Calcineurin inhibitors - bind to immunophilin molecules (cyclosporine binds to cyclophilin) -> prevent Calcineurin from binding to NFAT -> prevent tx. of IL-2 gene,

Binds to FKBP, inhibits mTor - prevents second phase of T-cell activation, like response of T-cells to ILs.  Prevents progression to S-phase of cell cycle.

Also prevents B-cell differentiation

Uses: Organ transplants (Tacrolimus > cyclosporine), RA, Crohn's.

Sirolimus is adjunctive agent, drug in stents

Toxicities

Cyclosporin + Tacrolimus:

nephropathy(20%), peripheral neuropathy, HTN, hyperglycemia, hyperlipidemia, hirsutism, gingival hyperplasia, cholelithiasis, infection

Cyclosporin: CYP450 3A - St. John's Wort interaction

Sirolimus: Bone marrow suppression, liver dysfxn, hypertriglyeridemia

Converted to mycophenolic acid, inhibits inosine monophosphate dehydrogenase - rate limiting enzyme in making GMP--> inhibits lymphocyte proliferation because they don't have salvage pathway

(inability to get raw materials to complete cell cycle results in apoptosis).

Uses: Prophylaxis of rejection for kidney, heart, liver xplants.  Used with calcineurin inhibitors and corticosteroids. Also used to treat lupus nephritis.

TOX: Severe GI irritation, bone marrow suppression. Increased risk of infection + lymphoma

Methotrexate: inhibits dihydrofolate reductase, inhibits synthesis of purines and amino acids - nephrotoxic, bone marrow suppression, mucositis, progressive haptotoxicity

Mercaptopurine: inhibits de novo purine metabolism

Cyclophosphamide - interferes with DNA replication  by cross-linking DNA molecules and transcription - irritates bladder

DMARDs - Disease Modifying Anti-Rheumatic Drugs

1. Hydoxychloroquine - immunosuppressive. GI, skin tox, macular damage. Can precipitate attacks of psoriasis or porphyria
2. Sulfasalazine - converted to 5-ASA and sulfapyridine, which inhibits B lymphocytes. Can cause blood cell disorders and hypersensitivity reactions.
3. Leflunomide - inhibits dihydroorotate dehydrogenase -> less UMP -> less ribonucleotide synthesis -> cell cycle arrest. Causes diarrhea, rash, alopecia, bone marrow suppression, hepatotoxicity.

1. Etanercept: Two TNF receptors fused with Fc region. Treats RA, ankylosing spondylitis, Crohn Disease. Increased risk of infection, Gi upset, local injection site reactions
2. Infliximab: anti-TNF MAb. Treats IBD, ankylosing spondylitis. Combined w/methotrexate for moderate to severe RA.  Infxn, GI upset, injection site reactions, exacerbation fo heart failure.
3. Adalimumab - MAb. Treats RA, Crohn's.  Increases infxn risk

1. Corticosteroids
2. Indomethacin, potent NSAID
3. Colchicine - inhibits depolymerization of microtubules, decreases leukotriene B₄, and impairs migration and function of granulocytes. Bad GI effects, can damage many organs. Used at low doses chronically.

Probenecid, sulfinpyrazone - competes with transporter that resorbs uric acid. Need large urine volume to prevent nephrolithiasis. Avoid in sulfa allergy.

Allopurinol: inhibits Xanthine Oxidase, which converts hypoxanthine into xanthine into uric acid.  Therefore prevents uric acid crystals form forming. Better for pts with gouty nephropathy. Also used to treat leukimic pts. 

Tox: Hypersensitivity, precipitation of acute gout.  Can rarely cause hematologic rxns like aplastic anemia or agranulocytosis. Increases plasma conc of drugs metabolized by xanthine oxidase.