Ibuprofen
Overview
Ibuprofen (icon or aɪ ; from the nomenclature iso-butyl-propanoic-phenolic acid) is a nonsteroidal anti-inflammatory drug (NSAID) used for relief of symptoms of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

,
as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 (pain reliever), especially where there is an inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 component, and dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...

.

Ibuprofen is known to have an antiplatelet effect, though it is relatively mild and somewhat short-lived when compared with aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 or other better-known antiplatelet drugs.
Encyclopedia
Ibuprofen (icon or aɪ ; from the nomenclature iso-butyl-propanoic-phenolic acid) is a nonsteroidal anti-inflammatory drug (NSAID) used for relief of symptoms of arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

,
as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 (pain reliever), especially where there is an inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 component, and dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...

.

Ibuprofen is known to have an antiplatelet effect, though it is relatively mild and somewhat short-lived when compared with aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 or other better-known antiplatelet drugs. In general, ibuprofen also acts as a vasodilator, having been shown to dilate coronary arteries and some other blood vessels. Ibuprofen is a core medicine in the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

's "WHO Model List of Essential Medicines", which is a list of minimum medical needs for a basic healthcare system.

Originally marketed as Brufen, ibuprofen is available under a variety of popular trademark
Trademark
A trademark, trade mark, or trade-mark is a distinctive sign or indicator used by an individual, business organization, or other legal entity to identify that the products or services to consumers with which the trademark appears originate from a unique source, and to distinguish its products or...

s, including Motrin, Nurofen
Nurofen
Nurofen is the brand name of a range of pain-relief medication made by Reckitt Benckiser. Introduced in 1983, the Nurofen brand was acquired following Reckitt Benckiser's acquisition of Boots Healthcare in 2005...

, Advil
Advil
Advil is a brand of ibuprofen, a nonsteroidal anti-inflammatory drug . Advil is manufactured by Pfizer and has been on the market since 1984.-History:...

, and Nuprin.

Medical uses

Ibuprofen is used primarily for fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

, dysmenorrhea
Dysmenorrhea
Dysmenorrhea is a gynecological medical condition of pain during menstruation that interferes with daily activities, as defined by ACOG and others. Still, dysmenorrhea is often defined simply as menstrual pain, or at least menstrual pain that is excessive...

 and inflammatory diseases such as rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

. It is also used for pericarditis
Pericarditis
Pericarditis is an inflammation of the pericardium . A characteristic chest pain is often present.The causes of pericarditis are varied, including viral infections of the pericardium, idiopathic causes, uremic pericarditis, bacterial infections of the precardium Pericarditis is an inflammation of...

 and patent ductus arteriosus
Patent ductus arteriosus
Patent ductus arteriosus is a congenital disorder in the heart wherein a neonate's ductus arteriosus fails to close after birth. Early symptoms are uncommon, but in the first year of life include increased work of breathing and poor weight gain...

.

Dosage

Ibuprofen has a dose-dependent duration of action of approximately four to eight hours, which is longer than suggested by its short half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...

. The recommended dose varies with body mass and indication. 1,200 mg is considered the maximum daily dose for OTC (Over The Counter) use, though, under medical direction
Medical direction
Medical Direction, or Online Medical Direction, allows a Paramedic or Emergency Medical Technician to contact a physician from the field via radio or other means to obtain instructions on further care of a patient...

, the maximum amount of ibuprofen for adults is 800 milligrams per dose or 3200 mg per day.

Unlike aspirin, which breaks down in solution, ibuprofen is stable, and, thus, ibuprofen can be available in topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...

 gel form, which is absorbed through the skin, and can be used for sports injuries, with less risk of digestive problems.

Ibuprofen lysine

In Europe, Australia, and New Zealand, ibuprofen lysine (the lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....

 salt of ibuprofen, sometimes called "ibuprofen lysinate" even though the lysine is in cationic form) is licensed for treatment of the same conditions as ibuprofen. The lysine salt increases water solubility, allowing the medication to be administered intravenously. Ibuprofen lysine is indicated for closure of a patent ductus arteriosus
Patent ductus arteriosus
Patent ductus arteriosus is a congenital disorder in the heart wherein a neonate's ductus arteriosus fails to close after birth. Early symptoms are uncommon, but in the first year of life include increased work of breathing and poor weight gain...

 in premature infants weighing between 500 and 1500 g (1.1 and 3.3 lb), who are no more than 32 weeks gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support, etc.) is ineffective.

With regard to this indication, ibuprofen lysine is an effective alternative to intravenous indomethacin, and may be advantageous in terms of kidney function.
Ibuprofen lysine has been shown to have a more rapid onset of action compared to acid ibuprofen.

Adverse effects

Common adverse effects include: nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...

, gastrointestinal ulceration/bleeding, raised liver enzymes
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...

, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...

, epistaxis, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

, priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...

, rash, salt and fluid retention, and hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

.
A study from 2010 has shown regular use of NSAIDs was associated with an increase in hearing loss.

Infrequent adverse effects include: esophageal ulceration, heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

, hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

, renal impairment
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

, confusion, and bronchospasm
Bronchospasm
Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...

.

Ibuprofen appears to have the lowest incidence of digestive adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s (ADRs) of all the nonselective NSAIDs. However, this holds true only at lower doses of ibuprofen, so OTC preparations of ibuprofen are, in general, labeled to advise a maximum daily dose of 1,200 mg.

Photosensitivity

As with other NSAIDs, ibuprofen has been reported to be a photosensitising
Photosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...

 agent.

However, this only rarely occurs with ibuprofen and it is considered to be a very weak photosensitising agent when compared with other members of the 2-arylpropionic acid class. This is because the ibuprofen molecule contains only a single phenyl moiety and no bond conjugation
Conjugated system
In chemistry, a conjugated system is a system of connected p-orbitals with delocalized electrons in compounds with alternating single and multiple bonds, which in general may lower the overall energy of the molecule and increase stability. Lone pairs, radicals or carbenium ions may be part of the...

, resulting in a very weak chromophore
Chromophore
A chromophore is the part of a molecule responsible for its color. The color arises when a molecule absorbs certain wavelengths of visible light and transmits or reflects others. The chromophore is a region in the molecule where the energy difference between two different molecular orbitals falls...

 system and a very weak absorption spectrum, which does not reach into the solar spectrum.

Cardiovascular risk

Along with several other NSAIDs, ibuprofen has been implicated in elevating the risk of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

 (heart attack), in particular, among those chronically using high doses.

Skin

Along with other NSAIDs, ibuprofen has been associated with the onset of bullous pemphigoid
Bullous pemphigoid
Bullous pemphigoid, also referred to as BP, is an acute or chronic autoimmune skin disease, involving the formation of blisters, more appropriately known as bullae, at the space between the skin layers epidermis and dermis.-Signs and symptoms:...

 or pemphigoid-like blistering.

Interactions

Drinking alcohol when taking ibuprofen increases risk of stomach bleeding.

According to the U.S. Food and Drug Administration, "ibuprofen can interfere with the antiplatelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

 effect of low-dose aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 (81 mg per day), potentially rendering aspirin less effective when used for cardioprotection and stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...

 prevention." Allowing sufficient time between doses of ibuprofen and immediate release aspirin can avoid this problem. The recommended elapsed time between a 400 mg dose of ibuprofen and a dose of aspirin depends on which is taken first. It would be 30 minutes or more for ibuprofen taken after immediate release aspirin, and 8 hours or more for ibuprofen taken before immediate release aspirin. However, this timing cannot be recommended for enteric-coated
Enteric coating
An enteric coating is a barrier applied to oral medication that controls the location in the digestive system, where it is absorbed. Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.Most enteric coatings work by...

 aspirin. But, if ibuprofen is taken only occasionally without the recommended timing, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal.

Erectile dysfunction risk

A 2005 study linked long term (over 3 months) use of NSAIDs, including ibuprofen, with a 1.4 times increased risk of erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....

.
The report by Kaiser Permanente and published in the Journal of Urology, considered that "regular non-steroidal anti-inflammatory drug use is associated with erectile dysfunction beyond what would be expected due to age and other condition".
The director of research for Kaiser Permanente added that "There are many proven benefits of non steroidals in preventing heart disease and for other conditions. People shouldn't stop taking them based on this observational study. However, if a man is taking this class of drugs and has ED, it's worth a discussion with his doctor".

Overdose

Ibuprofen overdose has become common since it was licensed for OTC use. There are many overdose experiences reported in the medical literature
Medical journal
A public health journal is a scientific journal devoted to the field of public health, including epidemiology, biostatistics, and health care . Public health journals, like most scientific journals, are peer-reviewed...

, although the frequency of life-threatening complications from ibuprofen overdose is low.
Human response in cases of overdose ranges from absence of symptoms to fatal outcome in spite of intensive care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen and include abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...

, nausea, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

, drowsiness, dizziness, headache, tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...

, and nystagmus. Rarely, more severe symptoms, such as gastrointestinal bleeding
Gastrointestinal bleeding
Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...

, seizures, metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...

, hyperkalaemia, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...

, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

, atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...

, coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

, hepatic dysfunction, acute renal failure
Acute renal failure
Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...

, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...

, respiratory depression
Hypoventilation
In medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...

, and cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...

 have been reported.
The severity of symptoms varies with the ingested dose and the time elapsed; however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs.

There is little correlation between severity of symptoms and measured ibuprofen plasma levels. Toxic effects are unlikely at doses below 100 mg/kg, but can be severe above 400 mg/kg (around 150 tablets of 200 mg units for an average man); however, large doses do not indicate the clinical course is likely to be lethal.
It is not possible to determine a precise lethal dose
Lethal dose
A lethal dose is an indication of the lethality of a given substance or type of radiation. Because resistance varies from one individual to another, the 'lethal dose' represents a dose at which a given percentage of subjects will die...

, as this may vary with age, weight, and concomitant diseases of the individual patient.

Therapy is largely symptomatic. In cases presenting early, gastric decontamination is recommended. This is achieved using activated charcoal; charcoal adsorbs the drug before it can enter the systemic circulation
Systemic circulation
Systemic circulation is the part of the cardiovascular system which carries oxygenated blood away from the heart to the body, and returns deoxygenated blood back to the heart. This physiologic theory of circulation was first described by William Harvey...

. Gastric lavage
Gastric lavage
Gastric lavage, also commonly called stomach pumping or Gastric irrigation, is the process of cleaning out the contents of the stomach. It has been used for over 200 years as a means of eliminating poisons from the stomach. Such devices are normally used on a person who has ingested a poison or...

 is now rarely used, but can be considered if the amount ingested is potentially life-threatening, and it can be performed within 60 minutes of ingestion. Emesis
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...

 is not recommended. The majority of ibuprofen ingestions produce only mild effects and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and renal function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...

 monitored. Since ibuprofen has acidic properties and is also excreted in the urine, forced alkaline diuresis
Forced diuresis
Forced diuresis may enhance the excretion of certain drugs in urine and is used to treat drug overdose or poisoning of these drugs and hemorrhagic cystitis.-Diuretics:...

 is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, there is minimal renal excretion of unchanged drug. Forced alkaline diuresis is, therefore, of limited benefit.
Symptomatic therapy for hypotension, GI bleeding, acidosis, and renal toxicity may be indicated. On occasion, close monitoring in an intensive care unit for several days is necessary. If a patient survives the acute intoxication, he or she will usually experience no late sequelae.

Detection in body fluids

Ibuprofen may be quantitated in blood, plasma, or serum to demonstrate the presence of the drug in a person having experienced an anaphylactic reaction, confirm a diagnosis of poisoning in hospitalized patients, or assist in a medicolegal death investigation. A nomogram that relates the ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in overdose patients has been published.

Miscarriage

A Canadian study published in the Canadian Medical Association Journal of thousands of pregnant woman suggests that those taking any type or amount of non-steroidal anti-inflammatory drugs (including ibuprofen, diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....

 and naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

) were 2.4 times more likely to miscarry
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...

 than those not taking the drugs.

Mechanism of action

Nonsteroidal anti-inflammatory drugs such as ibuprofen work by inhibiting
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 cyclooxygenase
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...

 (COX), which converts arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...

 to prostaglandin H2
Prostaglandin H2
Prostaglandin H2 is a type of Prostaglandin which is derived from arachidonic acid and is a precursor for many other biologically significant molecules.It is acted upon by:* prostacyclin synthase to create prostacyclin...

 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

s (which are mediators of pain, inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

, and fever) and to thromboxane A2
Thromboxane A2
Thromboxane A2 is a thromboxane. It is produced by activated platelets and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of...

 (which stimulates platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

 aggregation, leading to the formation of blood clots
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...

).

Like aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

, indomethacin, and most other NSAIDs, ibuprofen is considered a nonselective COX inhibitor; that is, it inhibits two isoforms
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...

 of cyclooxygenase, COX-1 and COX-2. The analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

, antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

, and anti-inflammatory activity of NSAIDs appears to be achieved mainly through inhibition of COX-2, whereas inhibition of COX-1 would be responsible for unwanted effects on platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

 aggregation and the gastrointestinal tract.
However, the role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain and different compounds cause different degrees of analgesia and gastric damage.

In order to achieve the beneficial effects of ibuprofen and other NSAIDS without gastrointestinal ulceration and bleeding, selective COX-2 inhibitor
COX-2 inhibitor
COX-2 selective inhibitor is a form of non-steroidal anti-inflammatory drug that directly targets COX-2, an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this...

s were developed to inhibit the COX-2 isoform without inhibition of COX-1.

Chemistry

Ibuprofen is only very slightly soluble in water. Less than 1 mg of ibuprofen dissolves in 1 ml water (< 1 mg/mL). However, it is much more soluble in alcohol/water mixtures as well as carbonated water

Stereochemistry

Ibuprofen is produced industrially as a racemate. The compound, like other 2-arylpropionate derivatives (including ketoprofen
Ketoprofen
Ketoprofen, 2--propionic acid is one of the propionic acid class of non-steroidal anti-inflammatory drug with analgesic and antipyretic effects...

, flurbiprofen
Flurbiprofen
Flurbiprofen is a member of the phenylalkanoic acid derivative family of non-steroidal anti-inflammatory drugs used to treat the inflammation and pain of arthritis...

, naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

, etc.), does contain a stereocenter in the α-position of the propionate
Propionate
The propanoate or propionate ion is C2H5COO− .A propanoic or propionic compound is a salt or ester of propanoic acid....

 moiety. As such, there are two possible enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...

s of ibuprofen, with the potential for different biological effects and metabolism for each enantiomer.

Indeed, the (S)-(+)-ibuprofen (dexibuprofen
Dexibuprofen
Dexibuprofen is a non-steroidal anti-inflammatory drug. It is the active dextrorotatory enantiomer of ibuprofen. Most ibuprofen formulations contain a racemic mixture of dexibuprofen [-iboprofen] and -ibuprofen....

) was found to be the active form both in vitro and in vivo.

It was logical, then, that there was the potential for improving the selectivity and potency of ibuprofen formulations by marketing ibuprofen as a single-enantiomer product (as occurs with naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...

, another NSAID).

Further in vivo testing, however, revealed the existence of an isomerase
Isomerase
In biochemistry, an isomerase is an enzyme that catalyzes the structural rearrangement of isomers. Isomerases thus catalyze reactions of the formwhere B is an isomer of A.-Nomenclature:...

 (alpha-methylacyl-CoA racemase
Alpha-methylacyl-CoA racemase
In enzymology, an alpha-methylacyl-CoA racemase is an enzyme that catalyzes the chemical reaction-2-methylacyl-CoA \rightleftharpoons -2-methylacyl-CoAHence, this enzyme has one substrate, -2-methylacyl-CoA, and one product, -2-methylacyl-CoA....

), which converted (R)-ibuprofen to the active (S)-enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...

.

(R)-ibuprofen
(S)-ibuprofen


Synthesis

The synthesis of this compound is a popular case study in green chemistry
Green chemistry
Green chemistry, also called sustainable chemistry, is a philosophy of chemical research and engineering that encourages the design of products and processes that minimize the use and generation of hazardous substances...

. The original Boots synthesis of ibuprofen consisted of six steps, started with the Friedel-Crafts acetylation of isobutylbenzene. Reaction with ethyl chloroacetate (Darzens reaction
Darzens reaction
The Darzens reaction is the chemical reaction of a ketone or aldehyde with an α-haloester to form an α,β-epoxy ester, also called a "glycidic ester"...

) gave the α,β-epoxy ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...

, which was hydrolyzed and decarboxylated to the aldehyde. Reaction with hydroxylamine
Hydroxylamine
Hydroxylamine is an inorganic compound with the formula NH2OH. The pure material is a white, unstable crystalline, hygroscopic compound. However, hydroxylamine is almost always provided and used as an aqueous solution. It is used to prepare oximes, an important functional group. It is also an...

 gave the oxime
Oxime
An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organic side chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds...

, which was converted to the nitrile
Nitrile
A nitrile is any organic compound that has a -C≡N functional group. The prefix cyano- is used interchangeably with the term nitrile in industrial literature. Nitriles are found in many useful compounds, one example being super glue .Inorganic compounds containing the -C≡N group are not called...

, then hydrolyzed to the desired acid:


An improved synthesis by BHC required only three steps. This improved synthesis won the Presidential Green Chemistry Challenge Greener Synthetic Pathways Award in 1997.

After a similar acetylation, hydrogenation
Hydrogenation
Hydrogenation, to treat with hydrogen, also a form of chemical reduction, is a chemical reaction between molecular hydrogen and another compound or element, usually in the presence of a catalyst. The process is commonly employed to reduce or saturate organic compounds. Hydrogenation typically...

 with Raney nickel
Raney nickel
Raney nickel is a solid catalyst composed of fine grains of a nickel-aluminium alloy, used in many industrial processes. It was developed in 1926 by American]] engineer Murray Raney as an alternative catalyst for the hydrogenation of vegetable oils in industrial processes...

 gave the alcohol, which underwent palladium-catalyzed carbonylation
Carbonylation
Carbonylation refers to reactions that introduce carbon monoxide into organic and inorganic substrates. Carbon monoxide is abundantly available and conveniently reactive, so it is widely used as a reactant in industrial chemistry.-Organic chemistry:...

:

History

Ibuprofen was derived from propionic acid
Propionic acid
Propanoic acid is a naturally occurring carboxylic acid with chemical formula CH3CH2COOH. It is a clear liquid with a pungent odor...

 by the research
Research
Research can be defined as the scientific search for knowledge, or as any systematic investigation, to establish novel facts, solve new or existing problems, prove new ideas, or develop new theories, usually using a scientific method...

 arm of Boots Group during the 1960s. It was discovered by Andrew RM Dunlop, with colleagues Stewart Adams, John Nicholson, Vonleigh Simmons, Jeff Wilson and Colin Burrows, and was patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....

ed in 1961. The drug was launched as a treatment for rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...

 in the United Kingdom in 1969, and in the United States in 1974. Dr. Adams initially tested his drug on a hangover
Hangover
A hangover describes the sum of unpleasant physiological effects following heavy consumption of alcoholic beverages. The most commonly reported characteristics of a hangover include headache, nausea, sensitivity to light and noise, lethargy, dysphoria, diarrhea and thirst, typically after the...

. He was subsequently awarded an OBE
Order of the British Empire
The Most Excellent Order of the British Empire is an order of chivalry established on 4 June 1917 by George V of the United Kingdom. The Order comprises five classes in civil and military divisions...

 in 1987. Boots was awarded the Queen's Award For Technical Achievement
Queen's Awards for Enterprise
The Queen's Awards for Enterprise is an awards programme for British businesses and other organizations who excel at international trade, innovation or sustainable development. They are the highest official UK awards for British businesses...

 for the development of the drug in 1987.

Availability

Ibuprofen was made available under prescription in the United Kingdom in 1969, and in the United States in 1974. In the years since, the good tolerability profile, along with extensive experience in the population, as well as in so-called Phase IV trials
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

 (post-approval studies), has resulted in the availability of ibuprofen over the counter in pharmacies worldwide, as well as in supermarkets and other general retailers.

North America

Ibuprofen is commonly available in the United States up to the FDA's 200 mg 1984 dose limit OTC, higher by prescription.

In Canada, the OTC dose limit is 400 mg.

In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the trade name Caldolor.
Ibuprofen was the only parenteral
Parenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...

 for both pain and fever available in the country prior to the approval of Ofirmev (acetaminophen) injection by the FDA.

Research

Ibuprofen is sometimes used for the treatment of acne, because of its anti-inflammatory properties, and has been sold in Japan in topical form for adult acne.

As with other NSAIDs, ibuprofen may be useful in the treatment of severe orthostatic hypotension
Orthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...

 (low blood pressure when standing up).

In some studies, ibuprofen showed superior results compared to a placebo in the prophylaxis of Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

, when given in low doses over a long time. Further studies are needed to confirm the results before ibuprofen can be recommended for this indication.

Ibuprofen has been associated with a lower risk of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

, and may delay or prevent it. Aspirin, other NSAIDs, and paracetamol (acetaminophen)
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 had no effect on the risk for Parkinson's.
In March 2011, researchers at Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....

 announced in Neurology that ibuprofen had a neuroprotective
Neuroprotection
Neuroprotection within the nervous system protects neurons from apoptosis or degeneration, for example following a brain injury or as a result of chronic neurodegenerative diseases....

 effect against the risk of developing Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

.
People regularly consuming ibuprofen were reported to have a 38% lower risk of developing Parkinson's disease, but no such effect was found for other pain relievers, such as aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 and acetaminophen. Use of ibuprofen to lower the risk of Parkinson's disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems. Further research is warranted before recommending ibuprofen for this use.

External links

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