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Flashcards in Pharm Exam 3 Deck (95):
1

What are the 6 mechanistic approaches or immune suppression

1. Inhibition of gene expression to modulate inflammatory responses
2. Cytotoxic agents to deplete expanding lymphocyte populations
3. Inhibition of lymphocyte signaling to block activation and expansion of lymphocytes
4. Neutralization of cytokines essential in mediating the immune response
5. Use of antibodies to deplete the immune system of specific cells
6. Blockade of co-stimulation to induce anergy

2

What 2 classes of cytotoxic agents are utilized in immunosuppression

Antimetabolites and Alkylating agents

3

What is the goal of cytotoxic agents?

To eliminate undesirable cells

4

What are nucleosides derived from?

Derivatives of purines and pyrimidines that are conjugated to ribose or deoxyribose

5

What are the 3 sets of reactions is nucleotide synthesis?

1. Synthsis of the ribonucleotides.
2. Reduction of ribonucleotides to deoxyribonucleotides
3. Conversion of deoxyuridylate (dUMP) to deoxythyridylate (dTMP)

6

What is the function of ribonucleotide reductase?

To reduce ribonucleotides to deoxyribonuccleotides. Thus catalyzing the formation of DNA.

7

In what ways do steroids act as Immune suppressors?

1. Inhibition of cytokine release
2. Decrease the activity to pattern receptors
3. Decrease Th cells
4. Decrease NK cell activity
5. Inhibit inflammatory gene expression
6. Inhibit phospholipase A2

8

What are the side effects of steroid use?

Hyperglycemia
weight gain
central obesity
severe swelling,
psychiatric symptoms,
gastric and duodenal bleeding,
adrenal suppression

9

What is the contraindication for steroid use?

Serious infection

10

How do alkylating agents produce their effects?

By adding a hydrocarbon group such a CH3. They interfere with DNA replication and gene expression.

11

What are the two types of antimetabolites?

Purine and pyrimadine analogs

12

Which nucleotide bases are Purines?

Adenine and Guanine

13

Which nucleotide bases are pyrimidines?

Thymine, Cytosine and Uracil

14

A nucleoside plus a phosphate group makes what?

A nucleotide

15

What are the functions of antimetabolites?

Antimetabolites are molecules that compete with essential components of metabolic processes thus inhibiting them.
1. Act to inhibit enzymes of nucleotide synthesis
2. The cell cannot replicate its genetic material

16

Examples types of antimetabolites

Purine analogs and pyrimidine analogs

17

Uses of antimetabolites

Antibacterial
Antifungal
Antiparasitic
Antineoplastic

18

4 categories of MOA by which antimetabolites produce their effects.

1. Inhibitors of folate metabolism
2. Inhibitors of purine metabolism
3. Inhibitors of ribonucleotide reductase
4. Nucleotide analogs

19

Cyclophosphamide

A highly toxic alkylating agent. It crosslinks DNA to itself by binding to DNA twice

20

What are the two Specific Lymphocyte Signaling Inhibitors

Calcineurin inhibitors and mTOR inhibitors

21

What is the end result of Specific Lymphocyte Signaling

Activated T cells which increase the production of IL-2

22

What is NFAT

Nuclear factor of activated T-cells

23

Steps in Specific Lymphocyte Signaling

1. Calcineurin dephosphorylates NFAT
2. Dephosphorylated NFAT moves into the nucleus
3. Dephosphorylated NFAT stimulates the transcription of IL-2

24

What is Calcineurin

A phosphatase enzyme which dephosphorylates NFAT

25

Example of a Calcineurin inhibitor

Cyclosporine

26

MOA of Cyclosporine

Cyclosporine binds to cyclophilin which inhibits the phosphatase activity of Calcineurin and prevents NFAT from entering the nucleus. Thus inhibits the production of IL-2.

27

Cyclosporine is extensively metabolized by

CYP3A

28

Side Effects of Cyclosporine

Opportunistic infection
(EBV and CMV)
Nephrotoxicity
Kidney damage
Hypertension
CNS problems

29

Cyclosporine is effective in suppressing T cell immunity if the T cells are still inactive or activated

Still inactive

30

What does mTOR stand for

Mammalian Target of Rapamycin

31

What is another name for Rapamycin

Sirolimus

32

What is the MOA of Rapamycin (sirolimus)?

It binds to FKBP 12 protein in the cytoplasm which then inhibits mTOR

33

What are the cellular level effects of Rapamycin?

Suppressor of RNA translation
Blocks the activation of IL-2
Inhibits the activation of T and B cells

34

Example of an mTOR inhibitor

Sirolimus (AKA Rapamycin)

35

What are the tissue level effects of mTOR inhibitors?

1. Impede vascular endothelial cell stimulation by vascular endothelial growth factor.
2. Reduce abnormally increased proliferation of endothelial cells and vascular smooth muscle cells
3. Alter the growth and proliferation of cancerous lymphocytes

36

Advantage of mTOR inhibitors over Calcineurin inhibitors?

mTOR inhibitors are not nephrotoxic.

37

Side effects of mTOR inhibitors?

- Mucositis (canker sores) *
- Anemia, thrombocytopenia or neutropenia *
- Interstitial Pneumonitis
- Infection
- Hyperglycemia
- Hyperlipidemia

38

Contraindications of mTOR inhibitors

None. can be a drug interaction with Calcineurin inhibitors

39

Tumor Necrosis Factor Alpha (TNF-a) does what

Initiates acute phase response.
Vasodilates venules, increasing blood flow.
Increases vascular permeability
Increases endothelial adhesiveness.
Increases synthesis of cytotoxic metabolites.

40

Tumor Necrosis Factor Alpha (TNF-a) is what kind of cell signaling protein?

A cytokine

41

Uses of TNF-a inhibitors

Auto immune diseases such as
- Crohn's
- Ulcerative colitis
- Psoriasis
- Ankylosing Spondytis (fusion of the axial skeleton)

42

Contraindications of TNF-a inhibitors.

- Latent TB
- Immunocompromise
- Active infection

43

Side effects of TNF-a inhibitors

- Injection site irritation
- Acute inflammatory infection
- Delayed inflammatory infection
- Heart failure
- liver failure
- demyelination of the CNS
- Cancer

44

MOA of TNF-a inhibitors?

Inhibition of the inflammatory process by inhibition of TNF-a. mAbs antagonize TNF-a by competitively binding to it's receptors. Fusion Proteins bind to free TNF-a in the blood inhibiting it from binding to its receptor.

45

What do B Cell biologics do

Target B cells for destruction or interfere with ability to mount an immune response

46

What are the 2 B Cell targets

CD20 and CD22

47

What is the function of CD20

It is present at all stages of B Cell differentiation Except the first and the last. It regulates the early steps in the activation of B Cell differentiation

48

MOA of B Cell biologics

1. As a B Cell depleting agent they inhibit the expression of CD20 which results in apoptosis of B Cells
2. As an immunomodulator they block the cytokines required for B cell;
- Maturation
- Memory induction
- Activation
- Proliferation

49

Uses of B Cell Biologics

- B Cell tumors
- Inflamatory Autoimmune Diseases
- Transplants

50

Contraindications of B Cell Biologics

- Active infection
- Latent infection (Hep C)

51

Early Side Effects of B cell Biologics

Common and Mild
- Hyper/ Hypotension
- chills
- Scratchy throat
- bronchospasm
- Mucocutaneous reactions
Rare and Severe
- Hypoxia
- MI
- Stroke
- ARDS
- Death

52

Late Side effects of B Cell Biologics

- Immunosuppression leading to infection
- Progressive multifocal leukoencephalopothy
(Inflammation of the white matter)

53

What are the targets for T cell biologics?

CD3, CD25 and CD28

54

Important functions of CD3 on T Cells

- All T cells express CD3.
- Nonspecific, influence all subtypes of T cells.
- Induce selective apoptosis of activated T cells after binding to CD3.

55

Important functions of CD25 on T Cells

- IL-2 receptor.
- Suppression of IL-2 receptor decreases inflammation.
- Suppress autoreactive T cells.

56

Uses of T Cell biologics

- T Cell Tumors
- Inflammatory Autoimmune diseases
- Transplant medicine

57

Contraindications of T Cell Biologics

Active infection

58

MOA of T Cell Biologics

Inhibit the expression of CD3 and CD25 proteins which are important for T Cell function leading to improper function or apoptosis

59

Side Effects of T Cell biologics

Immunosuppression
- N/V
- Diarrhea
- Hypotension
- SOB
- Headache

60

How are polyclonal antibodies produced?

Immunization of rabbits or horses with lymphoid cells.

61

What 2 things are required for T Cell activation

1. The antigen
2. The costimulator

62

Example of a T Cell costimulator

CTLA- 4 is a costimulator and is up regulated in activated T Cells. It is inhibited by CTLA-4Ig

63

MOA of Glatiramoids

- Binds major histocompatibility cells (MHC class II) on Antigen presenting cells (APS's)
- Increases Th2 suppressors

64

What can Th 2 cells do

May cross the Blood Brain Barrier and secrete anti-inflammatory cytokines

65

Indication for Glatiramoids

Treatment of MS

66

Contraindications of Glatiramoids

None

67

Side Effects of Glatiramoids

- Chest Pain

68

Inhibition of cytokines by steroids leads to inhibition of what?

IL 1,2, 6 and TNF-a

69

Folate is an essential cofactor in what?

Purine Ribonucleotide synthesis and cTMP

70

Which cells secrete TNF-a

Macrophages
Mast Cells
Activated Th cells

71

Example of a Fusion protein which binds TNF-a

Enteracept

72

MOA of AGI

Starch Blockers .
They bind to Glycosidase with a greater affinity than carbohydrates. This slows the absorption of carbohydrates in the GI tract. Also they stimulate GLP-1.

73

MOA of Biguanides

- Decrease in gluconeogenesis by activation of AMP Kinase
- Increase the action of insulin
- Delay GI absorption of glucose
- Stimulation of glycolysis
- Reduce plasma glucagon
- Enhance transcription of GLUT-4

74

MOA of Glucagon

- Stimulated by the sympathetic NS
- In the liver it binds to a G Protein receptor
- - This increases cAMP which then Protein Kinase A
- Increase Glycogenolysis increasing glucose
- Decreases Glycogen synthesis which increases available glucose
- increased Glycolysis (the use of glucose)

75

MOA of Insulin

- Up regulates GLUT-4
- Inhibits gluconeogenesis (reduces glucose)
- Facilitates uptake of amino acids thus increasing protein synthesis
- Inhibits lypolysis

76

MOA of Incretins

Two types
- DPP-4 inhibitors (Gliptins)
* Block DPP-4 enzymes from breaking down incretins GLP-1 and GIP leading to seduction in glucose
- Incretin mimetics
* are GLP-1 mimetics which cannot be degraded by DPP-4

77

MOA of Meglitinides

Bind to the SUR1 subunit (ATP sensitive K channel) it closes the K channel, thus depolarization which activates the Ca channel and exocytosis Insulin

78

MOA of Sulfonylureas

Bind to the SUR1 subunit (ATP sensitive K channel) it closes the K channel, thus depolarization which activates the Ca channel and exocytosis Insulin. Simmilar action to meglitinides but a different site on the SUR1.

79

MOA of Thiazolidinediones

- Decreases glucose by increasing glucose uptake by muscle and adipose cells.
- Also decrease of gluconeogenesis in the liver.
- Increase fatty acid storage (FFA leads to insulin resistance)

80

MOA of Somatostatin Analogs

- Produced by delta cells
- Binds to G Proteins and decreases cAMP
- Inhibits Hormones
* GH
* Insulin
* Glucagon
* Gastrin
* VIP
* Pancreatic Enzymes

81

MOA of GH Antagonists

- Blocks GH from coupling to its receptor in the liver
- GH in the liver releases IGF-1 thus GH Antagonists bloc the release of IGF-1

82

MOA of ACTH

1. Released from the AP
2. Binds to ACTH G protein receptors in the ZF
3. Increases cAMP
4. Activates PKA
5. Increase CA++
6. Synthesizes Cortisol

83

MOA of TH replacements

- Act similarly to steroids in that the mediate transcription
- Replace deficient endogenous T3 and T4
- Typically T4 because of 7 day half life vs. T3 1 day half life

84

MOA of antithyroids

2 types
- Thioamides
* Block iodine oxidation
* Block the coupling of iodinated tyrosines MIT and DID
* Do not block the uptake of iodine by the thyroid
- Radioactive Iodine 131I
* Destroys the thyroid by radiation

85

Second messenger action of Muscarinic receptor subtypes M1, M3 and M5 action

Formation of IP3 and DAG, increased intracellular calcium

86

Second messenger action of Muscarinic receptor subtypes M2 and M4 action

Opening of potassium channels, inhibition of adenylyl cyclase. Decreased cAMP

87

Alpha 1 receptor second messenger action

Formation of IP3 and DAG, increased intracellular calcium.

88

Alpa 2 receptor second messenger action

Inhibition of adenylyl cyclase, decreased cAMP.

89

Beta 1,2,and 3 second messenger action

Stimulation of adenylyl cyclase, increased cAMP.

90

Dopamine receptor subtypes D1 and D5 second messenger action

Stimulation of adenylyl cyclase, increased cAMP.

91

Dopamine receptor subtypes D2, D3 and D4 second messenger action

Inhibition of adenylyl cyclase, decrease in cAMP

92

Cholioceptors respond to

Receptors (both muscarinic and nicotinic) that respond to ACh.

93

Adrenoceptors respond to

Receptors that respond to catecholamines, such as NE and Epi.
Can be further divided into alpha and beta

94

Nicotinic receptors are located where?

The ganglion of the sympathetic and parasympathetic NS

95

Nicotinic receptors function by?

Opening of sodium, potassium channels leading to depolarization.