Exam 4 Inflammation, NSAIDs, and DMARDS Flashcards
Heat, redness, ___, pain, and loss of function are all characteristic of inflammation.
Swelling
Are TNF, IL-1, and chemokines all cytokines for acute or chronic inflammation?
Acute
What cytokines are characteristic of chronic inflammation?
IFN-y (T cells) and IL-12 (macrophages)
What kind of cells start off the inflammation process?
Phagocytes, which consume offending agents and release inflammatory mediators
What cells diffuse to the site of injury and aid with phagoyctosis, then produce signaling molecules that suppress inflammation that helps with tissue repair?
Leukocytes – WBCs
Which molecules help with leukocyte adhesion to blood vessel walls–selectins or integrins?
Integrins help with adhesion; selectins help with loose attachment.
For the following, say whether they are associated more with acute or chronic inflammation: Exudation of fluid and plasma proteins Fibrosis Lymphocytes and macrophages Neutrophils
Exudation and neutrophils are acute; fibrosis, lymphocytes, and macrophages are chronic.
What two ways can leukocytes injure tissue in acute inflammation?
Lysosomal enzymes (elastase), ROS and nitrogen species
How is arachidonic acid (eicosanoid precursor) produced?
It is cleaved from membrane phospholipids by phospholipase A2 (PLA2) (enzyme production suppressed by corticosteroids)
What effect does the eicosanoid PGE2 have on blood vessels, bronchi, and uterus?
Dilation for all three
What effect does the eicosanoid PGF2a have on blood vessels, bronchi, and uterus?
Constriction of all three
What effect does PGI2 have on blood vessels and platelets?
Dilates blood vessels; inhibits platelet aggregation
What effect does TXA2 have on blood vessels and platelets?
Constricts blood vessels; promotes platelet aggregation
Arachidonic acid is oxygenated in four different pathways. Which enzyme pathway produces prostaglandins and thromboxanes?
The COX pathway
Arachidonic acid is oxygenated in four different pathways. What does the lipoxygenase pathway produce?
Leukotrienes, lipoxins, HPETEs
TXA2, PGI2, PGE2, and PGF2a are all produced from what molecule?
PGH2 (which is produced from PGG2 by hydroperoxidase)
What enzyme converts arachidonic acid to PGG2?
Cyclooxygenase (COX) or PGH synthase
What physiological functions is COX-1 responsible for?
Housekeeping functions in various tisses such as gastric cytoprotection
What tissues especially is COX-2 located in?
Inflammatory and immune cells–stimulated by growth factors, tumor promoters, and cytokines
In what tissue is PGH2 converted into TXA2, a potent vasoconstrictor and platelet aggregator?
Within the platelets
In what tissues is PGI2 (vasodilator, platelet inhibitor) produced?
Healthy, undamaged vascular endothelia
From LTA4, LTB4, LTC4 and LTD4 are produced which two are bronchoconstrictors and involved in anaphylaxis? (The one remaining is chemotactic)
LTC4 and LTD4 are bronchoconstrictors and anaphylactic.
Which pathways of eicosanoid synthesis do corticosteroids block?
ALL, because they stimulate the synthesis of lipocortins, which inhibit PLA2, therefore decreasing the amount of arachidonic acid released.
Of prostaglandins, thromboxane, and leukotrienes, which two do NSAIDs inhibit through the COX pathway?
Prostaglandins and thromboxanes
Name one drug that inhibits the lipoxygenase pathway and one that antagonizes the leukotriene receptor
Zileuton blocks the lipoxygenase enzyme; montelukast and zafirlukast antagonize the receptor
What eicosanoid drug relaxes smooth muscles and expands blood vessels, so is used for erectile dysfunction?
Alprostadil – synthetic PGE1
What cytoprotective eicosanoid drug prevents peptic ulcer and terminates early pregnancy in combination with mifepristone?
Misoprostol – a PGE1 derivative
What eicosanoid drug constricts blood vessels, is topically active, and is used to treat glaucoma?
Latanoprost – PGF2a prodrug
What eicosanoid drug is a powerful vasodilator and inhibitor of platelet aggregation and is used to treat pulmonary arterial hypertension?
Prostacyclin (epoprostenol) – PGI2
Do NOT use with anticoagulants
Which type of arthritis is caused by CD4+ T cells recognizing self antigens, activating phagocytes by TNF, IL-1, and IL-6, and formation of IgM autoantibodies that form immune complexes with IgG?
Rheumatoid arthritis
What does DMARD stand for?
Disease-modifying anti-rheumatic drug
How do prostaglandins induce fever?
Prostaglandin production in the hypothalamus increase the body’s temperature set point, so the hypothalamus caused increased heat production
How do prostaglandins potentiate pain?
They produce hyperalgesia and potentiate the stimulation of nerve endings by histamine or bradykinin
What three actions do NSAIDs have?
Anti-inflammation, anti-pyretic, analgesic
What is the difference between aryl propionic and aryl acetic acids?
Aryl propionic acids have a methyl group off the alpha carbon that enhances activity and reduces side effects that aryl acetic acids lack.
What three ways to NSAIDs cause GI side effects such as dyspepsia, N/V, ulcers, hemorrhage, and blood loss?
- Acidity hurts lining
- Inhibition of cytoprotective PGEs in mucosa
- Inhibition of platelet aggregation – increased bleeding tendency
Take with food!
What NSAID irreversibly inhibits COX enzymes?
Aspirin
What major organ can be affected by NSAIDs?
The kidneys – renal failure, especially in pts with CV, hepatic, or renal diseases
What patient population is much more likely to have a hypersensitivity to NSAIDS?
Asthma patients – more arachidonic acid available to become pro-bronchoconstriction leukotrienes
What class of NSAIDS carries the risk of Reye’s syndrome?
The salicylates, including aspirin, salsalate and diflunisal.
What symptoms are characteristic of Reye’s? What can we do to prevent this?
Vomiting, delirium, and coma in children who have had the flu or chicken pox. Do not give aspirin to anyone under the age of 12.
What CNS effects can NSAIDs cause?
Tinnitus, dizziness, HA
What drugs can we use to prevent GI side effects?
Misoprostol (PGE1 analog), proton pump inhibitors, combination products.
What is a major mechanism of drug interaction with NSAIDs?
Competition for binding sites on serum albumin because NSAIDS are highly bound.
Ex: NSAIDs increase the plasma concentration of anticoagulants
What is the NSAID originally discovered in willow and poplar bark that also suppresses COX 2 expression?
Salicylic acid
True or false: Salicylic acid and acetylsalicylic acid (aspirin) have about the same potency.
False – ASA actually irreversibly inhibits COX and is 2x more potent
What cardiovasular effect does aspirin have?
Increased risk of bleeding but reduced risk of MI and CVA
What is salsalate?
A salicylic acid dimer that is hydrolyzed in the small intestine before absorption and does not cause GI bleeding.
What salicylate is a more potent and longer-lasting analgesic than aspirin with fewer side effects and less antipyretic activity?
Diflunisal
What two arylacetic acid NSAIDs are the most potent NSAIDs in use? Of these two, which one has a high incidence of side effects so is not suitable for long term use?
Indomethacin and diclofenac (which is also the most widely used in the world).
Indomethacin is not suitable for long-term use due to high SE profile.
Which arylacetic acid is a prodrug that has less side effects and is good for long term use for chronic inflammation?
Sulindac
Which arylacetic acid NSAID is somewhat selective for COX-2?
Diclofenac (also one of the most potent and widely-used NSAIDS in the world)
What arylpropionic acid has analgesic activity similar to centrally-acting narcotics?
Ketorolac – great for short-term management of moderate-severe pain
Of ibuprofen and naproxen, which is more potent and has a longer half-life? Which is sold as a racemic mixture?
Naproxen is more potent and longer-lasting. Ibuprofen is a racemic mixture (naproxen is pure S enantiomer)
What non-carboxylate NSAID belongs to the oxicam class, only requires a single daily dose, is as potent as indomethacin, and is somewhat COX-2 selective?
Meloxicam
What non-carboxylate NSAID is a prodrug with potent anti-inflammatory activity and minimum side effects but weak analgesic activity?
Nabumetone
What are some consequences of COX-1 inhibition?
Stomach irritation and ulceration, blockade of platelet aggregation, inhibition of uterine motility, inhibition of some renal functions, hypersensitivity reactions
How do selective COX-2 inhibitors increase the risk of heart attack and stroke?
They selectively reduce the production of PGI2 (prostacyclin) but do not alter TXA2. The imbalance leads to a heightened thrombotic response. They also elevate BP and accelerate atherogenesis.
What is structurally different in COX-2 selective NSAIDs?
Larger and more rigid substituents that fit well into COX-2 but not into COX-1.
Of our two selective COX-2 inhibitors, celecoxib and acetaminophen, which one all around more potent?
Celecoxib
What is the odd mechanism of action for acetaminophen?
It scavenges peroxynitrite, which is required for COX (PGHS) activity. However, in inflammation, acetaminophen is overwhelmed by the amount of peroxynitrite present so it has minimal anti-inflammatory properties.
In general, what is acetaminophen’s side effect like compared to aspirin?
Much better–lower GI SEs, well tolerated in coagulation disorders, no Teye’s, low hypersensitivity.
However, hepatotoxicity at high doses associated with overloading glutathione.
What is the common mechanism for DMARDs?
Immunosuppression
How does methotrexate suppress the immune system?
It looks like folic acid and inhibits two enzymes required for purine and pyrimidine synthesis, leading to a anti-proliferative, pro-apoptotic effect on inflammatory cells.
First line treatment! Predictable benefit.
What side effects do we worry about with methotrexate? How can we improve these side effects?
GI, stomatitis, rash, alopecia, myelosuppression, hepatotoxicity, rare but serious pulmonary toxicity. Contraindicated in pregnancy.
Administer with folic acid.
What prodrug DMARD inhibits pyrimidine synthesis (inhibits T cell proliferation) and undergoes extensive enterohepatic recirculation?
Leflunomide (Arava)
What side effects are associated with leflunomide?
Hepatotoxicity, diarrhea, alopecia, rash. Monitor liver damage. Never in pregnant women.
What DMARD inhibits protein secretion and can cause retinal toxicity?
Hydroxychloroquine
What side effects are associated with hydroxychloroquine?
Generally well tolerated but monitor for retinal toxicity.
Use in combo with MTX, but reduces MTX clearance
What DMARD prodrug, cleaved in the colon by bacteria, suppresses cytokine release from macrophages?
Sulfasalazine – in combo with MTX, monitor for myelosuppression
What three biologic TNF blockers can we use for rheumatoid arthritis?
Infliximab (Remicade), adalimumab (Humira), and etanercept (Enbrel)
Which of the three TNF blockers is human and given SC every 2 weeks?
Adalimumab (Humira) - antibody to TNFa (in combo with MTX)
Which TNF blocker is chimeric and given every 8 weeks?
Infliximab (Remicade) - antibody to TNFa
Which TNF blocker is a TNFa receptor/Fc antibody fragment chimera that competitively inhibits TNFa binding?
Etanercept (Enbrel) - use with MTX
What DMARD is a recombinant version of human IL-1 receptor antagonist and cannot be combined with TNF blockers?
Anakinra (Kineret)
How does rituximab work?
This humanized monoclonal antibody induces apoptosis of CD20+ cells (B cells), reducing antibody production and activation of T cells
+MTX
Risk of serious infection
What DMARD inhibits co-stimulation of T cells by APCs?
Abatacept (Orencia) – fusion of CTLA-4 and Fc region of antibody binds CD80/86 on APCs
What side effects do we worry about with abatacept?
Risk of serious infection and increased risk of lymphomas. Can be used with other DMARDS but NOT TNF-a blockers.
