Download Final - lgh

NEURO MUSCULAR
PHYSIOLOGY AND BLOCK
DR IMRAN SHAUKAT
DR JAHANZAIB
SUPERVISOR
DR ZIA
NEUROMUSCULAR
PHYSIOLOGY


Deals with structure and function of
muscles and motor neuron supplying
these fibres (muscles)
The basic unit of neuromuscular junction
is known as motor unit
Motor unit




Motor unit = a motor neuron + all muscle fibers
it controls
Axon of a motor neuron divides into many
branches
Each muscle fiber is controlled by a branch from
only one motor neuron
Single motor unit consisting of one motor
neuron and the muscle fibers it innervates
Motor unit
NEUROMUSCULAR JUNCTION

Definition.



The synapse b/w axon of motor neuron and
Skeletal fibre is called NMJ.
The nerve end makes a junction with the
muscle fibre..
Motor end plate
- The entire structure, the nerve terminal and
muscle fibre
is called motor end plate.
Synaptic space


Synaptic cleft/gutter
Definition
space b/w nerve terminal and fibre membrane.


20-30nm wide
Bottom of cleft there are numerous folds of
muscle membrane called sub-neural folds which
increases the surface area at which synaptic
transmitter can act.
EVENTS OCCURING DURING
NM TRANSMISSION


At rest transmembrane potential is about -90mv
(-ve inside) Normally depolarization of about 40
mv occurs bringing the transmembrane potential
to -50mv
Action potential spreads over the nerve terminal,
 It opens voltage gated calcium channels.
 Calcium diffuses interacellular of the nerve
terminal
 Intracellular Ca influences on the Ach
vesicles.
EVENTS OCCURING DURING NM
TRANSMISSION

When nerve impulse reaches the NMJ,




Approx 50-100 vesicles of Ach are released
Approx 12000 molecules of Ach are present in each
vesicles.
Vesicles fuse with plasma membrane and empty
their Ach into the synaptic space by the process
of exocytosis.
Two molecules of Ach binds with single Ach
receptor
Action of Ach on the post synaptic
membrane

Ach receptors are gated ion channels

Located near the sub-neural folds on post
synaptic membrane
Two alpha, and one each beta, delta, epsilon
sub units


Out of which only alpha unit constitute the
binding site for Ach.
Ach gated ion channel
 Remain
constricted until two molecules
of Ach binds with single Ach receptor
 conformational
change, will cause opening of
the channel.
 Brings a potential change at muscle fibre
membrane called End plate potential,
 Generates action potential at the muscle
membrane
 Depolarization will occur that causes muscle
contraction by the help of actin and myosine
filaments
Ach gated ion channel
 Whole
sequence of events occurs in 510msec
 Repolarisation will occur when Ach
receptors are inactived and K+ moves
out.
 Ach once released into the synaptic
space continues to activate Ach
receptors as long as it persists in the
space
 Rapidly removed by enzyme
Acetylcholinesterases into acetyl co and
choline
Acetylcholine synthesis and choline
recycling
Synthesis takes place in cytoplasm of
nerve terminal
 With the help of enzyme (CAT),
mitochondria provides energy for the
synthesis
 Ach is then taken up into the synaptic
vesicles by an active vesicular transport,
where it is stored

Acetylcholine synthesis and choline
recycling
Ach is splitted by enzyme
Acetycholinesterases into acetate and
choline at the postsynaptic membrane.
 Choline is then actively re-absorbed into
the nerve terminal to be re-used in the
forming of new Ach.
 Some of choline is also formed by the
liver.

ANIMATION
NEURO MUSCULAR BLOCKS

Neuromuscular blocking agents (drugs)
provide Skeletal muscle relaxation to
facilitate
Endotreacheal Intubation
Mechanical Ventilation
Optimizing surgical operating conditions
HISTORY OF NEUROMUSCULAR
DRUGS

HISTORY
1494 - Tales of travelers killed by poison darts
1551 - Ourari” or “cururu” meaning “bird killer”
1812 - Curarized cat kept alive by artificial respiration
1912 - Curare used to prevent fractures during ECT
1941 - Initial use by Griffith, Culler, and Rovenstine
1951 - Succinylcholine chloride first used in Stockholm
INTRODUCTION OF NEW DRUGS
1494 - 1942
1947 - 1951
1960’s
1970’s
1980’s
1990
1991
1992
1994
1999
Curare
Succinylcholine chloride, Gallamine,
Metocurine, Decamethonium
Alcuronium
Pancuronium bromide, Fazadinium
Vecuronium bromide, Atracurium besylate
Pipecuronium bromide
Doxacurium chloride
Mivacurium chloride
Rocuronium bromide
Rapacuronium bromide
STRUCTURAL CLASSES OF
NONDEPOL.ARIZING RELAXANTS


Amino Steroids: Rocuronium bromide,
Vecuronium bromide, Pancuronium
bromide, Pipecuronium bromide.
Benzylisoquinoliniums: Atracurium
besylate, Mivacurium chloride,
Doxacurium chloride, Tubocurarine,
Gallamine, Metocurine
NEUROMUSCULAR
DRUGS
Depolarizing agents
 Non-depolarizing


Depolarizing agents
 (phase 1) block
 agents
have agonist action on Ach receptors
 These agents resemble Ach, so mimic the action
Ach
 Bind with Ach receptors
 Generating action potential in similar way of Ach
NEUROMUSCULAR
DRUGS
 These
agents are not metabolised by
acetylcholinesterases so their concentration in the
synaptic cleft does not fall rapidly
 Continuous end plate potential depolarization will
leads to muscle relaxation
 End plate cannot repolarized as long as
depolarizing agent binds to Ach receptors
 Recovery only occur when drug diffuses away from
the receptor and its plasma level falls.
 SC is metabolized by plasma cholinesterase.
NEUROMUSCULAR
DRUGS

Phase 2 block
High doses of depolarizing agent b/w (317mg/kg) generates phenomena known as
phase 2 block, previously called dual block, in
this features of short lived depolarizing block
changes into non depolarizing block
characterized by fade of train of four, which may
be reversed by anticholinesterases
Salient Features of NM Blocking
(depolarizing) Drugs
Muscle fasciculation followed by relaxation
 Fast dissociation from receptor
 Block is not reversed by neostigmine
 Potentiate by hypothermia,resp.alkalosis.
 Repeated/continuous use leads to phase 2
block.

Non–depolarizing agents
Competitive antagonist at Ach receptors
 Non-depolarizing drugs compete with the
alpha subunits binding sites of nicotinic
receptors

Incapable to produce conformational
change in Ion channel
 As the receptors are bound by NDMR,
Ach is prevented to bind it’s receptors
 No End plate potential

Features of non-depolarizing
neuromuscular blocking drugs
No muscular fasciculation
 Have slow onset(1-5) mins and slow
dissociation from receptors.
 Are reversed by anticholinesterases.
 Relaxed muscle remains responsive to
other mechanical or electrical stimuli..
 Effect potentiate by volatile agents,
acidosis and hypokalemia.

Differences bw Dep/ NDMR block
SUXAMETHONIUM





Introduced in 1952
Depolarizing neuromuscular blocker
PRESENTATION
50 mg/ml (2 ml amp)
Mode of Action
Nicotinic receptors
Metabolism
degraded not by acetylcholinesterase but by
butyrylcholinesterase, a plasma cholinesterase
SUXAMETHONIUM



Indication
Rapid sequence Induction
Electroconvulsive therapy
Onset Of Action
30 sec (highly lipid soluble)
Effect may last up to 10 min
Dose
Intravenous 1-2 mg/kg
SUXAMETHONIUM
Contraindications
recent burns (24 hrs after uptil 6 months)
spinal cord trauma causing paraplegia
raised potassium levels (> 5.5mg%)
severe muscle trauma
history of malignant hyperpyrexia
SUXAMETHONIUM

Adverse effects
CVS
Bradycardia (2nd dose +children)
Metabolic
Increase potassium level
Raised intracranial and intraocular pressure
Prolonged paralysis (absent or atypical plasma
cholinestrase)
Anaphylaxis
Muscle pains
ATRCURIUM




Nondepolarizing neuromuscular blocking agent
Benzyl isoquinolinium compound
PRESENTATION
10mg/ml (2.5 -5 ml)
METABOLISM
Ester Hydrolysis (non specific esterases)
Hofmann Elimination
ATRACURIUM


DOSAGE
0.3-0.5 mg/kg body wt (intubation dose)
duration 30-40 min
0.1mg/kg body wt (maintenance dose)
duration 10-20min
Average infusion rates of 11 to 13 mcg/kg per
minute in ICU
SENSITIVITY
stored at 2-8 C
use within 14 days if at room temp
ATRCURIUM

SIDE EFFECTS
Hypotension and tachycardia
Histamine release
Bronchospasm
Laudanosine toxicity (excitation of cns
,increasing mac, --- seziures)
Allergic reactions
MIVACURIUM



Nondepolarizing neuromuscular blocking agent
(short acting 10 min)
Benzylisoquinoline derivative
METABOLISM
Metabolised by cholinesterase
Duration of action prolong if plasma
cholenestrase minimum or absent
Hepatic or renal dysfunction prolong action
Edrophonium a better reversal than neostigmine
in this case
MIVACURIUM

DOSAGE
0.15-0.2 mg/kg b wt intubating dose
4-10 micro gm/kg b wt maintainace by
infusion
Sensitivity
Unlike atracurium its shelf life is 18
months at room temp
MIVACURIUM

Side Effects
Histamine release (Slow IV induction)
CVS Manifestations may Occur
Pancuronium can markedly prolong its
effect (SMITH)
PANCURONIUM




Nondepolarizing neuromuscular blocking agent
DOSAGE
0.08-0.12 mg/kg/bw intubation dose
0.01 mg/kg/bw maintenance dose every 20-40
min
SENSITIVITY
upto 6 months at room temp
PRESENTATION
2 mg/ml clear solution
PANCURONIUM

METABOLISM
Renal 40%
Liver 10%
Effect of this drug may be prolonged in
renal diseases
PANCURONIUM

SIDE EFFECTS
Hypertension and Tachycardia (vagal
bockade+sympathetic stimulation)
Caution in CAD
Arrhythmias (especially if combined with
halothane)
Allergic reaction (bromide)
vecuronium



Nondepolarizing neuromuscular blocking
agent
Monoquaternary compound
DOSAGE
0.08-0.12 mg/kg/bw intubation dose
0.01 mg/kg/bw maintainace dose (15-20)
or
1-2 mic/kg/min infusion
vecuronium


METABOLISM
Renal 25%
Biliary 40%
PREDESPOSING FACTORS (prolong effect)
Female gender
Renal Failure
Corticosteroid therapy (Critical illness myopathy/
polyneuropathy)
Sepsis
vecuronium


PRESENTATION
4mg and 10 mg powder form
should be discarded after 24 hrs
ADVANTAGE
Safe in cardiac patients
ROCURONIUM



Provides rapid onset of action ( similar to
suxamethonium) Onset 45-60 sec
Monoquaternary steroid
DOSAGE
0.45-0.9 mg/kg. intubation dose
0.15 mg/kg/ maintainace dose
or
5-12 micro gm/kg/min in infusion form
Increase dosage in infants 1mg/kg and 2 mg/kg
in children
ROCURONIUM

METABOLISM
Liver (mostly)
Kidneys (To some extent)
Effect may be prolonged in liver disease
and pregnancy
ROCURONIUM


ADVANTAGE
suitable alternate for suxamethonium in RSI
DISADVANTAGE
Much longer duration of action even more than
atracurium
SIDE EFFECTS
Vagolytic properties
Cis Atracurium

Purified form of one of the 10 isomers of
actracurium besylate.
Three times more potent than atracurium

MODE OF ACTION

Binds to cholinergic receptors on the
motor end-plate to antagonize the action
of acetylcholine, resulting in a competitive
block of neuromuscular transmission
Cis Atracurium

ADVANTAGES
Amount of laudanosine is produced less due to
its high potency hence less chances of toxicity
Dose not effect blood pressure and HR
No release of Histamine
Elimination through Hoffmann so safe in renal
and liver diseases
Cis Atracurium

DOSAGE
0.1-0.15 mg/kg intubation dose (2 min)
1-2 mcg/kg maintainace dose in infusion
form
Duration of action of drug is like of
intermediate acting
Pipecuronium




Bisquaternary Steroid compound
Similar structure as Pancuronium
More potent than pancuronium
DOSAGE
0.06-0.1 mg/kg intubation dose
Children require less dosage than adults
Pipecuronium
EXCRETION
Renal mainly 70%
Biliary 20%
CONTRAINDICATION
Increase duration in
Hepatic diseases on other hand do not
effect duration of action
COMPARISON OF NMB IN SIDE
EFFECTS