Anti-Inflammatory And Disease Modifying Agents

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NSAIDS main purpose, mechanism, use

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anti-inflammatory, anti-pyretic, and analgesic effects

mild to moderate pain

inhibits the formation of prostaglandins by blocking cyclooxygenase enzymes

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COX -1 vs. COX-2 expression
COX= cyclooxygenase

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Cox-1 is constitutively expressed (always on) to produce prostaglandins that synthesize mucin and bicarbonate into lumen of stomach (Cox-2 selective inhibitors spare GI side effects

Cox-2 an inducible enzyme, facilitates inflammation

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thromboxane A2 vs.
PGE2 and PGI2 effects

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Thromboxane A2 is vasocontrictor while PGE2 and PGI2 (prostacyclin) are vasodilators

PGI2 dec uterine tone, PGE2, inc uterine tone

PGI2 dec platelet aggregation TXA2 inc platelet aggregation

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Cox inhibitors and Platelet aggregation

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PGE1 and PGI2 inhibit aggregation

TXA2 stimulate aggregation

COX-2 block PGI2 so inc likelihood of clots

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COX inhibitors and the kidney

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COX inhibitors reduce renal function by blocking:

PGE2 and PGI2 which inc renin release
PGI2, E2 and E1 inc glomelular filtration, H2O clearance and Na excretion

thromboxane causes renal vasoconstriction

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Prostanoids and reproductive system

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prostaglandins can induce abortion

can stimulate and initiate labor

NSAIDS help with dysmenorrhea- uterine contractions during menstruation causing pain

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Prostanoids and CNS and PNS

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PGE1 and E2 inc body temp
PGD2 induces sleep
PGE's inhibit NE from postganglionic sympathetic nerve endings

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Prostanoids and Neuroendocrine

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anterior pituitary hormone secretion is altered

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Bone metabolism and Prostanoids

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stimulate bone turnover- role in loss after menopause

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Prostanoids and the eye

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PGE and PGF lower IOP

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The only irreversible NSAID is

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aspirin

COX enzymes must be resynthesized

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Therapeutic effects of NSAIDS

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-antiinflammaory (symptomatic relief- do not arrest progression of disease),
-analgesic,
-antipyretic

-Acetaminophen- is not antiinflammatory- does not act on PNS.

-Analgesia- chronic postoperative pain or pain from inflammation well controlled. Not pain from viscera however except menstruation.

50% reduction in colon cancer
Bartter's syndrome (renal prostaglandins are high)

Aspirin used prophylactically for coronary artery disease

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Adverse/Positive effects of NSAIDS

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Disrupt protective effects of gastric mucosa (Cox-2 less harmful)

Can cause renal problems- renal failure, salt retention -> edema,

PGI2 suppresses aggregation so blocking this increases likelihood of thrombotic event- COX 2-s have no effect on TXA2 and are selective for this and inc risks for clots.

NSAIDS may exacerbate hypertension

Can prevent pre-term labor

Useful in premature babies for closure of ductus arteriosus (indomethacin)

TXA2 stimulates aggregation fo platelets- NSAIDS block this- good for coronary disease

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Non selective COX inhibitors

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Acetylsalicylic acid (Aspirin)
Methy salicylate (Ben Gay)
Diflunisal
Sulfasalazine

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Aspirin mechanisms and uses

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-readily absorbed, short HL
-irreversible more selective for Cox-1
-metabolism of aspirin is saturable- so toxic levels can be reached quickly

Anti-inflammatory effects (interferes with leukocyte adhesion)

Analgesia- reduced inflammation and dec in PGE and F

Antiplatelet by dominantly blocking TXA2 (lasts 8-11 days) so plateletes need to be replaced -> dont take NSAIDS within 7 days of surgery (can inc risk of MI)

Used for RA, Osteoarthritis, prophylactic for coronary artery disease

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inflammation phases

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1: leukocytes bind to epithelial cells
2: activated for phagocytosis or for release of lysosomal enzymes, free radicals, arachidonic acid metabolites (prostanoids, leukotrienes)
3: amplify inflammatory stimulus and mediate endothelial injury

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Aspirin intoxication and tx

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fatal if ingested in high amounts

headache, dizziness, hearing loss, dim vision, mental confusion, sweating, thirst, hyperventilation, fatigue

-need to remove agent from stomach via activated charcoal, alkalinize urine for inc excretion, and correct acid-base abnormalities

reyes syndrome: numerous organ failure and brain and liver damage due to aspirin given to children with viral illness

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Diflunisal

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non selective COX inhibitor

not converted to salicylic acid

more potent antiiflammatory than aspirin

Can be given topically or systemically for mild to moderate pain, osteoarthritis, rheumatoid arthritis

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Acetaminophen

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-No anti-inflammatory actions
-Does not inhibit peripheral Cox enzymes and therefore does not inhibit platelet aggregation nor cause GI problems
-therapeutic for analgesia and antipyresis, children with viral infections, gout, or if aspirin is contraindicated with peptic ulcer or bleeding problems

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Acetaminophen toxicity

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fatal hepatic necrosis, possible acute renal failure can occur

tx: gastric lavage and addition of sulfhydryl compounds to replenish glutathione which is depleted

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Indomethacin

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oral, IV, suppository or topical
-non selective cox-1 and cox-2 inhibitor
-used for RA, Osteoarthritis, eye pain, gouty arthritis, closure of ductus arteriosus in premies

33% need to stop taking drug because of adverse GI effects

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Sulindac

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Oral formulation half as potent as Indomethacin

pro-drug metabolized to active sulfide

non selective for Cox-1 or Cox-2 inhibition

same adverse effects and uses as rest of NSAIDS

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Profens and proxen- list and advantages

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Ibuprofen
Naproxen
Fenoprofen
Ketoprofen
Flurbiprofen

better tolerated than aspirin and indomethacin

all non-selective Cox inhibitors, AAA

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Ibuprofen

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Advil

not recommended during pregnancy or breast feeding

less anti-inflammatory then other NSAIDS

Also used for patent ductus arteriosus as alternative for indomethacin

remember all are aaa and non selective

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Naproxen

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-increased cardiovascular risk with long term use
-similar to ibuprofen in most other ways

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Fenoprofen

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rarely used bc of interstitial nephritis

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Ketoprofen

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high potency propionic acid derivative

in addition to COX inhibition

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flurbiprofen

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complex mech- also inhibits TNF-a and NO synthesis

Ophthalmic form to inhibit intraoperative miosis

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Tolmetin

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As efficacious as aspirin but better tolerated

non specific cox inhibitor,

AAA effects

used for arthritis, rheumatic disease in juvenile form

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Ketorolac

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-potent analgesic

-used for short term tx of moderately severe acute pain

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Piroxicam

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adv is long 1/2 life so only single dose

non selective cox inhibitor

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Cox-2 selective agents, advantages/disadvantages, uses

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-Preserve anti-inflammatory and analgesic effects without adverse GI and platelet effects bc of Cox-1 inhibition

-can cause renal toxicity and adversely effect bone repair

-used for RA osteoarthritis and adenomatous polyposis

-inc CV risk for all COX 2 inhibitors,
- all NSAIDS that inhibit COX 2- selectively or not have to include warning for MI and stroke except aspirin

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COX-2 selective inhibitors list

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meloxicam 18
Diclofenac 29
Celecoxib 30
Rofecoxib 267 (very selective) removed from market

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celecoxib

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COX 2 selective

similar to other NSAIDS with fewer GI effects and much less prothrombotic risks like Vioxx

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Diclofenac

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COX 2 selective

used for RA, osteoarthritis and ankylosing spondylitis

severe hepatic rxns may occur

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Meloxicam

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slightly COX 2 selective

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Etodolac

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sustained release-

slightly cox 2 selective

post operative pain with temporary renal issues

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DMARDS

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Disease modifying anti-rheumatic drugs

target underlying causes of RA and not just reduce sx (like NSAIDS) but also reduce disease progression

improvement cant take weeks to months so combine with NSAIDS for immediate relief of pain/inflammation

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Methotrexate

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DMARD

inhibits AICAR, thymidylate synthetase and polymorphonuclear chemotaxis to decrease autoimmune destruction

used for RA, inhibited by Leucorvin

concurrent use of NSAIDS inhibits clearance of methotrexate so toxicity develops rapidly

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Cyclophosphamide

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DMARD

cross links DNA and decreases cell replication to suppress immune response

dose-dependent infertility and bone marrow suppresion are potential problems

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Cyclosporine

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DMART

regulates gene transcription dec IL-1 and IL-2 receptor production, dec T cell dependent B cell function

significant nephrotoxicity risk

avoid grapefruit juice (inc bioavailability)

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azathioprine

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DMARD

converted to mercaptopurine- disrupts purine nucleic acid metabolism

used for transplantation

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rituximab

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DMARD

monoclonal antibody that binds to CD20 (surface fo B lymphocytes and initiates lysis

for RA in combo with methotrexate for patients with inadequate response to TNF antagonist therapies

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TNF alpha inhibitors list

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Adalimumab
Infliximab
Entanercept

TNF is in synovial fluid in RA and plays a significant role in inflammation, disease progresson and joint destruction

MAB cross link TNF receptor to reduce T-cell function and macrophage activity

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ADALIMUMAB

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Anti-tnf MAB prevents TNF from interacting with p55 and p75 cell surface receptors to decrease T cell activity

Effective RA therapy solo, or in conjunction with methotrexate

inc risk of opportunistic infections such as TB

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Infliximab

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25% mouse and 75% human MAB that binds TNFa and inactivates like adalimumab

adverse is severe hepatic rxn, death

inc opportunisitc infections and reports of worsening of demyelinating syndromes like MS

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Entanercept

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TNFa inhibitor

fusion protein with Fc fragments of human IgG1 and TNF receptor. Blocks TNFalpha and beta and lymphotoxin alpha.

Use for RA alone or methotrexate, juvenile arthritis and ulcerative colitis.

adverse: opportunistic infections and lymphomas

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abatacept

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other RA

fusion protein mimics endogenous CTLA4 which competes for CD28 (T cell surface protein) for CD80 and CD86 (on APC) and prevents second signal for T cell activation -> no release of inflammatory cytokines

reserved for those who didn't respond to TNF inhibitors or DMARDS

do not combine with ANTI-TNF

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Sulfasalazine

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reduces IgA and IgM

30% discontinue due to toxicity

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Leflunomide

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other RA

inhibits dihydroorotate dehydrogenase via active metabolite A77-1726 which reduces T cell proliferation and autoantibody production by Bcells

Efficacy for RA is equal to methotrexate but do not combine

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Gold formulations

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alters macrophage activity to reduce cytokines

highest bioavailability after IM injection and high efficacy against RA

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Antimalarials

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cholorquine, hydrocholoroquine etc. suppress T lymphocytes, improve RA symptoms but less efficacious then DMARDS

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principles of combination DMARD therapy

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TNF alpha inhibitors are combined with methotrexate if monotherapy is insufficient

NSAIDS with DMARDS for immediate alleviation of symptoms

monitor closely for toxicity