Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology
Immunopharmacology 1
Learning Objectives
Answer mechanism and side effect questions about cyclosporine, tacrolimus, mycophenolate, azathioprine, and anti-D immunoglobulin
List the most commonly used monoclonal antibodies
Explain information related to cytokines (recombinant forms)
CYCLOSPORINE AND TACROLIMUS
λMechanism of action:
–Bind to cyclophilin (cyclosporine) or FK-binding protein (tacrolimus) → ↓ calcineurin (cytoplasmic phosphatase) → ↓ activation of T-cell transcription factors → ↓ IL-2, IL-3, and interferon-γ
λUses:
–Cyclosporine is DOC for organ or tissue transplantation (+/– mycophenolate, +/– steroids, +/– cytotoxic drugs)
–Tacrolimus used alternatively to cyclosporine in renal and liver transplants
λSide effects: nephrotoxicity (both), gingival overgrowth (cyclosporine)
MYCOPHENOLATE
An inhibitor of de novo synthesis of purines, has adjunctive immunosuppressant actions, permitting dose reductions of cyclosporine to limit toxicity.
AZATHIOPRINE
Immunosuppressant converted to 6-mercaptopurine—same properties as 6-MP.
ANTI-D IMMUNOGLOBULIN
λHuman IgG antibodies to red cell D antigen (rhesus antigen)
λUses: Administer to Rh-negative mother within 72 hours of Rh-positive delivery to prevent hemolytic disease of newborn in subsequent pregnancy
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Section X λ Immunopharmacology
MONOCLONAL ANTIBODIES
Table X-1-1. Clinical Uses of Monoclonal Antibodies
Mab |
|
Clinical Uses |
Abciximab |
Antiplatelet—antagonist of IIb/IIIa receptors |
|
Infliximab |
Rheumatoid arthritis and Crohn disease—binds TNF |
|
Adalimumab |
Rheumatoid arthritis and Crohn disease—binds TNF |
|
Trastuzumab |
Breast cancer—antagonist to ERB-B2 (Her 2/neu) |
|
Daclizumab |
Kidney transplants—blocks IL-2 receptors |
|
Muromonab |
Kidney transplant—blocks allograft rejection |
|
Palivizumab |
Respiratory syncytial virus—blocks RSV protein |
|
Rituximab |
Non-Hodgkin lymphoma—binds to surface protein |
|
CYTOKINES (RECOMBINANT FORMS)
Table X-1-2. Clinical Uses of Interferons
Interferon-α |
Hepatitis B and C, leukemias, melanoma |
Interferon-β |
Multiple sclerosis |
Interferon-γ |
Chronic granulomatous disease →↑ TNF |
Chapter Summary
λThe mechanism of action, uses, and toxicities associated with cyclosporine are presented. Azathioprine converts to 6-mercaptopurine, making it a useful immunosuppressant.
λAnti-D immunoglobin is given to Rh-negative mothers shortly after parturition to prevent hemolytic disease in future births.
λTable X-1-1 summarizes the clinical uses of monoclonal antibodies. Table X-1-2 summarizes the clinical uses of recombinant cytokines.
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Immunopharmacology 2
Practice Questions
1.A patient is treated with an immunosuppressant drug following a liver transplant. The drug is known to bind to cyclophilin and inhibit the actions of calcineurin. For what drug toxicity should this patient be monitored?
A.Pulmonary fibrosis
B.Hypotension
C.Hypoglycemia
D.Nephrotoxicity
E.CHF
2.Which one of the following agents has utility in the management of acute coronary syndromes such as unstable angina?
A.Abciximab
B.Interferon-α
C.Aldesleukin
D.Filgrastim
E.Trastuzumab
Answers
1.Answer: D. This patient is being treated with cyclosporin, a drug that binds
to cyclophilin and inhibits calcineurin. As a result, the transcription of various T-cells factors such as IL-2, IL-3, and Interferon-γ are inhibited. Cyclosporin is associated with nephrotoxicity, gingival hyperplasia, hyperglycemia, hypertension, and hirsutism.
2.Answer: A. Abciximab is an antibody-based drug that targets glycoprotein IIb/IIIa receptors. Binding of the drug to these receptors results in decreased platelet aggregation by preventing the cross-linking reaction. It is useful in acute coronary syndromes such as unstable angina and post-angioplasty.
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SECTION XI
Toxicology