How Genes Influence Allopurinol Allergy?

What Is Allopurinol?

Allopurinol is a drug that prevents the build-up of uric acid in the blood, which is a primary cause of conditions like gout and kidney stones.

Gout is characterized by the deposition of monosodium urate (uric acid) crystals in body tissues like the joints.

Allopurinol is metabolized (broken down into smaller molecules) in the liver, and around 80% of orally ingested Allopurinol is excreted via urine.

The most commonly used form of Allopurinol is orally ingestible tablets. However, Allopurinol is also available in the IV form.

Gout treatment using Allopurinol is usually a long-term one, and patients can expect their condition to improve after taking the drug for a few months.

How Does Allopurinol Work?

Allopurinol gets metabolized into oxypurinol in the liver.
Oxypurinol inhibits the enzyme xanthine oxidase that converts hypoxanthine to xanthine and xanthine to uric acid.
The inhibition of xanthine oxidase results in the increased re-utilization of hypoxanthine and xanthine for nucleotides (building blocks of DNA and RNA). This decreases the production of new uric acid.
As a result, there is less uric acid in urine and serum.
Due to a lowered uric acid concentration in serum, Allopurinol encourages the uric acid in the joints to dissolve, thereby relieving gout symptoms.

Though there may be an increase in hypoxanthine and xanthine levels after taking Allopurinol, the risk of their deposition in kidney tissues and joints is less than that of uric acid because they are more soluble and more quickly eliminated by the kidneys.

Allopurinol and its metabolites (intermediaries or end-products of metabolism) are mainly eliminated via the kidneys.

Therefore, any accumulation of Allopurinol in patients with kidney conditions can be a cause of concern.

For this reason, people with kidney conditions must always inform their doctor of their condition before taking Allopurinol.

What Are The Side Effects Of Allopurinol?

If you experience any side effects from taking Allopurinol, you must stop the medication immediately and report it to your healthcare provider.

Allopurinol may cause drowsiness, so you must not operate any heavy machinery, drive or perform tasks that require you to be alert.

Other common side effects of Allopurinol include

Skin rash
Diarrhea
Nausea
Abnormal results of Liver Function Tests (LFT)
Aggravation in gout symptoms if you have the condition

Though many mild side effects caused by Allopurinol may subside within a few days to weeks, you must report to your doctor if you experience any of the following severe side effects:

Raised bumps on your skin
Reddish-purple spots on your skin
Scales on your skin
Fever
Chills
Difficulty in breathing
Swelling in your face or throat
Signs of liver injury include loss of appetite, tiredness, fatigue, weight loss, yellowish coloration of the eyes and skin, dark-colored urine, and pale-colored stool.

How Does Allopurinol Interact With Other Drugs?

Allopurinol oral tablets may interact with other medications, nutritional supplements, and herbs that you may be taking.

Therefore, it is always recommended that you inform your doctor about all medications and supplements you are taking before taking Allopurinol.

Some common medications that Allopurinol interacts with and causes adverse effects are:

Ampicillin or amoxicillin

Ampicillin and amoxicillin are antibiotics used in treating bacterial infections.

If you take either of these medications along with Allopurinol, you may have an increased risk of developing a skin rash.

Thiazide diuretics (like hydrochlorothiazide)

Thiazide diuretics are commonly used in treating hypertension (high blood pressure).

However, taking thiazide diuretics with Allopurinol may cause an increased risk of side effects like skin rash, diarrhea, nausea, or a flare-up of gout symptoms.

Mercaptopurine

Mercaptopurine is a drug used in the treatment of cancer and some autoimmune diseases.

Taking Allopurinol while taking mercaptopurine can increase the levels of mercaptopurine in the blood.

This rise in mercaptopurine levels in the blood can trigger side effects of the drug such as black tarry or clay-colored stools, decreased appetite, fever, chills, nausea, vomiting, rash, or itchy skin among others.

To prevent this from happening, your doctor may reduce your dosage of mercaptopurine.

Azathioprine

Azathioprine is an immunosuppressive drug (used to suppress the immune system reaction) used in treating conditions like rheumatoid arthritis, ulcerative colitis, kidney transplants, etc.

If you are taking azathioprine, taking Allopurinol can increase the blood levels of this drug by blocking the enzymes that help break down azathioprine.

Unfortunately, this results in side effects of azathioprine such as abdominal pain, nausea, vomiting, loss of appetite, unusual bruising, fatigue, etc.

So, before your doctor prescribes Allopurinol, they may reduce your azathioprine dosage.

Cyclosporine

Cyclosporine is an immunosuppressant medication, and taking Allopurinol with it can increase cyclosporine levels in the blood.

Therefore, your doctor may need to alter your cyclosporine dosage if they prescribe Allopurinol to you.

Other drugs that may interact with Allopurinol are blood thinners like warfarin, capecitabine (an anti-cancer drug used to treat breast cancer, gastric cancer, and colorectal cancer), and didanosine (used in treating HIV).

Allopurinol: Gene-Drug Interactions

HLA-B Gene and Allopurinol

The HLA-B gene is a part of the Human Leukocyte Antigen or HLA complex.

The HLA complex helps the immune system differentiate between the body’s proteins and those of foreign origin, like viruses and bacteria.

Due to this property of HLA genes, they are responsible for drug hypersensitivity reactions.

A type of the HLA gene called the HLA-B*58:01 is strongly associated with severe Cutaneous Adverse Drug Reactions with Allopurinol treatment.

This type is more common in the Asian population, particularly in people of Korean, Han-Chinese, or Thai descent.

In addition, people of Thai descent with the HLA-B*58:01 type were also found to be at an increased risk of Allopurinol-induced Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).

To avoid these skin conditions, people who have the HLA-B*58:01 gene must be prescribed an alternative drug to Allopurinol, or the drug dosage must be reduced.

HLA-B*58:01, therefore, acts as a genetic marker for screening Thai people who may be at risk for Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).

ABCG2 Gene and Allopurinol

ATP-Binding Cassette subfamily G member 2 or the ABCG2 gene is a part of the ATP-Binding Cassette family.

This gene provides instructions for making transport proteins that help in the movement of molecules across cell membranes.

In the intestine, the ABCG2 protein is responsible for releasing a substance called urate into the urine.

This protein also helps eliminate chemotherapeutic drugs from organs and tissues.

Changes (or mutations) in the ABCG2 gene have been associated with gout.

These changes reduce the body’s ability to remove urate from blood, which causes a rise in blood urate levels.

This excess urate begins to accumulate in the joints as uric acid crystals, resulting in gout.

rs2231142 is a single nucleotide polymorphism (SNP) in the ABCG2 gene. It is also called Q141 or C421A.

The A allele of this SNP is the risk allele and makes one susceptible to gout.

Genotype	Effect
CC	Normal
AC	1.74x increased risk of gout
AA	Causes Gout

Recommendations For The Safe Use Of Allopurinol

Kidney Diseases

If you have a kidney condition, you may not efficiently clear Allopurinol and its metabolites.

This increases the levels of the drug in the body, making you susceptible to its side effects.

Allopurinol may also decrease kidney function in such individuals.

Depending on some factors, an alternate drug or altered dosage may be suggested.

Pregnancy and Breastfeeding

Allopurinol should not be used in pregnant women without consulting a doctor.

It is known to be a category C pregnancy drug which means that animal studies have shown adverse effects on the fetus or that there aren’t enough studies to show Allopurinol is safe for pregnant women.

In emergency cases, Allopurinol may be given to pregnant women but only after a thorough evaluation by a doctor.

It has been found that Allopurinol passes into breast milk and may cause side effects in the baby.

So, if you are breastfeeding, you must inform your doctor about the same before taking Allopurinol.

Children and Elders

There aren’t enough studies that show the effects of Allopurinol in children below 18 years of age.

Therefore, Allopurinol must be avoided for treating gout in children below 18 years.

The kidneys in older adults do not function as efficiently as they do in younger adults.

This impaired kidney function in seniors impacts Allopurinol clearance from the body and increases the risk of side effects of the drug in this age group.

Other Pre-existing Medical Conditions

If you have any of the following pre-existing medical conditions, you must inform your doctor before taking Allopurinol:

Liver disease
Diabetes
Congestive heart failure
High blood pressure
Chemotherapy

This information also helps your doctor determine the appropriate dosage of Allopurinol for you.

Water Intake

While taking Allopurinol, you must consume at least eight glasses of water every day or as directed by your doctor.

This is because drinking plenty of water or fluids helps your body get rid of the excess urate (uric acid).

Alcohol Consumption

Allopurinol may make you drowsy.

If you take alcohol with Allopurinol, it can increase drowsiness.

Additionally, alcohol may reduce the effectiveness of Allopurinol.

So, it is recommended that you reduce or avoid alcohol intake while taking this drug.

Genetic Testing

Genetic testing gives a deeper insight into how your body may react to a specific drug and your risk of developing side effects.

It also helps your doctor determine the appropriate dosage of a particular drug for you.

Allopurinol is not indicated in carriers of the HLA-B*58:01 as they are at risk of developing skin-related adverse reactions to the drug.

Analyze Your Genetic Response to Allopurinol

Summary

Allopurinol is an effective drug used in treating gout and kidney stones as it prevents the build-up of uric acid in the body.
Allopurinol works by inhibiting the enzyme xanthine oxidase that participates in the formation of uric acid from hypoxanthine and xanthine.
Allopurinol may cause side effects like drowsiness, skin rash, diarrhea, etc.
Allopurinol is known to interact with medications like ampicillin, amoxicillin, mercaptopurine, etc.
HLA-B*58:01, a type of the HLA-B gene, is associated with severe skin-related adverse effects of Allopurinol in a few Asian subpopulations.
To ensure safe consumption of Allopurinol for gout, you must inform your doctor about any existing medical conditions, pregnancy, and lactation.
Genetic testing is advisable before Allopurinol therapy to determine if you have the HLA-B*58:01 variant.

References

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