Thioguanine

Posted: January 5th, 2023

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Thioguanine

The paper focuses on the thioguanine drug, which is used to treat leukemia. It gives substantial background about the medication, and shows how both doctors and patients should consider the possible side effects that are likely to occur when taking thioguanine. The study gives valuable information concerning pharmacokinetic variability associated with thioguanine, which gives much awareness about the drug’s metabolism. Bedsides, the paper offers some insight into studies performed to recommend dosage in accordance with a patient’s genetics, and formulates a patient case study to illustrate how thioguanine helps to treat leukemia. The report encourages practitioners to be conversant with the properties of the medication to improve patient outcome.

Drug Background

Thioguanine is a medication used in treating a particular kind of cancer called acute myeloid leukemia (AML). It works as a chemotherapy drug that inhibits or halts further growth of the cells causing the cancer (Dean). A patient takes the medication orally after or before consuming a meal as instructed by a practitioner. Unless the doctor directs otherwise, one should consume a lot of fluids while on this drug. The dosage for Thioguanine could differ from one person to the other depending on their reaction to medication, weight, and general medical condition (Dean). Users of the medication should not increase medication without consulting a specialist, and should not use it for longer than the recommended duration. Taking more dosages or prolonging the time of use does not imply that the condition will improve much faster, instead one only increase their risk for experiencing serious side effects (Dean). However, a patient should use the medication as regularly as indicated to achieve the best outcome. An essential factor to consider when using the drug are the possible side effects that are likely to occur, although this may vary from one person to the other. Some of the side effects that a person may have to inform their doctor about if they fail to disappear, include nausea, vomiting, sore throat and mouth, headache, and loss of weight and appetite (Dean). However, serious side effects such as bloody vomit, bloody stool, swelling of the stomach, and change in skin color may require urgent intervention. Inter-individual variability that could prompt adjustment in dosage, include pregnancy, comorbidity, age, and ability to respond to the drug (Dean). Thus, it is essential to first examine a patient to determine if administering Thioguanine will not cause any serious effects.

Cause of Variability

Thioguanine can be termed as drug that suppresses purine metabolism. The drug causes cytotoxic repercussions though adding thiodeoxyguanosine triphosphate to one’s deoxyribonucleic acid (DNA). The medication also incorporates thioguanosine triphosphate into the ribonucleic acid. The drug acts as an inhibitor for RAC1 (ras-related C3 botulinum toxin substrate 1), which evokes cellular death of generated T cells (Derijks et al. 46). Once it enters a cell, the HPRT (hypoxanthine-guanine phosphoribosyltransferase) changes the drug to 6-thioguanosine monophosphate where it again converts to 6-thioguanosine diphosphate (Derijks et al. 46). Finally, the drug transforms to 6-thiodeoxyguanosine diphosphate and 6-thiodeoxyguanosine triphosphate, respectively when it cause cell toxicity upon entering the DNA. The brief drug metabolism provides a basis for the cause of variability with regard to the drug.

Thioguanine’s drug variability or pharmacokinetic variability largely depends on the drug’s metabolism. Thioguanine’s pharmacokinetic variability occurs from variations between individuals (patients) in the taking in, distribution, removal, and metabolism of the medication. Thus, a particular dosage could cause dissimilar drug concentration effects depending on an individual. Derijks et al. (48) perform a systematic literature review with the objective of understanding pharmacokinetic variability of thioguanine in people with inflammatory bowel disease and find no connection between thioguanine concentration and dosage per kg body weight (Derijks et al. 48). Furthermore, the researchers find no substantial variations in thioguanine concentrations between patients with serious effects and patients without any severe concern.

Gene Allele

It is imperative to know the possible functional effects, population prevalence, and dosing associated with thioguanine. Some of the functional effects already identified as relating to the medication, include mouth sores, loss of appetite, and vomiting (Hao, Li-Talley, Buck and Chen). However, the effects differ depending on one’s genes or possible mutations that could alter their genetic composition and alignment. The population prevalence for those using thioguanine is growing with the increasing cancer cases reported in the United States. Production of the drug is expected to pummel in the near future if the current trend of infection prevails (Hao, Li-Talley, Buck and Chen). More fundamentally, it is essential to watch the dosing depending on the level of severity, age, past medical history, and existence of other medications.  

Thioguanine contains thioguanine nucleotides as the main active metabolites. The enzymes nudix hydrolase 15 (NUDT15) and TPMT (thiopurine methyltransferase) are responsible for metabolizing and inactivating the active metabolites in thioguanine (Dean). Thus, patients with low activity of one or both enzymes are exposed to higher chances of developing effects associated with the drug, and are likely to experience toxicity effects, encompassing developing a condition known as myelosuppression, which is associated with serious suppression of the bone marrow. Nevertheless, one’s reaction to the medication would also depend on the variations of their alleles. For example, a person regarded as normal metabolizer, or who has two sets of the CYP2C19 gene that is associated with normal activity is likely to respond to the reactions quite effectively (Dean). Nevertheless, those termed as poor or intermediate metabolizers could experience significant constraints in breaking down medications, thus increasing the chances for experiencing serious side effects. It would mean the standard dose of thioguanine, which is 2mg/kg per day used orally, or 3mg/kg per day if the initial dose fails to produce anticipated results within four weeks, may not function as projected (Dean). More fundamentally, one’s race cannot largely determine how they respond to the medication, but their phenotype, especially their blood type could significantly influence reactions and possible effects (Dean). The FDA recommends for testing any deficiencies in NUDT15 and TPMT levels, particularly for those experiencing cases of myelosuppression. The FDA, according to Dean, further endorses considering other medication for individuals with high deficiency levels of NUDT15 or TPMT, or both, and lower dosages for those lacking function allele, suggesting that a more significant reduction of the dosage may be needed for patients who are poor metabolizers of NUDT15 or TPMT.

Clinical Implications

The primary clinical implication of thioguanine medication are that clinicians must be conversant with how the drug functions, and prepare health workers to deal with patients taking the drug. More health facilities are equipping their staff with advanced knowledge regarding all the aspects of the drug, and individual practitioners are increasingly identifying sources that give latest and credible findings about how thioguanine medication works and its possible effects on consumers (Hao, Li-Talley, Buck and Chen). The increased urge to be conversant with thioguanine could be attributed to the fact that compared to all forms of cancers, cases of leukemia have escalated rapidly, from about 28,600 incidences in 1998 to approximately 60,000 by beginning of 2018, an increase of 110% (Hao, Li-Talley, Buck and Chen). The researchers further state that the year 2006 and 2007.witnessed the worst upsurge in leukemia cases ever witnessed (Hao, Li-Talley, Buck and Chen). Doctors are also turning their attention to the drug, trying to understand its components and application because the mortality rate associated with the condition has risen from about 21,000 in 1998 to more than 24,000 in 2018 (Hao, Li-Talley, Buck and Chen). The steadily ascending infection curve means that health workers must be conversant with possible treatment options that could help affected individuals lead a healthy life. Other than acquiring information from various resources about the drug’s components and use, health facilities are adequately preparing their work stations and employees to deal with the possible aftermath associated with taking thioguanine (Hao, Li-Talley, Buck and Chen). All these increased effort are aimed towards providing better services for leukemia patients.

Genetic Tests to Guide Dosage

Various scholars have performed genetic tests to provide direction on the proper dosage for thioguanine. Dean, for example, reports of a study, which reveals that people with decreased activity either enzymes nudix hydrolase 15 or thiopurine methyltransferase are largely exposed to higher effects of thioguanine, and are likely to experience higher levels of side effects associated with toxicity. Such patients could also develop a condition called myelosuppression, which is associated with suppression of the bone marrow. The findings affirm that thioguanine works differently in people, chiefly due to their varying genetic composition.

Patient Case Scenario

A 46-year-old lady awoke few hours after falling asleep after developing serious chills. She felt weak the whole day and assumed it could be due to the house chores he has been performing in the past few days. A few hours after trying to catch her sleep again, the lady starts sweating profusely, which prompts her husband, a 50-year-old mechanic, to bring her to the hospital.

The patient is aware of her surrounding and depicts this in the way she dresses, speaks, and relate with others. She appears to be concerned about her situation, and thinks something bad could be happening to her.

Subjective Data

• Feels fluctuating fever
• Reports relentless fatigue for the past few days
• Incidences of nose bleeding in the past month
• Increased sweating at night
• Decreased body weight

Objective Data

• Temperature: 38⁰C
• Blood pressure: 145/90
• Skin color and texture: itchy red spots on the skin
• Heart rate: 1.14 

Diagnosis

Examining the client’s blood sample via a complete blood count reveals an irregular white cell count. Further tests, including an assessment of a sample of bone marrow from the pelvic bone and a needle biopsy that utilizes a specialized needle to retrieve samples from areas of the body showing abnormal development. The diagnosis reveals the client suffers from acute myeloid leukemia.

Treatment

The patient will take thioguanine 40-mg orally once a day until the situation subsidizes. However, it is imperative to engage in continuous follow-up to ensure the patient does not develop adverse effects, and to monitor the recovery process.

Works Cited

Dean, Laura. “Thioguanine Therapy and TPMT and NUDT15 Genotype.” NCBI, 7 August, 2020, https://www.ncbi.nlm.nih.gov/books/NBK100663/. Accessed 1 June 1, 2021.

Derijks, Luc et al. “Pharmacokinetics of 6-Thioguanine in Patients with Inflammatory Bowel Disease.” Therapeutic Drug Monitoring, vol. 28, no. 1, 2006, pp. 45-50.

Hao, Taisen, Li-Talley Min, Buck Alison and Chen WenYong. “An Emerging Trend of Rapid Increase of Leukemia but Not All Cancers in the Aging Population in the United States.” Scientific Reports, vol. 9, https://www.nature.com/articles/s41598-019-48445-1