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Immunosupr/glucocort
UVa med pharmacology block 2
| Question | Answer |
|---|---|
| Cyclosporine A | Calcinurin inhib Binds cyclophilin - inhib. T cell function - Transplantation - Certain autoimmune disorders T1/2 6hr wide distribution, excr in bile, met'd CYP450 in liver Side fx gingival hyperplasia |
| Tacrolimus (FK506) | Calcinurin inhib - Binds FKBP Inhibs T cell function 100x more potent than cyclosporineA T1/2 2-4hrs met'd liver decr sidefx than cycA |
| Sirolimus (rapamycin) | Cytotoxic - binds mTOR stops entry into G1/S - decr T cell prolif/AB production Transplantation peak @ 1hr, excr feces met'd CYP450 sidefx hyperlipidemia, can incr nephrotoxicity |
| Azothioprine | cytotoxic - purine anti-metabolite prodrug of 6-mercaptopurine transplantation (w/cycA or prednizone) peak 1-2hrs sidefx decr dividing cells (GI, BM), infection, leukopenia, thrombocytopenia |
| Mycophenolate (mofetil) | cytotoxic - inhibis IMP dehase stops denovo purine synthesis kidney transplant (w/cycA, corticos) rapidly abs, excr urine sidefx doesn't affect pur salvage pways incr selectivity for immune system |
| Cyclophosphamide | cytotoxic - alkylates DNA - targets B>T cells supress humoral immunity (BM pxs) T1/2 3-12hrs |
| Methotrexate | cytotoxic - inhibs purine synthesis autoimmune disease T1/2 8-15hrs excr kidney CI: Pregnancy, breast feeding |
| Cortisol | corticosteroid - anti-inflamm T1/2 short (8-12hrs) sidefx: HTN, hypglycemia w/glycosuria, decr immun response, incr pep ulcers, myopathy, cataracts, osteoporosis withdrawal toxicity |
| Fludrocortison | corticosteroid 125X more portent mineralcoriticoid fx salt-losing andrenogenital synd T1/2 short (8-12hrs) sidefx: HTN, hypglycemia w/glycosuria, decr immun response, incr pep ulcers, myopathy, cataracts, osteoporosis withdrawal toxicity |
| Prednisone/prednisolone | corticosteroid - anti-inflamm, immunosuppression 4x glucocort potency than cortisone T1/2 intermed 12-36hrs sidefx: HTN, hypglycemia w/glycosuria, decr immun response, incr pep ulcers, myopathy, cataracts, osteoporosis withdrawal toxicity |
| 6alpha-methylprednisolone & Triamcinolone | corticosteroid - glucocorticoid only anti-inflamm, immunosuppression 5x cortisone potency T1/2 intermed 12-36 sidefx: HTN, hypglycemia w/glycosuria, decr immun response, incr pep ulcers, myopathy, cataracts, osteoporosis withdrawal toxicity |
| Betamethasone & Dexamethasone | corticosteroid - glucocorticoid only 25X cortisol potency T1/2 long 36-72 hrs sidefx: HTN, hypglycemia w/glycosuria, decr immun response, incr pep ulcers, myopathy, cataracts, osteoporosis withdrawal toxicity |
| Antithymocyte globulin (rabbit Ab) | polyclonal Ab - bind CDs & MHC 1/2 on surface of T lymphs ->direct cytotoxicity transplantation/immunosuppression sidefx: xenogenic proteins can elicit major side fx |
| Murumonab | Anti-CD3 monoclonal Ab - binds ε chain of CD3 Transplantation, immunosuppression sidefx: cytokine release syndrome |
| Daclizumab/Basiliximab | Anti-IL2R/Anti-CD25 - prevs cytokine binding to receptor decr immune response Transplantation/immunosuppression |
| Infliximab/Adalimumab | monoclonal Anti-TNF - prevs cytokine binding to receptor Transplantation, immunosuppression, RA |
| Etanercept | anti-TNF monoclonal Ab (tnf-R fused to Fc-IgG - prevs cytokine binding to receptor Transplantation, immunosuppression, RA |
| What is the difference in potency between Tacrolimus and Cyclosporine A? | Tacrolimus is 100x more potent. |
| What kinds of Mineralcorticoid effects does Cortisol have? | Virtually none. It is almost a pure Glucocorticoid (still has VERY small mineral activity, but not enough for clinical effects) |
| What are the major Clinical Indications for: Prednisolone? | Adrenal Insufficiency Anti-Inflammatory Immunosuppression |
| Which hormone regulates the release of Cortisol? | ACTH |
| What are the major Clinical Indications for: Cortisone? | Adrenal Cortical Insufficiency Anti-Inflammatory |
| What are the major Clinical Indications for: Prednisone? | Adrenal Insufficiency Anti-Inflammatory Immunosuppression |
| What are the major Clinical Indications for: Cortisol (Hydrocortisone)? | Adrenal Cortical Insufficiency Anti-Inflammatory |
| What are side effects of using Azathioprine? | It affects all rapidly dividing cells, including bone marrow, GI, resulting in Leukopenia, Thrombocytopenia, and GI problems. Increased risk of infection/malignancy (like all immunosuppressive drugs) |
| What is the mechanism of action for Methotrexate? | Inhibits Dihydrofolate Reductase --> Inhibits Synthesis of Purines, Thymidylate, & Methionine. Immunosuppression of DNA synthesis in T/B Cells. |
| What two drugs are considered the most important Immunosuppressive agents in Transplantation and Autoimmune Disorders? | Cyclosporine A Tacrolimus |
| What is a major side effect of Sirolimus? | Hyperlipidemia, in a dose-dependent and reversible way. *Increases Triglycerides, LDL, Lipoprotein. |
| How long can it take for a patient to fully re-establish the HPA axis after going through Glucocorticoid Immunotherapy? | Up to a year. Thus, withdrawal from Corticosteroids is a slow process. |
| What can override diurnal patterns as well as negative feedback for ACTH? | Stressful stimuli (Cold, Pain, Infection, Hypoglycemia, Surgery, Fear) --> Marked increases in plasma adrenocortical steroids. |
| Where is Cortisol synthesized? | Inner zone of Adrenal Medulla (Zonae Fasciculata) |
| What is Cortisol's effect on Skeletal Muscle? | It is required for normal function (Patients with Addison's show weakness and fatigue, but the mechanism is unknown). It breaks down muscle due to its effect on protein metabolism. |
| What is an important factor to consider when withdrawing from Glucocorticoid therapy? | High levels of circulating Glucocorticoids suppress its de-novo synthesis and release, by suppressing ACTH and CRH release. Thus, a patient taken off of supplemental Glucocorticoids may suffer from Acute Adrenal Insufficiency. |
| What controls the release of ACTH? | Corticotropin Releasing Hormone (CRH) from the Hypothalamus. |
| What is Cyclophosphamide used for clinically? | Large doses orally to bone marrow patients to suppress Lymphoid Elements. |
| What are the major Clinical Indications for: Fludrocortisone? | - Replacement therapy in Addisons Disease - Salt-Losing Adrenogenital Syndrome (Fludrocortisone has 125x the Na+ retaining potency of Cortisol) - Adrenal Insufficiency |
| Why are Corticosteroid effects not immediate? | Because it acts at the gene level, and changing gene expression takes time to show effects. |
| How do "Cytotoxic" drugs affect Immunosuppression? | They have a common mechanism in preventing the Clonal Expansion of B and T Lymphocytes. |
| How does Tacrolimus affect T-Cells? | Diffuses into Cytoplasm of T-Cells --> Binds FKBP --> Inhibition of Calcineurin --> Inhibition of Cytokine expression. *Calcineurine starts a cascade that leads to Cytokine expression. |
| What kinds of Glucocorticoid effects does Aldosterone have? | None. It is a pure Mineralcorticoid. |
| What are the major Clinical Indications for: 6-a-Methylprednisone Triamcinolone Betamethasone Dexamethasone | Anti-Inflammatory Immunosuppression *Even less mineralcorticoid effects than Cortisol, thus not used for Adrenal Insufficiency (There are other glucocorticoids used for this purpose: Cortisol Prednisone, Fludrocortisone, etc.) |
| Which Immunosuppresant drugs are toxic to the kidney? | Cyclosporine, Tacrolimus (and Sirolimus enhances Cylcosporine's nephrotoxicity) |
| What are the effects on Lipid distribution by Cortisol? | Redistributes body fat from periphery to the: - Face - Neck / Superclavicular *Most extreme example: Cushing's Syndrome (Moon Faces / Buffalo Hump / Skinny Legs) |
| What is the mechanism of Cyclophosphamide's affect on the immune system? | Alkylates DNA, thus affecting all cell types, but proliferating cells are more susceptible. B more than T, thus suppresses Humoral Immunity more than anything else. |
| Where is ACTH released from? | Anterior Pituitary |
| What are some CNS effects of Cortisol? | Improve Awareness Effects Mood *These mechanisms are unknown |
| How does Cyclosporine affect T-Cells? | Diffuses into Cytoplasm of T-Cells --> Binds Cyclophilin --> Inhibition of Calcineurin --> Inhibition of Cytokine expression. *Calcineurin starts a cascade that leads to Cytokine expression. |
| At what time of the day do ACTH levels normally peak? | Early morning hours --> Glucocorticoid levels peak at ~ 8am. |
| What is Methotrexate used for clinically in Immune Suppression? | Autoimmune Diseases |
| What are Glucocorticoids synthesized from? | Cholesterol |
| What is a popular method used to reduce the doses of steroids used in immunotherapy? | Alternate day doses. This can be done because it takes longer than 24hrs to reverse the cellular effects already made. *Reduces side effets, but must be introduced gradually. |
| What is Cortisol's effect on Phopholipase A2? | Inhibits Phospholipase A2 *Contributes to Anti-Inflammatory response. Reduces Prostaglandin and Leukotriene production. |
| What is the difference between the mechanism of action of Sirolimus and Tacrolimus? | Sirolimus blocks Cytokine SIGNAL TRANSDUCTION, whereas Tacrolimus blocks Cytokine PRODUCTION. |
| Where is Aldosterone synthesized? | Outer Zona Glomerulosa |
| Why does Cortisol have such little Mineralcorticoid activity, even though it binds to Mineralcorticoid receptors with equal affinity to Aldosterone? | It is inactivated once bound to the mineralcorticoid receptor by 11-b Hydroxysteroid Dehydrogenase. Aldosterone is resistant to this enzyme. |
| What are the four classes of Immunosuppressive drugs? | Adrenocortical steroids Cyclosporine A and Tacroliumus (FK506) Cytotoxic drugs Antibodies |
| What is the major use for Mycophenolate Mofetil? | Kidney transplant, in combo with Cyclosporine and Corticosteroids. |
| How is Azathioprine used in Immunosuppression therapy? | Transplant Rejection, usually in combination with Cyclosporine or Prednisone. The combination therapies can be used in low dosage. |
| What is an advantage of using Mycophenolate Mofetil over Azothioprine? | It is more selective for immune system than other actively dividing cells (It does not affect Purine Salvage pathways). |
| What are Cortisol's effects on the CV system? | - Potentiate Beta Adrenergic effects --> Hypertension (Due to increased HR, and increased Peripheral Vasoconstriction) |
| Which Immunosuppressants are metabolized by P450? Why is this important? | Cyclosporine, Sirolimus. Must be careful with people who have liver disease. |
| What is Mycophenolate Mofetil's mechanism of action? | It's active metabolite, Mycophenolic Acid, is a potent inhibitor of Inosine Monophosphate Dehydrogenase, which is critical for de novo Purine biosynthesis. |
| What is Sirolimus used for clinically? | Used only by specialists. Usually used with Corticosteroids for Immunosuppression. |
| What does the term "Allogenic" mean? | Refers to cells that have become "Autoimmune" by invasion of virusus, or cancers. They present peptides via MHC1 and are not recognized by CD8 T cells as belonging to the host. |
| What is the mechanism of Azathioprine's action? | It is converted to Thio-IMP, which inhibits de novo Purine Synthesis and Nucleotide Salvage pathways in actively dividing cells. |
| What are some uses for Adrenocortical Steroids in Immunotherapy? | Preventing Transplant Rejection Autoimmune Disorders Pre-Op |
| What are the metabolic effects from Cortisol? How can these effects be a Complication? | - Activates Gluconeogenesis in Liver - Activates Protein breakdown to provide A.A's for Gluconeogenesis. - Activates Lipolysis to provide Glycerol for Gluconeogenesis. Complication: Can exacerbate Hyperglycemia in Diabetics. |
| What is the mechanism by which Glucocorticoids suppress the immune system? | - Inhibit Proliferation of T-Cells by rendering T-Cells unresponsive to IL-1. - Suppress the production of Cytokines at the gene level. |
| What are the Anti-Inflammatory and Immunosuppressive actions of Cortisol? | - Suppress numbers of circulating Lymphocytes, Eosinophils, Monocytes, and Basophils. *Effect in 4-6hrs - Inhibits proliferation and inflammatory responses by inhibiting Cytokine synthesis. |
| What are some of the major side effects of Glucocorticoid Therapy? | - Hypertension - Hyperglycemia + Glycosuria - Increased Infection/Malignancy - Peptic Ulcers - Myopathy - Cataracts - Osteoporosis |
Created by:
sam.mrosenfeld
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