Orphenadrine (sold under many brand names) is an

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous syste ...

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalati ...

of the

ethanolamine Ethanolamine (2-aminoethanol, monoethanolamine, ETA, or MEA) is an organic chemical compound with the formula or . The molecule is bifunctional, containing both a primary amine and a primary alcohol. Ethanolamine is a colorless, viscous liquid ...

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provide ...

class; it is closely related to

diphenhydramine Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected int ...

. It is a

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therap ...

that is used to treat muscle pain and to help with motor control in

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms bec ...

, but has largely been superseded by newer drugs. This substance is considered a dirty drug due to its multiple mechanism of action in different pathways. It was discovered and developed in the 1940s.

Medical use

Orphenadrine is a

skeletal muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

. It is used to relieve pain caused by muscle injuries such as strains and

sprains A sprain, also known as a torn ligament, is an acute soft tissue injury of the ligaments within a joint, often caused by a sudden movement abruptly forcing the joint to exceed its functional range of motion. Ligaments are tough, inelastic fibers ...

, in combination with rest and physical therapy. A 2004 review found fair evidence that orphenadrine is effective for acute back or neck pain, but found insufficient evidence to establish the relative efficacy of the drug in relation to other drugs in the study. Orphenadrine and other muscle relaxants are sometimes used to treat pain arising from

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

but there is no evidence they are effective for that purpose. A 2003

Cochrane Review Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health profess ...

of the use of

drugs to improve motor function in

found that as a class, the drugs are useful for that purpose; it identified one single-site randomised, cross-over study of orphenadrine vs placebo. Although orphenadrine and other anticholinergics have largely been superseded by other drugs; they have a use in alleviating motor function symptoms, and appear to help about 20% of people with Parkinson's.

Side effects

Orphenadrine has the side effects of the other common antihistamines in large part. Stimulation is somewhat more common than with other related antihistamines, and is especially common in the elderly. Common side effects include dry mouth, dizziness, drowsiness, constipation, urine retention, blurred vision, and headache. Its use in Parkinson's is especially limited by these factors. People with

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

, digestive problems such as peptic ulcers or

bowel obstruction Bowel obstruction, also known as intestinal obstruction, is a mechanical or functional obstruction of the intestines which prevents the normal movement of the products of digestion. Either the small bowel or large bowel may be affected. Signs a ...

, or sphincter relaxation disorders, or with enlarged prostate, bladder problems, or

myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, dro ...

, should not take this drug.Orphenadrine Citrate Extended release label
Revised October 1998 Continuous and/or cumulative use of

medications, including first-generation antihistamines, is associated with higher risk of cognitive decline and dementia in older people.

Pharmacology

Orphenadrine is known to have this pharmacology: * Nonselective mACh receptor

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

(

, 58% as potent as atropine) Various monographs and package inserts, nursing manuals, journal articles and so forth have proposed the theory that this anticholinergic (atropine-like) activity, NMDA antagonism and possible local anaesthetic and miscellaneous analgesic effects may be the reason for orphenadrine's efficacy against muscle and other pain. These reasons are behind the use of orphenadrine and other drugs of a number of types which are used with paracetamol, aspirin, naproxen, and similar agents with or without opioid analgesics to more effectively manage pain of various types. * H₁ receptor

(

) *

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

(K_i value of 6.0 ± 0.7 μM, one hundred times less potent than

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptio ...

, which binds with a K_i of 59 nM) * NDRI ( norepinephrine and dopamine reuptake inhibitor) * Na_v1.7, Na_v1.8, and Na_v1.9 sodium channel blocker *

HERG hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...

potassium channel blocker Potassium channel blockers are agents which interfere with conduction through potassium channels. Medical uses Arrhythmia Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic age ...

History

George Rieveschl was a professor of chemistry at the

University of Cincinnati The University of Cincinnati (UC or Cincinnati) is a public research university in Cincinnati, Ohio. Founded in 1819 as Cincinnati College, it is the oldest institution of higher education in Cincinnati and has an annual enrollment of over 44, ...

and led a research program working on

antihistamines Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provid ...

. In 1943, one of his students, Fred Huber, synthesized

. Rieveschl worked with

Parke-Davis Parke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although Parke, Davis & Co. is no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history. In 1970 ...

to test the compound, and the company licensed the patent from him. In 1947 Parke-Davis hired him as their Director of Research. While he was there, he led the development of orphenadrine, an analog of diphenhydramine. Prior to the development of

amantadine Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wi ...

in the late 1960s and then other drugs, anticholinergics like orphenadrine were the mainstay of Parkinson's treatment.

Formulation

Orphenadrine has been available as a citrate salt and a hydrochloride salt; in the US as of February 2016 the citrate form was available in tablets, extended release tablets, compounding powder and by injection for acute use in a hospital setting. Orphenadrine is often available mixed with

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat in ...

, paracetamol/acetaminophen,

ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...

, and/or

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically us ...

. The brand names Norflex and Norgesic are formulations of the citrate salt of orphenadrine and Disipal is the hydrochloride salt.

Chemistry

Orphenadrine is a

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

with a

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ma ...

added to one of the phenyl rings.

Stereochemistry

Orphenadrine has a chiral center and two enantiomers. When employed as a therapeutic agent, it is typically supplied as the racemate.

References

External links

* {{Navboxes , title =

Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

, titlestyle = background:#ccccff , list1 = {{Histamine receptor modulators {{Ion channel modulators {{Ionotropic glutamate receptor modulators {{Monoamine reuptake inhibitors {{Muscarinic acetylcholine receptor modulators CYP2D6 inhibitors CYP3A4 inhibitors Diphenhydramines H1 receptor antagonists Muscarinic antagonists Muscle relaxants Norepinephrine reuptake inhibitors NMDA receptor antagonists Sodium channel blockers Potassium channel blockers 2-Tolyl compounds