SKELETAL MUSCLE

RELAXANTS

9/26/2018 1
 Classification on basis of site of action
and mechanism of action
A) PERIPHERALLY ACTING
Neuromuscular blockers
Non depolarizing agents
Isoquinoline derivatives steriod derivatives

 Tubocurarine Pancuronu ium

 Doxacurium Pipecuronium
 Atracurium Rapacuronium
 Metocurine Rocuronium
 Mivacurium Vecuronium

Depolarizing agents
 Suxamethonium (Succinylcholine)
 Decamethonium

9/26/2018 2
Neuromuscular Junction
1: Cholinergic motor neurone,2:
motor end-plate, 3: vesicles, 4:
NMR, 5: mitochondrion
Depolarizing agents:
Succinyle choline

These drugs are structural analogue of acetylcholine .

They either act as antagonists ( non depolarizing)
OR
agonist (depolarizing)

These drugs are used to increase the safety of general anesthetics

These are used parentrally

9/26/2018 4
 B) Centrally acting (spasmolytic drugs)
Diazepam ( act through GABA A) receptors)
Baclofen (GABA B) receptors
Dantroline ( act directly by interfering release of
calcium from sarcoplasmic reticulum)
Note:
these drugs are used to control spastic muscle tone as
in epilesy ,multiple scelerosis ,cerebral palsy, stroke,

9/26/2018 5
 Mechanism of Sk. muscle
contraction
Initiation of impulse

Release of acetylcholine

Activation of nicotinic receptor at motor end

plate

Opening of ion channel, passage of Na+ ,

depolarization of end plate
9/26/2018 6
 Mechanism cont’d

Muscle contraction.

Neuromuscular blocking agents used in

clinical practice interfere with this process.

Drugs, can block neuromuscular transmission/

or muscle contraction by acting

9/26/2018 7
 Presynaptically:
To inhibit acetylcholine synthesis or release (practically not used).
As they may have whole body unspecific nicotinic as well as
muscarinic effects

Postsynaptically:
To block the receptor activity.
To block ion channel at the end plate

Clinically these drugs are only used as an adjuvant to general anesthesia,

(only when artificial respiration is available.)

They interfere with the post synaptic action of

acetylcholine.

9/26/2018 8
 Non depolarizing (majority):
Act by blocking acetylcholine receptors.

In some cases (in higher doses), act by blocking ion channels.

Depolarizing:
act as agonists at acetylcholine receptors

9/26/2018 9
 Mechanism of action
(non depolarizing agents)

a) At low doses:
These drugs combine with nicotinic receptors and prevent
acetylcholine binding.as they compete with acetycholine for
receptor binding they are called competitive blockers

Thus prevent depolarization at end-plate.

Hence inhibit muscle contraction, relaxation of skeletal muscle

occurs.

9/26/2018 10
 Their action can be overcome by increasing conc. of
acetylcholine in the synaptic gap(by inhibition of
acetyle choline estrase enzyme)
e.g.: Neostigmine ,physostigmine edrophonium
Anesthetist can apply this strategy to shorten the
duration of blockage or over come the overdosage.

9/26/2018 11
 At high doses
These drugs block ion channels of the end plate.

Leads to further weakening of the transmission and

reduces the ability of Ach-esterase inhibitors to
reverse the action.

9/26/2018 12
 ACTIONS
All the muscles are not equally sensitive to blockade.

Small and rapidly contracting muscles are paralyzed

first.

Respiratory muscles are last to be affected and first to

recover.

9/26/2018 13
 Pharmacokinetics:
Administered intravenously

Cross blood brain barrier poorly (they are poorly lipid

soluble)

Some are not metabolized in liver, their action is

terminated by redistribution, excreted slowly and
excreted in urine unchanged (tubocurarine,
mivacurium, metocurine).

They have limited volume of distribution as they are

highly ionized.
9/26/2018 14
 Atracurium is degraded spontaneously in plasma by
ester hydrolysis ,it releases histamine and can
produce a fall in blood pressure ,flushing and
bronchoconstriction. is metabolized to laudanosine(
which can provoke seizures),Cisatracurium with
similar pharmacokinetics is more safer.

non depolarizers are excreted via kidney ,have long

half life and duration of action than those which are
excreted by liver.

9/26/2018 15
 Some (vecuronium, rocuronium) are acetylated in liver.( there
clearance can be prolonged in hepatic impairment)

Can also be excreted unchanged in bile.

They differ in onset, duration and recovery (see table)

Uses: as adjuvant to anesthesia during surgery.

Control of ventilation (Endotracheal intubation)
Treatment of convulsion

9/26/2018 16
 Drug interactions

Choline esterase inhibitors such as neostigmine,

pyridostimine and edrophonium reduces or overcome
their activity but with high doses they can cause
depolarizing block due to elevated acetylcholine
concentration at the end plate.

Halogenated hydrocarbons ,aminoglycosides

,calcium channel blockers synergize their effect.

9/26/2018 17
 Unwanted effects
Fall in arterial pressure chiefly a result to ganglion
block , may also be due to histamine release this may
give rise to bronchospasm (especially with
tubocurarine ,mivacurium ,and atracurium)

Gallamine and pancuronium block, muscarinic

receptors also, particularly in heart which may
results in to tachycardia.

9/26/2018 18
 DEPOLARIZING AGENTS
DRUGS Suxamethonium ( succinylecholine)
Decamethonium
Mechanism of action:
These drugs act like acetylcholine but persist at the synapse at
high concentration and for longer duration and constantly
stimulate the receptor.

First, opening of the Na+ channel occurs resulting in

depolarization, this leads to transient twitching of the muscle,
continued binding of drugs make the receptor incapable to
transmit the impulses, paralysis occurs.

The continued depolarization makes the receptor incapable of

transmitting further impulses.
9/26/2018 19
 Therapeutic uses:
When rapid endotracheal intubations is required.

Electroconvulsive shock therapy.

Pharmacokinetics:
Administered intravenously.

Due to rapid inactivation by plasma cholinestrase,

given by continued infusion.

9/26/2018 20
 SUCCINYLCHOLINE
• It causes paralysis of skeletal muscle.
Sequence of paralysis may be different from that of
non depolarizing drugs but respiratory muscles are
paralyzed last

Produces a transient twitching of skeletal muscle

before causing block

It causes maintained depolarization at the end plate,

which leads to a loss of electrical excitability.
It has shorter duration of action.
9/26/2018 21
 It stimulate ganglion sympathetic and para
sympathetic both.

In low dose it produces negative ionotropic

and chronotropic effect

In high dose it produces positive ionotropic

and chronotropic effect.
9/26/2018 22
 It act like acetylcholine but diffuse slowly to
the end plate and remain there for long enough
that the depolarization causes loss of electrical
excitability

If cholinestrase is inhibited ,it is possible for

circulating acetylcholine to reach a level
sufficient to cause depolarization block.
9/26/2018 23
 Unwanted effects:
Bradycardia preventable by atropine.

Hyperkalemia in patients with trauma or burns

this may cause dysrhythmia or even cardiac arrest.

Increase intraocular pressure due to contracture of

extra ocular muscles .
increase intragastric pressure which may lead to
emesis and aspiration of gastric content.
9/26/2018 24
 Malignant hyperthermia: rare inherited condition
probably caused by a mutation of Ca++ release
channel of sarcoplasmic reticulum, which results
muscle spasm and dramatic rise in body temperature.
(This is treated by cooling the body and administration of Dantrolene)

Prolonged paralysis: due to factors which reduce the

activity of plasma cholinesterase
genetic variants as abnormal cholinesterase, its severe deficiency.
anti -cholinesterase drugs
neonates
liver disease

9/26/2018 25
 Characteristics of neuromuscular-blocking drugs

9/26/2018 26
Some properties of neuromuscular blockers

Drug Elimination Approximate potency

relative to Tubocurarine

Atracurium spontaneous 1.5

Doxacurium kidney 6
Mivacurium Plasma cholinesterase 4
Metocurine Kidney 40% 4
Tubocurarine Kidney 40% 1
Panacurium Kidney 80% 6
Rocuronium Liver 70-80%,kidney 0.8
vecuronium Liver 75-90%,kidney 6
pipecuronium Kidney ,liver 6
Rapacuronium liver 0.4
9/26/2018 27
9/26/2018 28
 DANTROLENE
It acts directly
It reduces skeletal muscle strength by interfering with
excitation-contraction coupling into the muscle fiber, by
inhibiting the release of activator calcium from the
sarcoplasmic stores.

It is very useful in the treatment of malignant hyperthermia

caused by depolarizing relaxants.

This drug can be administered orally as well as intravenously.

Oral absorption is only one third.

29
Half life of the drug is 8-9 hours.
9/26/2018
 Baclofen
It acts through GABA B receptors

It causes hyper polarization by increased K+ conductance reducing calcium influx

and reduces excitatory transmitter in brain as well as spinal cord

It also reduces pain by inhibitory substance P. in spinal cord

It is less sedative

It is rapidly and completely absorbed orally

It has a half life of 3- 4 hours

It may increases seizures in epileptics

It is also useful to prevent migraine.

9/26/2018 30