Exam 2 Flashcards by Jon Beckloff

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Organ systems in Anaphylaxis?

What drives a sudden drop in blood pressure?

How does death from anaphylaxis usually occur?

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The Inflammatory Pathway

Inducers

Sensors

Mediators

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Antirejection Therapy

What are included in the Tx options?

Monoclonal Antibodies?

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Salicylate

Aspirin

High doses are limited by?

Used infrequently for?

What is different compared to other NSAIDs?

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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?

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Anti CD20 3 meds CD20 ALA

Mechanism

Directed against what on what cells?
Inhibits ____ ____ and induces?
How long suppressed?

Tx indication 3

AEs 3

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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

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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?

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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 __

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Prostaglandins as therapeutic targets

THe NSAIDs

What do they do?

Prevent generation of?

Limits? Think symptoms

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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

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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?

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Thromboxane

TXA2 is an unstable metabolite of? Half life?

TXA2 functions?

Mediates platelet?

Mediates smooth muscle?

Activates?

Clinical Relevance?

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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

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Allopurinol and Azothio

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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?

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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?

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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?

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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? 1. Syndrome? 2. Blood? 3. 3 things 4. \_\_\_ 5. 2 things 6. 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? 1. Inhibits what enzyme what is this in guanine nucleotide synth? 2. This is critical for? therefore? 3. 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 1. Compliment cascade is activated 2. Inflammation and tissue damage ensues 3. Inflammation, smooth muscle proliferation, and vessel occlusion ensues 4. T lymphocytes react with graft antigens and produce cytokines 5. Performed antibodies react with transplant antigens 6. 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?