Pharm Immunomodulators

Front 1

Name the five classes of immunosuppressive agents

Back 1

Corticosteroids, cytotoxic drugs, T-cell specific drugs, antibody therapy, cytokine/receptor antagonists

Front 2

Name 5 corticosteroids

Back 2

hydrocortisone, prednisone, methyl prednisolone, betamethasone, triamcinalone

Front 3

Give the pathway for glucocorticoid release from the adrenal cortex.

Back 3

CRF from the hypothalamus stimulate the ACTH release from the pituitary --> ACTH stimulates synthesis and secretion of glucocorticoids from the adrenal cortex.

Front 4

Give the pathway for mineralocorticoid release from the adrenal cortex.

Back 4

Same as glucocorticoids, but mineralocorticoids are less dependent on ACTH

Front 5

What are the major products of glucocorticoids and mineralocorticoids?

Back 5

glucocorticoids = cortisol… mineralocorticoids = aldosterone

Front 6

What effects do low or high circulating levels of cortisol have on CRF (ACTH --> corticoids)?

Back 6

Low --> stimulation of CRF release… High --> inhibition of CRF

Front 7

Besides CRF, what can stimulate pituitary release of ACTH?

Back 7

inflammatory cytokines, like IL-1 and TNF

Front 8

given that ACTH/cortisol is at its low at midnight and at its peak at 6:00 a.m., when would you give therapeutic glucocorticoids? Why?

Back 8

at 6:00 to avoid inhibition of natural production of ACTH at other times during the day

Front 9

What is ACTH used for?

Back 9

diagnostics

Front 10

What are the two homeostasis effects of corticosteroids?

Back 10

1. Sodium homostasis and, 2. glucose homostasis

Hint 10

None

Front 11

What is the effect of aldosterone?

Back 11

Na+ retention --> water retention

Front 12

What is the effect of cortisol?

Back 12

increased energy in the form of glucose in times of stress

Front 13

What is the mechanism of cortisol?

Back 13

cortisol increases liver glycogen storage, increases glucogenesis, and decreases the peripheral use of glucose..

Front 14

During cortisol secretion and resulting glucogenesis and glycogen storage, what is the source of glucose?

Back 14

breakdown and decreased production of muscle proteins… and loss of bone matrix

Front 15

How is cortisol like aldosterone?

Back 15

like aldosterone, cortisol causes Na+/water retention

Front 16

Besides, glucose storage and Na+ retention properties of cortisol, what other two effects does cortisol have?

Back 16

renal loss of Calcium and redistribution of body fat

Front 17

Glucocorticoids effect DNA transcription as part of their mechanism, how do glucocoriticoids gain access to the DNA?

Back 17

they diffuse through the membrane and bind cytoplasmic receptor to form a complex --> then complexes are transported to the nucleus --> where they are involved in gene transcription, e.g., NFkB.

Hint 17

None

Front 18

What is the major therapeutic effects of glucocorticoids?

Back 18

anti-inflammatory effects

Front 19

What are the 4 anti-inflammatory effects of glucocorticoids?

Back 19

1. decrease granulocyte and monocyte function… 2. they also decrease the numbers of monocyte, eosinophils, and lymhocytes… 3. Inhibit cytokine and growth factor synthesis, which decreases vascular permeability… 4. They also increase intracellular levels of annexins or lipocortins, which block the activation of phospholipase A2

Front 20

What are the downstream effects of increasing intracelluar annexins and lipocortins?

Back 20

block activation of phospholipase A2 --> block production of arachidonic acid--> block PGG, TXA2, leukotrienes --> block cellular inflammatory response, e.g., phagocytic macrophage responses --> which in turn inhibits T-cell cell medicated activation (which requires leukotrienes and antigen presentation)

Front 21

What are the indications for glucocorticoids?

Back 21

hypersensitivities rxns

Front 22

What is the clinical use of corticosteroids with cleaved side chains?

Back 22

topical (skin diseases, as well mucus membrane diseases like asthma, and rhinitis), since they will not have a systemic affect

Front 23

Name the 5 corticosteroids

Back 23

(HPMTB): hydrocortisone, prednisone, methylprednisolone, triamcinolone, betamethasone

Front 24

Give the relative potency of the 5 synthetic corticosteroids for anti-inflammatory activity.

Back 24

hydrocortisone (1)< prednisone (4) < methyl prednisolone (5) < triamcinalone (5) < betamethasone (25-40 and 10 for topical activity)

Front 25

Most corticosteroids are available in topical, oral and injectable forms, what is the exception to this?

Back 25

prednisone is only available in oral form

Front 26

how can on manage therapeutic doses of corticosteroids without significantly depressing the hypthalmic-pituitary axis?

Back 26

give every other day… and in the morning

Front 27

Review the side effects of glucocorticoid therapy…

Back 27

page 191 of syllabus

Front 28

name 3 cytotoxic drugs used as immunomodulators

Back 28

azathioprine, cyclphosphamide, methotrexate

Front 29

How do cytotoxic drugs work to modulate the immunity

Back 29

they block cell division, and thus have a negative inductive phase effect (they don't effect the effector phase)

Front 30

which cytotoxic drug is a derivative of 6 mercaptopurine? And what is its mechanism of action?

Back 30

azathioprine --> metabolized to 6-MP, which blocks purine synthesis --> its metabolites are incorportated into DNA --> inhibit DNA synthesis

Front 31

What are the 5 clinical indication for azathioprine?

Back 31

1. Transplant rejection… 2. Severe rheumatoid arthritis… 3. Severe SLE… 4. Wegener's granulomatosis… 5. Polyarteritis nodosa (attack of small an medium sized arteries)

Front 32

T/F azothiorine blocks both B and T cell mediated immunity

Back 32

TRUE

Front 33

What is the mechanism of action of cyclophosphamide?

Back 33

cyclophosphamide is an alkylating agent related to nitrogen mustard that cross links DNA… like azathioprine, it blocks the inductive phase of immunity

Front 34

T/F cyclophosphamide blocks both B and T cell immunity.

Back 34

false… it's primarily B cell modulating

Front 35

What is the major use of cyclophosphamide of chronic inflammatory diseases?

Back 35

Wegener's granulomatosis, nephrotic syndrome, polyarteritis nodosa, and SLE

Front 36

What is the major SE of cyclophosphamide?

Back 36

hemorrhagic cystitis, due to urine excreted metabolites

Front 37

What are the 3 mechanism of action of immunomodulator cytotoxic drug, methotrexate?

Back 37

1. methotrexate inhibits DHFR and prevents DNA synthesis of rapidly dividing cells… 2. and blocks other folate dependent enzymes… 3. its anti-inflammatory effects may be due to inhibition of neutrophil chemotaxis

Front 38

What are the immunomodulation clinical indications for methotrexate?

Back 38

Rheumatoid arthritis, Crohn's disease

Front 39

Name 2 T-cell specific drugs used in immunomodulation.

Back 39

Cyclosporine and tacrolimus

Front 40

What effect does cyclosporine have on T-cell activation?

Back 40

it's proposed that it may decrease essential T-cell growth factors, IL-2 and gamma interferon (which activates macrophages)

Front 41

Which T-cell is primarily targeted by cyclosporin?

Back 41

T-helper cells and spares T-suppressor cells

Front 42

What does cyclosporin bind and what is the effect of this binding?

Back 42

binding of cyclosporin to cyclophilin blocks the generation of calcineurin (which is a signal for DNA synthesis) … it may also bind lymphokine regulators

Hint 42

None

Front 43

What is the primary indication for cyclosporine?

Back 43

prevent transplant rejection… it's also used Rx hypersensitivities, including aplastic anemia, juvinile diabetes, psoriasis, and uveitis

Front 44

What is the major toxic side effect of cyclosporine?

Back 44

nephrotoxicity and hypertention, and others such as hypertrichosis, encephalopathy, hepatotoxicity…

Front 45

What precaution can be taken to miminize toxic effects of cyclosporine?

Back 45

monitor for low serum cholesterol, which increases the risk of toxicity

Front 46

Which immunosuppressive drug may reactivate EB virus, and increased one's risk of lymhoma.

Back 46

cyclosporin

Hint 46

None

Front 47

What is the main clinical indications for tacrolimas?

Back 47

Tacrolimas: prevent liver and kidney graft rejection… also dermatitis and other allergic conditions mediated by T-cells

Hint 47

None

Front 48

What are the 2 mechanism of action of tacrolimas?

Back 48

1. like cyclosporine, it decreases IL-2 and other lymphokines… however it 10-100 x more potent… 2. It also inhibits calcineurin phosphatase

Front 49

What are the toxic SE of tacrolimas?

Back 49

Like that of cyclosporine: nephrotoxicity and hypertention, and others such as hypertrichosis, encephalopathy, hepatotoxicity… HOWEVER, it has more neurological complications, i.e., headaches

Front 50

Name 2 drugs used in human monoclonal antibody therapy

Back 50

infliximab and omalizumab

Hint 50

None

Front 51

What is infliximab used to treat? And what is its mechanism of action

Back 51

infiximab are antibodies against TNF-∂ and used to treat Crohn's disease and Rheumatoid arthritis

Front 52

What are 3 adverse side effects of infliximab use?

Back 52

increased infection (e.g., TB), lymphoma and exacerbation of MS

Front 53

What is the clinical indication for Omalizumab? And what is its mechanism of action?

Back 53

It is a humanized monoclonal Ab IgE… used to Rx asthma

Front 54

Give one example of a cytokine/receptor antagonist used to modulate the immune system.

Back 54

Etanercept

Front 55

What is etanercept's mechanism of action?

Back 55

Etanercept has two binding domains, one binds to TNF with the Fc domain of human IgG and the other binds to TNF and the other binds to a phagocyte, thus both inhibiting TNF and eliminating it

Front 56

Name 5 immunopotentiators

Back 56

IV gammablobulin, interferons ∂, ß and gamma, Levamisole, IL-2 and BCG

Front 57

What is the mechanism of action for the immunopotentiating of IV gamma globulin?

Back 57

passive immunity for people that Ig of their own… painful intramuscular admin has been replaced by IVIG preparations

Front 58

What are the 4 indications for IV gamma globulins?

Back 58

1. Hypogammaglobulinemia… 2. Idiopathic autoimmune thrombocytopenia… 3. Prevention of infection in B cell malignancies… 4. Kawasaki's disease

Front 59

what are the adverse rxns of IV gamma globulin Rx?

Back 59

Anaphylatoid rxns (must be given slowly)… 2. If given to congenitally difficient IgA patients, there may be high circulating levels of anti-IgA, thus give a prep w/o IgA

Front 60

What is the mechanism of action of BCG?

Back 60

it was used as a vaccine for TB, , but it has been shown to stimulate macrophage and T-cell function

Front 61

What is the indication for BCG use?

Back 61

bladder malignancies and colon cancer

Front 62

What is the mechanism of action for Levamisole? What is it used to Rx?

What is the mechanism of action of gamma interferon?

Back 62

it’s a anti-helminthic drug that enhances T-cell and macrophage function…. It's used as an adjuvant to Rx colon cancer

Gamma interferon activates macrophages

Hint 62

None

Front 63

What is the mechanism of action of IL-2? What is it used to Rx? What are the adverse SE?

Back 63

it's a T-cell growth factor... used to Rx renal cell carcinoma…. Hypothyroidism, capillary leak syndrome --> fatal pulmonary edema

Front 64

Between ∂, ß and gamm interferon, which is produced by activated T-cells and serves to activate macrophaes?

Back 64

gamma

Front 65

given that gamma interferon activates macrophages, in which two disease is its use indicated?

Back 65

chronic granulomatous disease and visceral leishmansiasis

Hint 65

None

Front 66

Which interferon is used to treat MS?

Back 66

Beta interferon

Front 67

Which interferon is used to Rx, hairy cell leukemia, other malignancies, Hep B and C, Kaposi's sarcoma… etc.?

Back 67

alpha interferon

Front 68

In determining Ab origin, what do the following represent? momab, ximab, zumab, umab

Back 68

mo = mouse, xi =chimeric human, zu = humanized, umab = human (pure)