Scenario and Implications Drug Interaction

Drug Interaction Scenario

Drug interactions involve pharmacokinetics and pharmacodynamics interactions. Pharmacokinetics occurs when a drug interacts with another drug at the level of absorption, metabolism, or even excretion. A clinical application applies the effective and safe management of drugs therapeutically. The relationship between drug concentrations and how they respond pharmacologically has helped in applying pharmacokinetic principles in situations of actual patients. On the other hand, pharmacodynamics gives the relationship between the concentration of drugs at the site of action and the effects like the intensity of therapeutic, time course, and the adverse effects. The binding of drugs with the receptors determines the influence of drugs at the site of action. In most drugs, the intensity of the impact of the drugs is determined by the concentration at the receptor site.

In this assignment, the drug interaction scenario is between Febuxostat and Azathioprine since each drug interaction pair will have a scenario associated with it. The drug interaction to be managed is that of a patient taking Febuxostat due to a recent gout flare-up and Azathioprine due to a liver transplant that happened two years ago. The patient has a record of immunosuppressive agents that have repeatedly failed, but the condition is now stable (Gerriets & Jialal, 2021). The mechanism of action of Febuxostat is that it is used to manage chronic hyperuricemia in adults who suffer from gout and those who have an intolerance to allopurinol. It does this since it is a xanthine oxidase inhibitor. The therapeutic effect of this drug is achieved by lowering the uric acid of serum. This is the febuxostat primary mechanism action evidenced by reduced purine synthesis.

The pharmacokinetic profile of febuxostat is a xanthine oxidoreductase developed to help treat gout. After multiple-dose administration of febuxostat, the pharmacokinetic parameters include about 85% of oral availability. It also consists of an oral clearance of 10.5 ± 3.4 L/h and a distribution volume at a steady state of 48 ± 23 L. its administration is once daily. There is no significant accumulation of this drug (Gerriets & Jialal, 2021). For those patients with gouts, this drug has little data on the pharmacokinetics of febuxostat on these patients. This drug is metabolized extensively by oxidation which is 35%, and through acyl glucuronidation, up to approximately 40%. The concentration reductions percentages of serum urate are less in patients with gout since multiple doses reduce it by 80%.

Mechanism of Action of Febuxostat

On the other hand, the mechanism of action of Azathioprine is not well-defined. Still, it is related to the synthesis of purine inhibition which occurs along with the inhibition of B and T cells (Logan et al., 2020). A metabolite of Azathioprine which is 6-thioguanine triphosphate, helps activate rac 1 when stimulated with CD28. This then induces apoptosis of T cells mediated through the action of rac 1 on protein kinase that is mitogen-activated. The incorporations of its metabolites are the halt division and replicating DNA. The metabolites of this drug mediate most of the toxic and immunosuppressive effects. Azathioprine is rapidly absorbed through the G1 system but does not penetrate the blood-brain barrier. Its metabolism occurs in the liver and is excreted via kidneys, increasing renal failure toxicity levels.

The structure of Azathioprine is as follows.

Mechanism of Action of Azathioprine

Based on interaction, Azathioprine, an immunosuppressive agent, is first metabolized to mercaptopurine. The drug interaction between xanthine oxidase inhibitors and thiopurine immunosuppressants, Azathioprine, and mercaptopurine, is well known (Mohammadi & Kassim, 2021). After that, it is then converted by a metabolizing enzyme called xanthine oxidase to inactive products. Febuxostat impacts Azathioprine by inhibiting xanthine oxidase, which may lead to high plasma concentrations of Azathioprine, which then causes toxicity. The studies revealing the co-administration of febuxostat with medicines metabolized by xanthine oxidase are limited. Therefore, it is not recommendable for patients to use febuxostat when treated with Azathioprine like in our case scenario. However, in this case, Azathioprine has proved to be the only stable immunosuppressive agent for the patient. Therefore, the two cannot be separated; hence the patient should be monitored closely in this case. It would mean reducing the azathioprine dose to avoid haematological effects.

The clinical consequences of the interaction between these two drugs result in myelosuppression. It is due to the inhibition of the xanthine oxidase enzyme, which increases the azathioprine concentrations and the 6-MP active metabolites (Jordan & Gresser, 2018). In a case series of drug interactions obtained from the United States and Drug Administration Adverse Event Reporting System, nineteen cases of patients who received febuxostat with Azathioprine reported myelosuppression events. Sixteen of those cases required hospitalization, and most of them reported discontinuation of those two drugs. The limitation is that complications due to immunosuppression may lead to mortality and morbidity due to the drug interaction of febuxostat and thiopurine.

In the therapeutic effect of managing gout, xanthine oxidase is inhibited by allopurinol and is involved in the catabolism of Azathioprine (Jordan & Gresser, 2018). The use of inhibitors of xanthine oxidase and Azathioprine may cause myelosuppression. Sulfasalazine inhibits the Thiopurine methyltransferase enzyme hence inhibiting the metabolism of Azathioprine. This increases myelotoxicity since the Thiopurine methyltransferase enzyme is involved in the metabolism of the immunosuppressant drugs Azathioprine. When there is a lack of this enzyme, the patient is therefore at risk of potential suppression of bone marrow which is fatal due to these drugs. It can also lead to inflammatory disorders that are chronic and increased cardiovascular diseases which are adverse effects due to the interactions of these drugs.

The use of Azathioprine as a stable immunosuppressive agent in the treatment of liver transplants is not recommendable with febuxostat (Logan et al., 2020). This is because febuxostat can increase blood levels for Azathioprine to high levels. However, since other immunosuppressive agents have failed for this patient, the two can be used. Hence, the dosage level of Azathioprine should be reduced to a certain recommendable level to avoid effects to the patient’s body that may be adverse therefore causing further damage to the tissues due to effects like inflammatory disorders.

In a present evaluation, the revealed outcomes concluded an increase in adverse events incidence. These adverse events increased due to an increase in liver function impairment (Jordan & Gresser, 2018). The probability of this occurrence is due t the side effects of this patient in the case scenario having an impairment of the living function that is pre-existing. It applies primarily due to the hypersensitive reactions generally. According to the findings, for such a patient with impaired liver function due to a transplant, the febuxostat dosage should not exceed 80mg of daily dosage. The dosage should remain consistent according to the current information provided by febuxostat. This is the recommended dose for treating gout for a patient suffering from a liver transplant.