Pharm Exam 3 Flashcards
(95 cards)
1
Q
What are the 6 mechanistic approaches or immune suppression
A
- Inhibition of gene expression to modulate inflammatory responses
- Cytotoxic agents to deplete expanding lymphocyte populations
- Inhibition of lymphocyte signaling to block activation and expansion of lymphocytes
- Neutralization of cytokines essential in mediating the immune response
- Use of antibodies to deplete the immune system of specific cells
- Blockade of co-stimulation to induce anergy
2
Q
What 2 classes of cytotoxic agents are utilized in immunosuppression
A
Antimetabolites and Alkylating agents
3
Q
What is the goal of cytotoxic agents?
A
To eliminate undesirable cells
4
Q
What are nucleosides derived from?
A
Derivatives of purines and pyrimidines that are conjugated to ribose or deoxyribose
5
Q
What are the 3 sets of reactions is nucleotide synthesis?
A
- Synthsis of the ribonucleotides.
- Reduction of ribonucleotides to deoxyribonucleotides
- Conversion of deoxyuridylate (dUMP) to deoxythyridylate (dTMP)
6
Q
What is the function of ribonucleotide reductase?
A
To reduce ribonucleotides to deoxyribonuccleotides. Thus catalyzing the formation of DNA.
7
Q
In what ways do steroids act as Immune suppressors?
A
- Inhibition of cytokine release
- Decrease the activity to pattern receptors
- Decrease Th cells
- Decrease NK cell activity
- Inhibit inflammatory gene expression
- Inhibit phospholipase A2
8
Q
What are the side effects of steroid use?
A
Hyperglycemia weight gain central obesity severe swelling, psychiatric symptoms, gastric and duodenal bleeding, adrenal suppression
9
Q
What is the contraindication for steroid use?
A
Serious infection
10
Q
How do alkylating agents produce their effects?
A
By adding a hydrocarbon group such a CH3. They interfere with DNA replication and gene expression.
11
Q
What are the two types of antimetabolites?
A
Purine and pyrimadine analogs
12
Q
Which nucleotide bases are Purines?
A
Adenine and Guanine
13
Q
Which nucleotide bases are pyrimidines?
A
Thymine, Cytosine and Uracil
14
Q
A nucleoside plus a phosphate group makes what?
A
A nucleotide
15
Q
What are the functions of antimetabolites?
A
Antimetabolites are molecules that compete with essential components of metabolic processes thus inhibiting them.
- Act to inhibit enzymes of nucleotide synthesis
- The cell cannot replicate its genetic material
16
Q
Examples types of antimetabolites
A
Purine analogs and pyrimidine analogs
17
Q
Uses of antimetabolites
A
Antibacterial
Antifungal
Antiparasitic
Antineoplastic
18
Q
4 categories of MOA by which antimetabolites produce their effects.
A
- Inhibitors of folate metabolism
- Inhibitors of purine metabolism
- Inhibitors of ribonucleotide reductase
- Nucleotide analogs
19
Q
Cyclophosphamide
A
A highly toxic alkylating agent. It crosslinks DNA to itself by binding to DNA twice
20
Q
What are the two Specific Lymphocyte Signaling Inhibitors
A
Calcineurin inhibitors and mTOR inhibitors
21
Q
What is the end result of Specific Lymphocyte Signaling
A
Activated T cells which increase the production of IL-2
22
Q
What is NFAT
A
Nuclear factor of activated T-cells
23
Q
Steps in Specific Lymphocyte Signaling
A
- Calcineurin dephosphorylates NFAT
- Dephosphorylated NFAT moves into the nucleus
- Dephosphorylated NFAT stimulates the transcription of IL-2
24
Q
What is Calcineurin
A
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.
