIATE THE PERIPHERAL SYMPTOMS OF CONVULSION
• TO PROVIDE CONTROLLED VENTILATION (OBSTRUCTIVE
AIRWAY DISEASE)
Comparision of Non-depolarise and Depolarising agents
 Comparision of Non-depolarise and Depolarising agents

D-TC SCh

Initial
contraction
Reversal of
blockade
Effect of
Myasthenia
Gravis on
potency