Mechanism of action of aspirin - AbsoluteAstronomy.com

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...

causes several different effects in the body, mainly the reduction of inflammation

Anti-inflammatory

Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

, analgesia (relief of pain), the prevention of clotting, and the reduction of fever

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...

. Much of this is believed to be due to decreased production of prostaglandins and thromboxanes. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the 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) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine

Serine

Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac

Diclofenac

Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....

and ibuprofen

Ibuprofen

Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

), which are reversible inhibitors. However, other effects of aspirin, such as uncoupling oxidative phosphorylation

Oxidative phosphorylation

Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...

in mitochondria, and the modulation of signaling through NF-κB, are also being investigated.

History of discovery

The mechanism of aspirin's analgesic, anti-inflammatory and antipyretic properties was unknown through the drug's heyday in the early- to mid-twentieth century; Heinrich Dreser

Heinrich Dreser

Heinrich Dreser was a German chemist, responsible for the aspirin and heroin projects at Bayer AG. He was a key factor in the creation of the widely used modern drug, Codeine. On December 21, 1924, Dreser died of a stroke....

's explanation, widely accepted since the drug was first brought to market, was that aspirin relieved pain by acting on the central nervous system

Central nervous system

The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

. In 1958 Harry Collier, a biochemist in the London laboratory of pharmaceutical company Parke Davis, began investigating the relationship between kinins

Kinin-kallikrein system

The kinin-kallikrein system or simply kinin system is a poorly understood system of blood proteins that plays a role in inflammation, blood pressure control, coagulation and pain...

and the effects of aspirin. In tests on guinea pig

Guinea pig

The guinea pig , also called the cavy, is a species of rodent belonging to the family Caviidae and the genus Cavia. Despite their common name, these animals are not in the pig family, nor are they from Guinea...

s, Collier found that aspirin, if given beforehand, inhibited the bronchoconstriction

Bronchoconstriction

Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus....

effects of bradykinin

Bradykinin

Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...

. He found that cutting the guinea pigs' vagus nerve

Vagus nerve

The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...

did not affect the action of bradykinin or the inhibitory effect of aspirin—evidence that aspirin worked locally to combat pain and inflammation, rather than on the central nervous system. In 1963, Collier began working with University of London

University of London

-20th century:Shortly after 6 Burlington Gardens was vacated, the University went through a period of rapid expansion. Bedford College, Royal Holloway and the London School of Economics all joined in 1900, Regent's Park College, which had affiliated in 1841 became an official divinity school of the...

pharmacology graduate student Priscilla Piper to determine the precise mechanism of aspirin's effects. However, it was difficult to pin down the precise biochemical goings-on in live research animals, and in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

tests on removed animal tissues did not behave like in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

tests.

After five years of collaboration, Collier arranged for Piper to work with pharmacologist John Vane at the Royal College of Surgeons of England

Royal College of Surgeons of England

The Royal College of Surgeons of England is an independent professional body and registered charity committed to promoting and advancing the highest standards of surgical care for patients, regulating surgery, including dentistry, in England and Wales...

, in order to learn Vane's new bioassay

Bioassay

Bioassay , or biological standardization is a type of scientific experiment. Bioassays are typically conducted to measure the effects of a substance on a living organism and are essential in the development of new drugs and in monitoring environmental pollutants...

methods, which seemed like a possible solution to the in vitro testing failures. Vane and Piper tested the biochemical cascade

Biochemical cascade

A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...

associated with anaphylactic shock (in extracts from guinea pig lungs, applied to tissue from rabbit

Rabbit

Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...

aorta

Aorta

The aorta is the largest artery in the body, originating from the left ventricle of the heart and extending down to the abdomen, where it branches off into two smaller arteries...

s). They found that aspirin inhibited the release of an unidentified chemical generated by guinea pig lungs, a chemical that caused rabbit tissue to contract. By 1971, Vane identified the chemical (which they called "rabbit-aorta contracting substance," or RCS) as a 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....

. In a June 23, 1971 paper in the journal Nature
Nature (journal)
Nature, first published on 4 November 1869, is ranked the world's most cited interdisciplinary scientific journal by the Science Edition of the 2010 Journal Citation Reports...

, Vane and Piper suggested that aspirin and similar drugs (the non-steroidal anti-inflammatory drug

Non-steroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics or nonsteroidal Anti-inflammatory medicines , are drugs with analgesic and antipyretic effects and which have, in higher doses, anti-inflammatory...

s or NSAIDs) worked by blocking the production of prostaglandins. For this discovery, Vane was awarded both a Nobel Prize

Nobel Prize

The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...

in Physiology or Medicine

Nobel Prize in Physiology or Medicine

The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

in 1982 and a knighthood. Later research showed that NSAIDs such as aspirin worked by inhibiting cyclooxygenase

Cyclooxygenase

, the enzyme responsible for converting 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,...

into a prostaglandin.

Effects on cyclooxygenase

There are at least two (and possibly three) different cyclooxygenase isozymes: COX-1 and COX-2. Aspirin is non-selective and irreversibly inhibits both forms. Normally COX produces prostaglandins, most of which are pro-inflammatory, and thromboxanes, which promote clotting. Aspirin-modified COX-2 produces lipoxins, most of which are anti-inflammatory. Newer NSAID drugs called COX-2 selective inhibitors have been developed that inhibit only COX-2, with the hope for reduction of gastrointestinal side-effects.

However, several of the new COX-2 selective inhibitors have been recently withdrawn (see Vioxx), after evidence emerged that COX-2 inhibitors increase the risk of heart attack. It is proposed that endothelial cells lining the microvasculature in the body express COX-2, and, by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems. Since platelets have no DNA, they are unable to synthesize new COX once aspirin has irreversibly inhibited the enzyme, an important difference with reversible inhibitors.

Effects on prostaglandins and thromboxanes

Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase

Cyclooxygenase

(COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine

Serine

residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac

Diclofenac

Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....

and ibuprofen

Ibuprofen

Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

), which are reversible inhibitors.

Low-dose, long-term aspirin use irreversibly blocks the formation of 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...

in 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...

s, producing an inhibitory effect on platelet aggregation

Platelet

. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks. 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A₂ release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.

Prostaglandins are local hormone

Hormone

A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...

s (paracrine) produced in the body and have diverse effects in the body, including but not limited to transmission of pain information to the brain, modulation of the hypothalamic

Hypothalamus

The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelet

Platelet

s that form blood clots. Heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The side-effect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin.

Other methods of action

Aspirin has been shown to have three additional modes of action. It uncouples oxidative phosphorylation

Oxidative phosphorylation

in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons. In short, aspirin buffers and transports the protons. When high doses of aspirin are given, aspirin may actually cause fever due to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. Additionally, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion, which is an important step in immune response to infection; however, there is currently insufficient evidence to show that aspirin helps to fight infection. More recent data also suggests that salicylic acid and its derivatives modulate signaling through NF-κB. NF-κB is a transcription factor

Transcription factor

In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...

complex that plays a central role in many biological processes, including inflammation.

Salicylate sensitivity

Salicylate sensitivity, also known as salicylate intolerance, is any adverse effect

Adverse effect

In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...

that occurs when a normal amount of salicylate

Salicylic acid

Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

is introduced into a person's body. People with salicylate intolerance are unable to consume a normal amount of salicylate without adverse effect

Adverse effect

s.

Salicylate sensitivity differs from salicylism, which occurs when an individual takes an overdose of salicylates. Salicylate overdose can occur in people without salicylate sensitivity, and can be deadly if untreated. For more information, see aspirin poisoning

Aspirin poisoning

Aspirin poisoning or salicylism can be acute or chronic. A single overdose may cause acute poisoning; continuous usage of an elevated dosage over long periods of time may cause chronic poisoning. Acute overdose has a mortality rate of 2%. Chronic overdose is more commonly lethal with a mortality...

.

Salicylates are derivatives of salicylic acid that occur naturally in plant

Plant

Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...

s and serve as a natural immune hormone and preservative

Preservative

A preservative is a naturally occurring or synthetically produced substance that is added to products such as foods, pharmaceuticals, paints, biological samples, wood, etc. to prevent decomposition by microbial growth or by undesirable chemical changes....

, protecting the plants against disease

Disease

A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

s, insects, fungi, and harmful bacteria

Bacteria

Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

. Salicylates can also be found in many medication

Medication

A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

s, perfume

Perfume

Perfume is a mixture of fragrant essential oils and/or aroma compounds, fixatives, and solvents used to give the human body, animals, objects, and living spaces "a pleasant scent"...

s and preservatives. Both natural and synthetic salicylates can cause health problems in anyone when consumed in large doses. But for those who are salicylate intolerant, even small doses of salicylate can cause adverse reactions.

Reye's syndrome

Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

and liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, as well as causing hypoglycemia

Hypoglycemia

Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...

. The exact cause is unknown, and while it has been associated with aspirin

Aspirin

consumption by children with viral illness, it also occurs in the absence of aspirin use.

The disease causes fatty liver with minimal inflammation and severe encephalopathy

Encephalopathy

Encephalopathy means disorder or disease of the brain. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of global brain dysfunction; this syndrome can be caused by many different illnesses.-Terminology:...

(with swelling of the brain). The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

s. Jaundice

Jaundice

Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

is not usually present.

Early diagnosis is vital; while most children recover with supportive therapy, severe brain injury or death are potential complications.

The source of this article is wikipedia, the free encyclopedia. The text of this article is licensed under the GFDL.