08.2 Pharmacology of Neuromuscular Transmission

8/6/2019 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: [email protected]


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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


A


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Depolarizing

SUCCINYLCHOLINE



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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

Documents

08.2 Pharmacology of Neuromuscular Transmission