Txs for autoimmune disease

Question 1

What are our calcineurin inhibitors?

Answer 1

• Cyclosporin

- Tacrolimus

Question 2

Discuss the structure of cyclosporin? (Where do we get it, what is the active component)

Answer 2

Cyclosporine is a hydrophobic cyclic peptide produced by nonribosomal peptide synthesis in the fungus Tolypocladium inflatum Gams. The ring contains a novel 9-carbon amino acid at position 1 that is essential for biological activity, as are the residues involved in the formation of intramolecular hydrogen bonds

Question 3

Principal effects of cyclosporin and mechanism of action?

Answer 3

The principal effect is to inhibit the activation and proliferation of CD4+, and CD8+ T-cells.

These effects are the result of inhibition of transcription of cytokine encoding genes (e.g., IL-2). Within the cell, cyclosporine binds with high affinity to the intracellular protein cyclophilin. The cyclosporinecyclophilin complex is a potent inhibitor of calcineurin, a phosphoprotein phosphatase.

Inhibition of this phosphatase blocks the nuclear translocation of a transcription factor (NF-ATc) required for the expression of the IL-2 gene.

Question 4

Discuss the weird pharmacology of cyclosporin

Answer 4

Alright so this guy is water insoluble. We need to administer it in a vehicle containing EtOH and oil when giving it IV, and if we must give it orally, put it in a gelatinous capsule.

Metabolism is mediated by CYP3A4, so we see increased clearence with phenytoin, phenobarbital, or really anything that induces P-450.

Inhibitors of CYP3A4 such as erythromycin, ketoconazole, amphotericin B and St. John’s wart help increase activity (as you might expect)

Question 5

Toxicity of cyclosporins?

Answer 5

nephrotoxicity, neurotoxicity (tremor, seizure), hypertension, hirsutism, hyperlipidemia, gingival hyperplasia

Question 6

Discuss the general structure of tacrolimus and what makes it better than cyclosporin

Answer 6

A macrocylic lactone-lactam antibiotic structurally unrelated to cyclosporine. It is 50-100 times more potent than cyclosporine, and has less nephrotoxicity. In addition to its use in the prevention of transplant rejection and GVHD, topical application of tacrolimus is used to treat atopic dermatitis

Question 7

Mechanism of Tacrolimus?

Answer 7

Effects on immune system are virtually identical to those of cyclosporine.

However, tacrolimus primarily binds to another cytoplasmic protein (FKBP-12) to form a complex that also inhibits calcineurin

Question 8

Discuss the pharmacology differences of Tacrolimus when compared to cyclosporine

Answer 8

Also metabolized in the liver;
shorter half-life than cyclosporine - thus after three day iv loading it is given orally twice daily. Used primarily for prophylaxis after kidney and liver transplants; also for rescue therapy in patients experiencing graft rejection

Question 9

Toxicities of Tacrolimus

Answer 9

Toxicities: nephrotoxicity, neurotoxicity (tremor, headache, seizures, insomnia), hypertension, inhibition of pancreatic β-cell function (i.e diabetes), and increased risk of lymphoma

Question 10

What the fuck is Pimecrolimus?

Answer 10

Structurally similar to tacrolimus; also binds to FKBP-12 which results in inhibition of calcineurin; used for topical treatment of atopic dermatitis - 2nd-line therapy ONLY because of increased risk of lymphoma and malignant melanoma.

Question 11

What is Sirolimus (Rapamycin) and how does it differ from Tacrolimus and cyclosporine?

Answer 11

Structurally related to tacrolimus, but with an entirely different mechanism of action. It is as effective as cyclosporine in preventing acute rejection after renal transplantation.

Because it has little if any renal toxicity, it can be included with cyclosporine to prevent transplant rejection. Sirolimus is also used to prevent neointimal proliferation and restensosis after stent placement in coronary arteries

Question 12

Discuss the mechanism of action for Sirolimus (Rapamycin)

Answer 12

Like tacrolimus, rapamycin binds to FKBP-12. However, instead of inhibiting calcineurin activity, the sirolimus-FKBP complex inhibits the activity of the PI 3- kinase-related kinase protein mTOR (Mammalian Target Of Rapamycin), which modulates a variety of intracellular signaling pathways that regulate the transcription and translation of genes involved in cellular proliferation.

Inhibition of mTOR is manifested as a lack of response to growth stimulatory signals, and inhibition of T and B cell proliferation

Question 13

Discuss the metabolism of Sirolimus (Rapamycin)

Answer 13

Metabolized in the liver primarily by the same enzyme (CYP3A4) responsible for the metabolism of cyclosporine and tacrolimus. Used as part of combination therapy after renal transplant, and experimentally after islet cell transplantation.

Everolimus, a sirolimus analogue, offers more predictable oral absorption.

Question 14

Side effects of sirolimus (rapamycin)

Answer 14

anemia, thrombocytopenia, and hyperlipidemia; there is a higher incidence of post-surgical lymphocoele in transplant patients receiving sirolimus; contraindicated for use after liver or lung transplantation

Question 15

Describe mycophenolate mofetil and what do we with it

Answer 15

a prodrug metabolized to the “antimetabolite” mycophenolic acid (MPA). Used in solid organ transplant recipients as a single agent or in combination with low dose cyclosporine or tacrolimus to reduce calcineurin-inhibitor toxicity.

Question 16

Mechanism of action for mycophenolate mofetil

Answer 16

mycophenolate mofetil is hydrolyzed by liver esterases to MPA, which is a potent inhibitor of inosine monophosphate dehydrogenase, an enzyme required for de novo purine biosynthesis. Selectivity is based on the fact that in T and B cells, the major source of purines is de novo synthesis rather than HPRT (hypoxanthine guanine phosphoribosyl transferase) mediated salvage.

Question 17

When do we use mycophenolate mofetil and what do we worry about in regards to is absorption

Answer 17

recommended for use after renal and heart transplantation; should not be administered with antacids containing magnesium or aluminum hydroxide because of decreased absorption

Question 18

Side effects for mycophenolte mofetil

Answer 18

Diarrhea, leukopenia

Question 19

Talk about azathioprine and what we use it for.

What toxicities do we worry about?

Answer 19

another anti-proliferation prodrug – active metabolite 6-mercaptopurine is a purine analog that disrupts de novo purine biosynthesis and inhibits DNA replication. Used in combination therapy with prednisone -/+ CsA/tacrolimus) to prevent orgran rejection, or as an adjunct DMARD for treatment of severe RA.

Toxicity = GI distress and leukopenia.

Question 20

What the hell is a Disease-Modifying Anti-Rheumatic Drug

Answer 20

DMARDs represent a mixed group of compounds with demonstrated anti-rheumatoid activity despite unrelated, and often poorly understood, mechanisms of action.

Although traditionally used as secondary agents when traditional NSAIDs fail, certain DMARDs are now utilized as “first-line” therapy (e.g. methotrexate, leflunamide, sulfasalazine) for rheumatoid arthritis upon diagnosis.

Given that clinical efficacy is delayed (i.e. months), early concomitant treatment with NSAIDs and glucocorticoids is common.

Question 21

What is the mechanism of action and general function of methotrexate (cellularly, not what we necessarily use it for, that question comes next)

Answer 21

a folic acid antagonist that allosterically inhibits dihydrofolate reductase (DHFR), the enzyme required for tetrahydrofolate production, a key component of nucleoside biosynthesis. Also appears to disrupt other enzymes required for nucleoside biosynthesis, such as AICARD transformylase.

Demonstrates cytotoxic and anti-proliferative activity on lymphocytes, which require de novo nucleoside synthesis for DNA/RNA replication. May block T cell activation due to inhibition of purine metabolism and adenosine accumulation

Question 22

What do we use methotrexate for and what do we worry about with it?

Answer 22

Commonly used as first-line therapy for moderate to severe RA or psoriasis, as well as cancer chemotherapy.

Side effects include ulcerative stomatitis and leukopenia/anemia – low-dose folic acid supplementation may ameliorate these symptoms.

Methotrexate is highly teratogenic and should not be used during pregnancy.

Question 23

Discuss the metabolism of sulfasalazine and its mechanism of action

Answer 23

a prodrug composed of a sulfonamide (sulfapyridine) and salicylate, processed by gut bacteria into 5-aminosalicylic acid. Mechanism of action is unclear, but may work by scavenging reactive oxygen species produced by neutrophils.

Question 24

What do we use sulfasalazine for? What do we worry about?

Answer 24

Relieves joint pain and swelling and induces remission in active RA. Also used for treatment of Crohn’s disease. Side effects include GI distress, leukopenia. Like other sulfonamides, sulfasalazine may trigger anaphylactic reactions in some patients.

Question 25

What do we use penicillamine for and how does it work?

Answer 25

dimethylcysteine produced by hydrolysis of penicillin. D-isomer shows antirheumatoid activity in ~75% RA patients, perhaps connected to decreased IL-1 production and collagen maturation in inflamed joints. Also used as a metal chelator for Wilson’s disease or heavy metal poisoning – cannot be combined with gold compounds

Question 26

Side effects of penicillamine?

Answer 26

Side effects include rashes, stomatitis, GI distress, and potential proteinuria, leukopenia and thrombocytopenia.

Contraindicated for patients who are pregnant or have history of renal disease

Question 27

Effects, use, and side effects for gold compounds

Answer 27

sodium aurothiomalate and auranofin can be used to reduce joint pain and swelling and slow progression of joint damage. Therapeutic effects are slow in onset (3-4 months).

Mechanism of action is unknown.

Side effects include rashes, stomatitis, proteinuria, thrombocytopenia, and potential neuropathy or hepatitis in some patients

Question 28

Effect, use, side effects for chloroquine/hydroxychloroquine

Answer 28

anti-malarial drugs often used in combination with methotrexate and sulfasalazine for treatment of mild to moderate RA.

Mechanism of action is unknown, with therapeutic efficacy only noted in ~50% patients with slow onset (2-4 months).

Ocular toxicity is a rare side effect.

Question 29

Discuss the function and side effects for leflunomide

Answer 29

a prodrug whose active metabolite inhibits dihydropteroate dehydrogenase, an essential mitochondrial enzyme in de novo pyrimidine biosynthesis.

Approved for use in treatment of active rheumatoid arthritis. Prevents expansion of activated lymphocytes, which cannot utilize the salvage pyrimidine pathway. Extremely long half-life; side effects include diarrhea, nausea, myleosuppression with blood cytopenias, and infrequent but severe hepatotoxicity.

Question 30

Mechanism of action for the exciting drug tofacitinib

Answer 30

1st approved inhibitor of Janus kinases – inhibits JAK3/JAK1 > JAK2, without affecting TYK2. Inhibits JAK/STAT signaling associated with multiple cytokines, including IFN-g, IL-6, and those that use the common gamma chain (e.g. IL-2, IL-4, IL-7, etc.).

Blocks T cell differentiation and production of pro-inflammatory mediators in joint tissue.

Question 31

What do we use tofacitinib for and what are the side effects we worry about

Answer 31

Approved for treatment of RA patients who have failed initial MTX therapy; can be used as monotherapy or in combination with MTX and other DMARDs.

Side effects include increased infections, lymphoma, neutropenia/anemia, and elevated LDL. Metabolized by CYP3A4; must be used cautiously with other drugs that affect CYP3A4 expression/activity

Question 32

Discuss monoclonal antibodies and recombinant proteins and what we tend to generally use them for

Answer 32

Monoclonal antibodies (mAbs) (and certain recombinant proteins derived from cellular receptors) are designed to specifically interact with a single target molecule, often neutralizing its activity. They are used as immunosuppressive agents in transplantation, inflammatory or autoimmune disorders

Question 33

Discuss the function and effects of the monoclonal antibody Muromonab

Answer 33

mouse monoclonal antibody directed against the ε chain of the T cell surface protein CD3; blocks engagement of the T cell receptor; once indicated for reversal of acute rejection of heart, liver, and kidney transplants.

Can non-specifically activate T cells upon first infusion to cause cytokine release syndrome, inducing an adverse, systemic inflammatory response. Hypersensitivity reactions may also occur.

Question 34

When do we use daclizumab and basiliximab and how do they work?

Answer 34

recombinant chimeric (human/mouse) monoclonal antibodies directed against the α chain (CD25) of the high-affinity IL-2 receptor; inhibits IL-2-mediated Tcell activation; reduces incidence of acute rejection when used in combination with cyclosporine/prednisone/azathioprine in kidney and cardiac transplantation.

Use of basiliximab can result in acute hypersensitivity reactions.

Question 35

Discuss etanercept

Answer 35

recombinant chimera of soluble p75-TNF receptor type II and Fc portion of human IgG; presumably acts by neutralizing free TNF. Used in treatment of rheumatoid arthritis, ankylosing spondylitis, and plaque psoriasis. Use of etanercept has been associated with increased incidence of demyelinating diseases

Question 36

Discuss anakinra

Answer 36

a recombinant nonglycosylated analog of human IL-1 receptor antagonist (IL-1RA); approved for treatment of rheumatoid arthritis and in patients with mutations in IL-1 RA gene; principal side effect is increased risk of serious bacterial infection.

Question 37

Discuss tocilizumab

Answer 37

humanized monoclonal antibody directed against IL-6 receptor that blocks the proinflammatory effects of IL-6; used to treat rheumatoid arthritis in patients unresponsive to TNF-α inhibitors

Question 38

Discuss rituximab

Answer 38

a recombinant chimeric (mouse/human) anti-CD20 monoclonal antibody that promotes complement mediated lysis of CD20-positive B cells; used to treat rheumatoid arthritis as well as non-Hodgkin’s lymphoma and chronic lymphocytic leukemia

Question 39

Discuss natalizumab

Answer 39

humanized monoclonal antibody against α4subunit of α4β1-integrin that inhibits lymphocyte migration through endothelial cell sites of inflammation; used for treatment of Crohn’s disease and multiple sclerosis. Use is associated with significant risk of JC virus induced progressive multifocal leukoencephalopathy (PML).

Question 40

Discuss abatacept. What do we use it for and what do we worry about?

Answer 40

a recombinant chimera of the extracellular domain of CTLA-4 and the Fc portion of human IgG1 used for treatment of rheumatoid arthritis; binds to CD80 and CD86 to block binding to CD28 and prevent T cell activation; works upstream from infliximab and etanercept.

Question 41

Discuss omalizumab

Answer 41

humanized monoclonal antibody that binds to immunoglobulin E (IgE); high levels of IgE are associated with allergic reactions; approved for treating moderate-to-severe allergic asthma that is unresponsive to corticosteroids.

Question 42

What the hell is fingolimod and what do we use it for?

Answer 42

fingolimod: when phosphorylated by sphingosine kinase 2, binds to sphingosine-1 phosphate receptors and blocks migration of lymphocytes out of lymph nodes; used to treat multiple sclerosis. Adverse effects associated with fatal infections.

Question 43

Discuss using thalidomide vs. Lenalidomide

Answer 43

Thalidomide is a sedative drug with immunomodulatory and anti-inflammatory properties, including inhibition of angiogenesis; used for treatment of multiple myeloma (usually in combination with dexamethasone), erythema nodosum leprosum (type 2 leprosy reactions).

Mechanism of action is unknown; toxicities include peripheral neuropathy (sometimes irreversible) and teratogenicity; should NEVER be given to pregnant women or women of childbearing potential.

Lenalidomide, an immunomodulatory derivative (IMiD) of thalidomide, is less teratogenic and approved for treatment of myeloma and myelodysplastic syndrome involving chromosome 5q31 deletion.

Question 44

What are anti-lymphocyte and anti-thymocyte globulins?

Answer 44

isolated from hyperimmune horse or rabbit serum after immunization with human thymic lymphocytes; contains antibodies to numerous T cell surface antigens; depletes peripheral T cells by blocking cell surface receptors and by direct cytotoxicity; used in combination with other immunosuppressive agents

Question 45

How does IVIG work?

Answer 45

purified, polyvalent human IgG used to replace antibodies in a variety of immunodeficiencies to confer passive immunity; also used to treat autoimmune disorders such as idiopathic thrombocytopenic purpura (ITP).

Precise mechanism of action in suppressing inflammation and autoimmunity remains controversial.

Question 46

What do we treat with IFN-B?

Answer 46

Multiple sclerosis

Question 47

What do we use epoetin alfa for?

Answer 47

recombinant erythropoeitin analogue that stimulates formation of red blood cells in anemic patients

Question 48

What do we use darbepoetin alfa for?

Answer 48

Longer half life than epoetin alfa!

Use in cancer chemotherapy induced anemia is controversial because these agents may stimulate tumor cell proliferation.

In kidney failure patients, target hemoglobin levels should be below 12 g/dL. Higher levels have increased risk of stroke and cardiovascular side effects.

Methoxy polyethylene glycolepoetin beta has a very long biological half-life.