Lange Pharm Ch 36

Front 1

DMARD

Back 1

disease-modifying antirheumatic drugs

Front 2

cyclooxygenase (COX)

Back 2

enzyme at the head of the enzymatic pathway for prostaglandin synthesis

Front 3

cytotoxic drug

Back 3

interfere with essential cell processes. generally kill rapidly dividing cells; primarily for cancer & immunosuppression

Front 4

DMARDs

Back 4

modify inflammatory processes underlying rheumatoid arthritis; slow (weeks to months) onset

Front 5

NSAIDs

Back 5

inhibitors of COX. the term nonsteroidal differentiates them from steroid drugs that mediate anti-inflammatory effects through activation of glucocorticoid receptors (e.g., cortisol)

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Reye's syndrome

Back 6

rare syndrome of rapid liver degeneration and encephalitis in children treated with aspirin during a viral infection

Front 7

TNF-alpha

Back 7

Cytokine that plays a central role in inflammation

Front 8

uricosuric agent

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drug that increases the renal excretion of uric acid

Front 9

xanthine oxidase

Back 9

key enzyme in the purine metabolism pathway that ends with the production of uric acid

Front 10

Aspirin

Back 10

acetylsalicylic acid and is prototype of the salicylates.

Front 11

aspirin

Back 11

acetylsalicylic acid, is the prototypeof the salicylates

Front 12

Older nonselective NSAIDS besides aspirin

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ibuprofen, indomethacin & many more

Front 13

Celecoxib

Back 13

1st member of NSAID subgroup, the Cox-2 selective inhibitor. higher incidence of cardiovascular thrombotic events than non-selective

Front 14

COX

Back 14

enzyme that converts arachidonic acid into the endoperoxide precursors of prostaglandins, important mediators of inflammation.

Front 15

COX-1 and COX-2

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COX-1 is primarily expressed in noninflammatory cells. COX-2 is expressed in activated lymphocytes, polymorphonuclear cells & other inflammatory cells

Front 16

aspirin & nonselective NSAIDs

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inhibit both COX I and II & decrease prostaglandin and thromboxane synthesis. Release of prostaglandins necessary for homeostatic function is disrupted, as is release of prostaglandins involved in inflammation.

Front 17

Major difference between MOA of aspirin and other NSAIDs

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aspirin acetylates and thereby IRREVERSIBLY inhibits COX. Other NSAIDs are reversible. Therefore, aspirin's antiplatelet effect is longer

Front 18

NSAIDs antipyretic action

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NSAIDs suppress the prostaglandin synthesis in the CNS that is stimulated by pyrogens and thereby reduces fever

Front 19

COX inhibitors in GI

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COX inhibitors interfere with homeostatic function of prostaglandins. They reduce prostaglandin-mediated cytoprotection in the GI tract and autoregulation of renal function

Front 20

Aspirin dosages

Back 20

<300 mg/day - antiplatelet.
300-2400 mg/day: antipyretic & analgesic.
2400-4000 mg/day: anti-inflammatory effect. 1/2 life 3-5 hours at lower doses. elimination 1st order. excretion via kidney.
Aspirin is readily absorbed and is hydrolyzed in blood and tissues to acetate and salicylic acid.

Front 21

Aspirin toxicity

Back 21

gastric upset. With chronic use: gastric ulceration, upper GI bleeding & renal failure and interstitial nephritis. Increases bleeding time.
High doses: tinnitus, vertigo, hyperventilation & respiratory alkalosis
Very high doses: metabolic acidosis, dehydration, hyperthermia, collapse, coma, death.

Front 22

When prostaglandin synthesis is inhibited by aspirin, people with aspirin hypersensitivity (especially people w/nasal polyps)

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can experience asthma from increased synthesis of leukotrienes. This hypersensitivity precludes treatment with any NSAID.

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Nonselective NSAIDs (other than aspirin) toxicity

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They are also associated with significant gastrointestinal disturbance, but lower than with aspirin. Because all NSAIDs (except acetominophen) are cleared by kidney, renal disease increases toxic serum concentrations.

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Cox-2 selective inhibitors

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celecoxib, rofecoxib, valdecoxib. reduced risk of GI effects. Carry the same risk of renal damage as nonselective COX inhibitors. But increased risk of myocardial infarction and stroke. Several COX-2 inhibitors have been removed from the market.

Front 25

Acetaminophen

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only OTC non-antiinflammatory analgesic commonly available in the US.

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MOA of acetaminophen

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Unclear. Weak COX 1 and COX 2. may inhibit COX 3 in the CNS

Front 27

Per Krueger:
acetaminophen

Back 27

only has antipyretic & analgesic. not antiinflammatory. not antiplatelet

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Per Krueger:
acetaminophen SE

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hepatotoxicity

Front 29

Acetaminophen is metabolized in

Back 29

the liver.

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acetaminophen 1/2 life

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2-3 hrs in persons with normal hepatic function. Is unaffected by renal disease.

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MOA of toxicity in acetaminophen

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Oxidation to cytotoxic intermediates by phase I cytochrome P450 enzymes. This occurs if substrates for phase II conjugation reactions (acetate and glucuronide) are lacking.

Front 32

Acetaminophen overdose

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give acetylcystein. also people who regularly consume 3 or more alcoholic drinks per day are at increased risk of acetaminophen-induced hepatotoxicity.

Front 33

Disease-modifying antirheumatic drugs (DMARDS)

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aka "slow-acting antirheumatic drugs (SAARDs)" because it may take 6 weeks to 6 months for their benefits to become apparent. They slow or even reverse joint damage.

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Corticosteroids

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Intermediate rate of action between NSAIDs & DMARDs but can't use chronically & reserved for temporary control

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MOA of DMARDs

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Poorly understood. Darn

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Methotrexate

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DMARD: is cytotoxic & probably reduces the # of immune cells available to maintain inflammatory response. Many are used in treatment of cancer since cytotoxic & work on fast-replicating cells.

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DMARDs MOA

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interfere with the activity of T lymphocytes (sulfasalazine, hydroxychloroquine, cyclospirine) interfere with B lymphocytes (rituximab) or interfere with macrophages (gold compounds)

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TNA-alpha inhibitors

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infliximab, etanercept have also shown efficacy in RA.

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Anti-TNF-alpha drugs are given by

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injection

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Toxicity of DMARDs

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All disease-modifying agents can cause severe or fatal toxicities.Careful monitoring of patients is mandatory.

Front 41

Methotrexate

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initial DMARD for people with RA. Often used with TNF-alpha. Causes bone marrow suppression. Anti-cancer.

Front 42

Gout - Indomethacin

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potent NSAID inhibits inflammation of acute gouty arthritis. Reduces prostaglandin formation and the inhibition of crystal phagocytosis by macrophages

Front 43

Colchicine (in gout)

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a selective inhibitor of microtubule assembly, reduces leukocyte migration and phagocytosis. Also may reduce production of leukotriene B4 and decrease free radical formation

Front 44

Per Kruger:
Indomethacin

Back 44

NSAID used in gout

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Per Kruger:
MOA of colchicine used in gout

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Selective inhibitor of microtubule assembly

Front 46

Per Kruger:
SE of colchicine

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Kidney and liver toxicity, diarrhea.

(Per book: Overdose is often fatal)

Front 47

Uricosuric agents

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probenecid, sulfinpyrazone are weak acids that compete with uric acid for reabsorption by the weak acid transport machanism in the proximal tubules and thereby increase uric acid excretion.

Front 48

Per Krueger:
Probenecid and sulfinpyrazone

Back 48

Agent used to treat chronic gout by increasing uric acid secretion and excretion

Front 49

Uricosuric drugs are used orally to treat

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chronic gout. No value in acute episodes

Front 50

Uricosuric drugs are sulfonamides, therefore

Back 50

may share allergenicity with other classes of sulfonamide drugs.

Front 51

Xanthine oxidase

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The enzyme that converts hypoxanthine to xanthine and xanthine to uric acid.

Front 52

Allopurinol

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treats chronic gout by decreasing uric acid production by inhibiting the production of uric acid. (a xanthine oxidase inhibitor)

Front 53

febuxostat

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a nonpurine inhibitor of xanthine oxidase that is more selective than allopurinol and alloxanthine, which inhibit other enzymes involved in purine and pyrimidine metabolism

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inhibition of xanthine oxidase

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increases the concentrations of the more soluble hypoxanthine and xanthine and decreases the concentration of the less soluble uric acid so there is less likelihood of precipitation of uric acid.

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xanthine oxidase inhibitors

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are given orally in the management of chronic gout

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Allopurinol toxicity

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GI upset, rash, rarely peripheral neuritis, vasculitis or bone marrow dysfunction including aplastic anemia.

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allopurinol drug interaction

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inhibits the metabolism of mercaptopurine and azathioprine, drugs that depend on xanthine oxidase for elimination.

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Per Krueger:
NSAID contraindicated in gout

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Aspirin

Front 59

Per Krueger:
Allopurinol treats chronic gout by decreasing uric acid production by inhibiting

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Xanthine oxidase

Front 60

Per Krueger:
Causes bone marrow suppression

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Methotrexate

Front 61

Per Krueger:
NSAID available orally, IM and ophthalmically

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Ketoralac

Front 62

Per Krueger:
NSAID that is used for acute condition, such as pre-op anesthesia and has limited duration (<5 days) of use due to nephrotoxicity

Back 62

Ketoralac