Muscle Relaxants Flashcards
Anti-spastic Drugs
- Refers to agents specific for skeletal muscle
-
Reduce spasticity that interferes with daily living
- Such as that caused by cerebral palsy, multiple sclerosis, and spinal cord injuries
Anti-spasmodic Drugs
- Refers to an agent that relieves spasms
- Adjuncts to rest, PT, and other measures for relief of discomfort ass. with MSK disorders
- Widely used but not superior to NSAIDS
- May be used when NSAIDS are not effective for a particular patient
Classification of Drugs
Spasticity
Characterized by:
- ↑ activity in 1a afferents ⇒ ↑ tonic stretch reflexes
- ↑ flexor muscle spasms
- Muscle weakness
- Also input from higher centers in the CNS
Role of GABA
- GABA released from inhibitory interneuron in spinal cord
- Major role in modulating 1a afferents and alpha motor neurons
- Transmitter of the Ia “axon” is probably glutamate
- Two GABA receptors named A and B
GABA-A Receptors
-
Chloride ion channel
- Binding of GABA to the receptor ⇒ channel opens
- Chloride to flow down its electrochemical gradient
- Binding of GABA to the receptor ⇒ channel opens
-
Present on:
-
Dendrites of alpha motor neurons
- Reversal potential for chloride close to or more ⊖ than resting membrane potential
- Activation ⇒ influx of chloride ⇒ hyperpolarization or stabilization of the neuron
-
Terminals of 1a afferents
- Reversal potential for chloride above resting potential
- Activation ⇒ chloride efflux ⇒ depolarization
- GABA mediated depolarization alone is not robust enough to cause neurotransmitter release
- ⊗ neurotransmitter release by disrupting the activation of Na+ channels and Ca2+ influx
-
Dendrites of alpha motor neurons
GABA-A Receptor
Activation
Benzodiazepines ⊕ effect of GABA at GABA-A receptors
GABA-B Receptors
-
Metabotropic receptors
- ↑ K+ conductance ⇒ hyperpolarization of cellular membranes
- ↓ Ca2+ influx
-
Present on:
-
Terminals of the 1a afferents
- Mediates presynaptic ⊗ of the release of excitatory neurotransmitters
-
Dendrites of alpha motor neurons
- Causes hyperpolarization
-
Terminals of the 1a afferents
GABA-B Receptor
Activation
Baclofen mimics the action of GABA at GABA-B receptors
α2 Adrenergic Receptors
Activation ⇒ ↓ cAMP
- On 1a afferent terminal ⇒ ↓ release of glutamate
-
On alpha motor neurons ⇒ ⊗ activity of the neuron
- Mechanism is not clear
Benzodiazepines
MOA
Diazepam and other benzodiazepines:
Act by ⊕ allosteric modulation of GABA-A receptor activity in the CNS including the spinal cord
Interact with their own receptor on GABA-A complex ⇒ ↑ binding of GABA to its receptor site ⇒ more frequent opening of the chloride channel
Benzodiazepines
Effects
-
Antispastic effect in pts w/ spinal cord transection
- Action involves effects directly in the cord
- ↓ spasticity associated with many etiologies
- ↓ of muscle tone in pts w/ central lesions usu. requires large, sedating doses
Baclofen (Lioresal)
MOA
GABA-B agonist
Baclofen (Lioresal)
Pharmacokinetics
-
Rapidly and completely absorbed after PO administration
- Oral administration not always effective
- Long-term intrathecal infusion used
- T½ about 3-4 hr
- Excreted primarily unchanged through renal excretion
- Give cautiously (with reduced dosage) in pts w/ impaired renal function
Baclofen (Lioresal)
Uses
-
As effective as diazepam in reducing spasticity
- Alleviating sx of spasticity from MS
- Esp. flexor spasms and concomitant pain, clonus and muscular rigidity
- Value in pts w/ spinal cord injury and other spinal cord diseases
- Alleviating sx of spasticity from MS
- Less sedating than the benzodiazepine
-
May reduce muscle strength
- Less than benzodiazepines
- Not for skeletal muscle spasm from rheumatic disorders
- Baclofen has not helped patients with stroke
- Have not tolerated this drug well
Baclofen (Lioresal)
Adverse Effects
- May be teratogenic (category C)
- Most common adverse effect is drowsiness
- Hypotension
- GI problems (nausea most common, 4-12%)
- Hallucinations and seizures w/ abrupt withdrawal from oral administration
-
Malfunctioning of the pump can lead to significant withdrawal sx
- High fever, AMS, exaggerated rebound spasticity and rigidity
Tizanidine
MOA
Short-acting alpha-2 & imidazoline agonist
Tizanidine
Pharmacokinetics
-
PO is absorbed rapidly and completely
- Especially in the presence of food
- T½ ~ 25 hr
- Peak levels in ~ 15 hr
- Therapeutic action over by 6 hr
-
Extensive first-pass metabolism
- 95% of dose metabolized to inactive metabolites
- Clearance slowed in pts w/ renal impairment and in the elderly
Tizanidine
Uses
Similar to clonidine but much less potent in reducing blood pressure
Effective in pts w/ multiple sclerosis and spinal cord injury
Tizanidine
Adverse Effects
Mild to moderate:
- Includes dry mouth, sedation, dizziness, hypotension
- Can be minimized by slow dosage escalation
-
↑ aminotransferase activity in 5% of pts
- 3 deaths due to hepatic failure in pts taking this drug
- Safety in children or pregnant or nursing women not yet established
- CNS-depressant action of diazepam and ethanol may be additive w/ tizanidine
- May increase serum concentrations of phenytoin
Cyclobenzaprine
MOA
MOA probably involves:
- ↓ excitatory drive of descending serotonergic neurons to alpha motor neurons in ventral horn
- Structurally related to the tricyclic antidepressants
-
Some antimuscarinic effects
- Avoid in elderly and pts w/ glaucoma
Cyclobenzaprine
Uses
Tx acute muscle spasms and local pain associated w/ these musculoskeletal events
Cyclobenzaprine
Adverse Effects
- Antimuscarinic effects
- Avoid in elderly and pts w/ glaucoma
-
Prolongs QT interval
- Avoid in pts w/ arrhythmias and other heart related problems
Dantrolene (Dantrium)
MOA
Peripherally-acting antispastic agent:
- Binds to ryanodine receptor channel
- ⊗ activator Ca2+ release from SR
- Reduces skeletal muscle strength by a direct action w/in the muscle fibers
- Cardiac and smooth muscle are affected much less than skeletal muscle
Dantrolene (Dantrium)
Pharmacokinetics
Only ⅓ of oral dose is absorbed
T½ ~ 8 hr
Dantrolene (Dantrium)
Uses
Use in malignant hyperthermia
(Caused by general anesthetics and neuromuscular blocking agents)
Dantrolene (Dantrium)
Adverse Effects
Major adverse effects include:
- General muscle weakness
- Sedation
- Chemical hepatitis
Gabapentin
Non-selective, indirectly-acting GABA agonist
Used w/ reported success (limited data) in treating spasticity
Botulinum Toxin
Used by local injection into muscle w/ success
Riluzole (Rilutek)
-
MOA may involve:
-
⊗ glutamate release
- Presumably would also reduce neuronal degeneration
- Inactivation of voltage-dependent sodium channels
-
⊗ glutamate release
- Approved for spasticity in Amyotrophic Lateral Sclerosis
