Flashcards in Pharmacology: Immuno-Modulating Drugs Deck (138):
1
RA, SLE, Scleroderma, Sjogren's Syndrome, Goodpasture Syndrome, Wegener's Granulomatosis, Polymyalgia Rheumatica, and Guillane-Barree Syndrome are all examples of what?
Systemic Autoimmune Diseases
2
Type I DM, Hasimoto's Thyroiditis, Graves Disease, Celiac disease, Crohn's disease, UC, Addison's disease, Primary biliary cirrhosis, Sclerosine Cholangitis, and autoimmune hepatitis are all examples of what?
Localized Autoimmune Diseases
3
What are 2 branches of the immune system?
1. Innate: Nonspecific (1st line of defense)
2. Adaptive: Specific (2nd line of defense- Protects/Re-Exposure)
4
Both the innate and adaptive immune system have what 2 types of components?
Cellular and Humoral
5
Name 6 examples of glucocorticoids presented in class.
1. Cortisone
2. Prednisone
3. Triamcinolone
4. Betamethasone
5. Dexamethasone
6. Fludrocortisone
6
What is the MOA of glucocorticoids?
1. Regulate gene expression
2. Inhibits synthesis of eicosanoids
7
What type of immunity to glucocorticoids interfere with?
Cellular
8
What are the 4 anti-inflammatory effects of corticosteroids?
1. Redistributes components of cellular immunity
2. Inhibits function and secretions of antigen-presenting cells
3. Inhibits synthesis of pro-inflammatory eicosanoids
4. Decrease release of histamines by basophils and mast cells
9
What types of cells are redistributed by corticosteroids?
Neutrophils, lymphocytes (T and B cells), eosinophils, basophils
10
What pro-inflammatory eicosanoids are inhibited by corticosteroids?
Prostaglandins, leukotrienes, and thromboxanes
11
How do corticosteroids inhibit the synthesis of pro-inflammatory eicosanoids?
The decrease the expression of COX
(also decrease expression of COX-2)
12
What are the 4 autoimmune conditions corticosteroids are used for?
1. ITP
2. Autoimmune hemolytic anemia
3. Acute glomerulonpehritis
4. Auto-reactive tissue disorders
13
What types of transplants are corticosteroids used for?
Renal, heart, Liver, BM
14
What are corticosteroids the first line immunosuppressive agents for?
1. Solid organ recipient
2. Hematopoietic stem cell transplant recipients
15
Corticosteroids have a really long list of toxicities... name them.
-Osteoporosis
-Glaucoma
-Hyperglycemia (insulin resistance-steroid diabetes)
-Hypertension
-Hypothalamic – pituitary axis (HPA) suppression
-Adrenal insufficiency (AI) [isolated glucocorticoids deficiency with normal aldosterone secretion]
-Peptic ulceration
-Opportunistic infections
-Retention of Na, H2O (mineralocorticoids)
-Cataracts
-Causes muscle weakness on withdrawal
-Growth hormone inhibition
-Delayed wound healing
16
What is the MOA of Cyclosporine or Sandimune?
It binds cyclophilin, inhibits T-cell activation, decreases IL-2, IL-3, and IFN-gamma
17
What are 5 of the main clinical uses for cyclosporine?
1. Immune disorders
2. Human organ transplant
3. GVHD (Post-Hematopoietic stem cell transplant)
4. Dry eye syndrome
5. Ocular GVHD
18
True or False: Cyclosporine has an inhaled formula?
FALSE... but one is in the works
19
What types of transplants is cyclosporine used for?
Kidney, liver, pancreas, cardiac
20
What is cyclosporine combined with as standard prophylaxis for GVDH after an allogenic stem cell transplant?
Methotrexate
21
What specific autoimmune diseases is cyclosporine used for?
Uveitis, RA, Psoriasis, Asthma
22
What are the 2 forms cyclosporine is given in?
Oral or IV
23
What metabolizes cyclosporine and what is the consequence of this?
P450 CYP3A4 (in liver)
-Results in a lot of multidrug interactions
24
What is the concern with drug interactions and cyclosporine?
Drugs that diminish the liver enzyme system will INCREASE cyclosporine blood levels
25
What are some drugs that will interact with cyclosporine and INCREASE cyclosporine blood levels?
1. Diltiazem
2. Erythromycin
3. Ketoconazole
4. Danazol
5. Methyltestosterone
6. Oral Contraceptives
26
What is another concern with drug interactions and cyclosporine?
Worry about drugs that cause induction of the microsomal liver enzyme system and DECREASE the half-life and blood levels of cyclosporine
27
What are some drugs that interact with cyclosporine and DECREASE cyclosporine blood levels and half-life?
1. Carbamazepine
2. Isoniazid
3. Phenobarbital
4. Phenytoin
5. Rifampin
28
Cyclosporine slso has a very long lists of toxicities name them.
-Nephrotoxicity
-Hypertension
-Hyperglycemia
-Liver dysfunction
-Hyperkalemia
-Altered mental status
-Seizures
-Hirsutism
-Induces TGF-, promotes tumor invasion and metastasis, incidence of lymphomas, Kaposi’s sarcoma
29
What's the cyclosporine toxicity she noted as important and is in green on our PPT?
Induces TGF-, promotes tumor invasion and metastasis, incidence of lymphomas, Kaposi’s sarcoma
30
What kind of antibiotic is Tacrolimus (Prograf)?
Macrolide antibiotic
31
What is the MOA of tacrolimus?
It binds to immunophilin FK-binding protein (FKBP)
-This is similar to cyclosporine
32
True or False: Cyclosporin is more potent than tacrolimus in inhibiting immune response
FALSE...tacrolimus is more important
33
What are the clinical uses of tacrolimus?
Same as cyclosporine (especially for organ and stem cell tranplants)
34
Tacrolimus is effective for preventing rejection in solid organ transplant patients even after what?
Failure of standard rejection therapy (including anti-T-Cell antibodies)
35
What is tacrolimus used as a standard prophylactic agent (in combination with MTX or mycophenolate mofitel) for?
GVHD
36
How is tacrolimus administered?
Orally or IB
37
What metabolizes tacrolimus?
P450 enzymes in the liver... similar potential for drug interactions like cyclosporine
38
What are the toxicities associated with tacrolimus?
1. Renal
2. Neurotoxicity
3. Hyperglycemia
4. HTN
5. Hyperkalemia
6. GI Disturbances
39
True or False: Sirolimus binds to immunophilin (FKBP-12) and inhibits calcineurin
FALSE
40
What is the MOA of siromus?
-Sirolimus binds to immunophilin (FKBP-12) but doesn't inhibit calcineurin
-It blocks mTOR (mamallian target of rapamycin) which blocks the response of T-cells to cytokines)
"It is serious (SIROLUMIS) if you tear (mTOR) your immune system"
41
What is sirolimus a potent inhibitor of?
B-cell proliferation and immunoglobulin production
42
How is sirolimus given?
As an ORAL drug
43
What 2 things is sirolimus a substrate for?
P450 3A and P-glycoprotein
44
What are clinical uses of sirolimus?
Similar to tacrolimus
45
What are the toxicity of sirolimus?
-Profound myelosuppression, especially thrombocytopenia
-Hepatotoxicity
-Diarrhea
-Hypertriglyceridemia
-Headache
46
Which drug is a inosine monophosphate dehydrogenase (IMPDH) inhibitor?
Mycophenolate Mofetil
47
What is MMF hydrolyzed to in the body?
Mycophenolic acid, which is the active immunosuppressive moiety
MMF has enhanced bioavailability
48
When is mycophenolate mofetil used in solid organ transplant patients?
When they have refractory rejection or as an alternative to cyclosporine or tacrolimus in patients who don't tolerate these drugs
49
What is mycophenolate mofetil given in combination with?
Prednisone
50
What is mycophenolate mofetil used as prophylaxis for?
GVHD
51
What are 3 other applications of mycophenolate mofetil? (think autoimmune)
Lupus nephritis, RA, dermatologic disorders
52
What are the toxicities with Mycophenolate Mofetil?
-GI: Nausea, vomiting, diarrhea, and abdominal pain
-Headache
-HTN
-Reversible myelosuppression (primarily neutropenia)
53
Azathioprine, cyclosphosphamide, Leflunomide, Hydroxychloroquine, Vincristine, MTX, Cytarabine, and Pentostatin are all examples of what type of drugs?
Cytotoxic Agents
54
Antilymphocyte, Antithymocyte antibodies, Muromonab-CD3, IVIG, Rho(D) Immune Globulin Micro-Dose, and Hyperimmune Immunoglobulins are all examples of what?
Immunosuppressive Antibodies
55
What are antilymphocyte and antithymocyte antibodies used for?
The management of transplant
56
What 2 settings are muromonab-CD3 is used in?
Autoimmune disorders and transplantation settings
57
When is IVIG used for?
Autoimmune disorders, HIV, BM transplants
58
What is given to prevent hemolytic disease of newborns?
Rh0(D) Immune Globulin Micro-Dose
RHOGAM
59
What do you give for the treatment of RSV, CMV, VZV, Human Herpesvirus 3, HepB, Rabies, Tetanus, Digoxin OD?
Hyperimmune Immunoglobulins
60
What are monoclonal antibodies?
Humanized and chimeric monoclonal antibodies directed against specific receptors and antigens
61
What do monoclonal antibodies end in?
MAB
-Alemtuzumab, bevacizumab, cetuximab, gemtuzumab, rituximab, trastuzumab
62
What is the MOA of alemtuzumab?
Humanized IgG1 that binds CD52 on normal and malignant B and T lymphocytes, NK cells, monocytes, and macrophages
63
What are clinical uses of alemtuzumab?
Treatment of refractory B cell LL in patients treated with alkylating agents and who have failed fludarabine therapy
64
What are toxicities of alemtuzumab?
Lymphopenia, neutropenia, anemia, thrombocytopenia
65
What is the MOA of bevacizumab?
Humanized IgG1 monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF from binding to its receptor, especially endothelial cells
66
Simple words for the MOA of bevacizumab?
It's an antiangiogenic drug that inhibits growth of blood vessels (or angiogenesis) in tumors
67
What is bevacizumab used for?
First-line treatment of patients with metastatic colorectal cancer alone or in combination with 5-FU-based chemotherapy
68
What the toxicities of Bevacizumab?
Hemorrhage, GI perforations, Wound healing problems, HTN, proteinuria
69
What type of monoclonal antibody is cetuximab?
Human-mouse chimeric MAB
70
What does cetuximab target?
Epidermal growth factor receptor (EGFR)
71
What does binding of cetuximab to EGFR do?
It inhibits tumor cell growth via:
1. Decrease in kinase activity
2. Matrix metalloproteinase activity
3. Increased apoptosis
72
What are the clinical uses of cetuximab?
For patients with metastatic colorectal cancer with a tumor over-expressing EGFR
73
What is the MOA of Gemtuzumab?
It is a humanized IgG4 monoclonal antibody with a kappa light chain specific for CD33 found on leukemic blast cells in 80-90% of patients with AML
74
When can you use Gemtuzumab?
For relapsed CD33 acute myeloid leukemia (AML)
75
What are associated toxicities of gemtuzumab?
1. Severe myelosuppression (especially neutropenia)
2. Significant hepatotoxicity
3. Hypersensitivity reactions
76
What is the MOA of rituximab?
It is a chimeric murine-himan monoclonal IgG1 that binds to CD20 molecule on malignant B lymphocytes
77
What does rituximab cause?
1. Induction of apoptosis
2. Complement-mediated lysis
3. ADCC
78
What are the clinical uses for rituximab?
Relapsed or refractory low-grade or follicular, B-cell non-Hodgkin's lymphoma
79
Which drug is a recombinant DNA-derived, human monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor HER-2/neu?
Trastzumab
80
When do you give trastuzumab?
For treatment of metastatic breast cancer in patients whose tumors over-express HER-2/neu
81
What type of HS is characterized by the immune system detecting a drug-hapten conjugate and responding by generating IgE antibodies specific for the drug-hapten complex?
TYPE I
82
What is given to treat a Type I HS?
Prednisone or desensitization to drugs
83
When can allergy to certain drugs occur?
When the drug can't induce an immune response by itself and it covalently binds to a host carrier protein (hapten)
84
What is associated with autoimmune syndromes?
Type II HS
85
What is characteristic of a Type II HS?
IgG antibodies binding to drug-modified tissue that are destroyed by complement or phagocytic cells with Fc receptors
86
What is used for severe cases of Type II HS?
Immunosuppressive therapy
87
What are some examples of type II HS?
1. SLE following hydralazine or procainamide
2. Autoimmune hemolytic anemia resulting from methyldopa
88
What are serum sickness and vasculitic reactions examples of?
Type III HS
89
What are the clinical features of Type III HS reactions?
1. Urticarial and erythematous skin reuptions
2. Arthralgia or arthritis
3. Lymphadenopathy
4. Glomerulonephritis
5. Peripheral edema and fever
90
What are some drugs that can induce immune vasculitis?
1. Sulfonamides
2. Penicillin
3. Thiouracil
4. Anticonvulsants
5. Iodides
91
How long do type III HS reactions usually last?
6-12 days
92
What antibodies are involved in type III HS reactions?
IgM and IgG
93
What is useful for treatment of type III HS?
Glucocorticosteroids
94
What can be done in severe cases of Type III HS to remove the offending drug from circulation?
Plasmapheresis
95
What is inflammation of the blood vessels?
Vasculitis
96
What 4 things are used to treat vasculitis?
1. Steroids
2. Cyclophosphamide
3. Azathiprine
4. Plasma exchange
97
What does Goodpasture's Disease cause?
Rapid destruction of the kidneys and bleeding into the lung
98
What 3 things are done to treat Goodpasture's Disease?
1. Prednisolone
2. Cyclophosphamide
3. Plasma exchange
99
What is plasma exchange?
A mechanical procedure to remove antibodies from the blood by filtering or spinning to remove plasma
100
What kind of antibodies are found in the glomerular basement membrane in Good pastures disease?
Anti-GBM
101
What is a chronic disease with many manifestations including dermatologic and renal which is an autoimmune disease where the body's own immune system is directed against the body's own tissues?
SLE
102
What is the treatment for SLE?
1. Steroids: Prednisolone tabs, methylpredisolon IV
2. Cyclophosphamide
3. Azathioprine
103
What kind of antibodies are seen in immunoflouresence in SLE?
Antinuclear antibodies
104
Which disease has manifestations that include:
Dry eyes
Dry mouth
Dental cavities
Fatigue
Enlarged parotid glands
Difficulty swallowing or chewing
Change in sense of taste
Hoarseness
Oral yeast infections (eg candidiasis)
Skin rashes or dry skin
Vaginal dryness
Dry cough that doesn't produce sputum
Joint pain, swelling and stiffness
Sjogren's Syndrome
105
What are some of the first things that Sjogren's syndrome attacks?
The moisture-secreting glands
106
What is a treatment option for Sjogren's Syndrome?
Hydroxychloroquine (plaquenil)
107
What are 2 things that can be seen in dermatomyositis?
1. Diffuse alopecia
2. Poikiloderma in a photodistribution
108
What is dermatomyositis?
A CT disease related to polymyositis characterized by inflammation of the muscles and the skin
109
What does dermatomyositis most frequently affect?
Skin and muscles
-May also affect joints, esophagus, lungs, and less commonly, the heart
110
What are the treatment options for dermatomyositis?
-Prednisone (Deltasone®, Meticorten®,
Orasone®)
-Methotrexate (Folex®, Rheumatrex®)
- Azathioprine (Imuran®)
- Mycophenolate (CellCept®)
- Hydroxychloroquine (Plaquenil®)
-Chloroquine (Aralen®)
111
What are 2 characteristics of plaque psoriasis?
It is raised and roughened
112
What are 2 treatment options for psoriasis?
-Betamethasone (dipropionate )
(Diprolene®, Diprosone®),
0.05% cream
-Cyclosporin
113
What is the major difference between the different glucocorticoids?
Potency
114
True or False: Dexamathasone is 10 times more potent than prednisone
TRUE
115
Glucocorticoids interfere with what type of immunity?
CELLULAR MEDIATED
116
What kind of immunosuppression do patients with solid organ transplant require?
Lifelong
117
Patient who get a BM transplant need immunosuppression for how long?
6 months to 2 years
-You re-establish hematopoiesis with "new" T-cells, so its like it's brand new
118
Long term use of glucocorticoids refers to usage how long?
Months to years
119
Short term use of glucocorticoids refers to usage how long?
Days to weeks
120
What is a long term SE of glucorticoids?
Osteoporosis
121
Why do you have to be careful giving glucocorticoids to a diabetic?
Because it increases glucose levels (might have to adjust diabetes meds accordingly)
122
Why is there delayed wound healing seen with glucocorticoids?
Because of the increased glucose levels
123
What drug is it super important to check levels of daily to prevent organ rejection?
Cyclosporine (because of all the drug-drug interactions that can affect it's levels)
124
What drug is a second line agent for prevention of organ rejection?
Tacrolimus
125
Which drug taught is actually a pro-drug?
Mycophenolate mofetil
126
In using any type of antibody drug, what is required for it to work?
Either the antigen or receptor for the antibody has to be present in the disease for the drug to function
127
When is Rhogam given?
Within 72 hours of delivery
-Also at 28 weeks
128
What does it mean to be a targeted therapy?
It targets something specific to the disease... aka you have to do expression testing for the receptor to see if the drug even has the potential to work... this is seen with monoclonal antibodies
129
True or False: Bevacizumab is given with other drugs?
YES
-This drug is cytotoxic to CA cells and good cells
130
What BP is Bevacizumab contraindicated in?
Anyone with a systolic over 160
131
What level of proteinuria is bevacizumab contraindicated in?
2+ or more on dipstick
132
Generally, when is bevacizumab contraindicated?
28 days before and after surgery
133
What is an off label use for cetuximab?
Head and neck cancer
134
Why do some monoclonal antibodies have increased risk for HS reaction?
Because the have the mouse component... with increased % of the mouse component, there can be an increased risk of reaction
135
What do you give before MAB to reduce the issues of a potential HS reaction?
Tylenol or benedryl
136
How are MAB given?
Start at a low infusion rate and slowly increase once you see they aren't reacting
137
When is drug desensitization done for Type I HS?
When there are no other alternatives
-Example was a CF patient who became resistant to all antibiotics except one they were allergic too
138