Article

Allopurinol (Zyloprim, Aloprim)
February 01, 20190853

 

What is allopurinol?

Allopurinol is a prescription medication used to treat high levels of uric acid in the blood (hyperuricemia).1 It is sold under the brand names Zyloprim and Aloprim.

What is uric acid?

Uric acid is a natural break down product of a class of molecules called purines.

Purines are an important group of molecules in human cells. Individual members have very different jobs. Some of them are used as building blocks for DNA. Others are used as transport molecules. And still others are used by our cells to harness energy from our food.2

When our cells do not need a purine anymore, it is chopped up by an enzyme called xanthine oxidase. Xanthine oxidase converts purines into uric acid.2

 

Figure 1: Structure of uric acid
(iStockphoto/Molekuul)

 

Uric acid then moves into our blood stream.1 The kidneys filter uric acid out of our blood and into our urine. We can then flush the uric acid away.1

Why is hyperuricemia treated?

Even though uric acid is a normal molecule to have in our blood, it can be dangerous in high concentrations.

This is because uric acid does not dissolve well in blood. When too much uric acid is in the blood, the molecules can stick to each other and form crystals.1,3

 

Figure 2: Uric acid crystals under a microscope
Fluorescent uric acid by Bobjgalindo is licensed under CC 1.0.

 

Depending on where these crystals form, they can cause different conditions.

 

Gout

For many people, uric crystals cause gout.1,3 Gout occurs when uric crystals form inside joints.3

The immune system recognizes uric acid crystals in the joint as dangerous. Immune cells mount a massive defense when they find uric acid crystals forming. They call more white blood cells to the spot and create inflammatory chemicals to try to remove the crystals.1,3

The immune system recognizes uric acid crystals in the joint as dangerous. Immune cells mount a massive defense when they find uric acid crystals forming. They call more white blood cells to the spot and create inflammatory chemicals to try to remove the crystals.1,3

This causes redness, swelling and severe pain.1

The immune response can continue for a long time and become very intense. If the inflammation becomes severe enough, the immune response intended to breakdown the crystals can start breaking down the person’s own body.1

The immune response can be strong enough to even start breaking down nearby bone.1

 

Kidney stones and kidney disease

If uric acid crystals form in the kidney, they can cause kidney stones.4

Scientists are not entirely sure how this works. Some data suggests that the uric acid crystals form a base for calcium oxide crystals to stick to. Once the calcium oxide crystals begin forming, the crystal can grow into a kidney stone.4,5

High levels of uric acid in the blood also seem able to damage kidneys directly. Uric acid decreases the ability of the kidneys to filter blood and regulate blood pressure. This can lead to kidney disease and high blood pressure.6

 

 

Cardiovascular Disease

High levels of uric acid appear to damage the walls of our arteries. When the walls of arteries are damaged, they are prone to the build-up of plaque.3

The formation of plaque in artery walls is the basis of cardiovascular disease. Cardiovascular disease can lead to heart attacks and strokes.3

 

 

Other Diseases

Scientists have found some evidence that hyperuricemia may also play a role in the development of3:

  • congestive heart failure
  • type 2 diabetes
  • obesity

It is not yet fully clear how uric acid is connected to these diseases, though.3

How much uric acid is too much?

Most people have uric acid levels in their blood of around 0.5-1 mg/dL.3

Uric acid levels below 6.0 mg/dL (357 μm/dL) are considered safe.1

Concentrations of uric acid above 6.8 mg/dL (404 μm/dL) allow uric acid crystals to form.1

If you are given allopurinol, your doctor will be aiming to get your uric acid levels below 6.0 mg/dL.1

How do uric acid levels get too high?

There are several ways that uric acid levels in your blood can get too high.

Diet

Like humans, other plants and animals use purines to help run their cells.

When humans eat plants and animals that have a lot of purines, it can increase the amount of purines in our bodies.3

When our cells break down all these extra purines, it can cause hyperuricemia3

Foods that can increase uric acid levels include1,3:

  • meat
  • fish
  • dairy
  • beer
  • liquor
  • table sugar

 

Cancer

Individuals with cancer may experience high uric acid levels in their blood from all the extra purines made by their tumors’ quick growth.3

Common cancer treatments make this problem worse.7

Chemotherapy and radiation kill tumor cells quickly, which can release uric acid into the blood.1

Genetic disorders

Some people are born with genes that can cause hyperuricemia.

These include mutations that cause them to2:

  • make extra purines
  • break down too many purines

Both of these can lead to high levels of uric acid in their blood.2

 

How does allopurinol work?

Allopurinol is a xanthine oxidase inhibitor. This means it prevents the xanthine oxidase enzyme from turning purines into uric acid.26-29

If less uric acid is made from purines, there is less uric acid in the blood.1

 

Figure 3: Allopurinol interference in purine metabolism.2
Key step is highlighted in red.

 

Uses of allopurinol

Preventing gout flair ups

Allopurinol is not given during a gout attack.1

This is because allopurinol can cause new crystals to form when it is first taken. If this happens during a gout flair-up, it can make it harder to get your symptoms under control.1

Allopurinol is given after the symptoms from your first or second gout attack have been managed with other drugs (usually anti-inflammatory medications, steroids and/or opioids).1

Allopurinol is given long-term to lower your uric acid and prevent new attacks.1

Preventing kidney stones

People who have recurrent kidney stones and high uric acid levels may also be given allopurinol.1

Allopurinol decreases the amount of uric acid that has to be flushed into the urine. Lower uric acid levels in the urine help prevent crystals from forming.1

If fewer uric acid crystals form, calcium oxide will be less likely to use them as a base for a kidney stone.

Cancer therapy

Doctors may choose to give you allopurinol as part of your cancer treatment to prevent your uric acid levels from going too high when the cancer cells die.1

This is usually done to protect your kidneys from being damaged.1,8

It can also protect your arteries and prevent you from experiencing a gout attack during your therapy.

 

 

Dosage of allopurinol

Adults: Preventing gout

The proper dosage of allopurinol is the lowest dose that is able to bring your lower uric acid levels under 6.0 mg/dL.1

The most common dose is 200-300 mg per day.1

If this is not enough to bring your uric acid levels down to under 6.0 mg/dL, your dose will be increased until your doctor finds an amount that is effective.1

The maximum amount of allopurinol that should be taken per day is 800 mg.1,8

Any dose over 300 mg per day will be given in multiple, smaller doses throughout the day.8

Adults: Preventing kidney damage during cancer treatment

Allopurinol prescribed to protect your kidneys during cancer treatment is dosed at the high end of the safe range.

In most cases, your doctor will prescribe 600 or 800 mg per day for 2 or 3 days following treatment.8

Adults: Dosage with kidney disease

If you have any decrease in kidney function, you will likely be given a starting dose of allopurinol that is smaller than 200 mg per day.1

This is not because your kidneys need to be protected from allopurinol. It is because smaller doses of allopurinol are able to reach higher concentrations in your blood if your kidneys remove the medicine from your body more slowly.1

The more pronounced your kidney disease is, the lower your dose of allopurinol will be.8 If your kidney function is too impaired, you may not be able to take allopurinol at all.1

Children

Children are usually given allopurinol to protect their kidneys during cancer treatment.8

If a child is under 6 years old, their doctor usually prescribes 150 mg per day.8

Children between 6 and 10 years of age usually receive 300 mg per day.8

Children over the age of 10 can receive adult doses of allopurinol.8

 

 

Side effects of allopurinol

The most common side effects of allopurinol include1,8:

  • upset stomach and digestive problems
  • acute gout attack
  • rash

Images of the characteristic rash associated with a reaction to allopurinol may be viewed here.

Other side effects may include1,8:

  • sleepiness
  • fever
  • extreme skin reactions (blisters, peeling skin, patches of dying skin that may fall off)
  • hair loss
  • decreased red and white blood cell counts
  • liver inflammation
  • jaundice
  • changes in immune function
  • inflammation of blood vessel walls

The most severe reaction to allopurinol is allopurinol hypersensitivity syndrome. The symptoms of this syndrome include1:

  • fever
  • severe skin rash
  • over-activation of certain white blood cells (eosinophils)
  • liver inflammation
  • kidney failure

These symptoms may be followed by multi-organ failure and death.1

 

 

Warnings for allopurinol

General warnings

You should not take allopurinol if you are allergic to it or similar drugs.8

Seek medical attention if you get a rash within the first few weeks of starting allopurinol. This may be a sign you are developing the early stages of allopurinol hypersensitivity syndrome.8

Speak to your doctor about all medical conditions you have and any medications you take.

Kidney disease

If you have been diagnosed with kidney disease, make sure to tell your doctor. You should be given a lower dose of allopurinol to make sure blood levels of allopurinol do not go too high.1

Liver disease

If you have impaired liver function, your doctor will likely monitor you very closely while on allopurinol. She will want to keep an eye on your liver function to make sure the drug is not making your condition worse.8

Pregnancy

Pregnant women may be prescribed allopurinol. The FDA has classified allopurinol as a category C medication.8 This means tests on animals have shown damage to unborn babies, but it has not been proven in humans.9

Your doctor will decide if the benefits outweigh the risks in your case.

Breastfeeding

Allopurinol should not be taken by breastfeeding women. Scientists have been able to find allopurinol (and its metabolites) in breast milk. It is not clear what effect allopurinol might have on an infant, but to be safe doctors do not prescribe allopurinol for breastfeeding mothers.8

Childhood

Children may be given allopurinol at lower doses than adults to help decrease the risk of side effects.8

 

 

Drug interactions of allopurinol

There are few drugs that interact with allopurinol. Caution should be taken when allopurinol is taken with any of the following six medications1:

  • Azathioprine and 6-Mercaptopurine

Both of these medications are broken down by the xanthine oxidase enzyme.

When xanthine oxidase is inhibited by allopurinol, the body cannot deactivate these medications. This can allow a build-up of toxic levels of azathioprine or 6-mercaptopurine.

  • Warfarin and Theophylline

Both of these drugs are metabolized in the liver. Allopurinol can cause changes in liver function.

If this happens, levels of warfarin and theophylline in the blood may increase dangerously.

  • Ampicillin

Taking allopurinol with the antibiotic ampicillin appears to increase the risk of developing a skin rash.

  • Cyclophosphamide

Allopurinol taken at the same time as cyclophosphamide appears to increase the risk that your bones may make too few red and white blood cells.

Allopurinol compared to other drugs

There are a number of alternatives to allopurinol for treating high levels of uric acid in the blood. Some also work by inhibiting xanthine oxidase. Others work in completely different ways.1

Allopurinol vs. other xanthine oxidase inhibitors

There is one other xanthine oxidase inhibitor for the treatment of hyperuricemia levels available: febuxstat.1

Febuxstat is more potent than allopurinol. It requires lower doses to achieve the same lowering effects on uric acid blood levels.1

Doses for febuxstat are usually 40-120 mg per day.1

Compared to allopurinol, febuxstat requires less trial and error at the beginning of treatment to find the right dose.1

Febuxstat appears to be safer for individuals with kidney diseases. No dose adjustment is needed until kidney filtering rates drop very low (creatinine clearance < 30 mL/min).1

  • headache
  • dizziness
  • diarrhea
  • changes in liver function
  • changes in thyroid function

The structure of febuxstat is different enough from that of allopurinol that it is safe to take if you have had an allergic reaction to allopurinol.1

If you1:

  • have kidney disease, but a creatinine clearance > 30 mL/min and/or
  • have had an allergic reaction to allopurinol

your doctor is more likely to prescribe febuxstat than allopurinol.

Allopurinol vs. uricousuric agents

Another class of drugs that can be used to treat hyperuricemia are called uricousuric agents.1

These drugs work by increasing the amount of uric acid that the kidneys pump into the urine. This lowers the amount of uric acid in the body, and the blood.1

There are two uricousuric drugs that can be prescribed: probenecid and benzbromarone.1

Probenecid is the uricousuric medication available in the United States.1

Common dosage range is 500-3000 mg per day. This total amount is spread out over several smaller doses throughout the day.1

Side effects of probenecid include1:

gastrointestinal problems
rash
allergic reaction

Probenecid may increase the risk of toxic effects from certain other medications. You will likely not be given probenecid if you are also taking1:

  • penicillin
  • non-steroidal anti-inflammatory drugs (NSAIDS)
  • methotrexate

Benzbromarone is a more powerful medication than probenecid.1

It is nevertheless safe for individuals with kidney transplants or kidney disease (creatinine clearance > 25 mL/min).1

You are likely to be prescribed a uricousuric drug instead of allopurinol if1:

  • you are allergic to allopurinol
  • you are on medications that interact with allopurinol

You may be switched from a uricousuric drug to another medication if you build up a tolerance to it.1

Allopurinol vs. uricases

The last class of medications that can be used to treat high levels of uric acid in the blood are called uricases.

A uricase is an enzyme that can convert uric acid into allantoin.1

Allantoin is much more soluble in human blood then uric acid. It cannot form crystals to trigger any of the diseases associated with uric acid build-up.1

It is also easier to dissolve in urine, making it easier to flush out of the body.1

Most animals make their own uricase enzyme. Humans lost their uricase enzyme during evolution1.

Scientist have recreated the human uricase enzyme using gene technology. There are two forms of this enzyme available: pegloticase and rasburicase1.

Pegloticase

Pegloticase must be given as an IV.1

A normal dose of pegloticase is 8 mg every 2 weeks.1

Pegloticase is used as a last resort for the treatment of gout. Though effective, the side effects of pegloticase can be severe1

Individuals getting pegloticase may experience1:

  • injection site reactions
  • infusion reactions
  • bruising
  • muscle and bone pain
  • digestive problems
  • infection
  • chest pain
  • worsening heart failure
  • anaphylactic shock
  • death

Many people develop antibodies that attack pegloticase after several treatments. These antibodies make the drug useless.1

Pegloticase should not be used in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.1

In these individuals, pegloticase can cause their red blood cell to break open. Their blood can then no longer carry oxygen to the body.1

You may be given pegloticase if1:

  • you are unable to take any of the other uric acid lowering drugs
  • no other medications are lowering your uric acid levels enough

 

Rasburicase

Rasburicase is a uricase enzyme that is given to cancer patients with tumor lysis syndrome.1,7

Tumor lysis syndrome occurs when too many cells die at once during cancer treatment. It can cause7:

  • abnormal heart beat
  • kidney failure
  • seizures
  • death

One of the mediators of tumor lysis syndrome is believed to be high levels of uric acid.7

In this emergency situation, doctors choose to inject rasburicase because it works much faster than other drug options.7

The side effects of rasburicase are similar to those of pegloticase.

Rasburicase cannot be used safely by individuals with G6PD deficiency.7

 

 

Abuses of allopurinol

Allopurinol has little effect on brain function. With the exception of rare reports of sleepiness, allopurinol does not appear to effect brain signaling.8

The risk of abuse of allopurinol is very small.

 

 

Allopurinol FAQs

  • How long does it take for allopurinol to lower uric acid levels?

If your doctor has found the right dosage for you, it usually takes between one and three weeks for your uric acid levels to fall below 6.0 mg/dL.8

  • Should you be taking allopurinol and colchicine together?

If your doctor has prescribed allopurinol and colchicine, you should take both of them, as prescribed.

Allopurinol and colchicine work in two different ways to help prevent your gout symptoms from returning.

Allopurinol decreases the amount of uric acid in your blood. This helps prevent uric acid crystals from forming.1,3,8

Colchicine prevents your immune system from responding so dramatically to uric acid crystals.1

Using allopurinol and colchicine together helps ensure that your gout symptoms do not return.1

  • Can allopurinol get you high?No. In rare cases, allopurinol may make you sleepy. It has not been reported that it can cause any kind of high.8
  • Should you drink alcohol with allopurinol?

Drinking alcohol may be unhelpful while taking allopurinol.1

Alcoholic beverages may increase the amount of purines in your body. This can increase the amount of uric acid in your blood and cancel out the effects of your medicine.1

It does not appear all alcohol raises uric acid in the blood the same amount.

Beer seems to have the greatest effect, followed by liquors. Studies show that wine may not increase your uric acid levels at all.1

  • What happens if I stop taking allopurinol?

If you stop taking allopurinol without being told to do so by your doctor, it is likely that the level of uric acid in your blood will increase.

This puts you at risk for a gout attack or kidney stone. It also may increase your risk of cardiovascular disease, diabetes, kidney disease, obesity and hypertension.

 

References

1. Burns CM, Wortmann RL. Latest evidence on gout management: what the clinician needs to know. Therapeutic advances in chronic disease. 2012;3(6):271-286.

2. Jinnah HA, Sabina RL, Van Den Berghe G. Metabolic disorders of purine metabolism affecting the nervous system. Handbook of clinical neurology. 2013;113:1827-1836.

3. Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC nephrology. 2013;14:164.

4. Sakhaee K, Maalouf NM, Sinnott B. Clinical review. Kidney stones 2012: pathogenesis, diagnosis, and management. The Journal of clinical endocrinology and metabolism. 2012;97(6):1847-1860.

5. Kaneko K, Yoshida N, Okazaki K, et al. Urinary stone analysis in a patient with hyperuricemia to determine the mechanism of stone formation. Nucleosides, nucleotides & nucleic acids. 2011;30(12):1072-1076.

6. Kang DH, Nakagawa T, Feng L, et al. A role for uric acid in the progression of renal disease. Journal of the American Society of Nephrology : JASN. 2002;13(12):2888-2897.

7. Dinnel J, Moore BL, Skiver BM, Bose P. Rasburicase in the management of tumor lysis: an evidence-based review of its place in therapy. Core evidence. 2015;10:23-38.

8. US National Library of Medicine. National Institutes of Health. Allopurinol Drug Label Information. Last updated January 31, 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=682dd8b8-fc6e-47c5-95b7-82d7ad96b750. Accessed July 30, 2017.

9. Chemistry Hazards and Emergency Medical Management. US Department of Health and Human Services. FDA Pregnancy Categories. Last updated April 29, 2017. https://chemm.nlm.nih.gov/pregnancycategories.htm. Accessed July 31, 2017.

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