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Final: Ch 55 - Immunopharmacology DRUGS

Terms in this set (46)

Glucocorticoids
Calcineurin Inhibitors
Proliferation signal blockers
Mycophenolate mofetil
Thalidomide
Cytotoxic Agents
Antibodies
what are the immunosuppressive agents?
Glucocorticoids:
Prednisone
Prednisolone
Dexamethasone
Cortisone
MOA: bind glucocorticoid (nuclear) receptors (unbound exist in cytoplasm, ligand-bound translocate)
-Bind to GRE in promoters --> transcription
-Influence function of transcription factors --> regulate growth factors, cytokines, and more

Reduces the size and content of lymphoid organs, not toxic to proliferating cells in bone marrow

Interfere with cell cycle of activated lymphoid cells:
-Cytotoxic to subset of T-cells
MOA more related to modifying cellular function*: cellular > than humoral, but antibody responses do ↓

CA: Wide variety of uses, including contact hypersensitivity, ITP, asthma, RA, pre-treat before immune-responsive treatments like blood transfusions, first-line for transplants

AE - insomnia, behavioral changes (hypomania), ulcers Metabolic: weight gain and redistribution, diabetes, acne
Cyclosporine
Tacrolimus
what are the two calcineurin inhibitors?
Cyclosporine A (CsA)
MOA: Calcineurin inhibitor
-Peptide antibiotic, binds cyclophilin, forms complex, inhibits calcineurin
--Can't activate transcription of IL or IFN by act. T-cells

CA: Used in organ transplantation, + general immunosuppressive (RA, psoriasis, asthma)

Administered i.v. or orally (slow and limited GI absorption); opthalmic

Metabolized by P450 3A's in liver --> many drug:drug interactions
-Req. individual dosage adjustments

Single agent or combined with glucocorticoids

Toxicities:
Nephrotoxicity, Hepatotoxicity
HTN, Hyperglycemia, hyperkalemia
Altered mental state, seizures, hirsutism
Increased rate of some blood cancers: lymphoma
Tacrolimus (FK 506)
MOA: Calcineurin inhibitor
-MOA similar to CsA, but binds to immunophilin FK-binding protein (FKBP); complex then inhibits calcineurin
Per weight, 10-100x more potent than CsA

Macrolide antibiotic produced by Streptomyces tsukubaensis

Administered i.v. or orally

CA: Used in organ transplantation, + general immunosuppressive (RA, psoriasis, asthma); Also, topical preparation available for atopic dermatitis and psoriasis

Metabolized hepatically by P450s → DDI considerations

Toxicities:
Nephrotoxicity, Hepatotoxicity
HTN, Hyperglycemia, hyperkalemia
Altered mental state, seizures, hirsutism
Increased rate of some blood cancers: lymphoma, + GI complaints
Sirolimus (rapamycin)
Everolimus
Tofacitinib

By blocking mTOR (responsible for proliferation) we block the proliferation of T and B cells, and therefore block the production of antibodies
-mTOR is a PI3K related kinase protein involved in regulating cell growth, proliferation, metabolism and angiogenesis
-Blocking mTOR can inhibit IL-driven T-cell proliferation, B-cell proliferation and Ab production
what are three Proliferation signal inhibitors? how do they work?
Clinical applications:
Solid organ transplants (prevent rejection)
Prevention/therapy for steroid-refractory GvH disease with stem cell transplants
Coated stents help prevent restenosis
Topically used for dermatological disorders (psoriasis, etc.)

Adverse Effects:
-severe myelosuppression (esp. thrombocytopenia)
-hepatotoxicity
-diarrhea, headache, pneumonities, hypertriglyceridemia
-Less nephrotoxicity than calcineurin inhibitors --> PSIs more attractive front-line therapies
what are the clinical applications of the Proliferation signal inhibitors? what are the AE?
Sirolimus (Rapamycin)
Proliferation signal inhibitor

-Oral administration, t½ 60 h
-Rapid absorption, P450 metabolism, P-gp substrate

-Significant DDI, esp. with CsA --> higher blood concentrations; steady-state monitored

-Used alone and in combination therapies with other immunosuppressants (steroids, calcineurin inhibitors, etc.)
Everolimus
Proliferation signal inhibitor

-Derivative of sirolimus
-Shorter t½ (43 h)

Absorption, elimination, metabolism, and combination therapies = Sirolimus
Tofacitinib
Proliferation signal inhibitor

Targeted synthetic small molecule that disrupts JAK-STAT signaling pathway → inhibition hematopoiesis & immune cell function

-Oral, t1/2 ~ 3h
-Extensive liver metabolism

-CA: mod-severe RA who failed/intolerant to MTX (csDMARD) - Conventional synthetic DMARD - although categorized as conventional synthetic DMARD, it functions as a biologic

AE: Infection (URT, urinary tract), malignancies
Mycophenolate Mofetil (MMF)
Semisynthetic derivative of mycophenolic acid (the active moiety that leads to immunosuppression)

PK:
Admin. oral and i.v.
Oral rapidly metabolized to MA
NOT P450 3A system; drug interactions still occur. Blood levels monitored

MOA: inhibits T- and B-cell responses, including mitogenic activity by inhibition of de novo synthesis of purines (through IMPDH (enzyme) inhibition)

CA:
-solid organ transplants (1st line in chronic allograft vasculopathy in cardiac transplants)
-Prevention/tx of acute and chronic GvHD with stem cell transplants
-Also lupus, RA, IBD, skin

AE: GI upset, headache, HTN, reversible myelosuppression (esp. neutropenia)
Thalidomide
MOA: Immunomodulatory agent:
-Inhibits angiogenesis
-Anti-inflammatory: inhibits TNF-a, ↑ IL-10
-↓ phagocytosis by neutrophils
-Alters adhesion molecules, enhances cell-mediated immunity
-sedative drug

Clinical applications:
-Multiple myeloma at diagnosis and relapse
-Leprosy, skin manifestations of lupus

AE:
Teratogenesis → very regulated prescription/use
peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, ↑risk of DVT (combined with anticoagulant regularly)
Azathioprine
Cyclophosphamide
Leflunomide
Hydroxychloroquine
Vincristine
Methotrexate
Cytarabine
Pentostatin
what are the cytotoxic agents? (8)
Azathioprine
cytotoxic agent

MOA: Prodrug of 6-mercaptopurine- purine antagonist
-Antimetabolite. Inhibits lymphoid cell proliferation
primary MOA: DNA synthesis inhibition needed for cellular proliferation

Metabolism note: Xanthine oxidase (XO) splits mercaptopurine into 6-thiouric acid --> renal excretion along with small amts of parent prodrug and mercaptopurine
expect interaction with what drug? allopurinol : ¼ dose

CA:
-Maintenance of renal allografts, other solid tissues
-Manage acute glomerulonephritis
-Manage renal component of lupus
-RA, Crohn's, MS

AE:
-Bone marrow suppression
-Rash, fever, GI upset (higher doses)
-Hepatic dysfunction with mild jaundice (rare)
Cyclophosphamide
cytotoxic agent

MOA: Alkylating agent: Cross-links DNA to prevent cell replication
Very efficacious immunosuppressive. Prodrug.

CA:
-Cancer treatment: Destroys proliferating lymphoid cells (also some resting cells)
-Autoimmune disorders: 30-40% suppression of T-cell & B-cell function
-LSE, Autoimmune hemolytic anemia, Ab-induced pure red cell aplasia, Wegener's granulomatosis

Adverse effects:
High doses = risk of pancytopenia (deficiency of all three cellular components of the blood (red cells, white cells, and platelets) → usually combined with stem cell transplants
-Does not prevent future GvH in allogeneic transplants
-Hemorrhagic cystitis
-GI, cardiac, electrolyte disturbances, alopecia
-Sterility, birth defects
-Cancer - mutates the DNA
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