Multi-Systems: Autoimmune Treatments Flashcards
1
Q
What are the (3) signals req’d for T Lymphocyte activation?
A
- MHC from APC w/ Antigenic Peptide presented to TCR
- Co-stimulatory binding of APC CD 80/86 to T-cell CD 28
-
Self-Reception of IL-2 on T-cell
- Stimulates activation, proliferation, and Effector function
2
Q
What are the (2) Calcineurin Inhibitors?
A
- Cyclosporine
- Cyclosporine –> Cyclophilin –> Calcineurin
- Tacrolimus (FK506)
- Tacrolimus –> FKBP-12 –> Calcineurin
- Calcineurin + Calmodulin + Ca2+ –> dephosphorylates NFAT to activated NFAT
- -> inhibits IL-2 gene transcription
3
Q
What is the Mechanism of Cyclosprine?
A
- Inhibits Calcineurin - Protein phosphatase req’d for Transcription of IL-2 (T cell activator)
- Inhibition suppresses Cell-mediated immunity
- Normally, Calcineurin mediates Dephosphorylation of NFAT (Nuclear Factor of Activated T cells) –> NFAT nuclear translocation and IL-2 promoter binding –> Increased IL-2 exspression
- Cyclosprine binds to Cyclophilin, complex blocks Calcineurin activity –> Decreased IL-2 expression
4
Q
Clinical application of Cyclosporine?
A
- Immunosuppression
- Organ transplant recipients
- Tx of “Graft vs. Host” Disease in Bone Marrow Transplant recipients
- Can be used as a DMARD
-
CYP3A4 Mediated metabolism
- CYP3A4 inhibitors (Erythromycin or Voriconazole) can dramatically elevate Cyclosporine lvls
- –> Nephrotoxicity risk
5
Q
SEs of Cyclosporine?
A
- Nephrotoxicity especially when combined with Erythromycin or Voriconazole
- HTN
- Hirsutism
- Gum Hyperplasia (Gingival Hyperplasia)
- Neurotoxicity
- Hyperlipidemia
6
Q
Mechanism of Tacrolimus (FK506)?
A
- Calcineurin Ihibitor for Immunospupression
- 50x - 100x more potent than Cyclosporine
- Less Nephrotoxicity
- Binds to FKBP-12 –> Tacrolimus-FKBP complex –> inhibits Calcineurin and suppresses IL-2 expression
7
Q
Clinical use of Tacrolimus (FK506)?
A
- Immunosuppression
- prevents Graft vs Host disease
- Primarily used for Prophylaxis after Kidney (Renal)
and Liver Transplants - Rescue therapy
8
Q
SEs of Tacrolimus (FK506)?
A
- Nephrotoxicity (less than Cyclosporine)
- HTN
- Inhibition of Pancreatic Beta-Islet cells
- Increased risk of Lymphoma
- Neurotoxicity
9
Q
(3) Drugs that are Inhibitors of Cell Proliferation?
A
- Sirolimus
- Mycophenolate mofetil
- Azathioprine
10
Q
Mechanism of Sirolimus?
A
- Like Tacrolimus, binds to FKBP-12 forms complex
- HOWEVER, it does not inhibit Cacineurin, but instead blocks IL-2 responsiveness of T cells by
- *Inhibiting P13-kinase, mTOR kinase** (mammalian target of Rapamycine) which modulates Gene expression
- mTOR dysregulation is a/w Neoplasia
- mTOR inhibitors can be used in the treatment of some types of Malignancy
- Metabolized in the Liver by CYP3A4
11
Q
Clinical uses of Sirolimus?
A
- Immunosuppression for Organ Transplant recipients
- Prevention of Cardiac stent Restenosis
- Sirolimus-eluting Coronary artery stents inhibit Neointimal hyperplasia and decrease restenosis rates
-
Kaposi Sarcoma in transplant pts. –> lesion regression
- KS requires mTOR activity for growth
- Tuberous sclerosis - genes mutated in this disorder (TSC1 and TSC2) is to regulate mTOR
- Metabolized in Liver CYP3A4
12
Q
SEs of Sirolimus?
A
- Anemia
- Leukopenia
- Thrombocytopenia
- Hyperlipidemia (Increased Cholesterol and Triglycerides)
- Increased risk of Lymphocele in Transplant pts.
- Contraindicated in Liver and Lung pts.
- Diarrhea, Nausea, Constipation
13
Q
Mechanism of Mycophenolate Mofetil?
A
- Active metabolite –> Mycophenolic acid
–>Inhibitor ofIMP dehydrogenase, the rate-limigting step in thede novo synthesis of GMP
(Inosine monophoshate dehydrogenase, IMP dehyd.)
–> Inhibition is particulary toxic to B and T lymphocytes which rely on de novo synthesis of Purine biosynthesis - Mycophenolic acid also binds to Type II IMP dehydrogenase isoform expressed in Lymphocytes
–> Impaired Lymphocyte proliferation
–> Immunosuppresion
14
Q
Clinical use of Mycophenolate Mofetil?
A
- Immunosuppresion of Solid Organ Transplants
- -> used w/ low dose Cyclosporine/Tacrolimus
- Recommended following Renal and Heart Transplant
- -> Should NOT be administered w/ Antacids (decreased absorption)
- Treats RA, Psoriasis, SLE, Inflammatory Bowel disease
15
Q
SEs of Mycophenolate Mofetil?
A
-
Myelosuppression (Bone Marrow Suppression cells)
- Leukopenia (WBCs)
-
GI symptoms
- Nausea
- Cramping
- Diarrhea
16
Q
Mechanism of Azathioprine?
A
- Active Metabolite is **6-mercaptopurine (6-MP)
- -> acts as a IMP dehydrogenase inhibitor
- -> Also Inhibits PRPP** an enzyme that catalyses the rate-limiting step in de novo Purine Synthesis
- Purine analog that Disrupts de novo Purine Biosynthesis (Both GMP and AMP)
- -> Inhibits DNA replication
17
Q
Clincial use of Azathioprine?
A
- Immunosuppression of Solid Organ Transplantation
- RA, Psoriasis, SLE, IBD
18
Q
SEs of Azathioprine?
A
- Leukopenia
- Diarrhea
19
Q
(6) Disease-Modifying Anti-Rheumatic Drugs (DMARDs)?
“MS CLPT”
A
- Methotrexate
- Sulfasaline
- Chloroquine
- Leflunamide
- Penicillamine
- Tofacitinib
20
Q
Mechanism of Methotrexate?
A
- Folic acid analog –> Antagonist
- Inhibits Dihydrofolate reductase (DHFR) and prevents Folate recycling –> Decreased Synthesis of Purine Nucleotides Metabolism and Adenosine accumulation
- Impaired Nucleic Acid synthesis
- -> Disproportionately affects rapidly dividing cells
21
Q
Clinical use of Methotrexate?
A
-
Immunosuppression - First-line therapy
- Sever RA
- Psoriasis
- Ankylosing Spondylitis
- Polymyositis
- Dermatomyositis
- SLE
- Wegener’s Vasculitis
- Antineoplastic - Used in combination w/ Chemotherapy for many Malignancies
- Ectopic Pregnancies
22
Q
SEs of Methotrexate?
A
-
Myelosuppression
- Leukopenia / Anemia
- GI hemorrhagic enteritis
- Ulcerative Stomatitis
- Contraindicated in Pregnancy
- Arachnoiditis
- Neurotixicity
- Pneumonitis
- Hepatic Toxicity
- Alopecia
23
Q
Mechanism of Sulfasalazine>
A
- In the Colon, bacteria break the AZO bond and free the Salicylate Derivative
- -> Acts locally as an Anti-inflammatory agent
- Prodrug - Mechanism unknown - thought to work by Scavenging of ROS produced by Neutrophils
- Induces Remission in Active RA and Crohn’s Disease
24
Q
Clinical use of Sulfasalazine?
A
- Rheumatoid Arthritis (RA)
- Polyarticular Juvenile Rheumatoid Arthritis (JRA)
-
Inflammatory Bowel Disease (IBD)
- Acute flares
- Maintenance of Remission
25
SE of Sulfasalazine?
* **GI distress**
* **Leukopenia**
* Allergic reaction to **Sulfa Moiety (Anaphylaxis)**
* Rash
* Fever
* Stevens-Johnson Syndrome
* Hepatitis
* Nephritis
* Bone marrow suppression
26
Mechanism of Penicillamine and USE?
* Produced by Hydrolysis of Penicillin
* **Anti-Rheumatoid activity** in ~75% of Patients
* Perhaps connected to **Decreased IL-1** **Production and Collagen maturation**
* **Metal Chelator** (Wilson's disease / Heavy Metal Poison)
* **NOT w/ Gold Compounds**
27
SEs of Penicillamine?
* Rashes
* Stomatitis
* GI distress
* Proteinuria
* Leukopenia
* Thombocytopenia
* **Contraindicated w/ Renal Disease and Pregnancy**
28
Mechanims of Hydroxychloroquine (Chloroquine)?
* **Antirheumatic -** Inhibitory effects on **Processing of Peptide Antigens** and their **Assembly into MHC** complexes by Macrophages
* Similar effecs on **Posttranslationional processing of Proteins** may account fot he Observed effects on Release of Cytokines
* TNF-α
* IL-1
* IFN-γ
* **Antimalarial**
29
Clinical use of Hydroxychloroquine?
* **Rheumatoid arthritis (RA)**
* **Juvenile Inflammatory Arthritis**
* **SLE**
* **Discoid Lupus**
* **Sjogren's Syndrome** (Salivary gland swelling and extraglandular features)
30
SEs of Hydroxychloroquine?
* **Retinopathy (Ocular Toxicity)**
* ****decreased visual acuitiy, scotomata, pigmented changes in Retina, Corneal deposits
* **Maculopapular Rash**
* Myopathy / Cardiomyopathy (Rare)
31
Mechanism of Leflunamide?
* Prodrug whose **Metabolie inhibits _Dihydroorotate dehydrogenase_** - essential **Mitochondrial enzyme** in
_**de novo** **Pyrimidine Synthesis**_
* Prevents **Expansion** of **Activated Lymphocytes**
32
Clinical use of Leflunamide?
* Rheumatoid Arthritis
33
SEs of Leflunamide?
* **Infrequent** but **Severe Hepatotoxicity**
* Diarrhea
* Nausea
* Myelosuppression
34
Mechanism of Tofacitinib?
* 1st approved **Inhibitor of Janus-Kinases**
* **Inhibits JAK/STAT signaling** a/w **Multiple Cytokines**
* Blocks **T cell Differentiation** and **Production of Pro-inflammatory** mediators
* Approved for pts who have **FAILED MTX therapy**
35
SEs of Tofacitinib?
* Increased infections
* Lymphoma
* Neutropenia / Anemia
* Elevated LDLs
36
Chimeric Abs?
* Binds to the **Fc region in Human**
* The **Antigen binding site** is **from a Mouse**
37
Humanized Abs?
* Binds the **Entire Ab** is **Human in origin**
* EXCEPT for the **CDR region**
* Responsible for the Ability of the Antigen Binding site to Bind to a Target Antigen
38
Daclizumab?
* **Chimeric** monoclonal Ab
* **Against CD 25 Alpha chain of the _IL-2 receptor_**
* **Inhibits IL-2 mediated _T cell activation_**
* _Reduces **Acute rejection**_ when _used w/ **Cyclosporine**_ in **_Kidney_ and Cardiac transplant**
39
Basiliximab?
* Chimeric
* **Against CD 25 Alpha Chain of _IL-2_**
* **Inhibits IL-2 mediated T-cell activation**
* **_Prophylaxis_ and Tx for _Acute Rejection_**
* BUT has **Acute HSN reactions**
40
Infliximab?
* **Chimeric** monoclonal Ab
* Against **_TNF-α_ (soluble and transmembrane forms)**
* **_Crohn's disease_**
* **Ulcerative colitis**
* **_RA_**
* **Psoriatic arthritis**
* **Increased Susceptibility to Infection,** esp. **Tuberculosis**
* Reactivation of **Hep B** and **Malignancies**, **Hepatotoxicity**
* Significant incidence of **Anti-Infliximab Antibodies**
41
Etanercept?
* Recombinant **Chimera** of soluble **p57-TNF receptor
Type II and Fc portion**of**human IgG**
* **Each molecule of Etanercept can _bind to and inactivate two TNF molecules_**
* Inhibiting the Inflammatory cascade downstream of this key cytokine
* Thought to act by **Neutralizing free TNF**
* A/w **increased incidence of Demyelinating Diseases** / **Multiple Sclerosis** and can **Reactivate Tuberculosis and Atypical Mycobacterial infections**, prediscposes to **Opportunistic Infections**
42
Adalimumab?
* **Human Chimeric** monoclonal Ab (Infliximab)
* Against **TNF-α (soluble and transmembrane forms)**
* **_Crohn's disease_**
* Ulcerative colitis
* **_RA_**
* Psoriatic arthritis
* Increased Susceptibility to **Infection, esp. Tuberculosis**
* Reactivation of **Hep B** and **Malignancies**, Hepatotoxicity
43
Abatacept?
* Recombinant **Chimeric** of the **Extracellular domain** of
* *CTLA-4** and the **Fc Portion of Human IgG** used for **RA**
* **Binds to CD80 and CD 86 to block binding to CD 28** and Prevent **T-cell activation**
* CTLA4 binds to CD80 and CD86 molecules on APCs
- -\> Blocking their ability to Co-stimulate (Primary stimulus being MHC - TCR), thus Blocking T cell activation
* **Used for Refractory Rheumatoid Arthritis**
44
Muromonab?
* Mouse Monoclonal Ab
* Against CD3 Surface protein of T cells
* Blocks engagement of T cell receptor - previously indicated for **Reversal of Acute rejection**
* **Can non-specifically Activate T cells** upon infusion, resulting in **Cytokine release** **syndrome
- -\> adverese, systemic inflammatory response**, HSN
* Voluntarily withdrawn from market
45
Anakinra?
* **Nonglycosylated analog** of **Human IL-1 Receptor Antagonist**
* **Used for Anti-TNF-α - refractory RA**
* ****It poses a significant **Increased risk of _Infection**_ when used in _**Combination w/ an Anti-TNF-α agent_**
* Approved for the treatment of RA
46
Tocilizumab?
* a **Humanized** monoclonal Ab
* Against **B lymphocyte stimulator (BAFF) - a member of the TNF family**
* Increased risk of Infection
47
Rituximab?
* Recominant **Chimeric**
* **Anti-CD20 monoclonal Ab** that **promotes Complement mediated Lysis of CD20-positive B cells**
* **RA, Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia**
48
Omalizumab?
* **Humanized monoclonal Ab**
* against **IgE** that is found on the Surfae of **Mast cells and Basophils**
* Drug blocks IgE-mediated Mast cell and Basophil Activation
* Used in the face of **Allergic reactions**
* **_Moderate to severe Allergic Asthma_** that is **Unresponsive** to **Inhaled Corticosteroids**
49
Alemtuzumab?
* Monoclonal Ab
* Against **CD52 Panlymphocyte (B and T cells**) **antigen**
* Used to treat **CLL**
* Used to Prevent **Acute Rejection**
50
Fingolimod?
* **Blocks the Migration of Lymphocytes out of Lymph Nodes**
* Rx for **MS**
* A/w **Fatal infections**
51
Natalizumab?
* Humanized monoclonal Ab
* Against A4 subunit of A4b1-integrin
* Results in the **Inhibition of Lymphocyte migration through the Endothelial cell sites of Inflammation**
* Rx for **Crohn's Disease** and **MS**
* A/w increased risk of **JC virus-induced Progressive Multifocal Lekoencephalopathy**
52
IFN-β
* Beta Interferon is a Type I interferon that **Induces a Potent Antiviral State in Target cells**
* Single Cystein to Serine substitution
* Rx for **MS**
* IFN-β decreases relapse frequency in the Relapsing/Remitting form of this disease
* **Flu-like symptoms**
* Fever, Myalgias, Malaise
* Neutropenia, Thrombocytopenia
* Exacerbation of Depression and Suicidality
53
(3) Colony Stimulating Factors that promote Hematopoeisis?
1. **Epoetin α**
* Recombinant **Erythropoeitin analogue** --\> RBCs in anemic pts.
2. **Darbepoeitn α**
* ****longer half life --\> RBCs in anemic pts.
* Possible stimulation of Tumor cell proliferation
* Increased risk of CV events
3. **Filgastrim**
* ****Stimulates Neutrophil proliferation and Maturation as well as Migration.
