PCOL:3102 NSAIDs, Allergies, and Asthma

prostaglandin synthesis

• antigen activates PTKs which will phosphorylate PLA2

• PLA2 makes arachidonic acid which depending on enzyme will make prostaglandin or leukotrienes

  • COX → prostaglandin

  • lipoxygenase → leukotrienes

types of prostanglandins made

• PGE2

• PGI2

• TXA2

effects depend on where it’s released. prostanglandins have short half-life so they don’t travel far which is why its effects are tissue specific

prostaglandin effect on blood vessels

• PGI2 and PGE2 cause vasodilation → increase blood flow

• TXA2 cause vasoconstriction → decrease blood flow

prostaglandin effect on platelets

• TXA2 increase blood clotting

• PGI2 decrease blood clotting

prostaglandin effect on sensory nerves

PGI2 and PGE2 lower threshold for pain stimulation (hyperalgesia) which can convert normally non-painful stimuli into painful stimuli

prostaglandin effect on brain

PGE2 in hypothalamus cause increase in body temp → fever

prostaglandin effect on uterus

can cause uterine contraction and relaxation

difference between where COX1 and COX2 work?

• COX1 is only one involved in platelets and stomach & GI, so main culprit in blood clotting and helps secrete mucus to protect stomach lining

• COX 2 is only one involved in inflammation, so COX2 main culprit in inflammation responses

• both in uterus and kidney

where are the diff prostaglandins released in?

• PGE2 in most tissues

• PGI2 in endothelium of vessels

• TXA2 in platelets

NSAIDs

non-steroidal anti-inflammatory drugs

• COX inhibitors so can inhibit both COX-1 and 2

• reduces inflammation by inhibiting COX-2

• many adverse effects from inhibiting COX-1 like stomach irritation

• non-selective and selective types

non-selective NSAIDs

• aspirin

  • better at treating blood clots than others because it’s an irreversible COX inhibitor so platelets have to wait till a new COX is born for it to get its clotting ability back

• ibuprofen

• naproxen

non-selective NSAIDs

celecoxib — inhibits COX2

what are NSAIDs used for?

• reduce inflammation from injury/stress (mild to moderate) as glucocorticosteroids more effective in that aspect

• reduce fever by immune or inflammatory activities

• analgesia (pain caused by inflammation)

• reducing CV events since it prevents TXA2 from platelets for blood clots (ONLY ASPIRIN USED)

why is there only one selective NSAID and why is it not used as much?

• celecoxib only one out there and has less toxic side effects than others

• it selectively inhibits COX-2 which is primarily involved in inflammation

• but it also prevents synthesis of PGE2 which causes vasodilation and prevent platelet aggregation

• platelets ONLY express COX1 which can make TXA2 to cause platelet aggregation and vasoconstriction

• without PGE2 made from COX2 in endothelium, there’s no brake pedal on COX1 and its TXA2 production → more adverse CV events

acetaminophen

• NOT NSAIDs

• non-selective COX1 and 2 inhibitor but its activity is substantially reduced in presence of peroxides that are often elevated at inflammatory sites

• so does not help with inflammation

• also not active in platelets and stomach/GI tract so it can’t affect blood clotting or GI disturbances

• still has the same analgesic and antipyretic effects

• associated with liver toxicity

histamine

• molecule synthesized and stored in most cells in body

• stored in intracellular vesicles

• released when vesicles fuse with plasma membrane

• binds to two main types of receptors: H1 and H2

histamine effecst and function

• acts as NT on H1R in CNS to promote wakefulness and nausea

• vasodilation causing increased blood flow to sites where histamine was released → anaphylaxis during systemic release of histamine which drastically decreases BP

• makes capillary walls leaky allowing plasma to seep into surrounding tissues

  • increased fluid in tissue causing swelling (edema)

  • increased fluid in nasal passages → congestion

  • increased fludi in lungs → difficulty breathing

• histamine stimulates peripheral nerves causing itchy sensation

• bronchoconstriction → difficulty breathing

triple response

• aka wheal and flare

• response of combo of H1 effects of histamine on blood vessels and nerves that produces hives

• red spot from capillary dilation

• flare (axon reflex) from histamine stimulation of sensory nerves which releases vasodilators and irregular reddening

• wheal: edema from leaky capillaries

first gen antihistamines

• diphenhydramine

• dimenhydrinate

• doxylamine

diphenhydrinate

• used for motion sickness and nausea

• better at preventing new symptoms then on-going symptoms

• combo of 2 drugs including diphenhydramine

dimenhydramine

• allergies / nasal congestion / hives

• drug of choice where histamine is primary mediator

doxylamine

• in sleep aids and cold medicine

• sedation!

• in nyquil

main adverse effects of antihistamines

• only for first gen

• sedation from blocking H1R in CNS cuz they can easily cross BBB

• anti-muscarinic effects from interacting with non-H1 receptors in periphery — dirty drugs!

second gen antihistamines

loratadine

• modified to not be able to cross BBB → no sedation

• more selective for H1R → less anti-muscarinic and other receptor side effects

asthma

recurrent episodic bouts of coughing and difficult breathing from airway inflammation

who are more at risk for asthma?

• people with allergies

• genetic factors

• people with no siblings and live in clean environment cuz they’re immune system isn’t trained → hygiene hypothesis

how do asthmatic episodes happen?

• starts with an allergen which triggers Th2 response characterized by IL-2 and IgE release

• IgE activates mast cell and eosinophils thru Ab receptor which causes histamine and leukotriene release (first wave)

• causes bronchoconstriction and mucus build up → difficulty breathing

• mast cells and IL-4 release attarcts other immune cells to trigger pro-inflammatory mediators (second wave)

• now at late phase so more constriction, mucus, and overall pro-inflammatory environment in airway

• if chronic → establishes hyperresponsive state

how is asthma managed?

• not curable

• immunosuppresive and anti-inflammatory drugs to reduce effects of mediator elease and reduce immune cells in airway

• bronchodilators to open up bronchia

how do leukotrienes mediate airway inflammation?

• leukotrienes produced by mast cells and eosinophils are primary mediators of bronchial constriction and edema

• leukotrienes made from arachidonic acid by lipoxygenases

• two types of leukotrienes: LTB4 and LTD4

  • LTB4 attracts neutrophils

  • LTD4 major factor in airway inflammation and difficulty breathing (major culprit) and attracts eosinophils

    • bronchoconstriction, increased capillary permeability

asthma maintenance therapy with glucocorticosteroids

• inhibits cytokine expression (IL-4) to reduce Th2 response

• this reduces IgE production and mast cell + eosinophil proliferation which release inflammatory mediators

• inhibits PLA2 which prevents leukotrienes from being made

• administered at lowest doses to prevent adverse effects

• ex. budesonide, fluticasone, prednisone

topical administration of glucocorticosteroids for asthma

• aerosolized version

• daily inhalation can produce long-term reduction in asthma symptoms

• budesonide and fluticasone

systematic administration of glucocorticosteroids for asthma

• oral / IV

• provide burst of anti-inflammatory and immunosuppresive activity → intermediate term relief

• reduction in airway inflammation can cause reduction in airway responsiveness sufficient to gain control of disease

• your reg glucocorticosteroid side effects

• prednisone

asthma maintenance therapy with inhibition of leukotriene pathways

• zileuton: inhibits lipoxygenase

• zafirlukast and montelukast: inhibits LTD4 receptor; preventing LTD4 release

asthma maintenance therapy with degranulation inhibitors

cromolyn used to prevent mast cell degranulation → no vesicular histamine release

• administered as powder aerosols so can cause irritation and cough

asthma maintenance therapy with bronchial dilators

• DO NOT reduce inflammation ONLY cause bronchodilation

• B2-adrenergic receptor agonists which is Gs-linked and dilates muscle

• long acting: vilanterol

• short acting: albuterol

• theophylline: inhibits cAMP breakdown from PDE which helps with muscle relaxation in bronchial muscles

asthma maintenance therapy with Th2 targeted immune responses

• dupilumab

• omalizumab

dupilumab

• Ab that binds IL-4 and prevent interaction with receptor

• reduces mast cell recruitment and mediator release along with reduced production of IgE

• increase risk of parasitic infections and anaphylactic rxns

omalizumab

• Ab binding to Fc domain of IgE to reduce IgE-mediated allergic responses

• prevents IgE from interacting with mast cells and eosinophils

• reduces levels of free IgE

• increase risk of parasitic infections and anaphylactic rxns

asthma maintenance therapy with eosinophil targeting

benralizumab

• Ab that binds to IL-5 receptor

• blocks IL-5 from binding which is involved in eosinophil recruitment

• opsonizes eosinophil and depletes them by ADCC

• increase risk of parasitic infections and anaphylactic rxns