Cyclobenzaprine
Discover related
4 sources
Mechanism of action
The exact mechanism of action of cyclobenzaprine has not been fully elucidated in humans, and much of the information available regarding its mechanism has been ascertained from early animal studies. There is some evidence that cyclobenzaprine exerts its effects at the supraspinal level, specifically within the locus coeruleus of the brainstem, with little-to-no action at neuromuscular junctions or directly on skeletal musculature. Action on the brainstem is thought to result in diminished activity of efferent alpha and gamma motor neurons, likely mediated by inhibition of coeruleus-spinal or reticulospinal pathways, and ultimately depressed spinal cord interneuron activity. More recently it has been suggested that inhibition of descending serotonergic pathways in the spinal cord via action on 5-HT2 receptors may contribute to cyclobenzaprine’s observed effects.
The centrally acting muscle relaxant cyclobenzaprine was thought to be an alpha 2-adrenoceptor agonist that reduced muscle tone by decreasing the activity of descending noradrenergic neurons. In the present study, we examined the effects of cyclobenzaprine on descending neurons by measuring the monosynaptic reflex in rats. Cyclobenzaprine reduced the monosynaptic reflex amplitude dose dependently and this effect was not inhibited by the alpha 2-adrenoceptor antagonists idazoxan and yohimbine. Cyclobenzaprine-induced monosynaptic reflex depression was not attenuated by noradrenergic neuronal lesions produced by 6-hydroxydopamine. However, cyclobenzaprine inhibited monosynaptic reflex facilitation induced by (+/-)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, a 5-HT2 receptor agonist, in spinalized rats markedly, and 5-HT depletion by DL-p-chlorophenylalanine inhibited the depressive effect of cyclobenzaprine on the monosynaptic reflex. These results suggest that cyclobenzaprine is a 5-HT2 receptor antagonist and that its muscle relaxant effect is due to inhibition of serotonergic, not noradrenergic, descending systems in the spinal cord.
Pharmacodynamics
Cyclobenzaprine is a skeletal muscle relaxant that works on areas of the brainstem to reduce skeletal muscle spasm, though its exact pharmacodynamic behaviour is currently unclear. Despite its long half-life, it is relatively short-acting with a typical duration of action of 4-6 hours. Cyclobenzaprine has been reported to contribute to the development of serotonin syndrome when used in combination with other serotonergic medications. Symptoms of serotonin syndrome may include autonomic instability, changes to mental status, neuromuscular abnormalities, or gastrointestinal symptoms - treatment with cyclobenzaprine should be discontinued immediately if any of these reactions occur during therapy.
Pharmacokinetics
Half-life
The effective half-life of cyclobenzaprine in young healthy subjects is approximately 18 hours. These values are extended in the elderly and those with hepatic insufficiency, with a mean effective half-life of 33.4 hours and 46.2 hours in these groups, respectively.
Cyclobenzaprine is eliminated quite slowly, with an effective half-life of 18 hours (range 8-37 hours; n=18) ... .
Absorption
The oral bioavailability of cyclobenzaprine has been estimated to be between 0.33 and 0.55. Cmax is between 5-35 ng/mL and is achieved after 4 hours (Tmax). AUC over an 8 hour dosing interval was reported to be approximately 177 ng.hr/mL.
After administration of a radio-labeled dose of cyclobenzaprine, 38-51% of radioactivity was excreted in the urine while 14-15% was excreted in the feces. Cyclobenzaprine is highly metabolized, with only approximately 1% of this same radio-labeled dose recovered in the urine as unchanged drug. Metabolites excreted in the urine are likely water-soluble glucuronide conjugates.
The volume of distribution of cyclobenzaprine is approximately 146 L. The combination of high plasma clearance despite a relatively long half-life observed with cyclobenzaprine is suggestive of extensive tissue distribution.
The approximate plasma clearance of cyclobenzaprine is 0.7 L/min.
Cyclobenzaprine is widely distributed into body tissues. ... It is not known if cyclobenzaprine crosses the placenta. The drug is extensively (about 93%) bound to plasma protein.
/MILK/ It is not known if cyclobenzaprine is distributed into milk in humans; however, the drug is distributed into milk in rats.
Metabolism
Cyclobenzaprine is extensively metabolized in the liver via both oxidative and conjugative pathways. Oxidative metabolism, mainly N-demethylation, is catalyzed primarily by CYP3A4 and CYP1A2 (with CYP2D6 implicated to a lesser extent) and is responsible for the major metabolite desmethylcyclobenzaprine. Cyclobenzaprine also undergoes N-glucuronidation in the liver catalyzed by UGT1A4 and UGT2B10, and has been shown to undergo enterohepatic circulation.
Ten metabolites of cyclobenzaprine, accounting for approximately 50% of the urinary radioactivity, were identified in the urine of dogs to which the labeled drug had been given orally. These included the 1,2-dihydrodiol, three phenolic derivatives, the N-oxide, the 10,11-epoxide, the 10,11-glycol, desmethylcyclobenzaprine, and the glucuronide conjugates of desmethylcyclobenzaprine and cyclobenzaprine. The metabolites were excreted in both the free and conjugated states. Unchanged cyclobenzaprine was present in only minor amounts.
Cyclobenzaprine is extensively metabolized, and is excreted primarily as glucuronides via the kidney. Cytochromes P-450 3A4, 1A2, and, to a lesser extent, 2D6, mediate N-demethylation, one of the oxidative pathways for cyclobenzaprine.
The absorption, distribution, excretion, and metabolism of 3-(5 H-dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-1-propanamine (cyclobenzaprine) were investigated in the rat, dog, rhesus monkey, and man. ... Major metabolites in the rat were phenolic derivatives but in man the major metabolites were 10,11-dihydroxynortriptyline and cyclobenzaprine glucuronide. ...
Cyclobenzaprine is extensively metabolized by both oxidative and conjugative pathways. Hepatic cytochrome P-450 (CYP) 3A4, 1A2, and (to a lesser extent) 2D6 isoenzymes are responsible for oxidative N-demethylation of the drug.Orally administered cyclobenzaprine is excreted in urine principally as inactive glucuronide metabolites; less than 1% of the drug is excreted renally as unchanged drug.
The fungus, Cunninghamella elegans, was used as a microbial model of mammalian drug metabolism to biotransform a tricyclic antidepressant, cyclobenzaprine. Seventy-five percent of this drug at a concentration of 1 mM was metabolized within 72 hr by C. elegans grown on Sabouraud dextrose broth. Milligram amounts of fungal metabolites were isolated by reversed-phase high performance liquid chromatography (HPLC) and their structures were characterized by 1H NMR spectroscopy, mass spectrometry, and UV spectroscopy analyses. The major fungal metabolites of cyclobenzaprine were 2-hydroxycyclobenzaprine (59%), N-desmethylcyclobenzaprine (21%), cyclobenzaprine trans-10,11-dihydrodiol (5%), N-desmethyl-2-hydroxy-cyclobenzaprine (3%), 3-hydroxycyclobenzaprine (3%), and cyclobenzaprine N-oxide (1%). These fungal metabolites were used as standards to investigate the metabolism of cyclobenzaprine by rat liver microsomes. Rat liver microsomes also biotransformed cyclobenzaprine to produce similar metabolites as the fungus. The isotope labeling of 2-hydroxycyclobenzaprine by 18O2 and the trans-configuration of the dihydrodiol suggested that these reactions were catalyzed by cytochrome P-450 monooxygenases in C. elegans. These results also demonstrated that the fungal biotransformation system could be used to predict and synthesize the mammalian drug metabolites.
Protein binding
Cyclobenzaprine is approximately 93% protein bound in plasma. It has been identified as specifically having a high affinity for human serum albumin.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.