Drug acting on PNS-Skeletal Muscle Relaxants for MBBS

1. SKELETAL MUSCLE RELAXANTS

2. • Drugs that act
Peripherally at neuromuscular junction
muscle fiber itself
centrally in cerebrospinal axis
Skeletal muscle relaxants are used to treat muscle spasm and spasticity
NM blocking agents GA are used –muscle relaxation for surgery
Centrally acting muscle relaxants-
↓muscle tone &
causes paralysis

3. Physiology of skeletal muscle contraction

5. • ↓Skeletal muscle tone & Cause some CNS depression by selective action in the
cerebrospinal axis without altering consciousness
Decrease muscle tone without reducing voluntary power
They selectively depress spinal & supra spinal polysynaptic reflexes involved in
the regulation of muscle tone without significantly affecting monosynaptically
mediated stretch reflex
All Centrally Acting muscle relaxants have some sedative property
They hv no effect on NM-transmission & on muscle fibres but ↓ upper motor
neuron spasticity & Hyperreflexia
Centrally Acting Skeletal Muscle Relaxants
 Chlorzoxazone-
Its mephenesin derivatives , but has a longer duration of action and better oral tolerance.

6. Diazepam:-
Prototype-benzodiazepines (BZD’s) which act in the brain on specific
receptors enhancing GABAergic transmission.
It reduces muscle tone by supraspinal rather than spinal action.
Sedation limits the dose which can be used for reducing muscle tone,
but gastric tolerance is very good.
It is particularly valuable in spinal injuries and tetanus.
Combined with analgesics, it is popular for rheumatic disorders
associated with muscle spasm
S/E-drowsiness, confusion, blurred vision, amnesia, disorientation, tolerance

7. Baclofen:-
It is an analogue of the inhibitory transmitter GABA; acts as selective
GABAB receptor agonist.
The primary site of action of baclofen is in the spinal cord where it
depresses both polysynaptic and monosynaptic reflexes.
A/E:- drowsiness, mental confusion, weakness & ataxia.
It ↓spasticity in many neurological disorders like
multiple sclerosis,
amyotrophic lateral sclerosis,
spinal injuries and
flexor spasms

8. Tizanidine:-
• It is central α2 adrenergic agonist reduces release of NA from nerve terminals.
• It also ↑ the release of inhibitory transmitter glycine.
• It is well absorbed orally.
• Indication: Musculo-spastic condition d/t neurological disorders & muscle
spasms of spinal origin.
• A/E: dry mouth, drowsiness, insomnia.
Methocarbamol:-
less sedative, longer acting used in reflex muscle spasms & chronic neurological
diseases.
Also used for orthopedic manipulations & in Tetanus.
8

9. Uses of centrally acting agent:
1. Acute muscle spasms like overstretching of muscles, sprains, tearing of
ligaments & tendons, dislocations & rheumatic disorder.
2. Torticollis, Lumbago, backache, neuralgias.
3. Anxiety & Tension.
4. Tetanus.
5. ECT- Diazepam along with SCh.
6. Orthopedic manipulations

10. -:Depolarizing Blockers:-
Succinylcholine:-
Quaternary ammonium compound
Other name-suxamethonium
Structure resemble – 2 molecule Ach
Linked together
Partial agonist + submaximal intrinsic activity-Nm receptor
Cause-initial fasciculations & later flaccid paralysis
It depolarize muscle end plates by opening of Na+ channels & initially produced
twitching and fasciculations – so called depolarizing blockers
Neuromuscular Blockers

11. MOA:-
•Acts like Ach but persist at the synapse at high conc and constantly stimulate
receptor
•DUAL MECHANISM: In many species dog, rabbit, rat, monkey & certain
conditions in man.
• Phase I Block:-
•Rapid in onset, results from persistent depolarization of muscle end plate
due to opening of Na+ channel
•Has classical features of depolarization block
•Block is not antagonized by anticholinesterase (neostigmine)
•Phase II Block:-
•Slow in onset, results from desensitization of the receptor to Ach,
•block is partially reversed by anticholinesterases.

12. In Normal skeletal muscle Ach rapidly hydrolyzed by acetylcholinesterase but Sch has longer action and not
hydrolyzed by cholinesterase-it maintained membrane potential above the threshold. when Ach binds to already
depolarized receptor leads to paralysis

13. Pharmacokinetics:-
 Onset of action is very rapid (within few sec)
 Hydrolyzed by Pseudo-cholinesterase (butyrylcholine esterase in plasma)-short duration of
action (3-8 min) to succinyl monocholine and choline
 “Succinylcholine apnea-
 Pt of Atypical Pseudo-cholinesterases / liver disease enzyme may be non-functional
(abnormal metabolism) due to genetical variation result in prolong apnea
 1 in 3000 pts have 2 abnormal genes (homozygous atypical) which will have a very long
blockade (6-8 h)
Sequence of paralysis:- short muscle are paralysed first
finger & orbit muscle→Limb & trunk muscle →Neck muscle → Intercostals-diaphragm
There is no anti-dote available
Fresh frozen plasma should be infused
Anaesthesia should be cont. until recovery from NM blocked
Pt should be ventilated artificially until full recovery

14. Pharmacological action:-
1.SKELETAL MUSCLE:
•Fasciculations → Paralysis
•Sequence of paralysis: neck, limbs → face, jaw, eyes, pharynx → trunk →
respiratory musculature Intercostals-diaphragm
•Onset & recovery rapid
•sequence of paralysis not distinguishable due to rapid hydrolysis
2.AUTONOMIC GANGLIA:- Stimulation
3.CVS:-
 Initial Bradycardia- due to cardiac muscarinic effect stimulation
 Followed by: Tachycardia & ↑ BP d/t stimulation of Sympathetic ganglia
 ↑ incidence of ventricular arrythmias- due to ↑K+

15. ADVERSE EFFECTS:-
Hyperkalemia:- due to excessive muscle fasciculation release K+ into the blood
Muscle pain/myalgia is due to initial fasciculation (muscle soreness)-which can be
decreased by pre-curarization with non-depolarizing agents
Sinus bradycardia-due to vagal stimulation
↑IOP-due to contraction of external ocular muscle

Aspiration of gastric content may occur due to ↑intragastric pressure (abdominal
muscle fasciculation)
↑se Intracranial pressure d/t slight ↑se in cerebral blood flow
Trismus-masseter spasm – ↑se in jaw muscle tone (children)

16. Succinylcholine apnoea
Malignant hyperthermia-
Especially when used with halothane
Rare inherited condition probably cause by mutation of Ca++ release channel of
Sarcoplasmic reticulum which result in muscle spasm and dramatic ↑in body
temp.co
Rx-treated with iv.dandrolene, rapid cooling, hyperventilate with inhalation of
100% O2 and control acidosis
Drug Interaction:-
• Succinylcholine×thiopentone
In vitro pharmaceutical interaction –chemically incompatible hence result in
precipitation when mixed in the same syringe

17. Contraindication:-
Head injury- ↑Intracranial pressure
Glaucoma- ↑IOP
Neuromuscular disorder i.e. paraplegia, hemiplegia, Duchenne muscular
dystrophy ,MG, burn, rhabdomyolysis-due to excessive muscle
fasciculation (hyperkalemia)

18. Uses:-
• Diagnostic endoscopies
• Endotracheal intubation-DOC due to short & fast action
• Orthopedic manipulation & for correction of dislocation of joints and reduction
of fractures including mandible(in dental practice)
• Electroconvulsive shock therapy-prevent convulsion, Cerebral hypoxia, trauma
• As adjuvant to GA to induce muscle relaxation

19. Competitive (Non-depolarizing) blockers
They have affinity for Nm receptor without any intrinsic activity
They compete with Ach for Nm receptor –called competitive blockers
Prevent binding of Ach to NM receptor-no opening of Na+ channel-No
depolarization(without any fasciculation), So Non-depolarizing blockers.
These compounds slowly dissociate from the receptors & transmission is
gradually restored-reversed by anticholinesterase
NM monitoring is done mostly by ulnar nerve
Claude Bernard showed experimentally the site of action of curare
Curare us a mixture of alkaloids and was used as an arrow poison
D-Tubocurarine is the most important alkaloid which had Nm blocking action

20. D-TUBOCURARINE:-
Obtained from “CHONDRODENDRON TOMENTOSUM”
Prototype drug of competitive blockers
It causes flaccid paralysis
Maximum propensity for releasing histamine and Ganglion blocked so causes
severe hypotension which can be reversed by calcium
Bronchospasm- due to histamine release
↓↓frequency of channel opening but does not affect duration or conductance of
single channel
Has longer duration of action
Metacurine-semi synthetic derivatives of d-tc with less cardiovascular effect

21. Pancuronium-
steroid compound
Only 10% is metabolized
Excreted in bile-caution use in biliary obstruction & renal disease
Cause vagal blocked and release of NA-tachycardia & ↑BP
Muscle relaxant of choice in arterial surgeries where BP maintenance is required or in
hypotensive pt.
Doxacurium:-
Most potent & longer acting muscle relaxant
Vecuronium:-
Most commonly used muscle relaxant for routine surgery
significant amount excreted in bile(40%)
It is most cardiovascular stable
It can cause poly-neuropathy on long term use in ICU

22. Atracurium:-
Metabolized by Hoffman degradation (95%) in plasma and ester hydrolysis (5%)
So recovery is rapid, reversal may not be required
It is relaxant of choice in
-Renal failure -Hepatic failure
-Neuromuscular disease -Neonates
 Metabolites-laudanosine can cross BBB & produce convulsion
Pipecuronium:- pancuronium derivatives.no vegolytic or ganglion blocked action so
cardiovascular stable
Rocuronium:-(intermediate acting-least potent) Fastest onset of action so it is non depolarizer
of choice for rapid sequence endotracheal intubations
Mivacurium:- metabolized by pseudocholinesterase
Short Duration of action- 15-21 min therefore muscle relaxant of choice for day care surgery
Don’t cross BBB & Placenta in significant amount so can be given safely
Cause histamine release

23. Pharmacokinetics:-
• Large molecules
• Highly ionized (not absorbed)
• Do not pass lipid membranes easily
• no CNS effects: can result in awake, paralyzed patient
• Low Vd
• Muscles with high blood flow receive more drug & are affected
earlier
• Metabolized in plasma/liver & excreted by kidney
• Atracurium & Cisatracurium are metabolized by Hoffman
elimination

24. Side effect:-
• Hypotension-ganglionic blocked-↓sympathetic stimulation
• respiratory paralysis
• Bronchospasm
• Aspiration of gastric contents
Drug Interaction:-
• NDB × Antibiotics (Aminoglycosides, Tetracycline, Clindamycin)& CCB-
potentiate effect of NDB
• NDB × GA(ether)-enhance the effect of NDB
• NDB × Thiazide loop diuretics- enhances competitive block by producing
hypokalemia
• Neostigmine reverses the muscle relaxant action

25. Directly acting Skeletal Muscle Relaxant
Dantrolene
MOA:-
• It inhibits release of Intercellular Ca++ via inhibition of ryanodine receptor
↓
No EC-coupling –No contraction
Used-
Malignant hyperthermia-DOC
Neuroleptic malignant syndrome
upper mortar neuron disorder like hemiplegia, paraplegia, cerebral palsy, multiple sclerosis-
↓spasticity
• SE:-
Muscle weakness, sedation, malaise, Diarrhoea, liver toxicity.

26. Quinine
Acts as directly acting muscle relaxant
It increase refractory period and decrease excitability of motor end
plates
It can be used in nocturnal leg cramp

27. Comparison b/w central & peripherally acting
agents
Centrally acting MR Peripherally acting MR
 ↓se muscle tone without reducing
voluntary power.
 Produce muscle paralysis. Voluntary
movements lost
 Selectively inhibit polysynaptic
reflexes in CNS.
 Block neuromuscular transmission
 Cause some CNS depression  No central effects
o Used in chronic & acute spastic
conditions, tetanus
o Used for short term surgical
procedure
 Administered- commonly Oral route  Administered- commonly I.v. route

28. Explain why:-
1.Why d-tubocurarine produces significant fall in BP?
Ans-its causes following
1.Ganglionic blocked-due to which sympathetic stimulation decrease which result
into vasodilatation
2.Histamine release-It is a potent vasodilator
3.Its reduces venous return due to paralysis of muscle of limbs and respiratory
muscle
2.Why for ocular surgery competitive blockers are preferred
Ans- they paralyse ocular muscle at dose which have little effect on larger muscles.
smaller muscle such as ocular and that of fingers are affected first & at low dose. So
it become easy to operate the patients without significantly affecting the other
systems

29. 3.Why succinylcholine is used for short surgical procedures?
Ans- succinylcholine is a depolarizing types of muscle relaxant.
Its is used for short surgical procedures because it induces rapid complete and predictable
paralysis with spontaneous recovery. Action of succinylcholine develops with such a rapidity that
it is not appreciated. Apnoea occurs within 45-90 second.it last for 2-5min.Recovery is also very
rapid.it is the most commonly drug used for passing tracheal tube.
4.Why succinylcholine produces prolonged apnoea in some patients?
5.Why Neuromuscular blockers are not absorbed orally?
Ans:- quaternary ammonium compound.