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.
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
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
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)
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
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
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
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