Dr. Arlene M.

Diaz
Dept.of Pharmacology
SWU-MHAM College of Medicine
A. Neuromuscular blocking agents
peripherally acting muscle relaxants
that acts at the myoneural junction and
impairs the transmission of impulses
from somatic neurons to skeletal –
muscle membranes.
B.Direct- acting muscle relaxant
 acts directly on the muscle fiber
by blocking the contractile process

C. Centrally acting drugs

 depress the transmission of
motor impulses at synapses within
CNS
 A. Nondepolarizing Drugs 
(Antidepolarizing or competitive
blocking agents) includes:
active principle from curare
1. Tubocurarine  (Chondrodendron tomentosum)
2. Metocurine Mech. of action – prevent ACH
3. Galamine – induced depolarization of the
4. Pancuronium
muscle end plate by
5. Vecuronium
6. Atracurium competitively inhibiting ACH at
7. Mivacurium the nicotinic - receptor of the
8. ORG 9426 neuromuscular junction.
ACH Na+, K+ entry
Channel opening
 Acetycholine -
the agonist is
displaced
Tubocurarine-
antagonist
occupies
Nicotinic
receptor
instead of
Acetylcholine

Nicotinic receptor
TUBOCURARINE CHANNEL
BLOCKED
 Mechanism of action of
ACH
competitive neuromuscular
Na+, K+ entry
Channel opening blocking drugs

acetycholine

Tubocurari
ne occupies
Nicotinic
receptor
instead of
Acetylcholi
Tubocurarine Channel blocked ne
Effects:
A. Tubocurarine
A.1. Paralysis  not all muscles are equally
sensitive to blockade by competitive blockers.
Order of Paralysis:
a. most susceptible are small rapidly
contracting muscle of face and eye.
b. Fingers
c. Limbs
d. Neck and trunk
e. Intercostals muscle
f. Lastly, diaphragm muscle
Neuromuscular blockade last from 10-20 minutes to
as long as 1-2 hours after a single administration.
Effects:
A. Tubocurarine

A.2. Ganglionic blockade  by blocking

nicotinic receptors at autonomic ganglia

A.3. Adrenal medulla may also be blocked

A.4. Release of histamine from mast

cells which may cause bronchospasm &
skin wheals.
Effects:
B. Pancuronium
 does not release histamine. It is 5x
more potent than Tubocurarine. It does
not cause a marked fall of B.P, but
moderate  in C.O. and mild  in B.P

C. Gallamine
 does not also release histamine nor
decreases blood pressure. It blocks the
cardiac vagus at the muscarinic site
causing sinus tachycardia,  C.O,  B.P
Non-surgical uses:
1. ICU for maintaining controlled resp.
2. Adjunct relaxation in electroshock
therapy in psychiatric patients
3. Diagnosis of Myasthenia Gravis
Metocurine- exact route of excretion is unclear
Tubocurarine - is partially metabolized by the liver
and excreted by the kidney
Pancuronium - is excreted by the kidney with only
minimal hepatic metabolism.
Gallamine,  excreted by the kidney
Vecuronium  shorter duration of action, has
minimal cardiovascular effect 15% - excreted by
kidney; 85% by bile.
Atracurium  short acting , undergoes
spontaneous breakdown in plasma to Laundanosine
(Hofmann elimination) by plasma and ester
hydrolysis.
Mivacurium-hydrolyze by plasma cholinesterase,
short acting , recovery is also of short duration
A. Anticholinesterases  Neostigmine,
Physostigmine and Edrophonium can
overcome the action non-depolarizing
neuromuscular blockers.

B. Halogenated Hydrocarbon anesthetics like

Halothane acts to enhance neuromuscular
blockade by exerting a stabilizing action at
the neuromuscular junction
C. Aminoglycoside antibiotics like streptomycin inhibit
acetylcholine release from cholinergic nerves by
competing with calcium ion. It synergize with
tubocurarine and other competitive blockers
(enhancing the block of ACH).

D. Calcium channel blockers increase the neuromuscular

block of tubocurarine and other competitive blockers
as well as depolarizing blockers.

E. Antiarrhythmic drugs (quinidine) enhance block

F. Local anesthetics  low dose  enhance block

Attaches to the nicotinic receptors and act
like acetylcholine to depolarize the junction,
but unlike acetylcholine which is destroyed
by acetylcholinesterase, the depolarizing
agent remain attached to the receptors for a
relatively longer time, providing a constant
stimulation of the receptor. Continous
binding of the depolarizing agent results to
desensitization to the effect of ACH and
blockade of sodium channels resulting to
flaccid paralysis.
Phase I (Depolarizing) Phase II (Desensitizing)
 The depolarizing  the continued
agents first cause the binding of the
sodium channels to open, depolarizing agent
resulting in renders the receptor
depolarization of incapable of
nicotinic receptor. transmitting further
impulses, as sodium
this cause a transient channel is now blocked
twitching of the muscle there is now
(fasciculations). repolarization and
desensitization to the
effect of acetylcholine.

This cause a flaccid

paralysis
 Membrane depolarizes
resulting in an initial
discharge which produces
transient fasciculations
Succinylcholine followed by flaccid
paralysis (depolarizing
Na+ phase)

- - - -
depolarized

+ + + +
Na+
 Phase II - Block
Membrane membrane repolarizes
but receptor is
desensitized to effect of
Acetylcholine.
ACETYLCHOLINE
succinylcholine (Desensitizing Phase)
produces flaccid paralysis
CHANNEL
CLOSED
+ + + +
repolarized

- - - -
1. Succinylcholine can liberate potassium from skeletal
muscle and can cause Hyperkalemia which may lead to
cardiac arrest in susceptible patients:

a. Burns
b.Nerve damage or neuromuscular disease
c. Closed head injury
d. Peritoneal infection
e. Renal failure

2. Transient  of IOP

3.  intragastric pressure – emesis

4. Muscle pain due to muscle damage

1. Apnea  most important especially in
patients with a genetic lack plasma CHE
(Pseudecholinesterase)

2. Hyperkalemia

3. With general anesthetic Halothane can

cause Malignant Hyperthermia (muscular
rigidity and hyperpyrexia) this is treated by
rapid cooling and by adm. of Dantrolene which
reduces heat production and muscle tone
OTHER FACTORS THAT INFLUENCE THE ACTION OF
NEUROMUSCULAR BLOCKING AGENTS:
2. LIVER DISEASE LEADS TO A DECREASE SERUM
CHOLINEESTERASES AND THEREFORE COULD
PROLONG THE DURATION OF ACTION OF
SUCCINYLCHOLINE.
3. PATIENTS USING ECHOTHIOPHATE – TREATMENT
OF GLAUCOMA ,CAN INCREASE THE DURATION OF
ACTION OF SUCCINYLCHOLINE.
3.PATIENTS WITH MYASTHENIA GRAVIS ARE HIGHLY
SENSISITIVE TO COMPETITIVE NEUROMUSCULAR
BLOCKING AGENTS. WHEN A DEPOLARIZING
AGENT IS ALSO GIVEN PHASE II OCCURS FASTER.
4. PATIENTS WITH EATON –LAMBERT SYNDROME
(SMALL CELL OR OAT CELL CARCINOMA ) ARE
SENSITIVE TO THESE AGENTS.
1. Unltrashort acting (5-10 mins) – Succinylcholine

2. Short acting (10-15 mins) – Mivacurium

3. Medium acting (15-30 mins) – Atracurium and

Vecuronium,rocuronium

4. Long acting (30 to 130 mins)

a. d-tubocurarine d. pipecuronium
b. metocurine e. doxacurium
c. pancuronium f. gallamine
 Cardiac and Histamine Release Side
Effects
Agent B.P H.R
Histamine
Release
Succinylcholine   or  slight
Sl.
Mivacurium Transient Sl.  slight

Minimal
Atracurium same same
effect

Vecuronium none none none

Pancuronium   slight
Gallamine slight
 
 Cardiac and Histamine Release Side
Effects
Agent B.P H.R
Histamine
Release
Tubocurarine high
 

Pipecurium none none slight

Doxacurium none none slight
Minimal
Metocurine none moderate
effect

Reversal of Non-depolarizing Neuromuscular Blockade

Cholinesterase inhibitors – Neostigmine,
Pyridostigmine or Edrophonium
 Neuromuscular Blockers
Drug Duration Characteristics

Depolarizing Agent

Succinylcholine 2 -4
• Very rapid onset (1-2) min &
duration.
- Useful for rapid sequence
intubation in emergencies
- Causes muscular fibrillatio, can
cause hyperkalemia
- Some patients have enzymes
polymorphism slow metabolism of
succinylcholine by
psuedocholinesterase ; these pts
have paralysis forseveral hour.
 Neuromuscular Blockers
Drug Duration Characteristics

Non-Depolarizing Agent
Tubocurarine < 60 min • Prototype drug, long duration of
action
- causes lower BP due to ganglionic
blockade and histamine release.

Pancuronium < 60 min • Long duration of effect, may cause

tachycardia
• Spontaneously decomposes in
Atracurium 15 min
plasma, so not renally cleared
- Drug of choice in patients with
renal or hepatic failure
- can cause histamine-associated
hypotension
SPASMOLYTIC DRUGS
are drugs that reduces or
ameliorate some of the symptoms of
spasticity. ( tonic stretch reflexes, flexor
muscle spasm and muscle weakness)

2 general categories
a. central acting
b. direct acting agents
Mechanism of Action:
Act directly on the contractile
mechanism of skeletal muscle by
interfering the release of Calcium from
the sarcoplasmic reticulum. USES- in
controlling spasticity due to injury,
strokes, cerebral palsy and multiple
sclerosis.Side effects- fatal hapatitis
Sarcoplasmic Ca ++
Reticulum
Ca++
Ca +
+
Block Ca
++

Contractile
Filaments
 1. Baclofen  an analog of GABA, reduces
transmission at monosynaptic extensor and
polysynaptic flexor reflex pathway in the
spinal cord. USES: spasticity due to traumatic
spinal cord injury ,cerebral palsy and MS
2. Cyclobenzaprine  related to tricyclic anti-
depressant relieves muscle spasm without
interfering skeletal muscle function.

3.Diazepam -benzodiazepine,facilitate inhibitory

action of GABA on alpha motor neurons activity
in the spinal cord. USES: spasticity due to cord
lesions in CP and muscle spasm
 Nerve action Potential Increase influx of Ca+1
Site of Action
of Agents Motor End Plate

Release of Acetylcholine
Block by non-
depolarizing Acetylcholine diffuses across synaptic cleft to the
Agents e.g nicotinic receptor located on the motor and plate
Tubocurarine (ACH binds to the alpha ∝ sub unit of Nicotinic II)

Enhance by Depolarizing [End-Plate Potential (EDP)] (with

depolarizing opening of the ion channels permeability to Na+ and
Agent e.g K+ ions)
Succingylchol
ine Muscle Action
Potential (MAP)

Block by Spread of Excitation in Muscle myofibril conduction

Dontrolene system
Muscle Contraction
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THY GOD!!!

A patient underwent a surgical

procedure and was given
tubocurarine. He developed
respiratory paralysis.