PHARMACOLOGY

SKELETAL MUSCLE
RELAXANT
PRESENTATION BY
GROUP 6
• RUDRANIL
BURHMAN
• UMUTHIJIMA
• SABIR AHMED
UMAR
• SAUMYA JAISWAL
 TABLE OF CONTENT

Introduction and classification+uses of

centrally acting drugs - Lohith

2.general mechanism of actionS - Sabir

3. Individual drugs part - Umutijima

4.centrally acting skeletal muscle

relaxants - part 2 Rudranil

5 Pharmacokinetics and dynamics -

Anupama

6.Uses and toxicity adverse effects -

Saumya
 Introduction and
classification

• Skeletal muscle relaxants (SMR) are drugs that reduce the muscle tone either by acting peripherally at the
neuromuscular junction (neuromuscular blockers) or centrally in the cerebrospinal axis or directly on the
contractile mechanism. They reduce the spasticity in a variety of neurological conditions and are also
useful in surgeries

• Skeletal muscle relaxant decrease skeletal muscle tone by peripheral or central action

• The neuromuscular blocking agents are used primarily in conjunction with general anaesthetics to provide
muscle relaxation for surgery, while centrally acting muscle relaxants are used mainly for painful muscle
 CLASSIFIC
ATION
Skeletal muscle relaxants may be classified as
follows:

1. Drugs acting peripherally at the NMJ

Competitive blockers (Nondepolarising agents)

Neuromuscular blocking agents are among the most commonly used drugs during general anesthesia. They
compete with acetylcholine and interfere with the transmission of nerve impulses resulting in skeletal muscle
relaxation. non-depolarizing muscle relaxants, which act as competitive antagonists. They bind (ACh) receptors
but do not produce an action potential. Thus, they prevent ACh from binding, and as a result, neural endplate
potentials do not develop
Depolarising blockers
Depolarizing muscle relaxants act as acetylcholine (ACh) receptor agonists by binding to the ACh receptors of
the motor endplate and generating an action potential. However, they are resistant to and not metabolized by
acetylcholinesterase, leading to persistent depolarization of the muscle fibers, resulting in the patient's well-
recognized muscle fasciculations and paralysis
2. Drugs acting centrally
Acts by depressing the polysynaptic pathaways in spinal and
supraspinal sites
• Diazepam
• baclofen
• mephenesin
• tizanidine.

—Most of the centrally acting skeletal muscle relaxants are available in

combinationwith one Or other NSAIDs. All of them cause certain degree
of sedation. They actby depressing polysynaptic pathways in spinal and
supraspinal sites. They are used to reduce spasm associated with
cerebral palsy, trauma, sprain, tetanus, multiplesclerosis, etc
3. Drugs acting directly on the
muscle
• Dantrolene
it affects the skeletal muscle contractile
mechanism. It inhibits the muscle contraction by
preventing the calcium release from the
sarcoplasmic reticulum. Adverse effects include
drowsiness, dizziness, fatigue, diarrhoea, muscle
weakness and rarely hepatotoxicity. Liver
function tests should be done to look for
hepatotoxicity.

Uses
Dantrolene is used in spastic disorders like
hemiplegia, paraplegia, spinal injuries, multiple
sclerosis and cerebral palsy. Dantrolene is the
drug of choice in malignant hyperthermia which
is due to excessive release of calcium from the
sarcoplasmic reticulum. Dantrolene blocks the
release of Ca++ from the sarcoplasmic reticulum
 uses of centrally acting
drugs

• Musculoskeletal disorders like muscle strains,sprains, myalgias, cervical root syndromes, herniated
disc syndromes, low backache, dislocations, arthritis, fibrositis and bursitis all cause painful muscle
spasms. Muscle relaxants are used with analgesics in these conditions.
• Spastic neurological disorders like cerebral palsy, multiple sclerosis, poliomyelitis, Skeletal Muscle
Relaxants 65 hemiplegia and quadriplegia are treated with diazepam or baclofen.
• Tetanus Diazepam is given IV.
• ECT Diazepam is given along with peripherally acting SMRs.
• Orthopaedic procedures like fracture reduction may be done after administering diazepam.
 Mechanism of action

1. Depolarizing blockers: succinyl choline (suxamethonium)

2. Non-depolarizing muscle relaxant (competitive blocker)
I. fade phenomenon
II. Phase I
III. Phase II
The site of action of both depolarizing and non-depolarizing blockers is the
end plate of the skeletal muscle fibres.
Mechanism of
action
• 1. The action potential (or electrical impulse signal)
reaches the nerve terminal in the presynaptic region.
• 2. Once the impulses reached the voltage-gated
Structure of the
calcium channels, the Ca+ channels will open leading
to the influx of Ca+ and bind to the cell membrane
which leads to release of acetylcholine (Ach.) into
Acetylcholine
the neuromuscular junction (NMJ)
• 3. Once the influx of Ca+ takes place, there will be
release of neurotransmitter known as Ach.
• 4. the Ach. Will go to the muscle membrane (post
synaptic membrane) where there is Ach. Receptor
and bind to it’s receptor.
• 5 & 6. Structural changes of the Ach.R which is
pentameric in nature (because its made up of 2-alpha,
1-betta, 1-gamma, 1-delta and 1-absulont subunit)
and the Ach. Structure will open leading to the influx
of Na+ and efflux of K+ (around end plate or pre-
junctional of the muscle fibres, there is Na+
channels) which will cause positive charge
(depolarization) of the muscles membrane and the
muscles will contract.
• 7. Ach. Will be hydrolysed by acetylcholinesterase to
acetate and choline and the ion channels will closed
(there will be no influx of Na+) leading to
repolarization of end plate potential and the muscles
will relax and wait for the next impulses.
 Depolarizing blockers: succinyl choline
(suxamethonium)

• These drugs depolarized the muscle membrane, because the structure of Ach. Is closely
resemble to that of Sch.
• Sch. Will bind to Ach.R (nicotinic receptor) and cause the opening of the muscle
membrane leading to the influx of Na+ and efflux of K+ causes depolarization of the
muscle.

• Non-depolarizing muscle relaxants (competitive blockers antagonist)

• In this condition the Ach is agonist while the d-TC (tubocurarine, d-tubocurarine or dtc) is
antagonist at Nm receptors.
• The NDMR will bind to the other site of Ach.R and causes the structural changes to Nm
receptors, which because the Ach. Cannot act on its receptor and there will be no influx
because no impulses is propagated so the muscle contraction will not occur.
The NDMR can act
on both:
• Post synaptic membrane and pre-synaptic membrane.
• In post-synaptic membrane the NDMR will bind to other site to prevent Ach. to
bind with its receptor and unable to induce ion channels opening and the end plate
potential will not occur (no depolarization of the membrane).

• But in pre-synaptic membrane the autostimulation of Ach. will inhibited by

NDMR, the release of Ach. will reduced more than in the firs twitch leading to a
condition known as FADE phenomenon (seen in train of four when there is
subsequent impulses, the muscle twitching will decreased/fade because NDMR
act on pre-synaptic and block the release of Ach.)
 Phase I and phase II
blocks

• Phase block I: when succinylcholine is given intranevously in the systemic

circulation, it will move to the synaps and stimulate the Nm type of receptor leading to
the movement of Na+ into the cell causing muscle depolarization, since Sch. cannot
metabolysed into the synap (metabolised in plasma by pseudocholinestrase) it will keep
on persistently depolarizing the Nm type of receptor which will leads to inactivation of
Na+ causes phase I block (inactivation of Na+ channels-no muscle contraction-muscle
will relax).
• Phase II block: the Nm receptor continuously stimulated, they get down degraded
and began to move into the muscle membrane, this is also called receptor down
regulation or desensitization (high dose of depolarizing muscles relaxants will act as
NDMR results from desensitization of the receptor to Ach., the Ach. Cannot act on Nm
receptors-resemble block produced by competitive blockers).
 PHARMACOLOGY OF PERIPHERALLY DONE BY

ACTING MUSLE RELAXANTS UMUTIJIMA SHYAKA

ANESTHESIA TECHNOLOGY

The individual Muscle relaxant drugs are:

1) D-tubocurare
2) Succinylcholine( suxamethonium)
3) Decamethonium(not used)
4) Pancuronium
5) Doxacurium
6) Pipecuronium
7) Vecuronium
8) Atracurium
9) Cisatracurium
10) Rcuronium
11) Mivacurium
12) sugamadex
 Classification
Depolarizing muscle relaxants-DMR Non depolarising muscle relaxants-NDMR

1. Succinylcholine 1. Pancuronium
2. Doxacurium
2. Decamethonium 3. Pipecuronium
4. Vecuronium
5. Atracurium
6. Cisatracurium
7. Rcuronium
8. Mivacurium
Differences between depolarizing and non-
depolarizing block

Depolarising Non-depolarlzing
1. Also called as phase I block 1. -
2. Block preceded by muscle fasciculations 2. No fasciculation
3. Depolarizing blocking drugs are called as 3. Called as pachycurare
leptocurare
4. No fading is seen (fading can be seen at higher 4. Shows fading on neuromuscular monitoring
doses, i.e. phase II block)
No post-tetanic facilitation 5. Exhibit post-tetanic facilitation

6. Does not require reversal rather cholinesterase 5. Reversed by cholinesterase inhibitors like
inhibitors (neostigmine) can prolong the depolarizing neostigmine
block by inhibiting pseudocholinesterase
 Depolarising muscle relaxants
I. Succinylcholine-SCh
Suxamethonium: It was introduced by Thesleff and Fold
in 1952 and was first used clinically by Bovet .
Chemically, it is dicholine ester of succinic acid.
Pharmacokinetics
• Onset of action is within 30-60 seconds
• Duration of action is < 10 minutes. Because of this early
onset and short duration Succinylcholine is the ideal
muscle relaxant for intubation.
• Dose: 1-2 mg/ kg
• Metabolised by Pseudocholine esterase
 SCh mechanism of action
• At neuromuscular junction succinylcholine acts like acetylcholine binding to the
same receptor site, producing the action potential and muscle contraction.
• Acetylcholine is immediately metabolized by acetylcholinesterase present at
neuromuscular junction but SCh metabolism depends o n the concentration gradient
between plasma and neuromuscular junction making excessive availability of
succinylcholine at neuromuscular junction.
• This produces repeated depolarization and contractions in all muscles which can
be directly visualized as fasciculations.
• Persistent depolarization will make the membrane to become refractory to SCh as
well as ACh for a transient period. This transient period is the period of relaxation.
This kind of block produced by succinylcholine is termed as phase I block.
 Systemic effects
• Cardiovascular system: Suxamethonium not only acts on nicotinic receptors but also on
muscarinic receptors producing bradycardia
• Hyperkalemia: the most prominent effect of SCh which occurs due to excessive muscle
fasciculations/contractions.
• Central nervous system (CNS): By causing contraction of neck muscles thereby
blocking jugular venous outflow SCh increases intracranial tension.
• Eye: Ocular muscles are multiple innervated muscles which undergo tonic contraction
after succinylcholine increasing the intraocular tension (IOT).
• GIT: Intragastric pressure is increased due to contraction of abdominal muscles. By
activating GI muscarinic receptors it increases GI secretions and peristalsis.
• Muscle pains (myalgia, muscle soreness): Muscle pains are due to excessive muscle
contractions. This complication however can be prevented by PRECURARISATION.
NON-DEPOLARIZING MUSCLE
RELAXANTS
• First muscle relaxant, d-tubocurare was used by Harold
Griffith.

• Nondepolarizing muscle relaxants ( DMR) are used (most

commonly in anesthesia) for:
 Maintenance of relaxation
 For intubation
 For precurarization
Mechanism of action: The DMR are the competitive antagonists
at acetylcholine receptor. They bind at the same site at which
acetylcholine binds preventing acetylcholine to bind thereby
preventing depolarization, action potential and muscle contraction
 Classification
According to the duration of action
According to chemical
I. Steroidal compounds
• Pancuronium – Vecuronium-Pipecuronium- Long acting Intermediate Short acting
Rocuroniwn -Rapacuronium acting
II. Benzylisoquinoline compounds D-tubocurarine Vecuronium Mivacurium
• d-Tubocurarine- Metocurine – Doxacurium- Gallamine Rocuronium Rapacuronium
Atracurium- Mivacurium - Cisatracurium -
Mivacurium Pancuronium Atracurium Gantacurium
(shortest acting)
III. Others( nolonger in use)
Pancuronium Metocurine
• Gallamine - Alcuronium -Onium chlorfumrates
• The basic difference between steroidal and Doxacurium Cisatracurium
benzylisoquinoline compounds is that histamine release is (longest acting)
seen with BZJQ compounds and vagolytic property with
steroidal compounds
Summary of pharmacology of nondepoloarising
muscle relaxants
Summary of pharmacology of nondepoloarising
muscle relaxants
 Sugammad
ex
• This is a novel reversing agent developed for terminating the action
of nondepolarizing muscle relaxants rocuronium and vecuronium.
• Directly binds to steroidal type of nondepolarizing muscle
relaxants to form a complex which gets eliminated unchanged
through kidney.
• The reversal of block with cholinesterase inhibitors(ex:
neostigmine) is slow (10- 15 min.) while reversal with sugammadex
is very fast (2- 3 minutes).
• Its side effects are mild precordial pain, nausea, alteration of taste
and rarely allergy. No cardiovascular effects have been noted.
 centrally acting skeletal muscle relaxants
RUDRAN
IL Neuromuscular blocking agents are used in clinical
BARMA Skeletal muscle
practice for conditions requiring paralysis, such as rapid
N relaxants are the drugs
sequence intubation, ADRS ( Acute distress respiratory
that affects skeletal
syndrome) and during general anaesthesia
muscle function and
Block cholinergic transmission between motors nerve
decrease the muscle
endings and Nicotine m ( neuromuscular ) receptor on the
tone.
end plate of skeletal muscles.
Neuromuscular physiology
1. Impulse travel to synaptic terminal ( synaptic knob)
2. When impulse present in synaptic knob, and its open the voltage gated ca 2+
channel, and Ca2+ influx.
3. This ca2+ will induce or provide energy to Ach ( Acetylcholine) which is present
in synaptic vesicles, and then they bind with the end synaptic membrane and
release Ach.
4. Release Ach will act on Acetylcholine receptor.
5. When Ach receptor induce by Ach, the receptor will have structural changes.
Since the structural changes , it will open the Ach receptor and influx of Na+ and
efflux of K+ ion and thus leads to depolarisation of muscle contraction and
generate action potential of muscle membrane.
Structure of Ach receptor is a pentameric in
nature consists of alpha, beta, delta, F cilion
Anaesthesia
Na+ channels are time dependent and |
categories into three phases are Analgesic,
Inactivated state, activated state, resting Amnesia,
phase Muscle
relaxants.
Analgesic- for reducing
Acetyl choline pain
| Amnesia- that is lose of
Hydrolysed by acetyl cholinesterase memories, because if
| patient stress more there
Acetate and choline will be influx of Na+
| voltage at the nerve
Receptor ion channel close ending, thus we cannot
| facilitate or manifest
End plate repolarise surgical or technical
| equipment
Muscle relaxation. Muscle relaxants- To
incubate during ADRS or
any other process.
 Two components of skeletal muscle relaxant

Depolarising muscle relaxants -

it is competitive in nature as
Non Depolarising muscle relaxants - It well as acts as a agonist .
Where Succinylcholine is a
is non competitive that’s having structural analog of
adjacent sites for binding of Ach Acetylcholine. Succinylcholine
binds with the Ach receptor
receptor and does not able to act . There and give instant depolarisation
that is Na+ influx gradient
is no passing of Na+ influx and doesn’t generating action potential ,
persistent partial
leads to depolarisation. It is also acts as depolarisation . After sometime
Na channel gets inactivate
a antagonists ( doesn't bind with the state . Does not dissociate with
receptor) Ach receptor. And leads to
flaccid paralysis ( face
paralysis)
 Pharmacodynamics (actions) ANUP
AMA
Skeletal muscle:-
Intravenous injection of non polarizing blockers rapidly Produces muscle weakness
followed by flaccid paralysis.
Small fast response muscle are affected first, finally it affect diaphragm & stops respiration.
The rate of attainment of peak effect & the duration for which it is maintained depands on
drug, it’s dose, anesthetic used, hemodynamic, renal/ hepatic status of patients with other
factors.
Autonomic ganglia:-
Because of cholinergic receptors in autonomic ganglia are nicotinic competitive
neuromuscular blockers produce some degree of ganglionic blockade.
Sch may cause ganglionic stimulation by its agonistic action on ganglionic nicotinic
receptor.
• Histamine release:-
• d-TC releases histamine from mast cells.
• Histamine release contributes to hypertension produced by d-TC.
• Flushing, bronchospasm & increased respiratory secretions are other effect.
• CNS:-
• All neuromuscular blockers are quaternary compounds, so they donot cross blood brain barriers. So,
administration has no central effect.
• GIT:-
• The ganglion blocking activity of competitive blockers may enhance postoperative pralytic Ileus after
abdominal operations.
• CVS:-
• D-Tubocurarine produces significant fall in BP
• HR may increases due to vagal ganglionic blockade. Pancuronium tends to cause tachycardia and rise in BP,
while atraccurium may cause hypotension.
• All new non depolarising drugs have negligible effects on BP&HR.
 Pharmacokinet
ics

• All neuromuscular blockers are not absorbed orally, because they donot cross cell membrane.
• Low volume of distribution donot penetrate placenta/blood brain barriers.
• Drug in administration muscle with higher blood flow receive more drug & are affected earlier.
• The duration of action of competitive blockers directly dependent on the elemination of t ½.
• Primary metabolism is in plasma/ liver & excretion through kidney.
• t1/2 =20-40 min
• With repeated administration redistribution sites are filled up and duration of action is
prolonged.
• The unchanged drug is excreted in urine as well as bile.
SAUMYA TOXI
JAISWAL CITY
1. Respiratory paralysis and prolonged apnoea is the most important
complication of neuromuscular blockers.

2. Flushing (due to histamine release ) is very common .

3.Fall in BP and cardiovascular collapse can occur, especially in

hypovolemic patients .

4. Cardiac arrhythmias.
 USES
1. The most important use of neuromuscular
blockers is as adjuvants to general
anaesthesia. By the use of these drugs,
adequate muscle relaxation can be
achieved at lighter planes.

2. Many surgical performed more safely and

rapidly by employing muscle relaxants.

3. They also reduce reflex muscle contraction

in the region undergoing surgery,
maintenance of controlled ventilation
during anaesthesia.

• e.g. endotracheal intubation,

laryngoscopy, bronchoscopy,
esophagoscopy
 Adverse
effects
1 Muscular weakness is the dose limiting
.

side effect.

2. Sedation, malaise, light headedness and

other central effects occur, but are less
pronounced than with centrally acting
muscle relaxants.

3. . Long term use causes dose dependent

serious liver toxicity in 0.1–0.5% patients.
Use in chronic disorders
 REFERENCE
UMUTHIJIMA SABIR AHMED UMAR
1. Essentials of MEDICAL PHARMACOLOGY Essential of medical pharmacology 8th edition KD Tripathi
8th edition KD Tripathi MD Pharmacology for medical graduates 4th edition Tara V. Shanbhag &
Smita Shenoy
2. SHORT TEXTBOOK OF ANESTHESIA 6th
Edition AjayYadav MD (Anaesthesiology).
OSMOSIS
LOHITH ABHISHEK
ANUPAMA 1. Essentials of MEDICAL PHARMACOLOGY 8th edition KD Tripathi MD SAUMYA JAISWAL
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RUDRANIL
BASIC AND CLINICAL PHARMACOLOGY – DR MURTADHA
ALSHAREFI
BERTRAM G. KATZUNG , SUSAN B. MASTERS, ANTHONY J. TREVOR