Calcineurin inhibitors toxicity

Liptak P, ivanyi B. Primer Histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat Clin Pract Nephrol 2006 2 398-404 ... 

One of the major drawbacks of calcineurin inhibitors is their ability to cause acute and chronic nephrotoxicity. Acute nephrotoxicity has been correlated with high calcineurin inhibitor doses and usually is reversible. Chronic toxicity, however, typically is irreversible and is linked to chronic drug exposure. Table 52—4 expands on the more common calcineurin inhibitor-induced adverse events. 

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

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. 

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. 

These agents have toxicities similar to ACE inhibitors but less cough. Anemia has been noted in patients on calcineurin inhibitors. 

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... 

Tubular cell toxicity This involves the cellular transport systems mentioned previously and is thus dose dependent to a degree. Examples of tubular cell toxins include aminoglycosides, calcineurin inhibitors, amphotericin, antiviral agents, cisplatin, methotrexate, contrast agents and cocaine. 

Langford CA, Klippel JH, Balow JE, James SP, Sneller MC. Use of cytotoxic agents and cyclosporine in the treatment of autoimmune disease. Part 2 Inflammatory bowel disease, systemic vasculitis, and therapeutic toxicity. Ann Intern Med 1998 129 49-58. Ponticelli C. Calcineurin-inhibitors in renal transplantation. Too precious to be abandoned. Nephrol Dial Transplant 2000 15 1307-1309. 

Knight RJ, Kahan BD.The place of sirolimus in kidney transplantation Can we reduce calcineurin inhibitor renal toxicity Kidney Int 2006 70 994-999. 

Toxicity The principal adverse reactions to cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, hyperhpidemia, and gum hyperplasia. Hyperuricemia may lead to worsening of gout, increased P-glycoprotein activity, and hypercholesterolemia. Nephrotoxicity occurs in the majority of patients treated and is the major indication for cessation or modification of therapy. Hypertension occurs in -50% of renal transplant and almost all cardiac transplant patients. Combined use of calcineurin inhibitors and glucocorticoids is particularly diabetogenic, although this apparently is more problematic in patients treated with tacrohmus see below). Especially at risk are obese patients, African American or Hispanic recipients, or those with family history of type 2 diabetes or obesity. Cyclosporine, as opposed to tacrolimus, is more hkely to produce elevations in low-density lipoprotein (LDL) cholesterol. 

Sirolimus (rapamycin) (Vezina et al. 1975) is widely used to prevent rejection in organ transplant. It is especially usefiil in kidney transplants because, different from cyclosporine and tacrolimus, it is not a calcineurin inhibitor and therefore is less toxic to the kidney. Sirolimus inhibits T-cell and B-cell activation. It binds to the immunophilin FKproteinl2, and this binary complex inactivates a serine-threonine kinase (mTOR) termed the mammalian target of rapamycin (Huang et al. 2003). The final effect is the arrest at phase G1 of cell cycle progression. This effect occurs not only in T cell and B cells, but it has been observed in many tumor cell lines. Semisynthetic derivatives of rapamycin, suitable for i.v. administration, have been developed as antitumor agents. Temsirolimus was approved by FDA in 2007 for advanced kidney cancer treatment (Hudes 2009). Everolimus was also approved for kidney cancer treatment in 2009 and for organ rejection prophylaxis in 2010. At present, phase III clinical trials are under way in a variety of tumors (Dansey 2006). 

Fenvalerate has low toxicity in mammals due to its rapid metabolic breakdown. It acts directly on nerve axons by prolonging sodium channel opening in cell membranes. Insects exposed to fenvalerate are quickly paralyzed exposure causes quick insect knockdown. In small animals, type II pyrethroids cause salivation, chewing, burrowing, choreoathetosis, and seizures. They also cause lower action potential amplitude, marked membrane depolarization, and eventual total neural activity blockade. Fenvalerate is likely to act both on peripheral and central nervous system. It is also a potent inhibitor of calcineurin (protein phosphatase 2B). 

---