Tacrolimus Cyclosporine

Griseofulvin, lAA, podophyllotoxin, taxol, vinblastine, vincristine Calcineurin inhibitors tacrolimus, cyclosporin A... 

Disulfiram-like reaction with ritonavir, tipranavir, diazoxide Increases levels and toxicity of tacrolimus, cyclosporine, lithium, and phenytoin... 

CYP3A5 Tacrolimus Cyclosporine Pharmacokinetic parameters 3 (non-expressor) associated with higher trough plasma concentrations 43, 44... 

Use of diuretics is generally cautioned in persons taking drugs with narrow therapeutic ranges (small differences between the effective and toxic doses), such as warfarin, steroids (i.e., prednisone), digoxin, tacrolimus, cyclosporine, valproic acid, phenytoin, and carbemaze-pine, as shifts in serum levels of sodium and potassium may affect serum levels of these drugs. Serum electrolyte shifts, notably sodium, can also cause an increase in serum... 

Cytokines. Figure 1 Inhibition of cytokine synthesis during activation of the specific immune system. The monoclonal antibodies Muromonab and Basiliximab are specific for the CD3 complex of the T-cell receptor, and for the IL-2 receptor on lymphocytes, respectively. Cyclosporin and Tacrolimus inhibit activation of cytoplasmic NF-AT, a transcription factor essential for activation of the IL-2 gene ( NFAT Family of Transcription Factors). Sirolimus interferes with mTOR signaling and inhibits IL-2 dependent proliferation. Red pharmaka, blue target proteins. 

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

Immunophillins are abundant proteins that catalyze the cis-trans isomerization of proline residues within proteins, generally to aid in protein folding. Immunophillins are not essential proteins, are the intracellular binding proteins of several immunosuppressive drugs. Cyclosporin A exerts its action after binding to cyclophilin. Tacrolimus and sirolimus predominantly bind to the protein FKBP-12 (FK binding protein-12). 

Haddad EM, McAlister VC, Renouf E et al (2006) Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev (4) CD005161... 

The introduction of PP2B (calcinemin) inhibitors revolutionized kidney transplantation. Cyclosporine A and tacrolimus (FK506) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. Cyclosporine A was in use clinically long before its mechanism of action was elucidated. 

Concurrent nephrotoxin use (e.g., aminoglycosides, polymixins, amphotericin B, foscamet, cyclosporine, tacrolimus, and NSAIDs)... 

Limited evidence indicates that cyclosporine, or possibly tacrolimus, may be effective as salvage therapy for patients who fail intravenous corticosteroid therapy.2 Surgical intervention may ultimately be necessary for medically refractory disease. 

Cyclosporine and tacrolimus are calcineurin inhibitors that are administered as part of immunosuppressive regimens in kidney, liver, heart, lung, and bone marrow transplant recipients. In addition, they are used in autoimmune disorders such as psoriasis and multiple sclerosis. The pathophysiologic mechanism for ARF is renal vascular vasoconstriction.41 It often occurs within the first 6 to 12 months of treatment, and can be reversible with dose reduction or drug discontinuation. Risk factors include high dose, elevated trough blood concentrations, increased age, and concomitant therapy with other nephrotoxic drugs.41 Cyclosporine and tacrolimus are extensively metabolized by... 

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... 

Determine if drug therapy may be contributing to ARF. Consider not only drugs that can directly cause ARF (e.g., aminoglycosides, amphotericin B, NSAIDs, cyclosporine, tacrolimus, ACE inhibitors, and ARBs), but also drugs that can predispose a patient to nephrotoxicity or prerenal ARF (i.e., diuretics and anti hypertensive agents). 

The calcineurin inhibitors cyclosporine and tacrolimus block T cell activation by inhibiting the production of IL-2. They are associated with significant adverse events, such as nephrotoxicity, cardiovascular disease, posttransplant diabetes, and neurotoxicity. 

Cyclosporine and tacrolimus belong to a class of immunosuppressants called the calcineurin inhibitors. These agents are considered by many to be the cornerstone of medical immunosuppression. The calcineurin inhibitors work by complexingwith cytoplasmic proteins (cyclosporine with cyclophylin and tacrolimus with FK binding protein 12). These complexes then inhibit calcineurin phosphatase, which results in reduced IL-2 gene transcription. The final outcome is a decrease in IL-2 synthesis and a subsequent reduction in T cell activation.7 11 20 21... 

FIGURE 52-2. Center-specific protocols may use RATG, an IL-2RA, or no induction therapy. In any situation, patients receive IV methylprednisolone prior to, during, or immediately following the transplant operation. The patient then will begin the maintenance immunosuppressive regimen. The center-specific protocol will specify which calcineurin inhibitor (cyclosporine or tacrolimus) is used in combination with mycophenolate mofetil or sirolimus with or without steroids. Patients then are monitored for signs and symptoms of rejection. 

Several studies have assessed the clinical efficacy of cyclosporine versus tacrolimus. Most of the studies have shown similar longterm patient and allograft survival, whereas some renal transplant studies have demonstrated improved renal function in tacrolimus-treated patients. The most significant difference between the two agents appears to be their adverse-reaction profiles (Table 52-4). 

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

ATC, lymphocyte immune globulin, antithymoglobulin equine AZA, azathioprine BUN, blood urea nitrogen CSA, cyclosporine Cl, gastrointestinal IL-2RA, interleukin 2 receptor antagonist MMF, mycophenalate mofetil OKT-3, muronomonab-CD3 PRED, prednisone SCr, serum creatinine SRL, sirolimus TAC, tacrolimus WBC, white blood cell. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Cyclosporine, tacrolimus, and sirolimus are all metabolized via the CYP3A4 pathway therefore, it would be anticipated that they would experience similar pharmacokinetic DDIs. Table 52-6 details some clinically relevant DDIs that occur... 

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... 

Substrates of the CYP3A4 isozyme will compete with cyclosporine, tacrolimus, and sirolimus for metabolism therefore, concentrations of both medications may be increased (usually by less than or equal to 20%). bnducers of the CYP3A4 isozyme will enhance the metabolism of cyclosporine, tacrolimus, and sirolimus therefore, concentrations of these medications may be decreased. 

ACE-I, angiotensin-converting enzyme inhibitors ARB, angiotensin-receptor blockers AZA, azathioprine CMV, cytomegalovirus CPK, creatinine phos-phokinase CSA, cyclosporine HMG-CoA, 3-hydroxy 3-methylglutaryl coenzyme A reductase K+, potassium LFTs, liver function tests Rl, renal insufficiency SCr, serum creatinine SRL, sirolimus TAC, tacrolimus TMP-SMX, trimethoprim-sulfamethoxazole. 

Although tacrolimus therapy is associated with increasing blood pressure, studies have found that tacrolimus has less dramatic effects on GFR and RBF than cyclosporine. In some clinical trials, tacrolimus caused less severe HTN and required significantly fewer antihypertensive medications at both 24 and 60 months after transplantation than cyclosporine.61-63 Thus conversion from cyclosporine-based immunosuppression to tacrolimus-based immunosuppression may be one way to minimize blood pressure increases in transplant recipients. Conversion to sirolimus also may be an alternative to the calcineurin inhibitors in patients with difficult-to-treat HTN because sirolimus therapy is less associated with increased blood pressure. Additionally, withdrawal or tapering of steroid therapy may be an effective strategy for lowering blood pressure. 

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

Tacrolimus has shown the propensity to cause less severe hyperlipidemia when compared with cyclosporine. Thus conversion from cyclosporine-based immunosuppression to tacrolimus-based immunosuppression may be one way to counteract this disease in transplant recipients.66 Studies demonstrate that steroid withdrawal in renal transplant patients lowered total cholesterol by 17% and LDL-C by 16% unfortunately, an 18% decrease in high-density lipoprotein (HDL) levels also was noted in these patients.66... 

Immunosuppressive medications. Steroid minimization and possibly withdrawal are effective strategies for the prevention of NODAT. Also, patients with worsening blood glucose levels after transplantation who are receiving tacrolimus may benefit from conversion to cyclosporine.74... 

Systemic therapies are seldom used for mild to moderate psoriasis, and are generally reserved for patients with moderate to severe psoriasis.17 29 Oral agents include sulfasalazine, acitretin, methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, and hydroxyurea. Parenteral agents include the biologic response modifiers alefacept, efalizumab, etanercept, infliximab, and many others, currently at various stages of research or approval for psoriasis. 

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