Orphenadrine (sold under many

brand names A brand is a name, term, design, symbol or any other feature that distinguishes one seller's goods or service from those of other sellers. Brands are used in business, marketing, and advertising for recognition and, importantly, to create and ...

) is an

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

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

of the

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

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 provides ...

class; it is closely related to

diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...

. 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 therapeu ...

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 neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

, but has largely been superseded by newer drugs. It is considered a

dirty drug In pharmacology, a dirty drug is an informal term for drugs that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly adverse drug reactions. Today, pharmaceutical companie ...

due to its multiple mechanisms of action in different pathways. It was discovered and developed in the 1940s.

Medical use

Orphenadrine is a skeletal muscle relaxant. It is used to relieve pain caused by muscle injuries such as strains and

sprains A sprain is a 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 made of collagen that connect two or m ...

, 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 synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

but there is no evidence they are effective for that purpose. In 2003, a

Cochrane Review Cochrane is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...

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. Orphenadrine is contraindicated in patients with

glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...

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, ...

, sphincter relaxation disorders, digestive problems such as

peptic ulcers Peptic ulcer disease is when the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus, gets damaged. An ulcer in the stomach is called a gastric ulcer, while ...

bowel obstruction Bowel obstruction, also known as intestinal obstruction, is a mechanical or Ileus, functional obstruction of the Gastrointestinal tract#Lower gastrointestinal tract, intestines which prevents the normal movement of the products of digestion. Ei ...

, or with

enlarged prostate Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or lo ...

bladder disorder Urinary bladder disease includes urinary bladder inflammation such as cystitis, bladder rupture and bladder obstruction (tamponade). Cystitis is common, sometimes referred to as urinary tract infection (UTI) caused by bacteria, bladder rupture occu ...

s; that is, they should not consume this drug. 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 these pharmacological properties: * Nonselective mACh receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the acetylcholine (ACh) neurotransmitter at synapses in the central nervous system, central and peripheral nervous system. These agents inhibit the parasympatheti ...

, 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

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.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 provides ...

) *

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

(K_i value of , one hundred times less potent than

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

, 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 Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels. Extracellular The following naturally-produced substances block sodium channels by binding to and occluding the extracellular pore opening ...

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 t ...

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 George Rieveschl (January 9, 1916 – September 27, 2007) was an American chemist and professor. He was the inventor of the popular antihistamine diphenhydramine (Benadryl), which he first made while searching for potential muscle relaxant drugs ...

was a professor of chemistry at the

University of Cincinnati The University of Cincinnati (UC or Cincinnati, informally Cincy) is a public university, public research university in Cincinnati, Ohio, United States. It was founded in 1819 and had an enrollment of over 53,000 students in 2024, making it the ...

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 provides r ...

. 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 because ...

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 () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

, paracetamol/acetaminophen,

ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes dysmenorrhea, painful menstrual periods, migraines, and rheumatoid arthritis. It can be taken oral administration, ...

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...

, 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 use ...

. 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 is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

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 (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

added to one of the

phenyl ring In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula , and is often represented by the symbol Ph (archaically φ) or Ø. The phenyl group is closely related to benzene and can be viewed as a benzene ...

Stereochemistry

Orphenadrine has a

chiral center In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...

and two

enantiomers In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

. When employed as a therapeutic agent, it is typically supplied as the

racemate In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

References

External links

* {{Navboxes , title =

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

, titlestyle = background:#ccccff , list1 = {{Histamine receptor modulators {{Ion channel modulators {{Ionotropic glutamate receptor modulators {{Monoamine reuptake inhibitors {{Muscarinic acetylcholine receptor modulators 2-Tolyl compounds CYP2D6 inhibitors CYP3A4 inhibitors Diphenhydramines H1 receptor antagonists HERG blocker M1 receptor antagonists M2 receptor antagonists M3 receptor antagonists M4 receptor antagonists M5 receptor antagonists Muscle relaxants Norepinephrine reuptake inhibitors NMDA receptor antagonists Potassium channel blockers Sodium channel blockers Dimethylamino compounds