MSK 02 and 06: Muscle Relaxants

Question 1

What is the mechanism of action of centrally acting skeletal muscle relaxants?

Answer 1

modify function of GABA receptors

Question 2

What is GABAA?

Answer 2

inhibitory anion channel – Cl- channel

• presynaptic inhibition of neurotransmitter release (through depolarization of primary afferent terminal due to Cl- outflow)
• postsynaptic inhibition of motor neuron excitability (through hyperpolarization of membrane potential due to Cl- inflow)

Question 3

What is GABAB?

Answer 3

G-protein linked receptor that activates K+ channels and deactivates Ca2+ channels

• 2 subunits: B1 and B2

Question 4

What are some benzodiazepines?

Answer 4

• diazepam
• lorazepam

Question 5

What is the mechanism of action of benzodiazepines?

Answer 5

• anxiolytic, anticonvulsant
• do not directly activate GABAA receptor
• enhance effect of GABA on GABAA receptor (GABA must be released for drug to have effect)
• increase frequency of Cl- channel opening in response to GABA
• main effect is slight neuronal membrane hyperpolarization and increase membrane conductance (less excitable)
• decreased action potential firing by motor neurons leads to decreased muscle tone

Question 6

What is flumazenil?

Answer 6

benzodiazepine receptor antagonist that can be used to reverse effects of benzodiazepines

Question 7

What is the mechanism of action of flumazenil?

Answer 7

competitive benzodiazepine antagonist at benzodiazepine receptor site on GABAA/benzodiazepine receptor complex

Question 8

What is the mechanism of action of baclofen?

Answer 8

• thought to act partly in spinal cord by directly activating GABAB receptors
• activation decreases cAMP (adenylyl cylcase)
• opening of K+ channels (membrane hyperpolarization – postsynaptic)
• inhibition of Ca2+ channels (decreased vesicular release – presynaptic)
• decreases excitability of neurons (including motor neurons) directly and through decrease in neurotransmitter release

Question 9

What are the therapeutic uses of baclofen and diazepam?

Answer 9

• acute muscle spasm and related pain
• muscle spasticity related to multiple sclerosis, spinal cord or MSK injury (ie. muscle strain), pain
• baclofen is also 2nd line treatment for trigeminal neuralgia (neuropathic pain condition that affects face)

Question 10

What are the adverse effects of benzodiazepines?

Answer 10

amnesia

Question 11

What are α2 receptors?

Answer 11

G protein coupled receptors activated by noradrenaline

Question 12

What is the mechanism of action of α2 receptors?

Answer 12

• pre-synaptically inhibits release of neurotransmitters from axon endings by ↓ Ca2+ influx
• post-synaptically activates K+ channels to hyperpolarize membrane potential
• attenuates nociceptive inputs to spinal cord neurons, ↓ pain signals and motor neuron output

Question 13

What is tizanidine hydrochloride?

Answer 13

centrally acting α2-adrenergic receptor agonist with analgesic and muscle relaxant properties

Question 14

What is the therapeutic use of tizanidine hydrochloride?

Answer 14

treatment of muscle spasticity caused by multiple sclerosis (MS), acquired brain injury, or SCI, myofascial pain, lower back pain, and trigeminal neuralgia

Question 15

What are the side effects of tizanidine hydrochloride?

Answer 15

drowsiness, dizziness, dose-related blood pressure decrease, dry mouth, general weakeness

Question 16

What significant drug-drug interaction does tizanidine hydrochloride have?

Answer 16

ciprofloxacin – inhibits metabolism of tizanidine in liver, resulting in exaggerated effect on CNS

Question 17

How does alcohol act as a muscle relaxant?

Answer 17

• enhances effect of GABA in brain/spinal cord, and causes general CNS depression
• can be effective in reducing muscle strain related discomfort

Question 18

What is the mechanism of action of cyclobenzaprine?

Answer 18

• inhibits monosynaptic (stretch) reflex
• antagonist at serotonin 5-HT2 receptor to decrease serotonin-mediated motor neuron excitability
• structurally similar to tricyclic antidepressants – inhibits reuptake of noradrenaline and serotonin (5-HT)
• strongly anti-muscarinic – leads to significant sedation through action on brain

Question 19

What is the mechanism of action of methocarbamol (Robaxin)?

Answer 19

• mechanism unknown
• may act as general CNS depressant

Question 20

What is the mechanism of action of orphenadrine?

Answer 20

• mechanism unknown
• methyl derivative of antihistamine diphenhydramine (Benadryl)
• strongly anti-muscarinic, sedating

Question 21

What are the therapeutic uses of cyclobenzaprine, methocarbamol, and orphenadrine?

Answer 21

• mostly used to treat muscle spasms (ie. pulled muscle)
• not effective for spasticity due to SCI

Question 22

What are the adverse effects of cyclobenzaprine and orphenadrine?

Answer 22

dry mouth, blurred vision, flushing, confusion, urinary retention

Question 23

What are the adverse affects of all centrally acting skeletal muscle relaxants?

Answer 23

• significant drowsiness, fatigue, may result in confusion
• muscle weakness/loss of coordination/slowed reaction time
• risk for injury due to excessive muscle weakness or mental clouding
• most drugs metabolized in liver, all excreted by kidneys, can have exaggerated effects in elderly
• negative effects on chronic conditions such as epilepsy, cardiovascular disease

Question 24

What is the mechanism of action of botulinum neurotoxins?

Answer 24

block vesicular release of acetylcholine at NMJ by cleaving docking proteins

• botulinum toxin A (Botox): cleaves SNAP 25
• botulinum toxin B (Myobloc): cleaves VAMP/Synaptobrevin (shorter action than type A)

results in weakening to flaccid paralysis of skeletal muscles that lasts 3-4 months

Question 25

What are the therapeutic uses of botulinum neurotoxins?

Answer 25

- cosmetic - ophthalmic – strabismus, blepharospasm - face and neck muscle spasms - hyperhidrosis – excessive sweating - pain – migraine, lower back pain, etc.

Question 26

How does botulinum neurotoxin A decrease muscle pain?

Answer 26

- injection of botulinum neurotoxin A slowly increases mechanical threshold of muscle nociceptors – associated with significant degradation of muscle SNAP 25 protein - in craniofacial muscle, BoNTA decreases extracellular glutamate concentration - BoNTA also blocks glutamate-induced sensitization of nociceptors (NMDA receptors) and increased muscle blood flow (CGRP receptors/NK1 receptors)

Question 27

What are the side effects of botulinum toxin?

Answer 27

- unintended local weakness muscles near site of injection - ptosis (drooping eyelid) after injection for blepharospasm and hemifacial spasm - transient flu-like symptoms, anaphylaxis, and excessive fatigue

Question 28

What is curare?

Answer 28

plant alkaloid used in poisons that results in death from paralysis of skeletal muscles - competitive antagonist at neuromuscular nicotinic receptor - used to develop NON-depolarizing neuromuscular blockers (ie. tubocurarine)

Question 29

What are some non-depolarizing neuromuscular blockers?

Answer 29

- tubocurarine - vecuronium - atracurium - 𝛼 bungarotoxin

Question 30

What are the side effects of tubocurarine?

Answer 30

histamine release (hypotension), increased salivation, autonomic ganglionic blockade, pooling of blood in extremities

Question 31

What are the side effects of vecuronium?

Answer 31

no histamine release or ganglion blockade

Question 32

What are the side effects of atracurium?

Answer 32

slight histamine release (hypotension) - useful in kidney/liver dysfunction, undergoes spontaneous hydrolysis

Question 33

What are the side effects of 𝛼 bungarotoxin?

Answer 33

results in rapid paralysis of skeletal muscles including diaphram death from respiratory failure, can be used for diagnostic purposes

Question 34

What are some depolarizing neuromuscular blockers?

Answer 34

- succinylcholine - dantrolene

Question 35

What is the mechanism of action of succinylcholine?

Answer 35

- nicotinic and muscarinic receptor agonist - induces nicotinic receptor desensitization - rapidly broken down by blood pseudocholinesterases - NOT broken down by acetyl-cholinesterase at NMJ

Question 36

What are the side effects of succinylcholine?

Answer 36

(stimulates all nicotinic, cholinergic receptors) - arrythmias (bradycardia) - hyperkalemia = ↑ K+ - dose-dependent alteration in cardiac output - emesis (vomiting) - muscular pain - increased intraocular pressure

Question 37

What are the therapeutic uses of neuromuscular blockers?

Answer 37

- surgical or procedural muscle relaxation – for skeletal muscle relaxation during general anesthesia - mechanical respiration – succinylcholine used to prevent respiratory effort in patients receiving mechanical ventilation

Question 38

What is the mechanism of action of dantrolene?

Answer 38

- acts to reduce release of Ca2+ from SR by blocking ryanodine receptors - muscle relaxation occurs due to ↓ Ca2+ - release of acetylcholine - depolarization of muscle membrane - release of Ca2+ from internal stores (SR) by activation of ryanodine receptors - binding of Ca2+ to myosin - sliding of mypsin along actin - muscle contraction

Question 39

What are the therapeutic uses of dantrolene?

Answer 39

- spasticity - malignant hyperthermia

Question 40

What are the adverse effects of dantrolene?

Answer 40

- generalized mild muscle weakness - transient drowsiness due to decrease release of Ca2+ from SR of neurons in CNS

Question 41

What is baclofen?

Answer 41

- GABAB receptor agonist - racemic drug, but R isomer is active - structurally analogous to GABA

Question 42

How do benzodiazepines act as positive GABAA receptor modulators?

Answer 42

- bind to 𝛼 subunit - act as positive allosteric modulators of GABAA receptor – effect requires presynaptic release of GABA - causes increased GABA on rate and affinity, which leads to higher frequency of open-channel bursts

Question 43

Describe the 3 different rings of benzodiazepines and their function.

Answer 43

- ring A: (6- ring, directly attached to large B ring) π-π stacking (substitution at 7 position increases activity) - ring B: (largest ring) proton-accepting group (ie. HBA) at position 2 is required – appending electron-rich ring to 1,2-bond can also act as proton acceptor - ring C: (5-phenyl) not required for binding, but increases lipophilicity – involved in π-π stacking

Question 44

What are class A benzodiazepines?

Answer 44

diazepam, lorazepam

Question 45

What are class B benzodiazepines?

Answer 45

alprazolam, triazolam - extra 3-N ring attached to large B ring

Question 46

Describe the ADME of benzodiazepines.

Answer 46

generally lipid soluble, orally bioavailable, and rapidly distributed to CNS