Skeletal muscle relaxant

1. SKELETAL MUSCLE RELAXANTS
DR. CARON D’SILVA

2. OBJECTIVES
 Describe:
 Types of Skeletal muscle relaxants (SMRs)
 Mechanism of action (MoA)
 Uses and side effects
 Contraindications

3. WHAT ARE SMRs?
 Skeletal muscle relaxants are drugs that reduce muscle tone
 Acting peripherally at the neuromuscular junction (NMJ)
 Directly on the contractile mechanism
 Centrally on the cerebrospinal axis
 Useful: during surgeries as adjuncts to anesthesia, spasticity due
to CNS disorders, muscle soreness in daily life

4. 4
NEUROMUSCULAR JUNCTION: NM RECEPTOR

5. SKELETAL MUSCLE CONTRACTION

6. 6
NM RECEPTOR IS A NA+ CHANNEL

7.  Sodium channel –transmembrane protein with two
functional gates
 Sodium ions pass only when both gates are open
 Opening of the lower (inactivation) gate is time dependent
 Whereas the upper gate opening is voltage dependent
 The channel possesses three functional states:
 (A). At rest the lower gate is open but the upper gate is closed
 (B). When the muscle membrane reaches threshold voltage, the
upper gate opens and sodium can pass to depolarize cells
 (C). Shortly after the upper gate opens the time-dependent lower
gate closes
 When membrane repolarizes to its resting voltage the
upper gate closes and the lower gate opens (A)
A. rest
B. open
C. inactive
7
NM RECEPTOR

8. CLASSIFICATION OF SMR

9. PERIPHERALLY ACTING SMR
 Competitive blockers, also called
non-depolarizing blockers
 Prototype: d-Tubocurarine
 Curare poison (arrow poison) from
plants Chondrodendron and
Stychnos sps.
 Quarternery ammonium alkaloid
(not absorbed, does not cross BBB,
used IM or IV)
MoA:

10. d-TC
• Actions: Skeletal muscle – muscular weakness followed by flaccid
paralysis
• Weakness in small muscles –eyes, fingers –then limbs, neck, trunk –last
diaphragm –respiratory paralysis can occur
• Consciousness preserved
• Recovery in opposite direction –diaphragm recovers first ..

11. PHARMACOLOGY OF d-TC
 Actions continued:
 Autonomic ganglia and adrenal medulla blocked at high doses –hypotension
 Histamine release –bronchospasm, increased tracheobronchial and gastric
secretions, hypotension
 PK: Quarternery ammonium alkaloid (not absorbed, does not cross BBB, used
IM/IV)
 Time of onset -5 min, duration -30 to 60 minutes –long acting
 Adverse effects: Respiratory paralysis – mechanical ventilation and reversal
using neostigmine or edrophonium (A Ch Inhibitors)
 Hypotension –Histamine release +ganglion blockade
 Bronchospasm –histamine release from mast cells –give antihistamines

12. SYNTHETIC NON-DEPOLARIZING SMR
Long acting
• Gallamine
• Pancuronium
• Pipecuronium
Intermediate
• Atracurium
• Vecuronium
• Rapacuronium
• Rocuronium
Short
• Mivacurium

13. FEATURES OF SYNTHETIC NON-DEPOLARIZING SMR
 Advantages : some have less histamine release, no ganglion blockade –no
hypotension
 More potent, shorter duration of action, spontaneous recovery
1. Atracurium: degraded spontaneously –Hofmann elimination, by plasma choline-
esterases, no renal metabolism – safe in renal patients
 Cisatracurium: isomer of atracurium –less metabolite(laudanosine) induced seizures, less
histamine release
2. Mivacurium: short acting but slow onset of action, metabolized by plasma
cholinesterases, more histamine release
3. Rocuronium: no hypotension, fast onset
4. Rapacuronium: fast onset, histamine release- bronchospasm
 Suggamadex-antidote for rocuronium and vecuronium overdose. Chelation action,
excreted renally

14. DEPOLARIZING SMR
 Succinylcholine (SCh,
suxamethonium)
 Quarternery ammonium
compound
 Resembles 2 joined ACh
molecules
 MoA:

15. PHARMACOLOGY OF SCh
 Actions:
 Skeletal muscle: rapid action on IV
administration (<1 min), lasts 5 to 10
min
 Initial twitching in chest, abdomen
followed by paralysis (due to action
potentials)
 CVS: initial hypotension and
bradycardia(vagal stimulation) followed
by hypertension and tachycardia (symp.
Stimulation)
 PK: fast onset, short duration of action
 Rapidly hydrolysed by pseudocholinesterase
 Genetic polymorphism –atypical
pseudocholinesterase –succinylcholine
apnea
 Mechanical ventilation and blood
transfusions required
 Avoided by checking dibucaine number: the
percent of pseudocholinesterase (PChE)
enzyme activity that is inhibited by dibucaine

16. SCh ADVERSE EFFECTS
 Post operative pain due to muscle fasciculations
 Hyperkalemia due to sudden release of K+ (muscle fasciculations)
 Cardiac arrhythmia
 Raised IOP, regurgitation – gastric content aspiration
 Malignant hyperthermia: genetic condition. Sudden increase in body
temperature and severe muscle spasm due to release of intracellular Ca++
from sarcoplasmic reticulum.
 Drugs causing malignant hyperthermia: SCh, halothane, isoflurane,
sevoflurane (a combination of general anesthetics)
 Treatment is Dantrolene

17. USES OF PERIPHERALLY ACTING SMR
 Adjuncts to anesthesia: Muscle relaxation is essential for surgery; SCh is used
during intubation for General anesthesia, removes cough reflex
 Minor procedures: Scopy(s)- laryngoscopy, bronchoscopy, intubation,
orthopedic procedures like fracture reductions
 Electroconvulsive therapy for treatment of depression –to prevent convulsions
 Spastic disorders –tetanus, athetosis
 Status epilepticus refractory to anticonvulsant medications
 Ventilated patients – to reduce chest wall resistance

18. DIRECTLY ACTING MUSCLE RELAXANT: DANTROLENE
 Dantrolene is a phenytoin analog
 Acts directly on the contractile
mechanism
 Prevents calcium release from
sarcoplasmic reticulum through
RyR1 channel (ryanodine receptors
blocker)
 Affects only skeletal muscle not
cardiac or smooth muscle - different
Ryanodine receptor subtype

19. DANTROLENE
 Used for treatment of malignant
hyperthermia –uncouples the heat-
generating mechanism of the
spastic muscle
 Hemiplegia, paraplegia, MS, spinal
cord injury
 Malignant neuroleptic syndrome
 A/E:
 Drowsiness, dizziness, fatigue,
muscle weakness, diarrhea
 Rarelt hepatotoxicity

20. BOTULINUM TOXIN
 Botulinum toxin: Acts at vesicles in cholinergic nerves (prevents fusion of vesicles to
membrane) -prevents ACh release
 Used in:
 Cerebral palsy (to reduce spasticity )
 Chronic migraine
 Primary axillary hyperhidrosis
 Cervical dystonia
 Blepharospasm
 Strabismus
 cosmetology
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21. As spasmolytic drugs
– Diazepam: GABAA agonist: facilitates GABA dependent Cl- influx
(frequency increases)
– Baclofen: GABAB agonist: K+ efflux increases
– Tizanidine: Alpha2 agonist: 1/10 to 1/15 of blood pressure lowering
effect of clonidine (muscle relaxant effect at lower dose than for
CVS effect)
Others: Mephenesin congeners –chlorzoxazone, carisoprodol
Thiocolchisoside (GABA mimetic), riluzole, gabapentin (inhibit
glutamate release in CNS)
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CENTRAL MUSCLE RELAXANTS

22. CENTRALLY ACTING MUSCLE RELAXANTS
 Diazepam (Benzodiazepine), Baclofen (GABA mimetic), Tizanidine (2
agonist)
 These drugs reduce the muscle tone by selective action in the
cerebrospinal axis, without altering the consciousness
 MoA: They depress the supraspinal polysynaptic and monosynaptic
reflexes
 They are used in: Acute muscle spasms, backache, neuralgia, anxiety
and tension induced increase in muscle tone, spastic neurological
diseases, tetanus, orthopedic manipulations
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23. DRUG INTERACTIONS AND CONTRAINDICATIONS
 Drug interactions:
 General anesthetics + SMR
=potentiation
 Anticholinesterases used for reversal of
effect of non-depolarizing blockers
 Aminoglycosides, calcium channel
blockers potentiate SMRs
 SCh + halothane –increased risk of
malignant hyperthermia
 Contraindications:
 Myasthenia gravis
 Severe hepatic/renal dysfunction
 Alcohol intake
 Hypersensitivity
 In case of SCh, low dibucaine number –risk
of apnea increases