Hydroxyurea; Work, Uses, Side Effects & Interactions

In the history of medicine, drugs are in a constant state of development. Most drugs you find nowadays in the pharmacy are more likely to be not present 50 years from now. Drugs are replaced when other more effective, easier and cheaper to produce alternatives are present. In modern medicine, new medications have to prove themselves better than the current gold standard via clinical trials.

Some drugs, on the other hand, have stood the test of time and has remained in clinical practice for decades. This doesn’t always mean they are the best but that other alternatives couldn’t replace them completely since they offer what others can’t, be it price, availability, fewer side effects or even method of administration. Hydroxyurea is a prime example of these medications. The drug was originally developed in the 19th century and remains an integral part of the therapy of many conditions whether alone or -more commonly- in combinations.

What is hydroxyurea?

Hydroxyurea has many names including hydroxycarbamide, hydrea or droxia. The drug was developed by accident and its medical uses weren’t recognized for 50 years after its first production. It is an inorganic compound that is not found in plants. It is formed by the reaction of calcium cyanate with hydrolamine nitrate and was found to exist in minute amount in the human body. The drug belongs to a wide family of anticancer medications called antimetabolites.

How does hydroxyurea work?

Hydroxyurea, like other antimetabolites, acts on the genetic material of cancer cells. It disrupts the replication of DNA by cancer -and normal- cells, which is an integral step in cellular multiplication. It also prevents the DNA from repairing itself after being damaged by other anticancer drugs making it ideal in combinations. The main action of this drug is on an enzyme called ribonucleoside diphosphate reductase.  This enzyme is the one that forms the sugar molecule found all DNA in our body. It is easy to assume, then, that this drug is hardly selective, and that normal cells are affected just like cancer cells, then what makes it, in fact, more selective to cancer cells? The answer is the rate of multiplication.

Cancer cells are cells that lost control over their functions and the rate of their multiplication due to their mutant DNA. If the drug is to act equally on all cells that need to rapidly create more DNA, then chances are that those cells are cancerous ones. Nevertheless, other normal cells of the body like skin and gonadal cells -sperms and ova- also replicate quickly, making them more susceptible. More on that will be discussed in the “side effects” section of the article.

Uses of hydroxyurea

1) Sickle cell anemia: Sickle cell anemia is a condition when the red cells are deformed into a sickle shape rather than the normal biconcave disc structure owing to a genetic abnormality in the hemoglobin gene The main problem in this condition is that the sickle shaped cells occlude small blood vessels causing a severe inflammation and death of tissues. Red cells are usually normal until they are exposed to a certain stressor whether cold, infection or drugs that converts them to sickle shaped cells. Sickle cell anemia was the first medical use of hydroxyurea and it continues to be used for the condition to this day.

Hydroxyurea helps convert the normal hemoglobin to fetal hemoglobin, which is a special type of hemoglobin that is immune to sickling. It also has a negative effect on white blood cells which are central in the production of inflammation that causes most symptoms of sickling.

2) Myeloproliferative neoplasms: Myeloproliferative neoplasms are a group of diseases that result from the uncontrolled proliferation of a single line of mature cells in the bone marrow. There are mainly 4 conditions: Essential thrombocythemia, polycythemia vera, primary myelofibrosis and chronic myelogenous leukemia. The excess number of cells produced in such conditions can have fatal outcomes such as blood clotting and hemorrhage; therefore, a rapid reduction of such number is required and the drug most commonly used for such purpose is hydroxyurea. Here, the main purpose of hydroxyurea is symptomatic relief and avoiding complications rather than a complete cure.

3) Psoriasis: Psoriasis is a skin condition that is caused by an inflammatory reaction leading to the production of plaques of reddish color covered by silver-colored scales. The reason for this appearance is the rapid uncontrolled division of skin cells. As mentioned before, skin cells are very rapidly dividing that on average, a person changes their skin every 2 weeks. Such condition can be effectively managed by steroids to limit inflammation which the main mechanism of the disease and hydroxyurea is used as a second-line therapy to limit the rapid division of skin cells.

Side effects

The main cause of side effects in hydroxyurea is that they inhibit the production and replication of DNA, therefore cells that need rapid replications are the most affected. The rest of the side effects are non-specific and are found in other drugs as well. The most common side effects of hydroxyurea are:

  • Increased risk of infections: White blood cells are our main line of defense against infections. The DNA inhibitory effect of hydroxyurea causes their numbers to fall especially neutrophils. Neutrophils are the first white blood cells to engage any pathogen especially bacteria. A fall in the number of neutrophils is quickly noticed in the body since they form the greatest bulk of white blood cells. Infections that are noticed in such conditions include bacterial infections like abscesses and furuncles, viral infections like common cold and influenza and fungal infections like candidiasis. If such fall in WBC is great enough, infections can be silent, necessitating careful monitoring of patients and prompt antibiotiuc therapy at the first sign of bacterial infections.
  • Skin irritation and rashes: Skin cells are one of the most commonly affected by hydroxyurea and this appears in the form of skin rashes, redness, vesicles and irritation.
  • Lips, gums and tongue: The same picture that appears on the skin can appear on any mucous membrane including the lips, the tongue, gums and vagina since those surfaces are covered by the same cellular lining like the skin -minus the hard keratin-.
  • Easy bruising and bleeding: Bleeding is controlled by several mechanisms and one of the main causes as to why we don’t bleed to death from a minor injury is our platelets. Platelets plug any defect in blood vessels and ensure that a blood clot is formed. Platelets are replaced every 1-2 weeks from their mother cells in the bone marrow. Hydroxyurea can affect the replication of such cells causing a fall in platelet number.
  • Diarrhea, vomiting and abdominal pain: Most drugs taken orally are liable to cause abdominal pain, nausea and vomiting since people react to oral medications differently, but hydroxyurea has an added harmful effect on the cell lining the gastrointestinal tract since they also replicate rapidly, so they are liable to be shed without replacement causing severe colics, diarrhea and even ulceration.
  • Neurological side effects: Some patients may report some neurological symptoms like headaches, dizziness and hallucinations. The mechanism for such side effects is largely not known, but it is thought to result from a deficiency of vitamin B12.
  • Anemia: Anemia due to hydroxyurea is not as severe as in other anticancer medications, but it can result from several mechanisms. It can be as a direct effect of hydroxyurea or from a parvovirus infection due to the immunosuppression produced by hydroxyurea which in turn causes bone marrow suppression or from vitamin B12 deficiency.
  • Other non-specific side effects include:
    • Constipation
    • Weight gain
    • Hyperpigmented patches on the skin
    • Anorexia
    • Breathlessness
    • Burning sensation during voiding
    • Elevated liver enzymes
    • Elevated creatinine and blood urea
    • Renal failure (very rare)

How do doctors monitor hydroxyurea patients?

  • The main concern in patients treated with hydroxyurea is the development of bone marrow failure, therefore, frequent blood testing is a necessity in the form of a complete blood count. Other special testing may also be needed depending on symptoms and the overall condition of the patient.
  • There have been reports of development of leukemia in patients chronically treated with hydroxyurea for sickle cell anemia, however, no reliable study provided reliable evidence of such occurrence. However, in patients treated with hydroxyurea for myeloproliferative neoplasms, the development of acute leukemia is a known occurrence and is anticipated and treated.
  • Vitamin B12 deficiency is commonly found in patients treated with hydroxyurea and therefore, it is usually administered as a routine.
  • Hydroxyurea has not been tested on pregnant women and is therefore considered generally unsafe and if its administration is necessary, careful monitoring of the fetus and the mother is done.