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Zorluk: OrtaPharmacologic Interventions

A 52-year-old man comes to the clinic for an urgent evaluation due to new-onset hand tremors and worsening headaches over the past three days. He underwent a deceased-donor renal transplantation eight months ago for end-stage renal disease secondary to polycystic kidney disease. His maintenance immunosuppression regimen consists of tacrolimus, mycophenolate mofetil, and low-dose prednisone. Two weeks ago, he was seen at a local urgent care clinic for a sore throat and thick, white, scrapable plaques on his tongue and buccal mucosa. He was prescribed a 14-day course of an oral medication for this condition. Today, his temperature is 37.1°C (98.8°F), blood pressure is 158/92 mm Hg, and pulse is 88/min. Physical examination is notable for a fine resting tremor in both hands. Laboratory studies reveal a serum creatinine of 2.4 mg/dL, which is significantly elevated from his baseline of 1.3 mg/dL measured one month ago. Which of the following medications was most likely prescribed at the urgent care clinic?

  1. A
    Acyclovir
  2. B
    Clindamycin
  3. FluconazoleCevap
  4. D
    Nystatin
  5. E
    Terbinafine

Cevap

Fluconazole
The correct answer is the oral triazole antifungal, fluconazole. The patient's initial presentation of thick, white, scrapable plaques on the oral mucosa is diagnostic of oropharyngeal candidiasis (oral thrush), a common opportunistic infection in solid organ transplant recipients on maintenance immunosuppression. His current symptoms of acute kidney injury (elevated creatinine), new-onset tremors, headache, and hypertension are hallmark features of calcineurin inhibitor (tacrolimus) toxicity. Tacrolimus is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme system. Fluconazole is a potent inhibitor of CYP3A4. When fluconazole is coadministered with tacrolimus, it significantly impairs tacrolimus clearance, leading to elevated systemic trough levels and subsequent nephrotoxicity and neurotoxicity. In clinical practice, if systemic azole therapy is required in a patient on a calcineurin inhibitor, empirical preemptive dose reduction of the calcineurin inhibitor and close therapeutic drug monitoring are mandatory.

Adım Adım Çözüm

1
Diagnose the antecedent condition described as thick, white, scrapable plaques on the oral mucosa.
The clinical description is highly specific for oropharyngeal candidiasis (oral thrush), an opportunistic fungal infection common in immunosuppressed patients.
Identifying the initial infection is necessary to determine which class of medication was prescribed at the urgent care clinic.
2
Identify the cause of the patient's current symptoms (tremors, headache, hypertension, and acute kidney injury).
The presentation is classic for calcineurin inhibitor (tacrolimus) toxicity.
Tacrolimus has a narrow therapeutic index; elevated serum levels cause prominent nephrotoxicity and neurotoxicity.
3
Determine which treatment for oral candidiasis precipitates tacrolimus toxicity.
Fluconazole.
Tacrolimus is extensively metabolized by the hepatic and intestinal cytochrome P450 3A4 (CYP3A4) system. Systemic azole antifungals, such as fluconazole, are potent inhibitors of CYP3A4, leading to decreased tacrolimus clearance and subsequent toxicity.

Anahtar Kavram

Pharmacokinetic interactions of CYP3A4 inhibitors with calcineurin inhibitors
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Pharmacologic Interventions

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