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Pathway Description
Orphenadrine Drug Action
Homo sapiens
Drug Action Pathway
Orphenadrine is a first-generation ethanolamine H1-antihistamine. H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Reducing the activity of the NF-κB immune response transcription factor through the phospholipase C and the phosphatidylinositol (PIP2) signalling pathways also decreases antigen presentation and the expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors. Furthermore, lowering calcium ion concentration leads to increased mast cell stability which reduces further histamine release. First-generation antihistamines readily cross the blood-brain barrier and cause sedation and other adverse central nervous system (CNS) effects (e.g. nervousness and insomnia). Second-generation antihistamines are more selective for H1-receptors of the peripheral nervous system (PNS) and do not cross the blood-brain barrier. Consequently, these newer drugs elicit fewer adverse drug reactions. Structurally, orphenadrine is similar to diphenhydramine. As a "dirty drug", orphenadrine acts on various receptors in the CNS. Orphenadrine can antagonize H1 receptors, NMDA receptors, and non-selectively antagonize muscarinic acetylcholine receptors (hence its use as an anticholinergic). It also blocks the HERG potassium channel along with Nav1.7, Nav1.8, and Nav1.9 sodium channels, and is a norepinephrine and dopamine reuptake inhibitor. Orphenadrine acts as an anticholinergic to treat muscle pain and relax skeletal muscle, though its use is reducing as better drugs are developed for motor control management with fewer off-target effects. By acting as a muscarinic antagonist, it can be used as an adjunct symptomatic treatment for parkinsonism and to relieve discomfort or pain from muscle spasm. In parkinsonism, there is reduced CNS dopamine - this dopamine deficiency in the striatum increases the stimulating effects of the cholinergic system, which often presents as hyperkinesia, tremor, and muscle rigidity. This excess stimulation is counteracted by the anticholinergic effect of orphenadrine. It may have a relaxing effect on skeletal muscle spasms and it has a mood elevating effect, though exact mechanisms for these effects are currently unclear (i.e. it is known to be due to a combination of neurotransmitter modulation, but the exact molecular signalling is not yet elucidated). It is metabolized in the liver.
References
Orphenadrine Drug Action References
Simons FE, Simons KJ: Histamine and H1-antihistamines: celebrating a century of progress. J Allergy Clin Immunol. 2011 Dec;128(6):1139-1150.e4. doi: 10.1016/j.jaci.2011.09.005. Epub 2011 Oct 27.
Pubmed: 22035879
Simons FE: H1-receptor antagonists. Comparative tolerability and safety. Drug Saf. 1994 May;10(5):350-80.
Pubmed: 7913608
Mignery GA, Sudhof TC: The ligand binding site and transduction mechanism in the inositol-1,4,5-triphosphate receptor. EMBO J. 1990 Dec;9(12):3893-8.
Pubmed: 2174351
Katzenschlager R, Sampaio C, Costa J, Lees A: Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst Rev. 2003;(2):CD003735. doi: 10.1002/14651858.CD003735.
Pubmed: 12804486
Scholz EP, Konrad FM, Weiss DL, Zitron E, Kiesecker C, Bloehs R, Kulzer M, Thomas D, Kathofer S, Bauer A, Maurer MH, Seemann G, Katus HA, Karle CA: Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656. Naunyn Schmiedebergs Arch Pharmacol. 2007 Dec;376(4):275-84. doi: 10.1007/s00210-007-0202-6. Epub 2007 Oct 27.
Pubmed: 17965852
Syvalahti EK, Kunelius R, Lauren L: Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung. Pharmacol Toxicol. 1988 Feb;62(2):90-4. doi: 10.1111/j.1600-0773.1988.tb01852.x.
Pubmed: 3353357
Rumore MM, Schlichting DA: Analgesic effects of antihistaminics. Life Sci. 1985 Feb 4;36(5):403-16. doi: 10.1016/0024-3205(85)90252-8.
Pubmed: 2578597
Pubill D, Canudas AM, Pallas M, Sureda FX, Escubedo E, Camins A, Camarasa J: Assessment of the adrenergic effects of orphenadrine in rat vas deferens. J Pharm Pharmacol. 1999 Mar;51(3):307-12. doi: 10.1211/0022357991772303.
Pubmed: 10344632
Desaphy JF, Dipalma A, De Bellis M, Costanza T, Gaudioso C, Delmas P, George AL Jr, Camerino DC: Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine. Pain. 2009 Apr;142(3):225-235. doi: 10.1016/j.pain.2009.01.010. Epub 2009 Feb 12.
Pubmed: 19217209
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