This document discusses muscle relaxants and neuromuscular junction blockers. It reviews muscle physiology and contraction. It describes drugs that treat muscle spasms like benzodiazepines, baclofen, quinine, and dantrolene. It also discusses neuromuscular junction blocking drugs like tubocurarine and succinylcholine that are used during anesthesia. These drugs work by interfering with transmission at the neuromuscular junction.

1. Spasmolytics and Skeletal
Muscle Relaxants
Hussein Hallak, Ph.D.
Al-Quds University

2. Muscle Relaxants &
Neuromuscular Junction Blockers
Objectives
 Discuss the physiology of skeletal muscle
control and contraction
 Describe the MOA of drugs used to treat
muscle spasticity
 Describe the MOA and uses of NMJ blocking
drugs
 Explain how anticholinesterases are used to
alter the effects of NMJ blocking drugs

3. Muscle Relaxants
Spasmolytics
Treat chronic spasticity
NMJ blockers
Surgical intervention

4. Review of Muscle Physiology

5. Review of Muscle Physiology
Motor cortex
 spinal cord (direct or indirect)
 anterior horn motor neuron
 NMJ
 Nicotinic receptor
 Depolarisation
 SR Ca2+ release
 contraction

6. Muscle Spasms
Characterised by repetitive nervous stimulation of
particular muscle groups within the body
Results from
 Musculoskeletal trauma
 Spinal trauma
 CNS trauma (including cerebral palsy)
 Disease – multiple sclerosis
 Limb position during sleep (nocturnal cramps)
Treat with spasmolytics

7. Spasmolytics
1. Benzodiazepines
2. Baclofen
3. Quinine
4. Dantrolene

8. 1. Benzodiazepines
Diazepam.
Binds to BZ receptors associated with GABAA
receptors causing opening of Cl- channels.
Cl- channels open causing hyperpolarisation to
inhibit neurotransmission.
Inhibit neurons in motor pathways within brain
predominantly and less so in spinal cord.
Indications – muscle spasm.
SE – sedation, nausea, hallucination.

9. 2. Baclofen
Stimulates GABAB receptors
Reduces Ca2+ influx into synaptic terminal to
reduce release of excitatory neurotranmitters

10. 2. Baclofen
GABAB receptors predominate in spinal cord
 stimulation of motor neurons
 release of Sub P  analgesia
Indications – chronic spasticity
eg MS, head & spinal cord trauma.
SE – sedation, nausea.

11. 3. Quinine
Cinchona tree bark used to treat malaria
 Excitability of motor endplate
 Refractory period of muscle
(time when another action potential cannot
initiate).
Indication – primarily for nocturnal cramps.
SE – Cinchonism – tinnitus, headache, nausea,
diarrhoea, vision disturbances, hypoglycaemia

12. 4. Dantrolene
 Ca2+ release from the SR
preventing cross bridge
formation
Indication – chronic
spasticity
e.g. head and spinal trauma
Stroke, cerebral palsy,
MS
SE – weakness, drowsiness,
fatigue (transient)

13. Central Acting Muscle Relaxants
 Methocarbamol (Robaxin)
 Cyclobenzaprine HCl (Flexeril)
 Chlorzoxazone (Muscol)
 Carisoprodol (Soma)
 Chlorphenesin Carbamate (Maolate)
 Orphenadrine Citrate (Norgesic)
 Metaxalone (Skelaxin)

14. Mechanism Of Action
 Lack Of Controlled Clinical Trials
Makes Assessing The Efficacy Of
These Medications Difficult
 However, They May Relieve:
 Muscle Spasm
 Decrease Pain By Relieving
Spasm

15. Mechanism Of Action
 Not Been Conclusively Determined
 Research Suggests :
 Nonspecific CNS Sedation
 Suppression Of Polysynaptic Spinal
Cord Transmission

16.  Decreased Alpha Motor Neuron
Traffic With A Decrease In Spasm
 May Act As An Antidepressant -
Mood Alterations

17. Medical Uses
 Used as an adjunct to rest and
physical therapy in patients with
acute Musculoskeletal pain and
spasm

18. Review of Muscle Physiology
Motor cortex benzodiazepines
 spinal cord (direct or indirect) baclofen
 anterior horn motor neuron
 NMJ (anticholinesterases)
 Nicotinic receptor NMJ blockers
 Depolarisation quinine
dantrolene  SR Ca2+ release
 contraction

19. Neuromuscular Blockers

20. Neuromuscular Blockers
 Interfere with transmission at the nmj
 Used as adjuncts to general anesthesia
 2 types
 Non-depolarizing - typified by
tubocurarine
 Depolarizing - typified by
succinylcholine

21. End-plate
muscle muscle
axon
nerve terminal
ach receptors
Neuromuscular transmission
ach’esterase

22. Curare
 South American Indian arrow poison
 Crude material called curare
 Active principle is tubocurarine
 Polar, water soluble
 Prevents access of ach to its receptor
(competitive antagonist)
 Prevents depolarization of end-plate
 Relaxes skeletal muscles

23. Tubocurarine
 Limited distribution in the body
 Acts for > 30 mins
 Jaw & eye paralyzed first
 Larger muscle (trunk & limbs) paralyzed
second
 Diaphragm paralyzed last
 Releases histamine - lowers BP

24. Other Non-depolarizing Agents
 Atracurium
 doxacurium
 mivacurium
 pancuronium
 vecuronium
 pipecuronium
 roncuronium

25. Specific Nondepolarizing
Agents
 Intermediate-duration agents (e.g.
Vecuronium & Roncuronium) --mainly
dependent on hepatic metabolism and
biliary excretion for elimination
 Intermediate-duration drugs are most
commonly used clinically {compared to
longer acting renal-excreted drugs}

26. Specific Nondepolarizing
Agents
 Vecuronium–
 Shorter duration of action compared to
Pancuronium;
 Minimal cardiovascular effects; 85% hepatic
metabolism/elimination
 Roncuronium:
 Most rapid onset among nondepolarizing blockers
 The drug of choice for rapid-sequence anesthesia
induction and intubation

27. Comments About Nondepolarizing Agents
 Atracurium
 Similar characteristics as Vecuronium
 Hoffman elimination inactivation {spontaneous
breakdown}
 Atracurium breakdown product --laudanosine
may accumulate due to very slow hepatic
metabolism and upon crossing into the brain
may cause seizures
 Seizures occur at laudanosine concentrations
above that obtained during surgical procedures;
However long-term use of atracurium within the
intensive care setting may result in
concentration sufficient to induce seizures

28. Specific Nondepolarizing Agents
 Mivacurium:
 Shortest duration of action among
nondepolarizing agents
 Rapid clearance of isomer mixture by
plasma cholinesterase activity
 Prolonged duration of Mivacurium action
in patients with renal failure {renal
failure is associated with reduced plasma
cholinesterase activity}

29. Depolarizing Type: Succinylcholine
 Consists of 2 ach molecules end-to-end
 Produces a depolarizing block
 Phase I - depolarizes the end-plate & adjacent
muscle
 Phase II - with continued presence, it desensitizes
the end-plate to ach
 Metabolized by plasma pseudocholinesterases

30. Succinylcholine
 Not metabolized at the nmj
 Plasma cholinesterase determines
 Concentration that reaches the nmj
 Duration of action
 Some people have atypical cholinesterase and can’t
metabolize succinylcholine; They over-react to the drug
 Block lasts only 10 to 15 minutes in normal patients
 Blockade NOT overcome by ach or ach’esterase
inhibitors

31. Depolarizating Blockers
Adverse Effects
 Hyperkalemia - not well understood
 Increased intraocular pressure
 Increased intragastric pressure
 Muscle pain - presumably because of
the unsynchronized contractions just
before paralysis