Indometacin
Encyclopedia
Indometacin or indomethacin (USAN and former BAN
) is a non-steroidal anti-inflammatory drug
commonly used to reduce fever
, pain
, stiffness, and swelling
. It works by inhibiting the production of prostaglandin
s, molecules known to cause these symptoms. It is marketed under many trade names, including Indocin, Indocid, Indochron E-R, and Indocin-SR.
Indomethacin has also been used clinically to delay premature labor, reduce amniotic fluid
in polyhydramnios
, and to close patent ductus arteriosus
.
Indomethacin is a potent drug with many serious side effects and should not be considered an analgesic for minor aches and pains or fever. The drug is best used as an anti-inflammatory, rather than an analgesic.
(COX) 1 and 2, enzymes that participate in prostaglandin synthesis from arachidonic acid
. Prostaglandins are hormone
-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation.
Prostaglandins also cause uterine contractions in pregnant women. Indomethacin is an effective tocolytic agent, able to delay premature labor by reducing uterine contractions through inhibition of PG synthesis in the uterus and possibly through calcium channel
blockade.
Indomethacin has two additional modes of actions with clinical importance:
These additional effects account as well for the analgesic and the anti-inflammatory properties.
Indomethacin readily crosses the placenta
and can reduce fetal
urine
production to treat polyhydramnios
. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects of vasopressin
on the fetal kidneys.
and intestines, which maintain the mucous lining
of the gastrointestinal tract
. Indomethacin, therefore, like other non-selective COX inhibitors can cause peptic ulcer
s. These ulcers can result in serious bleeding and/or perforation requiring hospitalization of the patient.
To reduce the possibility of peptic ulcers, indomethacin should be prescribed at the lowest dosage needed to achieve a therapeutic effect, usually between 50–200 mg/day. It should always be taken with food. Nearly all patients benefit from an ulcer protective drug (e.g. highly dosed antacids, ranitidine
150 mg at bedtime, or omeprazole
20 mg at bedtime). Other common gastrointestinal complaints, including dyspepsia
, heartburn
and mild diarrhea
are less serious and rarely require discontinuation of indomethacin.
Many NSAIDs, but particularly indomethacin, cause lithium
retention by reducing its excretion by the kidney
s. Thus indomethacin users have an elevated risk of lithium toxicity. For patients taking lithium (e.g. for treatment of depression
or bipolar disorder
), less toxic NSAIDs such as sulindac
or aspirin
, are preferred.
Indomethacin also reduces plasma renin activity
and aldosterone
levels, and increases sodium
and potassium
retention. It also enhances the effects of vasopressin
. Together these may lead to:
The drug may also cause elevations of serum creatinine
and more serious renal damage such as acute renal failure, chronic nephritis
and nephrotic syndrome
. These conditions also often begin with edema and hyperkalemia.
Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage). There were reports of worsening Parkinson's disease, epilepsy, and psychiatric disorders but these are not substantiated. Cases of life-threatening shock (including angioedema
, sweating, severe hypotension
and tachycardia
as well as acute bronchospasm
), severe or lethal hepatitis
and severe bone marrow damage have all been reported. Skin reactions and photosensitivity
are also possible side effects.
Due to its strong antipyretic
activity indomethacin may obscure the clinical course of serious infections.
Psychosis
has also been reported with prolonged use.
The frequency and severity of side effects and the availability of better tolerated alternatives make indomethacin today a drug of second choice. Its use in acute gout
attacks and in dysmenorrhea
is well-established because in these indications the duration of treatment is limited to a few days only, therefore serious side effects are not likely to occur.
or with potassium-sparing diuretic
s, because these combinations can lead to hyperkalemia and/or serious kidney failure. No examinations are necessary if only the topical preparations (spray or gel) are applied.
Generally, overdose in humans causes drowsiness, dizziness, severe headache, mental confusion, paresthesia
, numbness of limbs, nausea and vomiting. Severe gastrointestinal bleeding is also possible. Cerebral edema, and cardiac arrest with fatal outcome have been seen in children.
The treatment is symptomatic and largely the same as with diclofenac
. However, the possibility of severe GI tract symptoms should be particularly noted.
The risk of overdose after exaggerated local treatment with gel or spray is very limited.
in 1965. Its mechanism of action, along with several other NSAIDs that inhibit COX, was described in 1971.
British Approved Name
A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...
) is a 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...
commonly used to reduce 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."...
, stiffness, and swelling
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...
. It works by inhibiting the production of 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, molecules known to cause these symptoms. It is marketed under many trade names, including Indocin, Indocid, Indochron E-R, and Indocin-SR.
Indications
Clinical indications for indometacin include:- ankylosing spondylitisAnkylosing spondylitisAnkylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...
- arthritic goutGoutGout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
- Bartter syndromeBartter syndromeBartter syndrome is a rare inherited defect in the thick ascending limb of the loop of Henle. It is characterized by low potassium levels , increased blood pH , and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic...
- bursitisBursitisBursitis is the inflammation of one or more bursae of synovial fluid in the body. The bursae rest at the points where internal functionaries, such as muscles and tendons, slide across bone. Healthy bursae create a smooth, almost frictionless functional gliding surface making normal movement painless...
- cryoglobulinemiaCryoglobulinemiaCryoglobulinemia is a medical condition in which the blood contains large amounts of cryoglobulins - proteins that become insoluble at reduced temperatures. Cryoglobulins typically precipitate at temperatures below normal body temperature and will dissolve again if the blood is heated...
- dysmenorrheaDysmenorrheaDysmenorrhea 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...
(menstrual cramps) - Exertion headaches
- feverFeverFever 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...
and painPainPain 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."...
associated with malignant diseases (especially tumor fever associated with liver involvement, lymphogranulomatosis) - juvenile arthritisChildhood arthritisChildhood arthritis, also juvenile arthritis, is arthritis in a child.Childhood arthritis may be:* Transient & self-limited* ChronicChronic forms of arthritis seen in childhood are:* Ankylosing spondylitis* Psoriatic arthritis...
- nephrogenic diabetes insipidusNephrogenic diabetes insipidusNephrogenic diabetes insipidus is a form of diabetes insipidus due primarily to pathology of the kidney. This is in contrast to central/neurogenic diabetes insipidus, which is caused by insufficient levels of antidiuretic hormone /Argenine Vasopressin...
(prostaglandin inhibits vasopressinVasopressinArginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
's action in the kidneyKidneyThe 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...
) - osteoarthritisOsteoarthritisOsteoarthritis also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion...
- Paget's disease of bonePaget's disease of bonePaget's disease is a chronic disorder that can result in enlarged and misshapen bones. The excessive breakdown and formation of bone tissue causes affected bone to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints near the affected bones...
- paroxysmal hemicrania, hemicrania continuaHemicrania continuaHemicrania continua is a persistent unilateral headache that responds to indomethacin. It is usually unremitting, but rare cases of remission have been documented...
and migraineMigraineMigraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea... - Patent ductus arteriosusPatent ductus arteriosusPatent 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...
- pericarditisPericarditisPericarditis 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...
- pseudogout
- psoriatic arthritisPsoriatic arthritisPsoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, will develop in up to 30 percent of people who have the chronic skin condition psoriasis...
- Reactive arthritis (ReA)
- renal colicRenal colicRenal colic is a type of abdominal pain commonly caused by kidney stones.-Presentation:The pain typically begins in the abdomen and often radiates to the hypochondrium or the groin. The pain is often colicky due to ureteric peristalsis, but may be constant...
(pain due to kidney stones) - retinopathy of prematurityRetinopathy of prematurityRetinopathy of prematurity , previously known as retrolental fibroplasia , is an eye disease that affects prematurely-born babies. It is thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment. ROP can be mild and may resolve...
- rheumatoid arthritisRheumatoid arthritisRheumatoid 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...
- tendinitis
Indomethacin has also been used clinically to delay premature labor, reduce amniotic fluid
Amniotic fluid
Amniotic fluid or liquor amnii is the nourishing and protecting liquid contained by the amniotic sac of a pregnant woman.- Development of amniotic fluid :...
in polyhydramnios
Polyhydramnios
Polyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in 0.2 to 1.6% of pregnancies,,...
, and to close 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...
.
Indomethacin is a potent drug with many serious side effects and should not be considered an analgesic for minor aches and pains or fever. The drug is best used as an anti-inflammatory, rather than an analgesic.
Contraindications
- concurrent peptic ulcerPeptic ulcerA peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
, or history of ulcer disease - allergy to indomethacin, aspirin, or other NSAIDs
- patients with nasal polypsPolyp (medicine)A polyp is an abnormal growth of tissue projecting from a mucous membrane. If it is attached to the surface by a narrow elongated stalk, it is said to be pedunculated. If no stalk is present, it is said to be sessile. Polyps are commonly found in the colon, stomach, nose, sinus, urinary bladder...
reacting with an angioedemaAngioedemaAngioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
to other NSAIDs
- children under 2 years of age (with the exception of neonates with patent ductus arteriosus)
- severe pre-existing renal and liver damage
- caution: pre-existing bone marrow damage (frequent blood cell counts are indicated)
- caution: bleeding tendencies of unknown origin (indomethacin inhibits plateletPlateletPlatelets, 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) - caution: Parkinson's diseaseParkinson's diseaseParkinson's disease is a degenerative disorder of the central nervous system...
, epilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, psychotic disorders (indomethacin may worsen these conditions) - concurrent with potassium sparing diuretics
- patients who have a patent ductus arteriosusPatent ductus arteriosusPatent 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...
dependent heart defect (such as Transposition of the great vesselsTransposition of the great vesselsTransposition of the great vessels is a group of congenital heart defects involving an abnormal spatial arrangement of any of the primary blood vessels: superior and/or inferior vena cavae , pulmonary artery, pulmonary veins, and aorta...
) - significant hypertensionHypertensionHypertension 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...
(high blood pressure)
Mechanism of action
Indomethacin is a nonselective inhibitor of cyclooxygenaseCyclooxygenase
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) 1 and 2, enzymes that participate in prostaglandin synthesis from 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,...
. Prostaglandins are 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...
-like molecules normally found in the body, where they have a wide variety of effects, some of which lead to pain, fever, and inflammation.
Prostaglandins also cause uterine contractions in pregnant women. Indomethacin is an effective tocolytic agent, able to delay premature labor by reducing uterine contractions through inhibition of PG synthesis in the uterus and possibly through calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
blockade.
Indomethacin has two additional modes of actions with clinical importance:
- It inhibits motility of polymorphonuclear leukocytes, similar to colchicineColchicineColchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
. - It uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, like salicylates.
These additional effects account as well for the analgesic and the anti-inflammatory properties.
Indomethacin readily crosses the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and can reduce fetal
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
production to treat polyhydramnios
Polyhydramnios
Polyhydramnios is a medical condition describing an excess of amniotic fluid in the amniotic sac. It is seen in 0.2 to 1.6% of pregnancies,,...
. It does so by reducing renal blood flow and increasing renal vascular resistance, possibly by enhancing the effects of vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
on the fetal kidneys.
Adverse effects
Since indomethacin inhibits both COX-1 and COX-2, it inhibits the production of prostaglandins in the stomachStomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
and intestines, which maintain the mucous lining
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
of the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. Indomethacin, therefore, like other non-selective COX inhibitors can cause peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
s. These ulcers can result in serious bleeding and/or perforation requiring hospitalization of the patient.
To reduce the possibility of peptic ulcers, indomethacin should be prescribed at the lowest dosage needed to achieve a therapeutic effect, usually between 50–200 mg/day. It should always be taken with food. Nearly all patients benefit from an ulcer protective drug (e.g. highly dosed antacids, ranitidine
Ranitidine
Ranitidine is a histamine H2-receptor antagonist that inhibits stomach acid production. It is commonly used in treatment of peptic ulcer disease and gastroesophageal reflux disease . Ranitidine is also used alongside fexofenadine and other antihistamines for the treatment of skin conditions...
150 mg at bedtime, or omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
20 mg at bedtime). Other common gastrointestinal complaints, including 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...
, heartburn
Heartburn
Heartburn, also known as pyrosis or acid indigestion is a burning sensation in the chest, just behind the breastbone or in the epigastrium...
and mild 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...
are less serious and rarely require discontinuation of indomethacin.
Many NSAIDs, but particularly indomethacin, cause lithium
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
retention by reducing its excretion by 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. Thus indomethacin users have an elevated risk of lithium toxicity. For patients taking lithium (e.g. for treatment of depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
or bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
), less toxic NSAIDs such as sulindac
Sulindac
Sulindac is a non-steroidal anti-inflammatory drug of the arylalkanoic acid class that is marketed in the UK & U.S. by Merck as Clinoril.-Uses:...
or 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...
, are preferred.
Indomethacin also reduces plasma renin activity
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
and aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
levels, and increases sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
retention. It also enhances the effects of vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
. Together these may lead to:
- edemaEdemaEdema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
(swelling due to fluid retention) - hyperkalemiaHyperkalemiaHyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
(high potassium levels) - hypernatremiaHypernatremiaHypernatremia or hypernatraemia is an electrolyte disturbance that is defined by an elevated sodium level in the blood. Hypernatremia is generally not caused by an excess of sodium, but rather by a relative deficit of free water in the body...
(high sodium levels) - hypertension
The drug may also cause elevations of serum creatinine
Creatinine
Creatinine is a break-down product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body...
and more serious renal damage such as acute renal failure, chronic nephritis
Nephritis
Nephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....
and nephrotic syndrome
Nephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
. These conditions also often begin with edema and hyperkalemia.
Additionally, indomethacin quite often causes headache (10 to 20%), sometimes with vertigo and dizziness, hearing loss, tinnitus, blurred vision (with or without retinal damage). There were reports of worsening Parkinson's disease, epilepsy, and psychiatric disorders but these are not substantiated. Cases of life-threatening shock (including angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
, sweating, severe 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...
and 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...
as well as acute 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...
), severe or lethal hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
and severe bone marrow damage have all been reported. Skin reactions and photosensitivity
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...
are also possible side effects.
Due to its strong 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...
activity indomethacin may obscure the clinical course of serious infections.
Psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
has also been reported with prolonged use.
The frequency and severity of side effects and the availability of better tolerated alternatives make indomethacin today a drug of second choice. Its use in acute gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
attacks and in 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...
is well-established because in these indications the duration of treatment is limited to a few days only, therefore serious side effects are not likely to occur.
Necessary examinations during long term treatment
Patients should undergo regular physical examination to detect edema and signs of central nervous side effects. Blood pressure checks will reveal development of hypertension. Periodic serum electrolyte (sodium, potassium, chloride) measurements, complete blood cell counts and assessment of liver enzymes as well as of creatinine (renal function) should be performed. This is particularly important if Indomethacin is given together with an ACE inhibitorACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
or with potassium-sparing diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
s, because these combinations can lead to hyperkalemia and/or serious kidney failure. No examinations are necessary if only the topical preparations (spray or gel) are applied.
Animal toxicity and human overdose
Indomethacin has a high acute toxicity both for animals (12 mg/kg in rats and 50 mg/kg in mice) and for humans. Exact human data does not exist, but some fatal human cases, particularly in children and adolescents, have been seen.Generally, overdose in humans causes drowsiness, dizziness, severe headache, mental confusion, paresthesia
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
, numbness of limbs, nausea and vomiting. Severe gastrointestinal bleeding is also possible. Cerebral edema, and cardiac arrest with fatal outcome have been seen in children.
The treatment is symptomatic and largely the same as with diclofenac
Diclofenac
Diclofenac is a non-steroidal anti-inflammatory drug taken to reduce inflammation and as an analgesic reducing pain in certain conditions....
. However, the possibility of severe GI tract symptoms should be particularly noted.
The risk of overdose after exaggerated local treatment with gel or spray is very limited.
Usual dosage forms
- tablets or capsules 25 and 50 mg
- suppositories 50 and 100 mg
- modified-release Capsules 75 mg
- syrup (25 mg/5ml)
- injectable concentrate 50 mg for i.m. injection
- spray or gel
- patches containing 0.5% by weight
- 1% topical liquid
History
Indomethacin was discovered in 1963 and it was first approved for use in the U.S. by the Food and Drug AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in 1965. Its mechanism of action, along with several other NSAIDs that inhibit COX, was described in 1971.
External links
- Effects of Perinatal Indomethacin Treatment on Preterm Infants, academic dissertation (PDFPortable Document FormatPortable Document Format is an open standard for document exchange. This file format, created by Adobe Systems in 1993, is used for representing documents in a manner independent of application software, hardware, and operating systems....
) - Indomethacin, from MedicineNet
- Indomethacin, from Drugs.com
- Indocin: Description, chemistry, ingredients, from RxList.com