Tacrolimus Calcium-channel blockers

TACROLIMUS CALCIUM CHANNEL BLOCKERS Plasma concentrations of tacrolimus are t when given with diltiazem, felodipine and nifedipine however, they appear to protect renal function Uncertain, but presumed to be due to inhibition of CYP3A4-mediated tacrolimus metabolism Watch for side-effects of tacrolimus monitor ECG, blood count and renal and hepatic function... 

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. 

Drugs affected by voriconazole include the following benzodiazepines, calcium channel blockers, cisapride, coumarin anticoagulants, cyclosporine, ergot alkaloids, HMG-CoA reductase inhibitors, NNRTIs, phenytoin, protease inhibitors, pimozide, proton pump inhibitors, quinidine, prednisolone, rifabutin, sirolimus, sulfonylureas, tacrolimus, vinca alkaloids. 

Drugs that may be affected by fosamprenavir include the following Amiodarone, amitriptyline, benzodiazepines, calcium channel blockers, cisapride, contraceptives (oral), cyclosporine, ergot derivatives, HMG-CoA reductase inhibitors, imipramine, itraconazole, ketoconazole, lidocaine (systemic), methadone, pimozide, quinidine, rifabutin, sildenafil, tacrolimus, vardenafil, warfarin. 

Drugs that may affect tacrolimus include nephrotoxic agents (aminoglycosides, amphotericin B, cisplatin, cyclosporine), antifungals, bromocriptine, calcium channel blockers, cimetidine, clarithromycin, danazol, diltiazem, erythromycin, methylprednisolone, metoclopramide, carbamazepine, phenobarbital, phenytoin, rifamycins, cisapride, chloramphenicol, metronidazole, nefazodone, omeprazole, protease inhibitors, macrolide antibiotics, fosphenytoin, and St. John s wort. 

OESTROGENS 1. ANTICANCER AND IMMUNOMODULATING DRUGS - cidosporin, tacrolimus 2. CALCIUM CHANNEL BLOCKERS-nicardipine, nisoldipine, verapamil 3. DIURETICS-spironolactone Risk of gynaecomastia Inhibition of 2-hydroxylation or 17-oxidation of oestradiol in the liver, causing T oestradiol pool in the body Watch for gynaecomastia and warn patients... 

The calcium channel blocker mibefradil (Posicor ) was removed from the market in 1998. The headline for the Pink Sheets article describing this action was "Posicor Withdrawal Reflects Complexity of Interaction Profile" (59). Products identified as potentially dangerous in combination with mibefradil included cardiac drugs, such as amiodarone, flecainide, and propafenone oncologic products, such as tamoxifen, cyclophosphamide, etoposide, ifosfamide, and vinblastine and the immunosuppressant medications cyclosporine and tacrolimus. The sponsor s decision to withdraw mibefradil was based on the complexity of the drug interaction information that would have to be communicated to ensure safe usage. 

Severe recurrent, but usually reversible hjrpertrophic cardiomyopathy has been infrequently reported, both in adults and children (SEDA-19, 352) (SEDA-20, 346). Based on experimental data and one additional case report, the interaction of tacrolimus with calcium channel blockers in the cardiac muscle has been suggested as a possible mechanism (SEDA-21, 390). However, the role of tacrolimus in the development of cardiomyopathy is still hjrpothetical. Echocardiographic abnormalities were relatively common before and after liver transplantation in 12 adult patients, and there was no clear evidence that oral tacrolimus specifically alters cardiac function (13). Other investigators did not show differences in heart weight, ventricular thickness, or valve circumferences between 67 Uver transplant recipients treated with tacrolimus and 72 non-transplanted patients who died from end-stage liver disease (14). In addition, more than 80% of patients in both groups had left ventricular hypertrophy. 

Tacrolimus causes acute reversible renal dysfunction in renal [661-663,667], hver [290,664-666,679,680], heart [681-683] and pulmonary [684, 685] transplant recipients and in patients with immunologically mediated diseases [686]. Tacrolimus-induced GFR and RBF decrease is associated with an important increase in renal vascular resistance, both in humans and rodents [63,679,687-692]. Calcium channel blockers improved renal function in TAC-treated liver transplant recipients [693] and in animal models of TAC nephrotoxicity [689,694-6%]. Tacrohmus acute nephrotoxicity, similar to CSA, shows normal renal histology or non-specific changes such as isometric cytoplasmic vacuolation in tubular epithelial cells, microcalcification, giant mitochondria and lysosomes, and necrosis and early hyahnosis of individual smooth muscle cells in the afferent arterioles, which revert with drug reduction or discontinuation [697-699]. 

Since acute DIN appears to be dose related, pharmacokinetic and pharmacodynamic monitoring is an important means of preventing toxicity. However, the persistent presence of therapeutic or low cyclosporine concentrations cannot preclude nephrotoxicity. Calcium channel blockers may antagonize the vasoconstrictor effect of cyclosporine by dilating glomerular afferent arterioles and preventing acute decreases in renal blood flow and glomerular filtration. Lastly, decreased doses of cyclosporine or tacrolimus, primarily when used in combination with other non-nephrotoxic immunosuppressants, may minimize the risk of toxicity, but this may increase the risk of chronic rejection. 

A4 Amiodarone, azole antifungals, cimetidine, clarithromycin, cyclosporine, erythromycin, fluoroquinolones, grapefruit juice, HIV protease inhibitors, metronidazole, quinine. SSRIs, tacrolimus Antiarrhythmics, antidepressants, azole antifungals, benzodiazepines, calcium channel blockers, cyclosporine, delavirdine, doxorubicin, efavirenz, erythromycin, estrogens, HIV protease inhibitors, nefazodone. paclitaxel, proton pump inhibitors, HMG-CoA reductase inhibitors, rifabutin, rifampin, sildenafil, SSRIs, tamoxifen, trazodone, vinca anticancer agents... 

Imatinib increases serum tacrolimus levels and is therefore predicted to increase ciclosporin levels. Imatinib may also increases the levels of some benzodiazepines (e.g. midazolam), some calcium-channel blockers (e.g. nifedipine), oestrogens, paracetamol, pimozide, and warfarin. In one case lansoprazole was suspected to have raised imatinib levels. 

The concurrent use of basiliximab with azathioprine, muromon-ab-CD3 or mycophenolate is not associated with an increase in adverse effects or infections. The dose requirements of ciclosporin or tacrolimus may be altered by basiliximab. Basiliximab is reported not to interact with analgesics, anti-infective drugs, diuretics, beta blockers or calcium-channel blockers. 

Uncertain, but it seems likely that some calcium-channel blockers inhibit the cytochrome P450 isoenzyme CYP3A4 and/or P-glycoprotein, thereby reducing the metabolism of tacrolimus leading to increased blood levels. This is consistent with the findings of an in vitro study using human liver microsomes. ... 

Tacrolimus Tacrolimus can cause adverse events in recipients who are also taking calcium channel blockers. 

A renal transplant recipient developed severe nephrotoxicity related to a toxic tacrolimus trough concentration associated with diarrhea and use of a calcium channel blocker. 

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