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Pharm III > exam 1: NSAIDS, DMARDS, > Flashcards

exam 1: NSAIDS, DMARDS, Flashcards

1
Q

3 phases of inflammation

A

acute inflam
immune response
chronic inflam

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2
Q

what mediator do we really want to target

A

Prostaglandins

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3
Q

Stimulus –> Phopholipids –> arachidonic acid via phospholipase a2 –> leukotrienes via lipoxygenase or PG, TXA2, Prostacylcin via cyclooxygenase

*what inhibits where

A

Steroids inhibit Phospholipase
NSAIDS/ASA inhibit cyclooxygenase
Lipoxygenase inhibitors inhibit Leukotriene formation

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4
Q

ASA actions

A

Nonselective irreversible inhibitor of COX1,2

  • antiinflam
  • antipyretic
  • analgesic
  • anti platelet (irreversible)
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5
Q

PK of ASA

A

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
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6
Q

Metabolism of ASA

A 
low dose = first order
high dose (above 600 mg body burden) = zero order

*renal excretions (thus alkalinization of urine promotes excretion)

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7
Q

Uses for ASA

A 
mild to moderate pain
antipyresis
anti-inflamm (NSAID)
MI, thrombosis prophylaxis
long term use decreases colon CA
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8
Q

Adverse effect of ASA related to a/b balance

A

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

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9
Q

How does ASA effect platelets and bleeding. What caution should be taken

A

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)
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10
Q

How does ASA effect Uric acid levels

A

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)

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11
Q

What effects does ASA have on heart and lungs?

A

Heart - minimla in reg dose

Lungs: ASA asthma bc ARACHIDONIC acid is shunted to form leukotrienes

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12
Q

How does ASA affect the GI and how can this be addressed

A

GI upset, gastritis, ulcer, bleeding

*use buffered form, take with food, take combined with misoprostol

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13
Q

How does ASA affect kidneys?

A

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
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14
Q

What effects does ASA have on skin

A

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

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15
Q

which effects does ASA have first (at therapeutic dose).. simultaneous complications?

A

antiplt –> antipyretic –> analgesic –> uricosuric –> antiinflammatory

*SE: gastric intolerance, bleeding, hypersensitivity reactions, impaired hemostasis

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16
Q

ASA should be decreased during long term tx with…

A

oral anticoagulants, hypoglycemic agents etc

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17
Q

ASA should be avoided in pt with

A

gastric ulcer, severe hepatic damage, hypoprothrombinemia, vit K def, hemophilia, hypersens

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18
Q

What are fatal/poisonous doses of ASA

A

Fatal dose 20 g (10-30) of ASA

For methyl salicylate (oil of wintergreen) 4-5 mL

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19
Q

What is Reyes syndrome

A

cerebral edema in children with viral infections, NO ASA, the DOC is acetaminophen

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20
Q

What are the nonacetylated salicylates

A

Mg choline salicylate
Na salicylate
Salicyl Salicylate

*effective antiinflamm, less analgesic, NOT IRREVERSIBLE

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21
Q

What is Diflunisal

A

Salicylic acid derivative, no antipyretic

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22
Q

What is Celecoxib (celebrex) and indicated use? SE? CI?

A

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

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23
Q

What does COX 1 do? COX2?

A

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)

24
Q

General overview of nonspecific reversible inhibitors of COX1 and 2

A 
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
25
Q

What are general toxicities of nonspecific reversible inhibitors of COX1 and 2

A

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

26
Q

Indomethacin (indocin) MOA, use?

A

Reduce PMN migration, inhibit Phospholipase A

  • potent AI AR agent, high incidence of SE
  • used for PDA
27
Q

Diclofenac (Volatren): MOA, PK, SE?

A

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
28
Q

Ketorolac (Toradol): Use, PK, SE

A

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
29
Q

IBuprofen (motrin) PK, metab, use

A

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)

30
Q

Toxicity of Ibuprofen

A

low, NV, diarrhea, constipation, heartburn, GI bleeding, dizzy, light headed, HYPERURICEMIA

31
Q

Naproxen (Naprosyn) effect and metab

A

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
32
Q

Toxicity of Naproxen

A

GI disturbances, Heartburn, dyspepsia, ab pain, constipation, diarrhea
*gastric bleeding less severe than with asa

33
Q

Action of Piroxicam (Feldene)

A

Inhibits PMN migration, lymphocyte function

  • decreases oxygen radical production
  • long half life, high incidence of GI SE
34
Q

What is Nabumetone (Relafen)

A

prodrug with long half life

35
Q

Phenylbutazone

A

potent, serious GI, bone marrow SE, not in USA

36
Q

if someone is in active PUD give..

A

APAP

37
Q

hx of PUD but not active

A

celcoxib with or without antacids or some NSAIDS with misoprostol or prazoles (PPI)

38
Q

Why could APAP be preferred over ASA

A

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

39
Q

PK of APAP

A

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

40
Q

Actions of APAP (and actions APAP doesn’t have)

A

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

41
Q

SE of APAP

A

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

42
Q

How do you treat APAP intoxication

A

Gastric emptying, forced diuresis, hemodialysis

Antidote: N acetylcysteine (Mucomyst) (give IV ASAP w/in 10-12 hr)

43
Q

what mediator of chronic inflammation is is good to manipulate and why

A

TNF-alpha
source: macrophages
Effect: PG production

44
Q

How do gold salts work? toxicity?

A

Inhibit phagocytosis, uncouple ox phos, SUPPRESS CELL IMMUNITY

toxicity: bone marrow damage, enterocolitis

45
Q

Penicillamine (Cuprimine) use, Toxicity

A

Chelating drug effective in RA and wilsons

*LIVER: thombocytopenia, leukopenia, agrnulocytosis, aplastic anemia
KIDNEY: proteinuria, hypoalb, nephrotic syndrome

46
Q

Hydorzychloroquine (Plaquenil) MOA, toxicity

A

Antihistaminic, antichoinesterase and antiprotease; inhibits phagocytosis and stabilizes lysosomes

Toxicity: Pruritis, HEMOLYSIS (G6PD deficient), ototoxic

47
Q

Sulfasalazine (azulfidine) use, toxicity

A

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

48
Q

Infliximab (Remicade) MOA, use, SE

A

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

49
Q

RITUXIMAB (RITUXAN) moa, use

A
  • 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

50
Q

Adalimumab (Humira), MOA, use, SE

A

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

51
Q

Entanercept (Enbrel) MOA, admin, SE/CI

A

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

52
Q

Abatacept (Orencia) MOA, use, admin

A

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

53
Q

Leflunomide (Arava) MOA and admin. SE?

A

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

54
Q

Mycophenolate Mofetil (Cellcept)

A

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

55
Q

Anakinra (Kineret) MOA, use, CI

A

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

56
Q

Janus Kinase inhibitor: Tofacitinib (Xeljanz)

A

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

Pharm III (9 decks)

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