Mechanism of Action of Cyclobenzaprine
Cyclobenzaprine is an oral centrally acting 5-HT2 receptor antagonist that acts as a skeletal muscle relaxant by reducing tonic somatic motor activity, influencing both gamma (γ) and alpha (α) motor systems within the central nervous system, primarily at the brain stem level rather than the spinal cord. 1
Primary Mechanism
Cyclobenzaprine does not act directly on skeletal muscle or at the neuromuscular junction. Instead, it works through several central mechanisms:
- Acts primarily within the central nervous system at brain stem level rather than spinal cord 1
- Functions as a 5-HT2 receptor antagonist 2
- Reduces tonic somatic motor activity by influencing both gamma and alpha motor systems 1
- Structurally related to tricyclic antidepressants (specifically amitriptyline) 2
Secondary Mechanisms and Pharmacological Properties
Cyclobenzaprine exhibits several additional pharmacological properties that contribute to both its therapeutic effects and side effect profile:
- Demonstrates potent peripheral and central anticholinergic activity 2, 1
- Causes norepinephrine potentiation 2, 1
- Functions as a potent non-competitive antagonist of histamine H1 receptors, which likely contributes to its sedative effects 3
- Shows similarity to tricyclic antidepressants in pharmacological studies, including reserpine antagonism 1
- Causes slight to moderate increases in heart rate in animal studies 1
Pharmacokinetics
Understanding cyclobenzaprine's pharmacokinetics helps explain its clinical effects:
- Oral bioavailability ranges from 33% to 55% 1
- Highly bound to plasma proteins 1
- Extensively metabolized and excreted primarily as glucuronides via the kidney 1
- Metabolized by cytochromes P-450 3A4, 1A2, and to a lesser extent, 2D6 1
- Eliminated slowly with an effective half-life of 18 hours (range 8-37 hours) 1
- Accumulates when dosed three times daily, reaching steady state within 3-4 days at plasma concentrations about four-fold higher than after a single dose 1
Clinical Implications and Precautions
Important clinical considerations when using cyclobenzaprine:
- Concomitant use with monoamine oxidase inhibitors may increase the potential for serotonin syndrome 2
- Plasma concentration is generally higher in elderly patients and those with hepatic impairment 1
- Should be held on the day of operation according to the Society for Perioperative Assessment and Quality Improvement (SPAQI) consensus 2
- With long-term use, patients can experience withdrawal symptoms (malaise, nausea, headache) for 2-4 days after discontinuation 2
- Has potential to interact with sedatives and anesthetic agents 2
Side Effect Profile
The side effect profile is directly related to its mechanism of action:
- Anticholinergic effects: hallucinations, confusion, drowsiness, constipation, urinary retention, and dry mouth 2
- Sedation is the most common adverse effect, likely due to its non-competitive antagonism of histamine H1 receptors 4, 3
- Generally has a reasonable safety profile with less problematic overdoses compared to tricyclic antidepressants used for psychiatric conditions 5
Understanding cyclobenzaprine's mechanism of action helps explain both its therapeutic effects in reducing muscle spasm and its side effect profile, which is largely related to its anticholinergic properties and histamine H1 receptor antagonism.