Mefenamic acid is a member of the anthranilic acid derivatives (or fenamate) class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is used to treat mild to moderate pain. Its name derives from its systematic name, dimethylphenylaminobenzoic acid. It was discovered and brought to market by Parke-Davis as Ponstel in the 1960s. It became generic in the 1980s and is available worldwide under many brand names such as ''Meftal''.

Medical uses

Mefenamic acid is used to treat pain and inflammation in

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 ...

and

osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...

, postoperative pain, acute pain including muscle and

back pain Back pain is pain felt in the back. It may be classified as neck pain (cervical), middle back pain (thoracic), lower back pain (lumbar) or coccydynia (tailbone or sacral pain) based on the segment affected. The lumbar area is the most common ...

toothache Toothache, also known as dental pain,Segen JC. (2002). ''McGraw-Hill Concise Dictionary of Modern Medicine''. The McGraw-Hill Companies. is pain in the teeth or their supporting structures, caused by dental diseases or pain referred to the t ...

and menstrual pain, as well as being prescribed for menorrhagia. There is evidence that supports the use of mefenamic acid for perimenstrual migraine headache prophylaxis, with treatment starting two days prior to the onset of flow or one day prior to the expected onset of the headache and continuing for the duration of menstruation. Mefenamic acid is recommended to be taken with food.

Contraindications

Mefenamic acid is contraindicated in people who have shown

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

reactions such as

urticaria Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-last ...

and

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

to this drug or to other NSAIDs (e.g.

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 inc ...

); those with

peptic ulcer Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines ...

s or chronic inflammation of the gastrointestinal tract; those with

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Signs and symptoms Some of the si ...

; heart failure; after coronary artery bypass surgery; and during the third trimester of pregnancy.

Side effects

Known mild

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

of mefenamic acid include headaches, nervousness, and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

. Potentially serious side effects may include

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

gastrointestinal perforation Gastrointestinal perforation, also known as ruptured bowel, is a hole in the wall of part of the gastrointestinal tract. The gastrointestinal tract includes the esophagus, stomach, small intestine, and large intestine. Symptoms include severe abd ...

, peptic ulcers,

hematemesis Hematemesis is the vomiting of blood. It is always an important sign. It can be confused with hemoptysis (coughing up blood) or epistaxis (nosebleed), which are more common. The source is generally the upper gastrointestinal tract, typically abo ...

(vomiting blood), skin reactions (rashes, itching, swelling; in rare cases

toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later ...

) and rarely blood cell disorders such as agranulocytosis. It has been associated with acute liver damage. In 2008 the US label was updated with a warning concerning a risk of premature closure of the

ductus arteriosus The ''ductus arteriosus'', also called the ''ductus Botalli'', named after the Italian physiologist Leonardo Botallo, is a blood vessel in the developing fetus connecting the trunk of the pulmonary artery to the proximal descending aorta. It a ...

in pregnancy. In October 2020, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.

Overdose

Symptoms of overdosing include

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

problems, bleeding, rashes, confusion,

hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...

vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

s, and loss of consciousness. It is treated with induction of vomiting, gastric lavage,

bone char Bone char ( lat, carbo animalis) is a porous, black, granular material produced by charring animal bones. Its composition varies depending on how it is made; however, it consists mainly of tricalcium phosphate (or hydroxyapatite) 57–80%, calci ...

, and control of

electrolytes An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon di ...

and vital functions.

Interactions

Interactions are broadly similar to those of other NSAIDs. Mefenamic acid interferes with the anti–blood clotting mechanism of Aspirin. It increases the blood thinning effects of

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

and phenprocoumon because it displaces them from their plasma protein binding and increases their free concentrations in the bloodstream. It adds to the risk of gastrointestinal ulcera associated with corticosteroids and

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellul ...

s. It can increase the risk for adverse effects of methotrexate and

lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid ...

by lowering their excretion via the kidneys. It can increase the kidney toxicity of

ciclosporin Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...

and

tacrolimus Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogeneic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also ...

. Combination with

antihypertensive drug Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests th ...

s such as ACE inhibitors,

sartan Angiotensin II receptor blockers (ARBs), formally angiotensin II receptor type 1 (AT1) antagonists, also known as angiotensin receptor blockers, angiotensin II receptor antagonists, or AT1 receptor antagonists, are a group of pharmaceuticals tha ...

s and

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...

s can decrease their effectiveness as well as increase the risk for kidney toxicity.

Pharmacology

Mechanism of action

Like other members of the anthranilic acid derivatives (or fenamate) class of

NSAID Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...

s, it inhibits both isoforms of the enzyme

cyclooxygenase Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme (specifically, a family of isozymes, ) that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as pr ...

(

COX-1 Cyclooxygenase 1 (COX-1), also known as prostaglandin G/H synthase 1, prostaglandin-endoperoxide synthase 1 or prostaglandin H2 synthase 1, is an enzyme that in humans is encoded by the ''PTGS1'' gene. In humans it is one of two cyclooxygenases. ...

and

COX-2 Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) (The HUGO official symbol is PTGS2; HGNC ID, HGNC:9605), also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the ''PTGS2'' gene ...

). This prevents formation of prostaglandins, which play a role in pain sensitivity, inflammation and fever, but also in

hemostasis In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. This involves coagulation, ...

, kidney function, sustaining of pregnancy, and protection of the

gastric mucosa The gastric mucosa is the mucous membrane layer of the stomach, which contains the glands and the gastric pits. In humans, it is about 1 mm thick, and its surface is smooth, soft, and velvety. It consists of simple columnar epithelium, lamina ...

Pharmacokinetics

Mefenamic acid is rapidly absorbed from the gut and reaches highest concentrations in the

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

after one to four hours. When in the bloodstream, over 90% of the substance are bound to plasma proteins. It probably crosses the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

, and is found in the breast milk in small amounts. It is metabolized by the liver enzyme

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the prote ...

to the only weakly active 3'-hydroxymethylmefenamic acid. 3'-carboxymefenamic acid has also been identified as a metabolite, as well as carboxy

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

s of all three substances. Mefenamic acid and its metabolites are excreted via the urine (52–67%) and the faeces (20–25%, or less than 20% following another source). The parent substance has a

biological half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of two hours; the half-life of its metabolites may be longer.

History

Scientists led by Claude Winder from Parke-Davis invented mefenamic acid in 1961, along with fellow members of the class of anthranilic acid derivatives,

flufenamic acid Flufenamic acid (FFA) is a member of the anthranilic acid derivatives (or fenamate) class of nonsteroidal anti-inflammatory drugs (NSAIDs). Like other members of the class, it is a cyclooxygenase (COX) inhibitor, preventing the formation of pr ...

in 1963 and meclofenamate sodium in 1964. U.S. Patent 3,138,636 on the drug was issued in 1964. It was approved in the UK in 1963 as ''Ponstan'', in West Germany in 1964 as ''Ponalar'' and in France as ''Ponstyl'', and the US in 1967 as ''Ponstel''.

Chemistry

Synthesis

Analogous to fenamic acid, this compound may be made from

2-chlorobenzoic acid 2-Chlorobenzoic acid is an organic compound with the formula ClC6H4CO2H. It is one of three isomeric chlorobenzoic acids, the one that is the strongest acid. This white solid is used as a precursor to a variety of drugs, food additives, and dye ...

and 2,3-dimethylaniline.

Society and culture

Availability and pricing

Mefenamic acid is generic and is available worldwide under many brand names. In the US, wholesale price of a week's supply of generic mefenamic acid has been quoted as $426.90 in 2014. Brand-name Ponstel is $571.70. In contrast, in the UK, a weeks supply is £1.66, or £8.17 for branded Ponstan.

Research

While studies have been conducted to see if mefenamic acid can improve behavior in transgenic mouse models of Alzheimer's disease there is little evidence that mefenamic acid or other NSAIDs can treat or prevent Alzheimer's in humans; clinical trials of NSAIDs other than mefenamic acid for treatment of Alzheimer's have found more harm than benefit.A small controlled study of 28 human subjects showed improved cognitive impairment using mefenamic acid non-steroidal anti-inflammatory therapy.

References

Futher reading

* * * {{Ion channel modulators Nonsteroidal anti-inflammatory drugs Anthranilic acids GABAA receptor positive allosteric modulators