Week 5 (Quiz 3) (Anti-inflammatory) Flashcards
NSAIDS block
COX-1 and COX-2
NSAIDS desired effects come from:
COX-2
NSAIDS SE come from:
COX-1
Salicylates example
Aspirin
Salicylates mechanism
selectively acetylates serine residue in COX active site (irreversible) - more COX-1 selective therefore higher doses are needed to have COX-2 inhibition
4 A’s (Uses of salicylates)
- low doses: Anti-platelet (TIAs, stroke, MI prophylaxis)
- intermediate doses: Analgesic; Anti-pyretic (medium to
low grade fevers) - high doses: Anti-inflammatory (arthritis, joint swelling)
Propionic acid examples
Ibuprofen, Naproxen
Mechanism of propionic acids
competitively, reversibly binds COX active site
Use of propionic acids
anti-inflammatory, analgesic, antipyretic
SE of propionic acids
- less GI distress and ulcers than ASA
- acute renal insufficiency and chronic interstitial
nephritis (↑ vascular tone) - allergic reactions (rash, urticaria, bronchoconstriction)
COX-2 selective inhibitor examples
Celecoxib, rovecoxib
Mechanism of COX-2 selective inhibitors
drug is too large to bind COX-1 active site –> competitively binds COX-2 active site
Use of COX-2 selective inhibitors
osteoarthritis, RA, familial adenomatous polyposis, dysmenorrhea, acute pain
Goal of COX-2 selective inhibitors
to decrease the GI and vascular side effects common
with other NSAIDs
SE of COX-2 selective inhibitors
- Increase risk in CV events
- renal damage
- allergic reactions
Indomethacin mechanism
↓ movement of granulocytes into affected area
Indomethacin use
close a patent ductus arteriosus; acute gout
PGI2 effects
Decreased vascular tone, platelet aggregation and acid secretion
PGE2 effects
Decreased vascular tone
Increased gastric mucous production, pain sensation, and body temp
TXA2 effects
Increased vascular tone and platelet aggregation
Acetaminophen examples
APAP, Tylenol
Mechanism of acetaminophen
(most recent theory) conjugates with arachidonic acid in CNS (enzymes that do this are only in CNS) –> metabolite binds COX-1 and COX-2 to inhibit them
Use of acetaminophen
analgesic, antipyretic; pain/fever control in children with viral infections and adults with bleeding/GI risks; weak anti- inflammatory action
SE of acetaminophen
- almost none at therapeutic doses;
- allergic reactions (rash, urticaria, bronchoconstriction)
- highly hepatotoxic w/ overdose
When can acetaminophen be toxic?
When glutathione is used up
Synthetic prostanoids examples
Misoprostol
Mechanism of synthetic prostanoids
Synthetic PGE1 analog, enhances normal PGE1 effects
Decreased acid production
Synthetic prostanoids use
- prevention of NSAID-induced peptic ulcers
- maintenance of patent ductus arteriosus (PDA)
- induces labor
SE of synthetic prostanoids
abortifacient (NEVER give to pregnant pts); diarrhea
Early response in asthma
bronchoconstriction
Late response in asthma
bronchial hyperreactivity, inflammation, mucous plugging, smooth muscle hypertrophy
Presentation of asthma
coughing, episodic wheezing, dyspnea, chest tightness (esp. at night/early morning)
Pathophys of asthma
antigen binds preformed IgE on mast cells –> degranulation of leukotrienes, prostaglandins, histamine –> inflammation and bronchoconstriction
What are the two first line bronchodilators?
Short acting B2 agonists, long acting B2 agonists
What are the members of the first line short acting B2 agonists?
albuterol, terbutaline
What is the action of the short acting B2 agonists?
bronchodilation
What is the use for short acting B2 agonists?
inhaled for acute attacks of mild asthma
What are the SE of short acting B2 agonists?
tachycardia, hyperglycemia, hypokalemia, hypomagnesemia
What are the members of the first line long acting B2 agonists?
salmeterol, formoterol
What is the acton of long acting B2 agonists?
bronchodilation
What is the use for long acting B2 agonists?
adjunctive therapy with corticosteroids - long-term management
What are the SE for long acting B2 agonists?
tachycardia, hyperglycemia, hypokalemia, hypomagnesemia
What are the members of the first line inflammation inhibitors?
Corticosteroids, glucocorticoids
What are the 2 dangerous side effects of salicylates?
- GI bleeding
- Reye’s syndrome
Members of corticosteroids/glucocorticoids
beclamethasone, fluticasone, prednisone
Actions of corticosteriods and glucocorticoids
inhibit inflammatory cascade
Use of corticosteriods and glucocorticoids
long-term management by reducing inflammatory response
SE of corticosteriods and glucocorticoids
few if inhaler used properly
Inflammation inhibitors combination therapy
Salmeterol + fluticasone
Action of salmeterol + fluticasone
inhibits inflammatory cascade and bronchodilates
Use of salmeterol + fluticasone
long-term management
Two second line brochoconstriction blockers/bronchodilators
Ipratropium and montekulast
Ipratropium mechanism
muscarinic receptor antagonist, blocks vagally mediated bronchoconstriction
Ipratropium use
asthma, COPD - esp. in pts unable to tolerate β2 agonists
Ipratropium SE
few if inhaled
Montekulast mechanism
binds cysteinyl leukotriene receptor (CysLT1) - blocks action of leukotriene D4 (prevents bronchoconstriction)
Montekulast use
prophylactic treatment of chronic asthma/seasonal allergies (> 12 y/o)
Montekulast SE
Churg-Strauss syndrome (autoimmune vasculitis); elevated liver function tests; HA
Cromolyn mechanism
prevents degranulation of mast cells
Cromolyn use
asthma prophylaxis ONLY
Cromolyn SE
few
Zileuton mechanism
inhibits 5-lipoxygenase –> ↓ leukotriene synthesis
Zileuton use
chronic asthma prophylaxis
Zileuton SE
elevated liver function tests
RA is characterized by what two things?
1) lymphocytic infiltration of synovial joints
2) granulomatous extra-articular nodules
Presentation of RA
morning stiffness that resolves throughout day; symmetric joint involvement; systemic symptoms
Pathophys of RA
autoimmune; positive rheumatoid factor (anti-IgG antibodies) –> —> promotes release of IL-1, IL-6, TNF-α + activates T- cells –> activates B-cells to release autoantibodies + synovial inflammation and destructive changes (metalloproteases, osteoclasts)
Disease-modifying Anti-rheumatic Drugs (DMARDs) members
Methotrexate
Leflunomide
Sulfasalazine
Hydroxychloroquinone
Biologic Therapies
Anti-TNA-alpha antibodies
Entanercept
Methotrexate mechanism low dose
inhibition of lymphocyte proliferation (blocks
purine synthesis)
Methotrexate use
immunosuppressant for RA, psoriasis, Crohn’s, etc.; for cancer at high doses
Methotrexate SE
mucosal ulceration, nausea, cytopenia, liver cirrhosis, pneumonia-like illness
Methotrexate mechanism high dose
folate antagonist
Leflunomide mechanism
block pyrimidine synthesis; acts on dihydroorotate dehydrogenase to inhibit autoimmune lymphocyte proliferation
Leflunomide use
alternative to MTX
Leflunomide SE
hepatotoxic, myelotoxic, HTN
Steroids mechanism
binds nuclear receptors in cell cytoplasm –>
changes protein levels in cells; possibly indirect inhibition of phospholipase A2 and reduced expression of COX-2 in immune cells; ↓ both prostanoids and leukotrienes
Steroids use
RA, allergic disorders (asthma etc.); acceleration of lung maturation in premature infants; cancer chemotherapy (trigger apoptosis and appetite)
Steroids - 2 major SE
Osteoporosis and iatrogenic Cushing’s syndrome
Sulfasalazine (SSZ) mechanism
anti-inflammatory; antimicrobial
Sulfasalazine (SSZ) use
anti-inflammatory; antimicrobial
Sulfasalazine (SSZ) SE
leukopenia, hepatotoxic, hypersensitivity rxns
Hydroxychloroquinone mechanism
interferes with antigen processing; inhibits phospholipase A2
Hydroxychloroquinone use
malaria (primary); in combination with MTX/SSZ for autoimmune disorders
Hydroxychloroquinone SE
retinopathy
Anti-TNF-α Antibodies members
Infliximab, adalimumab
Anti-TNF-α Antibodies mechanism
binds/neutralizes TNF-α preventing downstream signaling and destructive symptoms
Anti-TNF-α Antibodies use
IV for autoimmune disorders; in combination with MTX (otherwise body develops antibodies to drug)
Anti-TNF-α Antibodies SE
Infusion rxns; increased risk of infection
Etanercept mechanism
genetically engineered fusion protein - binds TNF-α to prevent downstream signaling and destructive symptoms
Etanercept use
subQ for autoimmune disorders alone or in combination with MTX
Etanercept SE
local inflammation @ injection site; increased risk of infection
Presentation of gout
sudden onset of pain in first MTP; erythematous, swollen, exquisitely tender joint
Drug risk factor for gout
Thiazide diuretics
Why do you not treat gout with aspirin?
competes with uric acid for secretion via proximal kidney tubule
Three acute gout therapy drugs
Indomethacin
NSAIDS
Glucocorticoids
Three prophylactic/chronic gout treatments
Allopurinol
Colchicine
Probenecid
Allopurinol mechanism
purine analog –> competitive inhibition of uric acid synthesis; less likely to form crystals
Allopurinol use
chronic primary gout; secondary hyperuricemia (tumor lysis)
Allopurinol SE
hypersensitivity rxns; otherwise few side effects
Colchicine mechanism
plant alkaloid; depolymerizes MT by binding tubulin –> ↓ granulocyte ability to migrate to affected site
Colchicine use
gout prophylaxis
Colchicine SE
- acute: nausea, vomiting, abd pain, diarrhea
- chronic: myopathy, neutropenia, aplastic anemia,
alopecia
Probenecid/Sulfinpyrazone mechanism
weak organic acid; inhibits urate-anion exchanger (mediates uric acid reabsorption in proximal tubule) to promote clearance of uric acid
Probenecid/Sulfinpyrazone use
chronic hyperuricemia
Probenecid/Sulfinpyrazone SE
- S: GI distress
- P: drug-drug interactions
