1) Neuro-muscular blocking agents act at the neuromuscular junction to inhibit muscle contraction. 2) They work by competitively or non-competitively blocking acetylcholine receptors, preventing the endplate potential needed to trigger muscle action. 3) Examples include curare and tubocurarine which are competitive antagonists, and succinylcholine which is a depolarizing agent.

1. Neuro-Muscular Blocking agents &
Skeletal Muscle Relaxants
Presented By:
Heena Parveen,
M.Pharmacology,
Asst. Professor,
Dept. PHARMACOLOGY

2. Neuro-Muscular Blocking agents & Skeletal Muscle
Relaxants
Introduction
Synthesis ,Storage & Release of Neurotransmitters
Classification
Pharmacology of Prototype

3. Muscle contraction is the activation of tension-generating sites
within muscle cells.
In physiology, muscle contraction does not necessarily mean muscle
shortening because muscle tension can be produced without changes
in muscle length, such as when holding a heavy book or a dumbbell at
the same position.
The termination of muscle contraction is followed by muscle relaxation,
which is a return of the muscle fibers to their low tension-generating
state.
SKELETAL MUSCLE CONTRACTION:
Excluding reflexes, all skeletal muscles contractions occur as a result of
conscious effort originating in the brain.
The brain sends electrochemical signals through the nervous system to
the motor neuron that innervates several muscle fibers.

4. In the case of some reflexes, the signal to contract can originate in
the spinal cord through a feedback loop with the grey matter. Other
actions such as locomotion, breathing, and chewing have a reflex
aspect to them: the contractions can be initiated both consciously or
unconsciously.
NMJ:
A neuromuscular junction is a chemical synapse formed by the contact
between a motor neuron and a muscle fiber.
It is the site in which a motor neuron transmits a signal to a muscle fiber
to initiate muscle contraction. The sequence of events that results in
the depolarization of the muscle fiber at the neuromuscular junction
begins when an action potential is initiated in the cell body of a motor
neuron, which is then propagated by saltatory conduction along its
axon toward the neuromuscular junction. Once it reaches the terminal
bouton, the action potential causes a Ca2+ion influx into the terminal
by way of the voltage-gated calcium channels.

5. The Ca2+ influx causes synaptic vesicles containing the neurotransmitter
acetylcholine to fuse with the plasma membrane, releasing acetylcholine
into the synaptic cleft between the motor neuron terminal and the
neuromuscular junction of the skeletal muscle fiber.
Acetylcholine diffuses across the synapse and binds to and activates
nicotinic acetylcholine receptors on the neuromuscular junction.
Activation of the nicotinic receptor opens its intrinsic
sodium/potassium channel, causing sodium to rush in and potassium to
trickle out.
As a result, the sarcolemma reverses polarity and its voltage quickly
jumps from the resting membrane potential of -90mV to as high as
+75mV as sodium enters.

6. The membrane potential then becomes hyperpolarized when potassium
exits and is then adjusted back to the resting membrane potential.
This rapid fluctuation is called the end-plate potential.
Excitation–contraction coupling
Excitation–contraction coupling is the process by which a muscular
action potential in the muscle fiber causes the myofibrils to contract.
In skeletal muscle, excitation–contraction coupling relies on a direct
coupling between key proteins, the sarcoplasmic reticulum (SR)
calcium release channel (identified as the ryanodine receptor, RyR)
and voltage-gated L-type calcium channels (identified as
dihydropyridine receptors, DHPRs).
DHPRs are located on the sarcolemma (which includes the surface
sarcolemma and the transverse tubules), while the RyRs reside across
the SR membrane.

7. The close apposition of a transverse tubule and two SR regions
containing RyRs is described as a triad and is predominantly where
excitation–contraction coupling takes place.
Excitation–contraction coupling occurs when depolarization of skeletal
muscle cell results in a muscle action potential, which spreads across
the cell surface and into the muscle fiber's network of T-tubules,
thereby depolarizing the inner portion of the muscle fiber.
Depolarization of the inner portions activates dihydropyridine receptors
in the terminal cisternae, which are in close proximity to ryanodine
receptors in the adjacent sarcoplasmic reticulum.

8. The activated dihydropyridine receptors physically interact with
ryanodine receptors to activate them via foot processes (involving
conformational changes that allosterically activates the ryanodine
receptors).
As the ryanodine receptors open, Ca2+ is released from the sarcoplasmic
reticulum into the local junctional space and diffuses into the bulk
cytoplasm to cause a calcium spark.
Note that the sarcoplasmic reticulum has a large calcium buffering
capacity partially due to a calcium-binding protein called calsequestrin.
The near synchronous activation of thousands of calcium sparks by the
action potential causes a cell-wide increase in calcium giving rise to
the upstroke of the calcium transient.

9. The Ca2+ released into the cytosol binds to Troponin C by the actin
filaments, to allow crossbridge cycling, producing force and, in some
situations, motion.
The sarco/endoplasmic reticulum calcium-ATPase (SERCA) actively
pumps Ca2+ back into the sarcoplasmic reticulum.
As Ca2+ declines back to resting levels, the force declines and relaxation
occurs.
SLIDING FILAMENT THEORY
The sliding filament theory describes a process used by muscles to
contract. It is a cycle of repetitive events that cause a thin filament to
slide over a thick filament and generate tension in the muscle.
It was independently developed by Andrew Huxley and Rolf
Niedergerke and by Hugh Huxley and Jean Hanson in 1954.

10. Physiologically, this contraction is not uniform across the sarcomere; the
central position of the thick filaments becomes unstable and can shift
during contraction.
However the actions of elastic proteins such as titin are hypothesised to
maintain uniform tension across the sarcomere and pull the thick
filament into a central position.

12. Cross-bridge cycling is a sequence of molecular events that underlies the
sliding filament theory.
A cross-bridge is a myosin projection, consisting of two myosin heads,
that extends from the thick filaments.
Each myosin head has two binding sites: one for ATP and another for
actin.
The binding of ATP to a myosin head detaches myosin from actin,
thereby allowing myosin to bind to another actin molecule.
Once attached, the ATP is hydrolyzed by myosin, which uses the
released energy to move into the "cocked position" whereby it binds
weakly to a part of the actin binding site.

13. The remainder of the actin binding site is blocked by tropomyosin..
With the ATP hydrolyzed, the cocked myosin head now contains ADP +
Pi. Two Ca2+ions bind to troponin C on the actin filaments.
The troponin-Ca2+complex causes tropomyosin to slide over and unblock
the remainder of the actin binding site. Unblocking the rest of the
actin binding sites allows the two myosin heads to close and myosin
to bind strongly to actin.
The myosin head then releases the inorganic phosphate and initiates
a power stroke, which generates a force of 2 pN. The power stroke
moves the actin filament inwards, thereby shortening the sarcomere.
Myosin then releases ADP but still remains tightly bound to actin.

14. At the end of the power stroke, ADP is released from the myosin head,
leaving myosin attached to actin in a rigor state until another ATP
binds to myosin.
A lack of ATP would result in the rigor state characteristic of rigor
mortis.
Once another ATP binds to myosin, the myosin head will again detach
from actin and another cross bridges cycle occurs.

16. Cross-bridge cycling is able to continue as long as there are sufficient amounts
of ATP and Ca2+ in the cytoplasm.
Termination of cross bridge cycling can occur when Ca2+ is actively
pumped back into the sarcoplasmic reticulum.
When Ca2+ is no longer present on the thin filament, the tropo-myosin changes
conformation back to its previous state so as to block the binding sites again.
The myosin ceases binding to the thin filament, and the muscle relaxes.
The Ca2+ ions leave the troponin molecule in order to maintain the Ca2+ ion
concentration in the sarcoplasm.
The active pumping of Ca2+ ions into the sarcoplasmic reticulum creates a
deficiency in the fluid around the myofibrils.
This causes the removal of Ca2 ions from the troponin.
Thus, the tropomyosin-troponin complex again covers the binding sites on the
actin filaments and contraction ceases.

18. Curare :
It is the generic name for certain plant extracts used by south American
tribals as arrow poison for game hunting .
The animals got paralysed even if not killed by the arrow Natural sources
of curare are strychnous toxifera, Chondrodendron tomentosum
and related plants Muscle paralysing active principles of these are
tubocurarine,toxiferins, etc.
MECHANISM OF ACTION:
The site of action of both competitive and depolarizing blockers is the
end plate of skeletal muscle fibres.
This is produced by curare and related drugs Claude Bernard (1856)
precisely localized the site of action of curare to be the neuromuscular
junction.

19. He stimulated the sciatic nerve of pithed frog and recorded the
contractions of gastrocnemius muscle.
Injection of curare in the ventral lymph sac caused inhibition of muscle
twitches but there was no effect if the blood supply of the hind limb
was occluded. This showed that curare acted peripherally and not
centrally.
The competitive blockers have affinity for the nicotinic (NM) cholinergic
receptors at the muscle end plate, but have no intrinsic activity. The
Nm, receptor has been isolated and studied in detail.

21. It is a protein with 5 subunits (Alpha 2 , Beta, Eta, Gamma, Delta) which
are arranged like a rosette surrounding the Na2+ channel.
The two subunits carry two ACh binding sites; these have negatively
charged groups which combine with the cationic head of ACh +
opening of Na2+ channel.
Most of the competitive blockers have two or more quaternary N* atoms
which provide the necessary attraction to the same site, but the bulk of
the antagonist molecule does not allow conformational changes in the
subunits needed for opening the channel.
Competitive blockers generally have thick bulky molecules and were
termed Pachycurare by Bovet (1951).
ACh released from motor nerve endings is not able to combine with its
receptors to generate end plate potential (EPP).

22. d-TC thus reduces the frequency of channel opening but not its duration
or the conductance of a channel once it has opened.
When the magnitude of EPP falls below a critical level, it is unable to
trigger propagated muscle action potential (MAP) and muscle fails to
contract in response to impulse.
The antagonism is surmountable by increasing the concentration of Ach
invitro by anticholinesterases in vivo.
DEPOLARISING BLOCKERS:

23. Phase I block :
It is rapid in onset, results from persistent depolarization of muscle end
plate and has features of classical depolarization blockade.
This depolarization declines shortly afterwards and repolarization occurs
gradually despite continued presence of the drug at the receptor, but
neuromuscular transmission is not restored and phase II block
supervenes.
Phase II block :
It is slow in onset and results from desensitization of the receptor to
ACh.
It is, therefore, superficially resembles block produced by d-TC:
membrane is nearly repolarized, recovery is slow, contraction is not
sustained during tetanic stimulation and the block is partially reversed
by anticholinesterases.

24. PHARMACOLOGICAL ACTIONS:
Skeletal rmuscles:
Intravenous injection of nondepolarizing blockers rapidly produces
muscle weakness followed by flaccid paralysis.
Small fast response muscles (fingers, extraocular) are affected first;
paralysis spreads to hands, feet-arm, leg, neck, face-trunk-intercostal
muscles-finally diaphragm: respiration stops.
The rate of attainment of peak effect and the duration for which it is
maintained depends on the drug, its dose, anaesthetic used,
haemodynamic, renal and hepatic status of the patient and several
other factors.
Recovery occurs in the reverse sequence; diaphragmatic contractions
resume first.
Depolarizing blockers typically produce fasciculations lasting a few
seconds before inducing flaccid paralysis, but fasciculations are not
prominent in well-anaesthetized patients.

25. Apnoea generally occurs within 45-90 sec, but lasts only 2-5 min;
recovery is rapid.
Histamine release :
d-Tc releaseshistamine from mast cells. This does not involve immune
system and is due to the bulky cationic nature of the molecule.
Histamine release contributes to hypotension produced by d-TC;
flushing, bronchospasm and increased respiratory secretions are other
effects.
Intradermal injection of d-TC produces a wheal similar to that produced
by injecting histamine.
C.V.S :
d-Tubocurarine produces significant fall in BP. This is due to-
(a) Ganglionic blockade
(b) histamine release and
(c) reduced venous return-a result of paralysis of limb and respiratory
muscles

26. G.l.T :
The ganglion blocking activity of competitive blockers mav enhance
postoperative paralytic ileus after abdominal operations.
C.N.S :
All neuromuscular blockers are quaternary compounds-do not cross
blood-brain barrier. Thus, on i.v. administration no central effects
follow.
However, d-TC applied to brain cortex or injected in the cerebral
ventricles produces strychnine like effects.

27. PHARMACOKINETICS:
All neuromuscular blockers are polar quaternary compounds-not
absorbed oralIy, do not cross cell membranes, have low volumes of
distribution and do not penetrate placental or blood-brain barrier.
They are practically always given i.v., though i.m. administration is
possible.
Muscles with higher blood flow receive more drug and are
affected earlier.
Redistribution to non-muscular tissues plays a significant role in the
termination of surgical grade muscle relaxation, but residual block
may persist for a longer time depending on the elimination t1/2. The
duration of action of competitive blockers is directly dependent on the
elimination t1/2.

28. INTERACTIONS:
 Thiopentone sod. and SCh solutions should not be mixed in the same
svringe-react chemically.
 Central anaesthetics potentiate competitive blockers; ether in
particular as well as fluorinated hvdrocarbons.lsofluorane potentiates
more than halothane. Nitrous oxide potentiates the least. Ketamine
also intensifies non-depolarizing block Fluorinated anaesthetics
predispose to phase II blockade by SCh. Malignant hvperthermia
produced by halothane and isoflurane in rare individuals (genetically
predisposed) is more common in patients receiving SCh as well.
 Diuretics produces Hypokalemia which enhances competitive block.
 Calcium channel blockers Verapamil and others potentiate both
competitive and depolarizing neuromuscular blockers.

29. TOXICITY:
 Respiratory paralysis & prolonged Apnoea are the most common
problem.
 Fall in BP & Cardiovascular collapse can occur esp. in Hypovolemics.
 Precipitation of Asthma with d-Tc & other Histamine releasing
neuromuscular blockers.
 Post-operative muscle soreness may be complained after Sch.
USES:
 Severe cases of tetanus & status epilepticus ,which are not controlled
by diazepam & other drugs may be paralysed by a Neuromuscular
blocker.
 Convulsions and trauma from electroconvulsive therapy can be
avoided by the use of relaxants without decreasing the therapeutic
benefit.

30.  Assisted Ventilation : Critically ill patients in ICU often need
ventilatory support. This can be facilitated by continuous infusion of a
competitive neuromuscular blocker & reduces the chest wall
resistance to infusion.