Allopurinol
Encyclopedia
Allopurinol is a drug used primarily to treat hyperuricemia
(excess uric acid
in blood plasma
) and its complications, including chronic gout
.
of hypoxanthine
(a naturally occurring purine
in the body) and is an inhibitor
of the enzyme xanthine oxidase
. Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine
, resulting in the production of uric acid
, the product of human purine metabolism. In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine, which are converted to closely related purine ribotides adenosine
and guanosine monophosphate
s. Increased levels of these ribotides causes feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases both uric acid formation and purine synthesis.
(excess uric acid
in blood plasma
) and its complications. Allopurinol does not alleviate acute attacks of gout, but is useful in chronic gout to prevent future attacks. Likewise, allopurinol commonly is used as prophylaxis with chemotherapeutic treatments (Ex: mercaptopurine and thioguanine), which can rapidly produce severe hyperuricemia. Other established indications for allopurinol therapy include ischemic reperfusion injury, kidney stone
s with a uric acid component (uric acid nephrolithiasis), and protozoal infections (Leishmaniasis
).
Because allopurinol is not a uricosuric
, it can be used in patients with poor kidney
function. However, allopurinol has two important disadvantages: Its dosing is complex, and some patients will be hypersensitive to it. Therefore, use of this drug requires careful monitoring.
Allopurinol can be used in patients with poor kidney function, but it may also help them. A study of allopurinol use in patients with chronic kidney disease suggested that "Allopurinol decreases C-reactive protein
and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects."
A recent study has suggested that allopurinol can help reduce the effects of angina in ischaemic heart disease
by reducing the workload on the heart.
, to its active metabolite
oxypurinol
, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxypurinol within two hours of oral administration, whereas oxypurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxypurinol is believed to be responsible for the majority of allopurinol's effect.
, hepatitis
, worsened renal function, and, in some cases, allopurinol hypersensitivity syndrome. Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis
(TENS), two life-threatening dermatological
conditions.
Study finds HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions which includes Steven Johnson Syndrome and toxic epidermal necrosis caused by allopurinol.
Allopurinol can cause severe pancytopenia
if given with azathioprine
or mercaptopurine
, due to inhibition of xanthine oxidase, which metabolizes these drugs.
Allopurinol can lower blood pressure
in mild hypertension
.
It is suspected to cause congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
(excess uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
in blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
) and its complications, including chronic 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...
.
Mechanism of action
Allopurinol is a purine analog; it is a structural isomerIsomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
of hypoxanthine
Hypoxanthine
Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-Hydroxypurine. Hypoxanthine is a necessary additive in certain cell,...
(a naturally occurring purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
in the body) and is an inhibitor
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...
of the enzyme xanthine oxidase
Xanthine oxidase
Xanthine oxidase Xanthine oxidase Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species. Is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid...
. Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine
Xanthine
Xanthine , is a purine base found in most human body tissues and fluids and in other organisms. A number of stimulants are derived from xanthine, including caffeine and theobromine....
, resulting in the production of uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
, the product of human purine metabolism. In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine, which are converted to closely related purine ribotides adenosine
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
and guanosine monophosphate
Guanosine monophosphate
Guanosine monophosphate, also known as 5'-guanidylic acid or guanylic acid and abbreviated GMP, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of the phosphate group, the pentose sugar ribose, and the nucleobase...
s. Increased levels of these ribotides causes feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases both uric acid formation and purine synthesis.
Uses
The primary use of allopurinol is to treat hyperuricemiaHyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...
(excess uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
in blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
) and its complications. Allopurinol does not alleviate acute attacks of gout, but is useful in chronic gout to prevent future attacks. Likewise, allopurinol commonly is used as prophylaxis with chemotherapeutic treatments (Ex: mercaptopurine and thioguanine), which can rapidly produce severe hyperuricemia. Other established indications for allopurinol therapy include ischemic reperfusion injury, kidney stone
Kidney stone
A kidney stone, also known as a renal calculus is a solid concretion or crystal aggregation formed in the kidneys from dietary minerals in the urine...
s with a uric acid component (uric acid nephrolithiasis), and protozoal infections (Leishmaniasis
Leishmaniasis
Leishmaniasis is a disease caused by protozoan parasites that belong to the genus Leishmania and is transmitted by the bite of certain species of sand fly...
).
Because allopurinol is not a uricosuric
Uricosuric
Uricosuric medications are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule...
, it can be used in patients with poor 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...
function. However, allopurinol has two important disadvantages: Its dosing is complex, and some patients will be hypersensitive to it. Therefore, use of this drug requires careful monitoring.
Allopurinol can be used in patients with poor kidney function, but it may also help them. A study of allopurinol use in patients with chronic kidney disease suggested that "Allopurinol decreases C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
and slows down the progression of renal disease in patients with chronic kidney disease. In addition, allopurinol reduces cardiovascular and hospitalization risk in these subjects."
A recent study has suggested that allopurinol can help reduce the effects of angina in ischaemic heart disease
Ischaemic heart disease
Ischaemic or ischemic heart disease , or myocardial ischaemia, is a disease characterized by ischaemia of the heart muscle, usually due to coronary artery disease...
by reducing the workload on the heart.
Metabolism
Allopurinol is rapidly metabolized by its target, xanthine oxidaseXanthine oxidase
Xanthine oxidase Xanthine oxidase Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species. Is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid...
, to its active metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
oxypurinol
Oxypurinol
Oxypurinol is an inhibitor of xanthine oxidase. It is an active metabolite of allopurinol and it is cleared renally. In cases of renal disease, this metabolite will accumulate to toxic levels....
, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxypurinol within two hours of oral administration, whereas oxypurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxypurinol is believed to be responsible for the majority of allopurinol's effect.
Side-effects
Side-effects of allopurinol are rare, though significant when they occur. A small percentage of people develop a rash and must discontinue this drug. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophiliaEosinophilia
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 0.45×109/L . A marked increase in non-blood tissue eosinophil count noticed upon histopathologic examination is diagnostic for tissue eosinophilia. Several causes are known, with the most common being...
, 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"...
, worsened renal function, and, in some cases, allopurinol hypersensitivity syndrome. Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis
Toxic epidermal necrolysis
Toxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...
(TENS), two life-threatening dermatological
Dermatology
Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails....
conditions.
Study finds HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions which includes Steven Johnson Syndrome and toxic epidermal necrosis caused by allopurinol.
Allopurinol can cause severe pancytopenia
Pancytopenia
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
if given with azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
or mercaptopurine
Mercaptopurine
Mercaptopurine is an immunosuppressive drug.It is a thiopurine.-Uses:...
, due to inhibition of xanthine oxidase, which metabolizes these drugs.
Allopurinol can lower blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
in mild 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...
.
It is suspected to cause congenital malformations when used during pregnancy, and should be avoided whenever possible by women trying to conceive.
Brand names
Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name of Zyloprim. Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is now a generic drug sold under a variety of brand names including Allohexal, Allosig, Milurit, Alloril, Progout, Zyloprim, Zyloric, Zyrik and Aluron.External links
- Zyloprim (patient information)