Pharmacology Immunosupressant II Flashcards
Cyclosporine
- solubilized in ethanol
- p-glycoprotein & CYP3A4 substrate
- must monitor plasma concentration
- attaches to cyclophilin calcineurin inhibitor ..stops IL2
Tacrolimus
- cyp3A4 and p-glycoprotein substrate
- more potent than cyclosporine
- calcineurin inhibitor, attaches to FKBP. Stop IL2
Cyclosporine/tacrolimus use
- prophylaxis of solid organ allograft rejection
- treatment of GVHD after hematopoietic stem cell transplantation
- inflammatory disease
- cyclasporine drops for uveitis
- tacrolimus topically for psoriasis, dermatitis
- tacrolimus preferred agent because decreased acute rejection rates and better tolerated than cyclosporine
Calcineurin toxicities
Nephrotoxicity- vasoconstrictor effect on afferents renal arterial
Interstitial fibrosis
Hypertension
Neurotoxicity- tremor, parenthesis, headache, confusion, seizure
Hyperkalemia
Hyperglycemia
Diarrhea, nausea,vomiting
Hyperuricemia, hyperlipidemia, gum hyperplasia, hirsuitism ( seen with cyclosporine not tacrolimus )
Tacrolimus / cyclosporine Drug interactions
CYP3A4/ pglycoprotein inducer and inhibitors
-CYP3A4 inducer. Increases rate of metabolism->dec in serum levels —> inc risk of rejection. Inhibitor are opposite
- pglycoprotein. Inhibitors dec efflux-> inc serum level-> inc toxicity
- drugs that additive toxicity, nephrotoxicity,neurotoxicity
- cyclosporine and tacrolimus not used together
CYP3A4 inducers ( carbamazepine,phenobarbital,phenytoin,rifampin,efavirez,st johns wort)
CYP3A4 inhibitor (verapamil,diltiazim,Azole,macrolide antobiotics,dexmethasone,hiv and hcv protease inhibitors, grapefruit juice
Sirolimus combination adverse effects
Cyclosporine+sacrolimus= administer sacrolimus 4 hrs after csA.sicrolimus aggravates cyclosporine induced renal dysfunction.cyclosporine increase sacrolimus levels. Enhance anemia, leukopenia,thrombocytopenia, hypokalemia,diarrhea Tacrolimus+sirolimus= avoid combo. Both may enhance each other’s adverse effects.. sicrolimus May dec. tacrolimus concentrations
Mycophenolate mofetil
- anti metabolite, rapidly converted to mycophelonic acid
- selective, uncompetitive, reversible IMDPH inhibition-> inhibits guanine synthesis->traps cell in G1-S phase->apoptosis
- decreased lymphocyte function, T cell mediated B cell proliferation and function
- T and B lymphocytes highly dependent on de novo pathway for cell proliferation
Mycophenolate mofetic therapeutic use
- prophylaxis of organ rejection renal, cardiac,hepatic
- used in combination : calcineurin inhibitor+ MMF+ GC
- has largely replaced azathioprine in transplantation rejection prophylaxis
- prophylaxis / treatment GVHD
- treatment of psoriasis , lupus,Myasthenia graves
Mycophenolate mofetil toxicities
Leukopania Pure red cell a plasia Malignancy risk Diarrhea Nausea/vomiting Congenital anomalies in pregnancy Drugs that cause additive toxicities Absorption - antacids, cholestyramine Competition for tubular secretion - probenecid
Azathioprine MOA
- antimetabolite
Metabolism- xanthine oxidase and TPMT. Those deficient in TPMT at risk of severe life threatening myelosupression
6 MP-> TIMP
6-TIMP->MeMPN-> inhibit phosphoribosyl-pyrophosphate amidotransferase-> inhibits de novo purine synthesis
6-TIMP->6-TGMP ->6 TGTP-> 6TGTP is incorporated into DNA of proliferating cells-> induces strand break and mispairing -> apoptosis
Azathioprine therapeutic use
-prophylaxis of organ rejection used in combination calcineurin inhibitor and AZA and glucocorticoid
-RA
Inflammatory bowel disease
Acute glomerulonephritis
Azathioprine toxicities\ drug interactions
Bone marrow suppression - leukopenia Hepatoxicity- esp in patients with preexisting hepatic dysfunction Inc malignancy & infection Acute pancreatitis Skin rash Diarrhea Nausea SAFE IN PREGNANCY allopurinol/febuxostat xanthine inhibitor —> aza inactivation, increased AZA toxicity
Belatacept MOA
- selective T cell costimulation blocker
- binds to cd80(b71) and cd86 (b72) & blocks stimulation-> inhibits T cell activation cytokine production and proliferation.
Belatacept therapeutic uses
Maintenance therapy for prophylaxis of acute organ rejection in kidney transplant patients who are seropositive for EBV
Combination with basitliximab mycophenolate, and corticosteroid
Belatacept adverse effects
Post transplant lymphoproliferative disorder (PTLD) and other malignancies
PML or other serious infections
Sirolimus MOA
Serum levels should be monitored after start of therapy and dose adjustments Bcus bioavailability difference in each patient
- mTOR inhibitor.drug-FKBP-12-mTOR-> cell cycle arrest in G1-S phase
Inhibit cell growth, proliferation , angiogenesis, and metabolism
Mtor inhibitor therapeutic effect
Renal transplant w/reduced dose calcineurin inhibitor and glucocosteroid
CN sparing regime: cyclosporine tapering after 4-8 weeks only in patients with low to moderate immunologic risk
Cardiac and lung transplantation
Caution: delay treatment until surgical wound heals ( associated with bronchial anastomotic dehiscence first 30-90 days )
GVHD prevention and treatment
Drug eluting coronary stents to inhibit local cell proliferation and blood vessel occlusion
USE IN HEPATIC ALLOTRANSPLANTS ASSOCIATED WITH HELATIC ARTERY STENOSIS AND MORTALITY
Sirolimus toxicity
Myelosuppression- thrombocytopenia,anemia,leukopenia
Impaired wound healing, wound dehiscence. May decreased production of growth factors of angiogenesis, fibroblast proliferation
Hepatoxicity ( fatal hepatic necrosis has occurred )
Inc triglycerides, inc cholesterol ( dose dependent)
Peripheral edema, lymphedema, pleural effusion, pericardial effusions, pneumoitis
Diarrhea nausea vomiting headache arthalgia aphthous ulcers, acne
Sirolimus drug interactions
Cyp3A4 inducers and inhibitors
Cyclosporine or tacrolimus+ sirolimus - inc cni. Nephrotoxicity with deterioration of renal function.
Worsening dyslipidemia, esp hypertriglyceridema
Cyclosporine May inc risk of CNI induced hemolytic uremic syndrome
May inc sacrolimus conc. ->Inc risk of toxicity. Monitor serum blood levels,
Tacrolimus + sacrolimus competition at CYP3A4 , P-gp
