Tacrolimus toxicity

Cyclosporine, tacrolimus Ketoconazole, erythromycin, etc. CYP3A4 Cydosporine/tacrolimus toxicity... 

It is often difficult to differentiate ARF from acute rejection in the kidney transplant recipient, as both conditions may present with similar symptoms and physical examination findings. However, fever and graft tenderness are more likely to occur with rejection while neurotoxicity is more likely to occur with cyclosporine or tacrolimus toxicity. Kidney biopsy is often needed to confirm the diagnosis of rejection.42... 

TACROLIMUS DANAZOL Cases of t tacrolimus levels Uncertain Watch for early features of tacrolimus toxicity... 

CHLORAMPHENICOL ANTICANCER AND IMMUNOMODULATING DRUGS-TACROLIMUS Toxic blood levels of tacrolimus, usually on the second day of starting chloramphenicol Attributed to impaired clearance of tacrolimus by chloramphenicol 1 dose of nearly 80% of tacrolimus may be required to prevent toxicity. Watch for adverse effects (see below). Monitor tacrolimus plasma concentrations... 

Cardiac symptoms manifesting as myocardial ischemia are uncommon, but can occur through tacrolimus toxicity (22). 

Campo JV, Smith C, Perel JM. Tacrolimus toxic reaction associated with the use of nefazodone paroxetine as an alternative agent. Arch Gen Psychiatry 1998 55(ll) 1050-2. 

Among the differential diagnoses are acute rejection, ATN, and/or cyclosporine or tacrolimus toxicity (see Chap. 46). These processes are not mutually exclusive. Definitive diagnosis is made by renal biopsy. In the presence of an elevated serum creatinine level, clinicians may reduce the dose of cyclosporine or tacrolimus to minimize the potential for drug nephrotoxicity and hasten the recovery from ATN. This practice may result in subtherapeutic immunosuppressant concentrations and hasten the occurrence of acute rejection. DGF predisposes patients to acute rejection. Induction therapy (e.g., using antibody preparations) and delaying the initiation of cyclosporine or tacrolimus administration may be useful in this setting. 

Ocran KW, Plauth M, Mai I, Lochs H. Tacrolimus toxicity due to drug interaction with mibefradil in a patient after liver transplantation. Z Gastroenterol 1999 37 1025-1028. 

In an isolated case, metoclopramide may have increased tacrolimus levels, resulting in tacrolimus toxicity and acute renal failure. 

This appears to be the only reported case of tacrolimus toxicity, with metoclopramide, and, because of the number of complicating factors, it is by no means established. Its general significance is unclear. 

McLaughlin GE, Rossique-Gonzalez M, Gelman B, Kato T, Use of phenobarbital in the management of acute tacrolimus toxicity a case report. Transplant Proc (2000) 32, 665-8,... 

O Connor AD, Rusyniak DE, Mowry J. Acute tacrolimus toxicity in a non-trans-plant patient. Clin Toxicol (Phila) 2008 46(9) 838-40. 

Hooper DK, Fukuda T, Gardiner R, Logan B, Roy-Chaudhury A, Kirby CL, et al. Risk of tacrolimus toxicity in CYP3A5 nonexpressors treated with intravenous nicardipine after kidney transplantation. Transplantation 2012 93 806-12. 

Tacrolimus Toxicity has been reported in an HIV patient xmdergoing allogeneic HSCT [316 ]. Toxic levels of tacrolimus were due to the concurrent use of ritonavir. Concomitant use of ritonavir and tacrolimus leads to a reduction in the first pass and post-absorptive metabolism of tacrolimus, and its AUC may be increased up to 10-fold and half life may be prolonged for as long as 20 days. 

Cyclosporine is associated with hyperglycemia and central nervous system (CNS) toxicities, but to a much lower extent than tacrolimus. 

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Hydroxyurea is an older agent still used occasionally today for patients with psoriasis however, there have been recent precautions about its use in the elderly and cutaneous vasculitic toxicities in patients with myeloproliferative disorders.29 Toxicity associated with tacrolimus has limited its use in psoriasis. Azathioprine has a slow onset and significant toxicity.29 Oral corticosteroids are reserved for severe or life-threatening conditions such as severe psoriatic arthritis or exfoliative psoriasis prolonged oral steroid use should be avoided.10... 

After transplantation, immunosuppression must be used to prevent host rejection of the graft liver, usually with prednisone and tacrolimus or cyclosporine. Tacrolimus and cyclosporine are calcineurin inhibitors and require drug level monitoring because of a narrow therapeutic range and significant toxicity, including renal failure and neurotoxicity. 

Although cyclosporin A had been the only immunosuppressant product on the market for many years, two other actinomycete products provided new opportunities. These are rapamycin (sirohmus) and FK-506 (tacrolimus). They are both narrow spectrum polyketide antifungal agents, which are 100-fold more potent than cyclosporin as immunosuppressants and less toxic. Rapamycin and FK-506 sales in global markets reached 1.5 and 2 billion in 2007, respectively. ... 

Concentration dependent toxicity Aminoglycosides Cytotoxic agents Ciclosporin Digoxin Lithium Tacrolimus Theophylline Warfarin... 

Tacrolimus is used in situations where cyclosporine has been shown to be ineffective or cannot be used because of toxicity or otherwise. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants and in vitiligo. 

Whole blood tacrolimus concentrations as measured by ELISA may be helpful in assessing rejection and toxicity, median trough concentrations measured after the second week of therapy ranged from 9.8 to 19.4 mg/ml... 

Tacrolimus can be administered orally or intravenously. The half-life of the intravenous form is approximately 9-12 hours. Like cyclosporine, tacrolimus is metabolized primarily by P450 enzymes in the liver, and there is potential for drug interactions. The dosage is determined by trough blood level at steady state. Its toxic effects are similar to those of cyclosporine and include nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and gastrointestinal complaints. 

Toxicities of the PSIs can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache. Because nephrotoxicity is of major concern when administering calcineurin inhibitors, there is interest in increased early use of PSIs since renal toxicity is less common with these agents. However, increased use in stem cell transplantation regimens as graft-versus-host disease prophylaxis, particularly when combined with tacrolimus, has revealed an increased incidence of hemolytic-uremic syndrome. 

As for cyclosporine, its blood concentration is impacted by drugs that act on the CYP3A system. Drugs that inhibit this enzyme will increase its blood concentration and drugs that enhance the activity of CYP3A will decrease the blood concentration of tacrolimus. In combination with cyclosporine, it produces additive renal toxicity. 

The exact mechanisms of tacrolimus-induced diabetes are unknown. In one renal transplant patient with genetic susceptibility, tacrolimus was associated with insulin-dependent diabetes mellitus and the simultaneous occurrence of anti-glutamic acid decarboxylase antibody (1096). Within 2 months after conversion from tacrolimus to ciclosporin, the antibody was no longer detected and the patient s insulin requirements fell dramatically. Tacrolimus-induced direct beta cell toxicity, with... 

Adverse Effects. Common side effects of tacrolimus include gastrointestinal disturbances (cramps, nausea, diarrhea, constipation), weakness, fever, and skin rashes and itching. More serious problems include renal and central nervous system (CNS) toxicity (headache, anxiety, nervousness, seizures).41 Tacrolimus is also associated with problems with glucose metabolism (hyperglycemia, glucose intolerance), and can cause diabetes mellitus in certain individuals.73... 

Antibodies that block the interleukin-2 receptor, thus preventing interleukin-2 from activating T lymphocytes, have also been developed.24,62 These antiinterleukin-2 receptor agents, such as basiliximab (Simulect) and daclizumab (Zenapax), may be helpful in reducing the incidence of acute transplant rejection.13 Antibodies seem to be especially useful in the initial (induction) phase of antirejection treatment because these drugs can delay or supplant the use of more toxic immunosuppressants such as the glucocorticoids and calcineurin inhibitors (cyclosporine and tacrolimus).3,56... 

The most significant impact of these drugs on rehabilitation is related to their side effects, especially those of the immunosuppressants. These drugs are typically used in high doses to produce immunosuppressive effects, which are often achieved at the expense of serious and toxic side effects. Many immunosuppressants, especially the glucocorticoids, exert catabolic effects on bone, muscle, and other tissues. Other immunosuppressants, such as cyclosporine and tacrolimus, are neurotoxic and may cause peripheral neuropathies and CNS-related problems in balance and posture. 

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