MSK 02 and 06: Muscle Relaxants Flashcards
What is the mechanism of action of centrally acting skeletal muscle relaxants?
modify function of GABA receptors
What is GABAA?
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)
What is GABAB?
G-protein linked receptor that activates K+ channels and deactivates Ca2+ channels
- 2 subunits: B1 and B2
What are some benzodiazepines?
- diazepam
- lorazepam
What is the mechanism of action of benzodiazepines?
- 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
What is flumazenil?
benzodiazepine receptor antagonist that can be used to reverse effects of benzodiazepines
What is the mechanism of action of flumazenil?
competitive benzodiazepine antagonist at benzodiazepine receptor site on GABAA/benzodiazepine receptor complex
What is the mechanism of action of baclofen?
- 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
What are the therapeutic uses of baclofen and diazepam?
- 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)
What are the adverse effects of benzodiazepines?
amnesia
What are α2 receptors?
G protein coupled receptors activated by noradrenaline
What is the mechanism of action of α2 receptors?
- 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
What is tizanidine hydrochloride?
centrally acting α2-adrenergic receptor agonist with analgesic and muscle relaxant properties
What is the therapeutic use of tizanidine hydrochloride?
treatment of muscle spasticity caused by multiple sclerosis (MS), acquired brain injury, or SCI, myofascial pain, lower back pain, and trigeminal neuralgia
What are the side effects of tizanidine hydrochloride?
drowsiness, dizziness, dose-related blood pressure decrease, dry mouth, general weakeness
What significant drug-drug interaction does tizanidine hydrochloride have?
ciprofloxacin – inhibits metabolism of tizanidine in liver, resulting in exaggerated effect on CNS
How does alcohol act as a muscle relaxant?
- enhances effect of GABA in brain/spinal cord, and causes general CNS depression
- can be effective in reducing muscle strain related discomfort
What is the mechanism of action of cyclobenzaprine?
- 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
What is the mechanism of action of methocarbamol (Robaxin)?
- mechanism unknown
- may act as general CNS depressant
What is the mechanism of action of orphenadrine?
- mechanism unknown
- methyl derivative of antihistamine diphenhydramine (Benadryl)
- strongly anti-muscarinic, sedating
What are the therapeutic uses of cyclobenzaprine, methocarbamol, and orphenadrine?
- mostly used to treat muscle spasms (ie. pulled muscle)
- not effective for spasticity due to SCI
What are the adverse effects of cyclobenzaprine and orphenadrine?
dry mouth, blurred vision, flushing, confusion, urinary retention
What are the adverse affects of all centrally acting skeletal muscle relaxants?
- 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
What is the mechanism of action of botulinum neurotoxins?
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
What are the therapeutic uses of botulinum neurotoxins?
- cosmetic
- ophthalmic – strabismus, blepharospasm
- face and neck muscle spasms
- hyperhidrosis – excessive sweating
- pain – migraine, lower back pain, etc.
How does botulinum neurotoxin A decrease muscle pain?
- 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)
What are the side effects of botulinum toxin?
- 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
What is curare?
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)
What are some non-depolarizing neuromuscular blockers?
- tubocurarine
- vecuronium
- atracurium
- 𝛼 bungarotoxin
What are the side effects of tubocurarine?
histamine release (hypotension), increased salivation, autonomic ganglionic blockade, pooling of blood in extremities
What are the side effects of vecuronium?
no histamine release or ganglion blockade
What are the side effects of atracurium?
slight histamine release (hypotension)
- useful in kidney/liver dysfunction, undergoes spontaneous hydrolysis
What are the side effects of 𝛼 bungarotoxin?
results in rapid paralysis of skeletal muscles including diaphram death from respiratory failure, can be used for diagnostic purposes
What are some depolarizing neuromuscular blockers?
- succinylcholine
- dantrolene
What is the mechanism of action of succinylcholine?
- nicotinic and muscarinic receptor agonist
- induces nicotinic receptor desensitization
- rapidly broken down by blood pseudocholinesterases
- NOT broken down by acetyl-cholinesterase at NMJ
What are the side effects of succinylcholine?
(stimulates all nicotinic, cholinergic receptors)
- arrythmias (bradycardia)
- hyperkalemia = ↑ K+
- dose-dependent alteration in cardiac output
- emesis (vomiting)
- muscular pain
- increased intraocular pressure
What are the therapeutic uses of neuromuscular blockers?
- 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
What is the mechanism of action of dantrolene?
- 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
What are the therapeutic uses of dantrolene?
- spasticity
- malignant hyperthermia
What are the adverse effects of dantrolene?
- generalized mild muscle weakness
- transient drowsiness due to decrease release of Ca2+ from SR of neurons in CNS
What is baclofen?
- GABAB receptor agonist
- racemic drug, but R isomer is active
- structurally analogous to GABA
How do benzodiazepines act as positive GABAA receptor modulators?
- 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
Describe the 3 different rings of benzodiazepines and their function.
- 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
What are class A benzodiazepines?
diazepam, lorazepam
What are class B benzodiazepines?
alprazolam, triazolam
- extra 3-N ring attached to large B ring
Describe the ADME of benzodiazepines.
generally lipid soluble, orally bioavailable, and rapidly distributed to CNS
