exam 1: NSAIDS, DMARDS, Flashcards
3 phases of inflammation
acute inflam
immune response
chronic inflam
what mediator do we really want to target
Prostaglandins
Stimulus –> Phopholipids –> arachidonic acid via phospholipase a2 –> leukotrienes via lipoxygenase or PG, TXA2, Prostacylcin via cyclooxygenase
*what inhibits where
Steroids inhibit Phospholipase
NSAIDS/ASA inhibit cyclooxygenase
Lipoxygenase inhibitors inhibit Leukotriene formation
ASA actions
Nonselective irreversible inhibitor of COX1,2
- antiinflam
- antipyretic
- analgesic
- anti platelet (irreversible)
PK of ASA
simple organic acid good fast oral absorption
- Wide distribution, crosses placenta, slowly crosses BBB
- concentration may reach value 20x higher in mucosal cell than lumen of stomach
- Rapid hydrolysis in plasma, liver and RBC
- binds plasma proteins, competes with other acids for binding sites
Metabolism of ASA
low dose = first order high dose (above 600 mg body burden) = zero order
*renal excretions (thus alkalinization of urine promotes excretion)
Uses for ASA
mild to moderate pain antipyresis anti-inflamm (NSAID) MI, thrombosis prophylaxis long term use decreases colon CA
Adverse effect of ASA related to a/b balance
ASA is an acid, makes pH more acidic resulting in increased resp (stimulation). This increases O2 whil CO2 decreases ultimately resulting in resp alkalosis. Resp alkalosis will cause resp depression ultimately resulting in resp acidosis
At toxic doses: resp acidosis combined with metabolic acidosis (ASA is an acid), K loss, dehydration and cardiovascular collapse
How does ASA effect platelets and bleeding. What caution should be taken
ASA (no Na salicylate) inhibits plt aggregation thus increasing bleeding time (single dose 650 mg doubles)
- effect may last 8-10 d
- avoid ASA use in pt with:
1. hypoprothrombinemia
2. Vit K def
3. Hemophilia
4. Severe hepatic damage - avoid 1 wk before surgery and prior to labor (last three months of preg)
How does ASA effect Uric acid levels
at low dose (1-2 g) ASA decreases excretion (higher plasma urate)
At large doses (>5g), ASA is uricosuric (but these high doses often have bad GI SE)
What effects does ASA have on heart and lungs?
Heart - minimla in reg dose
Lungs: ASA asthma bc ARACHIDONIC acid is shunted to form leukotrienes
How does ASA affect the GI and how can this be addressed
GI upset, gastritis, ulcer, bleeding
*use buffered form, take with food, take combined with misoprostol
How does ASA affect kidneys?
Renal damage, acute renal failure, interstitial nephritis
- NSAIDS inhibit PG synthesis leaving actions of vasoconstricitors (Ang II, Catecholamines, vasopressin) unopposed
- PG synthesis normally antagonizes intrarenal effects of vasoconstrictors
What effects does ASA have on skin
Salicylic acid (not ASA) destroys epithelial cells, a keratolytic effect used for wart removal, corns, fungal infection and dermatitis (note that salts of salicylic acid have no effect on unbroken skin)
Methyl salicylates (oil of wintergreen) is irritating to skin and mucosa
which effects does ASA have first (at therapeutic dose).. simultaneous complications?
antiplt –> antipyretic –> analgesic –> uricosuric –> antiinflammatory
*SE: gastric intolerance, bleeding, hypersensitivity reactions, impaired hemostasis
ASA should be decreased during long term tx with…
oral anticoagulants, hypoglycemic agents etc
ASA should be avoided in pt with
gastric ulcer, severe hepatic damage, hypoprothrombinemia, vit K def, hemophilia, hypersens
What are fatal/poisonous doses of ASA
Fatal dose 20 g (10-30) of ASA
For methyl salicylate (oil of wintergreen) 4-5 mL
What is Reyes syndrome
cerebral edema in children with viral infections, NO ASA, the DOC is acetaminophen
What are the nonacetylated salicylates
Mg choline salicylate
Na salicylate
Salicyl Salicylate
*effective antiinflamm, less analgesic, NOT IRREVERSIBLE
What is Diflunisal
Salicylic acid derivative, no antipyretic
What is Celecoxib (celebrex) and indicated use? SE? CI?
reversible COX2 inhibitor, less GI adverse effects, oral admin
SE: Increased risk for cardiovascular disease
CI: GI dz (active PUD), asthma, breast feeding, preg, renal failure
What does COX 1 do? COX2?
COX-1: promotes inflam, protects against gastric irritation, promotes plt agg (TXA2), vasoconstriciton (TXA2)
COX2: inflam, protects GI, Inihbits platelet agg (PGI2), vasoDILATION (PGI2)
*this is why selectively inhibiting COX 2 increases risk heart dz (platelet aggregation and vasoconstriction uninhibited)
General overview of nonspecific reversible inhibitors of COX1 and 2
various chemical structures, similar effect of asa but are reversible *variable SE freq but basically the same *varible PHK DOC: Ibuprofen bc best SE profile Worst: indomethacin, phenylbutazone
What are general toxicities of nonspecific reversible inhibitors of COX1 and 2
GI: pain, bleeding, pancreatitis, diarrhea
CNS: HA, dizzy, donfusion
Lung: bronchoconstriction
BONE MARROW: Agranulocytosis, Aplastic anemia
NEPHROTOXICITY: Acute renal failure, interstitial nephritis, nephrotic syndrome
Heptatotoxic
Hypersensitivity rxns
Indomethacin (indocin) MOA, use?
Reduce PMN migration, inhibit Phospholipase A
- potent AI AR agent, high incidence of SE
- used for PDA
Diclofenac (Volatren): MOA, PK, SE?
Potent cox inhibitor, decreases Arachidonic acid bioavailability
- PO, liver metab T1/2 = 1-2 hr
- mostly GI SE
- combined with misoprostaol (arthotec) to decrease GI SE
Ketorolac (Toradol): Use, PK, SE
Used mostly as an analgesic in postop pain
- Oral, IV, IM admin, T1/2 4-8hr
- after 5 d of use, freq GI SE
- may be combined with opiates
IBuprofen (motrin) PK, metab, use
T1/2 2-4 hr, liver metab
*renal excretion of both metab and parent compound
DOC because lowest incidence of SE
Comb with ASA decreases ASA effect on platelet aggregation (bc ASA has shorter half life)
Toxicity of Ibuprofen
low, NV, diarrhea, constipation, heartburn, GI bleeding, dizzy, light headed, HYPERURICEMIA
Naproxen (Naprosyn) effect and metab
similar to ASA, IBuprofen
Oral, peak 1-2 hr, mean half life 13h
LONG ACTING! LESS DOSES NEEDED
- urine excretion
- crosses plaena, don’t give to preg
- bound to plasma proteins, displaces oral anticoagulants, hypoglycemic agents
Toxicity of Naproxen
GI disturbances, Heartburn, dyspepsia, ab pain, constipation, diarrhea
*gastric bleeding less severe than with asa
Action of Piroxicam (Feldene)
Inhibits PMN migration, lymphocyte function
- decreases oxygen radical production
- long half life, high incidence of GI SE
What is Nabumetone (Relafen)
prodrug with long half life
Phenylbutazone
potent, serious GI, bone marrow SE, not in USA
if someone is in active PUD give..
APAP
hx of PUD but not active
celcoxib with or without antacids or some NSAIDS with misoprostol or prazoles (PPI)
Why could APAP be preferred over ASA
Tolerated better, lacks undesirable SE of ASA (GI, blood clotting defects, a/b imbalance, auditory toxicity
*APA is not completely innocuous or safe
OD: fatal hepatic necrosis, thus handle with great care esp in kids
PK of APAP
oral, some plasma protein binding
Half 203 hr (increases with high dose)
Liver metab, conjugation, renal excretion
DOSE DEPENDENT FREE RADICAL PRODUCTION eliminated by GSH (reduced glutathione)
*if exhaust GSH supply, hepatic necrosis can occur
Actions of APAP (and actions APAP doesn’t have)
antipyretic
Analgesic
NO antiinflammatory
Use: mild, moderate pain, fever (kids), adjunct to antiinflam tx, combine with codeine and derivatives, sedatives, cough suppressants, tramadol, caffeine etc
NO influence on urate excretion
NO antiinflam effect
NO platelet effect
SE of APAP
sin rash, cross sensitivy with salicylates
- some neutropenia
- DOSE DEP FATAL HEPATIC NECROSIS
- adults: 10-15 g toxic, 25 g fatal
- elevated serum transaminase, LDH (signs)
- may progress to encephalopathy, coma and death
*intermediate metab is what is responsible for liver damage (toxicity when metab exceed available reduced glutathione); chronic alcohol increases toxicity
How do you treat APAP intoxication
Gastric emptying, forced diuresis, hemodialysis
Antidote: N acetylcysteine (Mucomyst) (give IV ASAP w/in 10-12 hr)
what mediator of chronic inflammation is is good to manipulate and why
TNF-alpha
source: macrophages
Effect: PG production
How do gold salts work? toxicity?
Inhibit phagocytosis, uncouple ox phos, SUPPRESS CELL IMMUNITY
toxicity: bone marrow damage, enterocolitis
Penicillamine (Cuprimine) use, Toxicity
Chelating drug effective in RA and wilsons
*LIVER: thombocytopenia, leukopenia, agrnulocytosis, aplastic anemia
KIDNEY: proteinuria, hypoalb, nephrotic syndrome
Hydorzychloroquine (Plaquenil) MOA, toxicity
Antihistaminic, antichoinesterase and antiprotease; inhibits phagocytosis and stabilizes lysosomes
Toxicity: Pruritis, HEMOLYSIS (G6PD deficient), ototoxic
Sulfasalazine (azulfidine) use, toxicity
tx IBD, and now RA (better tolerated than gold nad less toxic than penicillamine)
Toxicity: GI, Hep, blood dyscrasias (rare), monitor hep and marrow suppression 2-3 wk during first 3 mth
Infliximab (Remicade) MOA, use, SE
chimeric IgG1k MAB against TNFalpha
(human and murine)
*Crohns, RA, combined with methotrexate
(note that Adalimumab is approved for RA monotx)
IV
SE: HA, infusion rxn;
CI: INFECTIONS
RITUXIMAB (RITUXAN) moa, use
- chimeric murine/human MAB
- IgG immunoglobulin that binds to CD20, a b lymphcyte differentiation antigen on preB and mature B lympohcytes
- tx for NHL, and now potentially CLL
IV admin
Adalimumab (Humira), MOA, use, SE
recombinant human IgG1 MAB
100% human derived heavy and light chain
specific for TNF ALPHA
montx in RA (subq, 8-10 d half life)
Rash, flu like, fatigue
Entanercept (Enbrel) MOA, admin, SE/CI
Recombinant dimeric fusion protein consisting of extracellular ligand binding portion of human TNF recptor linked to Fc portion of human IgG1
THUS INHIBITS TNF
subq (SE: injection site rxn, infection, increase ab form)
CI: BONE MARROW SUPPRESSION, INFECTION, SEPSIS, vaccination, varicella, DM
Abatacept (Orencia) MOA, use, admin
Fully human recombinant fusion protein, second signal blocker of T cell activation
- compete with CD28 on T cell for CD80 and CD86 binding
- disturbs key mech of inflammation and progressive joint destruction in RA
- may affect host defenses against infection and malignancy
*IV, half life 13 d
Leflunomide (Arava) MOA and admin. SE?
inhibits DHODH (enzyme in de novo PYRIMIDINE synthesis)
- inhibits cytokine and growth factor
- inhibits induction of COX2
oral admin, half life 16h
SE:N/V, back pain, wt loss, anorexia
CI: hepatic/renal failrue
Mycophenolate Mofetil (Cellcept)
Prodrug ofr immunosuppressive agent mycophenolic acid (MPA)
*INHIBITS LYMPHCYTE PURINE SYNTHESISby reversible and noncompetitively inhibiting enzyme IMPDH
oral or IV
CI: active GI dz, diarrhea, infections
Anakinra (Kineret) MOA, use, CI
recomb non glycosylated form of human interleukin 1 receptor antagonist ) IL-1Ra
*inclinical studies, RA pt improved
subq, 4-6hr half life, renal elim
CI: hypersensitivity, renal dz
Janus Kinase inhibitor: Tofacitinib (Xeljanz)
primarily inhibits JAK1 and 3 and to lesser extent 2
*tx of adults with mod to severe RA who didn’t respond to methotrexate
- may precipitate serious infections and malignancy
- po, half life 3 hr
