Flashcards in Pharm Exam 3 Deck (95):
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
What 2 classes of cytotoxic agents are utilized in immunosuppression
Antimetabolites and Alkylating agents
What is the goal of cytotoxic agents?
To eliminate undesirable cells
What are nucleosides derived from?
Derivatives of purines and pyrimidines that are conjugated to ribose or deoxyribose
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)
What is the function of ribonucleotide reductase?
To reduce ribonucleotides to deoxyribonuccleotides. Thus catalyzing the formation of DNA.
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
What are the side effects of steroid use?
gastric and duodenal bleeding,
What is the contraindication for steroid use?
How do alkylating agents produce their effects?
By adding a hydrocarbon group such a CH3. They interfere with DNA replication and gene expression.
What are the two types of antimetabolites?
Purine and pyrimadine analogs
Which nucleotide bases are Purines?
Adenine and Guanine
Which nucleotide bases are pyrimidines?
Thymine, Cytosine and Uracil
A nucleoside plus a phosphate group makes what?
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
Examples types of antimetabolites
Purine analogs and pyrimidine analogs
Uses of antimetabolites
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
A highly toxic alkylating agent. It crosslinks DNA to itself by binding to DNA twice
What are the two Specific Lymphocyte Signaling Inhibitors
Calcineurin inhibitors and mTOR inhibitors
What is the end result of Specific Lymphocyte Signaling
Activated T cells which increase the production of IL-2
What is NFAT
Nuclear factor of activated T-cells
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
What is Calcineurin
A phosphatase enzyme which dephosphorylates NFAT
Example of a Calcineurin inhibitor
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.
Cyclosporine is extensively metabolized by
Side Effects of Cyclosporine
(EBV and CMV)
Cyclosporine is effective in suppressing T cell immunity if the T cells are still inactive or activated
What does mTOR stand for
Mammalian Target of Rapamycin
What is another name for Rapamycin
What is the MOA of Rapamycin (sirolimus)?
It binds to FKBP 12 protein in the cytoplasm which then inhibits mTOR
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
Example of an mTOR inhibitor
Sirolimus (AKA Rapamycin)
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
Advantage of mTOR inhibitors over Calcineurin inhibitors?
mTOR inhibitors are not nephrotoxic.
Side effects of mTOR inhibitors?
- Mucositis (canker sores) *
- Anemia, thrombocytopenia or neutropenia *
- Interstitial Pneumonitis
Contraindications of mTOR inhibitors
None. can be a drug interaction with Calcineurin inhibitors
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.
Tumor Necrosis Factor Alpha (TNF-a) is what kind of cell signaling protein?
Uses of TNF-a inhibitors
Auto immune diseases such as
- Ulcerative colitis
- Ankylosing Spondytis (fusion of the axial skeleton)
Contraindications of TNF-a inhibitors.
- Latent TB
- Active infection
Side effects of TNF-a inhibitors
- Injection site irritation
- Acute inflammatory infection
- Delayed inflammatory infection
- Heart failure
- liver failure
- demyelination of the CNS
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.
What do B Cell biologics do
Target B cells for destruction or interfere with ability to mount an immune response
What are the 2 B Cell targets
CD20 and CD22
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
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;
- Memory induction
Uses of B Cell Biologics
- B Cell tumors
- Inflamatory Autoimmune Diseases
Contraindications of B Cell Biologics
- Active infection
- Latent infection (Hep C)
Early Side Effects of B cell Biologics
Common and Mild
- Hyper/ Hypotension
- Scratchy throat
- Mucocutaneous reactions
Rare and Severe
Late Side effects of B Cell Biologics
- Immunosuppression leading to infection
- Progressive multifocal leukoencephalopothy
(Inflammation of the white matter)
What are the targets for T cell biologics?
CD3, CD25 and CD28
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.
Important functions of CD25 on T Cells
- IL-2 receptor.
- Suppression of IL-2 receptor decreases inflammation.
- Suppress autoreactive T cells.
Uses of T Cell biologics
- T Cell Tumors
- Inflammatory Autoimmune diseases
- Transplant medicine
Contraindications of T Cell Biologics
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
Side Effects of T Cell biologics
How are polyclonal antibodies produced?
Immunization of rabbits or horses with lymphoid cells.
What 2 things are required for T Cell activation
1. The antigen
2. The costimulator
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
MOA of Glatiramoids
- Binds major histocompatibility cells (MHC class II) on Antigen presenting cells (APS's)
- Increases Th2 suppressors
What can Th 2 cells do
May cross the Blood Brain Barrier and secrete anti-inflammatory cytokines
Indication for Glatiramoids
Treatment of MS
Contraindications of Glatiramoids
Side Effects of Glatiramoids
- Chest Pain
Inhibition of cytokines by steroids leads to inhibition of what?
IL 1,2, 6 and TNF-a
Folate is an essential cofactor in what?
Purine Ribonucleotide synthesis and cTMP
Which cells secrete TNF-a
Activated Th cells
Example of a Fusion protein which binds TNF-a
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.
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
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)
MOA of Insulin
- Up regulates GLUT-4
- Inhibits gluconeogenesis (reduces glucose)
- Facilitates uptake of amino acids thus increasing protein synthesis
- Inhibits lypolysis
MOA of Incretins
- 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
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
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.
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)
MOA of Somatostatin Analogs
- Produced by delta cells
- Binds to G Proteins and decreases cAMP
- Inhibits Hormones
* Pancreatic Enzymes
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
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
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
MOA of antithyroids
* 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
Second messenger action of Muscarinic receptor subtypes M1, M3 and M5 action
Formation of IP3 and DAG, increased intracellular calcium
Second messenger action of Muscarinic receptor subtypes M2 and M4 action
Opening of potassium channels, inhibition of adenylyl cyclase. Decreased cAMP
Alpha 1 receptor second messenger action
Formation of IP3 and DAG, increased intracellular calcium.
Alpa 2 receptor second messenger action
Inhibition of adenylyl cyclase, decreased cAMP.
Beta 1,2,and 3 second messenger action
Stimulation of adenylyl cyclase, increased cAMP.
Dopamine receptor subtypes D1 and D5 second messenger action
Stimulation of adenylyl cyclase, increased cAMP.
Dopamine receptor subtypes D2, D3 and D4 second messenger action
Inhibition of adenylyl cyclase, decrease in cAMP
Cholioceptors respond to
Receptors (both muscarinic and nicotinic) that respond to ACh.
Adrenoceptors respond to
Receptors that respond to catecholamines, such as NE and Epi.
Can be further divided into alpha and beta
Nicotinic receptors are located where?
The ganglion of the sympathetic and parasympathetic NS