Exam 2 Flashcards
Organ systems in Anaphylaxis?
What drives a sudden drop in blood pressure?
How does death from anaphylaxis usually occur?
The Inflammatory Pathway
Inducers
Sensors
Mediators
Antirejection Therapy
What are included in the Tx options?
Monoclonal Antibodies?
Salicylate
Aspirin
High doses are limited by?
Used infrequently for?
What is different compared to other NSAIDs?
PGI2
Important regulator in?
What are 3 major sources of PGI2
Acts as a potent ____? And an Inhibitor of what 3 things?
PGI2 is an important mediator of 2 things? Associated with acute inflammation
CLincial relevance: Where is it found in highest concentration?
Anti CD20 3 meds CD20 ALA
Mechanism
- Directed against what on what cells?
- Inhibits ____ ____ and induces?
- How long suppressed?
Tx indication 3
AEs 3
Anaphylaxis Treatment Goals?
- Counter the effects of?
What do you use?
- First and?
- There are NO what in an anaphylaxtic setting?
What is the mechanism of this drug? Acts on 3 things
- Increases bronchodilation and decreases release of inflammatory mediators from mast cells and basophils
- Increases rate and force of cardiac contractions
- Mediates vasocontriction, decreases edema, relieves airway obstruction, and increases blood pressure
Calcineurin Inhibitors
2 drugs?
AEs: Dose dependent
- Increase what? This is less in which one?
- Decrease ____ ____ can cause ____ ischemia and ___ tubular ____
- What disease can thay cause?
- K and Mg?
- Neurotoxicity ranging from? More with?
- Glycemia? More with?
- Lipidemia less with?
- Hirsutism less with?
- Gingival?
Eculizumab (Soliris)
Mechanism
Inhibits cleavage of?
Which one is a chemoattractant?
Which one is required for tha MAC?
Tx Indication
- Prevention of ____ ____ in transplanted ___, Investigated for use in?
AEs
6 SEs
Risk of serious __ with __
Prostaglandins as therapeutic targets
THe NSAIDs
What do they do?
Prevent generation of?
Limits? Think symptoms
SEs associated with chronic glucocorticoid use
• Given the vast array of biological effects mediated by prostaglandins, the use of prostaglandins blocking drugs should be considered based on the individual condition
Azothioprine Known as?
Mechanism
- Inhibits metabolism of? Is a prodrug of?
- Interferes with what type of replication?
- Lacks? What does this mean? Examples of this being a problem?
Treatment indications? 2 things
AEs? Blood ones? Toxic to? Inflammation of?
Thromboxane
TXA2 is an unstable metabolite of? Half life?
TXA2 functions?
Mediates platelet?
Mediates smooth muscle?
Activates?
Clinical Relevance?
Non Microbial Inducers and Sensors
Exogenous Examples? Think of? The sensors for allergens?
Asbestos
Endogenous inducers of inflammation- Signals are produced by? Sensors are able to detect?
How are cells and tissues able to distinguish between normal and stressed, damaged, or dysfunction states? What can they detect?
“separation strategy”
Examples supporting the things
Allopurinol and Azothio
TNF-a inhibitors? 3
Mechanism
What two are monoclonal antibodies to TNF?
The other one is?
Tx indication
3 things
AEs
- Increased susceptibility to?
- Suppression of?
- Failure?
- What disease?
Inflammasome case
Activation of the inflammasome has been strongly linked to Know this one you can answer the rest?
Inflammation is thought to promote?
Where would you expect inflammation to take place?
What might be inducers of the inflammation?
Case Study the Inflammasome
Inflammasomes are systems of innate immune receptors/ sensors: That are responsible for?
Inflammasomes have been linked to a variety of diseases?
Case study NSAIDs and GI toxicity
Salicylates (nonacetylated)
Diflunisal and Salsalate
No significant effect on?
Less frequent?
Generally tolerated by?
Relatively slow?
Questions to Consider for anaphylaxis
What comorbidities and medications would lead to poor outcome?
3 different ones
- Why would H1 or H2 antihistamines be benefitial during anaphylaxis? But they dont help?
- Would glucocorticoids help?
- What about bronchodilators?
Induction/Rejection Therapy
Horse anti-thymocyte globulin (ATGAM)
Mechanism
- Depleting?
- Blocks what?
- Broadly targets ___ and alters what 2 functions of them
Indication 3
AEs?
- Syndrome?
- Blood?
- 3 things
- ___
- 2 things
- K
H Receptor effects
Tissue, Effect, Clinical Effect, Receptors
Only 2 is H2, only one is H3
CNS
Lungs
Vas SM
Nerves
Heart
Stomach
Autoimmune drugs
1st line 3
2nd line 3
Experimental?
Mycophenolate
Mechanism?
- Inhibits what enzyme what is this in guanine nucleotide synth?
- This is critical for? therefore?
- More effective than what other drug? More tolerable than?
Tx indications?
3 transplants
What diseases?
AEs?
GI?
Blood?
Pharmacology of Immunosuppression
Immunosuppressive drugs can be grouped into 3 categories?
What are the goals for transplant immunosuppression?
Clinical Focus: LTs and Asthma
What are the most potent bronchoconstrictors in human?
Thousands of times more potent than?
What do allergens induce in pts?
Airways Remodeling:
LTs promote the proliferation of what two cell types?
LTs increase the deposition of? Which is an important feature of what disease?
LTs affect the human airway muscle tone, how does this work? 3 points
PGE2
One of the most? During inflammation what is it responsible for 3?
What do some of these stem from?
What about the other response?
Clinical relevance? Plays a role in the development of?
H3R
General
- Where is it expressed the most?
- Prevents excessive?
- Mediates ___ with no involvement of?
Immune
- Control of neurogenic ___ via what communication?
- What type of activity?
- Increase what capacity?
Relevance
- Type of receptor?
- Decreases release of what NTs? 5
- 2 things involving the brain
*
Review of Allergic Rxns
questions
The cyclooxtgenase pathway
The COX pathway produces? 2 things
COX isoforms?
COX-1 activity is typically present and expressed by? Produces what with “housekeeping” function
Examples of these function 4 things
Maintenance Therapy
Goals: 3 goals
Maintenance regimens?
Rejection of Transplant Tissues
Hyperacute
Acute
Chronic
- Compliment cascade is activated
- Inflammation and tissue damage ensues
- Inflammation, smooth muscle proliferation, and vessel occlusion ensues
- T lymphocytes react with graft antigens and produce cytokines
- Performed antibodies react with transplant antigens
- T lymphocytes react with transplant antigens
Physiologic Roots of Inflammation
A controlled inflammatory response is generally considered? But?
Acut inflammatory response:
Delivery of?
Triggered by?
Production of?
____ killing of pathogens
If neutrophils fail?
Cyclo pathyway
COX-2
Expression is?
As inflammation progresses what happens?
Both isoforms generate? who cares?
Epoxygenase Pathway
What enzyme converts AA into 4 EET isomers?
What are the 4 functions of EET?
EETs get converted into certain acids what causes this and what is the product? This decreases what? What inhibition is being evaluated for therapy?
Belatacept
MOA
Tx indication
AEs
Lipoxins: Resolution of Inflammation
Lipoxins are? They play a vital role in?
What 3 receptor types to Lipoxins have their effects on?
What are the 6 roles of Lipoxins?
Oxicams
Meloxicam- kinetics?
Selective for?
Fenamates
Meclofenamate
Tx of?
High incidence of?
Expressed in many tissues, such as the CNS, vascular smooth muscle and GI tract
General Function of H1R?
Functions in Immune modulation?
H4R
Expressed where?
General functions?
Functions in Immune modulation?
Clinical Relevance?
Antagonists?
Maintenance Therapy
5 major agents available
Histamine and Itch?
Roles of Histamine
Mediator of?
Released in the gut by? Increases?
Stored where? And acts as a? Occur in both?
PGF2a
Acts in the female?
Important role in?
Recent studies show important activity in 4 things?
Leads to? Suppressed by?
Clincial relevance in 3 disease states?
H2R
Physiological Relevance?
Clinical Relevance?
Antagonists?
AntiCD20
Endogenous Inducers: clinical relevance
Advanced glycation end products (AGEs)
The glycation of long lived proteins, such as collagen can result in?
AGEs are recognized alone by the receptor?
What situation would you expect the accumulations of AGEs?
Induction: Antibody Based Therapies
Drug?
Mechanism:
Indication:
AEs
Immediate Hypersensitivity?
Allergies?
Mechanism 3 of them
Inflammatory Mediators Overview
Mediators can be classified into 7 groups according to their biochemical properties
Vasoactive amines (_____)
- Secreted in what manner and when?
- What 2 things can it cause?
Vasoactive molecules (_____)
- Stored in what form or generated by?
- Cause what 2 things?
Complement proteins
- Produced by?
- ___ promotes ____ recruittment and Induce what type of degranulation? This affects?
Inflammatory cytokines
- What are 3 examples?
- Produced by many cell types but what are the two important ones?
- Have many roles but activation and induction of what is the example?
Chemokines
- Produced by? Control what 2 things towards the affected tissue?
Proteolytic Enzymes
- Degrades what things?
- Important roles in what 3 things?
Lipid Mediators
- Derived from?
- Why are these important?
Arachidonic Acid
- Synthesized from? Linked to?
- Different pathways can form different?
- – Vasoactive amines (histamine)
- Secreted in all-or-none manner when mast cells and platelets degranulate
- Can cause vasodilation and increased vascular permeability –
- Vasoactive molecules (serotonin)
- Stored in active form in secretory vesicle or generated by proteolytic processing of inactive precursors
- Cause vasodilation and increased vascular permeability
- Complement proteins
- Complement fragments are produced by several pathways
- C5a promotes leukocyte recruitment and induce mast-cell degranulation, affecting the vasculature
- Inflammatory cytokines
- Examples include tumor-necrosis factor-α (TNF-α), IL-1, IL-6, and many others
- Produced by many cell types, but most importantly by macrophage and mast cells
- Have several roles, including activation of the endothelium and leukocytes and induction of the acute-phase response
- Chemokines
- Produced by many cell types, and controls leukocytes extravasation and chemotaxis towards the affected tissues
- Proteolytic enzymes
- Degrades the extracellular matrix and basement-membrane proteins
- Have important roles in host defense, tissue modeling, and leukocyte migration
- Lipid mediators:
- These are derived from phospholipids that are present in cellular membranes
- These mediators represent an important focus of discussion, as they represent current targets of anti-inflammatory therapies
- Arachidonic Acid (AA)
- AA is synthesized from fatty acids, and is linked to membrane phospholipids
- Different pathways can form different metabolites of AA, as shown on the next slide
Prostaglandins
What common chemical structure is shared?
4 bioactive ones?
Each cell type generates one or two dominant producted which act as?
Prostaglandin production is typically?
When is production increased?
Immedicate Hypersensitivity and Anaphylaxis
Immediate Hypersensitivity Background
Clinical Manifestations?
Definition of Anaphylaxis
LTs and Asthma
Asthma is Characterized by?
Airway inflammation plays a key role in the pathogenesis of asthma this is characterized by what 3 things?
What LT appears to have an important role in asthma? Where are increased levels of this found?
Given this information what effects would you expect LTs to have on inflammatory cell?
From Atachidonic Acids
_____ are lipid signalling molecules derived from?
AA can be enzymatically metabolized by what 3 pathways?
IgE Overview
Is IgE common? Why is this?
IgE instegates immediate? How does it cause this?
Mast cell mediators:
Performed mediators are released de novo synthesis of lipid mediators produces symptoms withiin minutes what happens after?
H2R
General Functions? 4
Function in Immune Modulation? 5
Pharmacology of Autoimmune diseases
In what diseases would immunosuppression be useful? 3
Immunosuppressive drugs? 6 total but 3 classes
Mediators and Effectors of Inflammation
Inducers trigger? What can these be derived from? Many of these affect?
Cellular Mediators? Produced by? Some are stored in?
Other mediators?
How are allergic rxns classified?
Immediate hypersensitivity caused and triggered by?
Antibody mediated?
Immune complex mediated?
T lymphocyte mediated?
H3R
Clinical Relevance and Antagonists?
Physiological Relevance of H1R 5 things its involved in.
Clincal Relevance?
Antagonists? 4
Inflammasome case
Given the preceding information, what molecule(s) could be acting like inducers of inflammation (DAMPs or PAMPs) in the setting of atherosclerosis?
Histamine:
Principle mediator in?
What are the 4 receptors?
Metabolism of Histamine? Where is the enzyme that synthesizes it expressed? What can store histamine?
Lipid Mediators: Arachidonic Acid
Comes from what precursor? Only obtained?
Released from phospholipids by what enzyme?
This enzyme is stimulated by?
What type of drugs inhibit this?
Lipocortins? Another family? Suppression of?
____ supresses phospholipase A2 and?
Isoprotanes
What are they? How are they formed?
Levels in blood are much higher than?
What are the 2 isprostanes? What do they do?
Isoprostane levels might be indicative of?
Dont play a role in?
Histamine Receptor Summary
Known inducers of lipoxins? 2 kinds
mTOR Inhibitors 2
Mechanism
Tx indication
AEs
Mast Cell Mediators
Histamine, Serotonin, Vasoactive amines and Lipid mediators what do they cause?
LT inhibition Pharmacology
CysLT1 antagonists? What are their endings? Which one is preferred?
What medication is a 5-LO inhibitor what does it stop? Why is use limited? Toxicity of this drug is related to?
Nonacidic- Nabumetone only drug in class
Kinetics? Selective for?
Celecoxib?
Reduction in? Why is this?
What risks are dose related?
LT inhibition Clinical Use
Asthma: What are the 2 drugs that can be used in children or adults?
What are the 5 clinical effects of LT inhibition?
Microbial Inducers and Sensors
Exogenous inducers can be microbial or non microbial
Pathogen-associated molecular patterns (PAMPs)? What are they who carries them?
Virulence factors:
Unlike PAMPs they are not?
These factors cause what two negative affects which in turn causes?
Inflammasome
What is the inflammasome sensitive to?
Glucocorticoids
Name some
Inhibit the action of ____ in what 3 ways?
used to treat patients with?
Structure
Leflunomide
Mechanism
Indication
AEs?
Common themes of all NSAIDs
Most have the option of?
Have a dose and age related risk of?
Can cause or worsen?
Avoided in what patients?
Use with caution in?
Endogenous Inducers: Clinical relevance
Example of an inducer involved in chronic inflammation:
____ is cause by a build up of _______ crystals in joints, bones, and soft tissue
Hyperuricemia?
At higher concentrations?
When urate crystals reach a certain size, they are?
Phagocytosis triggers activation of?
Propanoic Acids
Naproxen (Aleve) and Ibuprofen (Advil)
High doses may have less?
Ibuprofen has a short? Naproxen?
Case study continued NSAIDs and GI Toxicity
Which factors are important in determining the risk for the development of NSAID induced GI bleeding?
What has been developed to prevent this?
What are the 4 leukotriene receptors?
Which one mediates bronchoconstrictions, mucus secretion, and airway edema?
Which one is a lower affinity receptor for LTB4?
Which is a high affinity receptor for LTB4, that mediates most of its chemoattractant and proinflammatory action?
Appears to play a role in intestinal barrier function and inflammatory disease?
Contributes to inflammation, vascular permeability, tissue fibrosis?
There are currently no specific antagonists to this receptor?
Presence of AA cysteine?
Acetaminophen a NSAID?
What is it generally considered?
But it Inhibits the synthesis of?
It has effects similar to?
LIPOX PATHWAY
Second major fate of what molecule?
Leads to the formation of what to things?
Synthesis is mediated by what 2 Proteins?
What is the first product of the pathway? This product can be converted into what 4 LTs?
Leukocytes have the ability to?
What diseases are leukotrienes involved in?
What would be causing exercise induced asthma?
What is the same and different with exercise and non?
PGD2
Sythesized in? What 2 things does it regulate?
What other places?
Involved in what type of reponse?
Clinical relevance?
Overview of Eicosanoid Functions
Examples of their function?
Regulation of what 3 things?
Acetic Acids
Diclofenac (Voltaren) and Indomethacin (indocin)
Diclo
Available as? When would this be useful?
Indomethacin?
Useful for the tx of?, potently? SEs?
Methotrexate
MOA
Indication
AEs
Histamine and Asthma
Cyclosporine and Tacrolimus what type of drugs?
Mechanism
Tx indication?
Induction Therapy
Goal:
Induction strategies?
What based therapy?
Drug used? Mechanism, Indication, AEs?
