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233 2nd midterm > Rheumatoid Arthritis, Gout, Hyperuricemia > Flashcards

Rheumatoid Arthritis, Gout, Hyperuricemia Flashcards

1
Q

name 5 groups of drugs that are antiinflammatory for rheumatoid arthritis

A
  1. Non-steroidal anti-inflammatory drugs (NSAIDs) and
    the coxibs.
  2. Disease-modifying antirheumatic drugs (DMARDs),
    including some immunosuppressants.
  3. The glucocorticoids. (steroidal)
  4. Anticytokines and other biological agents.
  5. Other drugs that do not fit into these groups,
    including antihistamines.
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2
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

2 types and their common drugs? (prototype and others)

A

do not have steroidal ring

  1. Nonselective Prototype: ibuprofen
    Others:
    • Propionic acid derivatives: naproxen, fenoprofen,
    ketoprofen, flurbiprofen
    • Acetic acid derivatives: diclofenac, ketorolac,
    indomethacin, etodolac, sulindac, piroxicam, meloxicam, nabumetone, tolmetin, mefenamic acid, meclofenamate, flufenamic acid
  2. Cyclooxygenase (COX)-2 selective (only)
    • Prototype: celecoxib
    • Others: rofecoxib, valdecoxib
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3
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

What are the 3 major therapetuic actions mainly through COX2 inhibition

A
  1. anti-inflammatory action: the decrease in prostaglandin E2 and prostacyclin reduces vasodilatation and, indirectly, edema. Accumulation of inflammatory cells is not directly reduced (indirect).
  2. analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5- hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin-mediated vasodilatation.
  3. antipyretic effect: interleukin-1 releases
    prostaglandins in the central nervous system, where they elevate the hypothalamic set point for temperature control, thus causing fever. NSAIDs prevent this.
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4
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

desribe pathway of phospholipids

A
  • Phospholipase A2 makes phospholipid into arachidonic acid which is metabolized by COX 1 and 2
  • Cox 1 and 2 metabolize to cyclic endoperoxides which are prostaglandins or prostacyclins
  • PGI2: vasodilator, hyperalgeics, decrease platelet agg
  • TXA2: vasocconstrcitor, thrombosis
  • other prostaglandins are forms PGF2a, PGD2, PGE2

5-lipoxygenase turns arachidonate into LTA4 that makes LTB4 and LTC4, LTD4

NSAIDS inhibit COX to inhibit conversion of arachidonate to cyclic endoperoxides glucocorticoids also inhibit induction of COX and phospholipase A2

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5
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

MOA?
what is the diff b/w COX-1 and COX-2 and their roles?

A

• Inhibit the activity of cyclooxygenase enzymes (COX-1
and/or COX-2).
• COX is an enzyme that catalyzes the conversion of
arachidonic acid to prostaglandin
• There are actually two major isoforms of the COX
enzyme: COX-1 and COX-2. COX-1 is a constitutive
enzyme, while COX-2 is an inducible enzyme.
• COX-1 play protective role, responsible for production of cytoprotective mucus in the stomach and for platelet aggregation (clotting).
• The main stimuli for COX-2 induction are inflammatory mediators, and thus COX-2 is typically associated with inflammation

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6
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

what are the 4 types and which COX do they inhibit?

A

Ibuprofen: Reversible inhibition of COX-1, weak inhibition of COX-2.

Aspirin: Irreversible acetylation of COX; weakly COX-1
selective. (both)

Paracetamol: Inhibition of COX-1, COX-2 and also the
recently identified COX-3 which occurs predominantly in the CNS (weak action).

Celecoxib: Selective inhibition of COX-2
– the enzyme that is induced in areas of inflammation.
– celecoxib is 10–20 x more active on COX-2 than COX-1

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7
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

metabolized by?
half lives long or short?
dosage forms?

A

• Most NSAIDs are well absorbed, and food has little effect on their bioavailability.
• Most NSAIDs undergo extensive hepatic metabolism,
many through either the CYP3A or CYP2C families.
• Many nonselective COX inhibitors have short to
intermediate half-lives (2 to 12 hours), requiring frequent administration. The newer COX-2 selective inhibitors typically have longer half-lives and are administered once daily.
• Many NSAIDs are available in topical dosage forms
• Indomethacin is also available as a rectal suppository.

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8
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

Indciations (3)

contraindications

A

pain, inflamm, fever

contra: active peptic ulcer - use paracetamol which has mild stomach effect

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9
Q
  1. Nonsteroidal Antiinflammatory Drugs (NSAIDs)

AE
nonselective (3)
COX-2 (1)
all (1)

A

Nonselective
• Gastrointestinal effects occur because of the inhibition of COX-1–mediated production of cytoprotective mucus in the stomach.
• Edema: PG inhibition leads to salt and water retention.
• Acute renal failure: Renal PGs often play a protective
role in high-risk patients by counteracting the effects of vasoconstrictors such as angiotensin 2 and vasopressin.
- angiotensin and vasopressin will be dominant and increase bp

COX-2 Selective
• Cardiovascular: by disruption of the balance between the platelet-activating effects of COX-1 and the platelet inhibiting effects of COX-2, more clots with switched balance

All
• Central nervous system (CNS): Confusion, dizziness,
depression, and hallucinations may occur. The
mechanism is not confirmed, but COX-2 is the most
abundant COX isoform in the CNS, and COX-2 may play a role in neurotransmission

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10
Q

Disease-modifying antirheumatoid drug (DMARD)

A

T cell with CD4 receptor will differentiate into T helper cell which gives rise to activated Th1
- Th1 cell acts on macrophage which releases cytokines like interleukin and TNFa which acts on osteoclast, fibroblast and release other inflamm cyto/chemokines

  • osteoclast and fibroblast release collagenase
  • Collagenase breaks fown collagen - erosion of cartilage and bone
  • Immuno DMARDs (methotrex) directly inhibit T cells
  • Anti TNF agents bind that bind to tnfa and prevent its parcipitation(anti cytokines)
  • DMARDS also stop erosion of catilage and bone
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11
Q

synthetic DMARD
methotrexate

MOA?

indication

A

Has marked anti-inflammatory action in rheumatoid disease and cytotoxic in the larger doses used to treat cancer.

MOA
Folate antagonist and thus interferes with thymidylate synthesis (which is essential for DNA synthesis)

Indication
Rheumatoid arthritis; also used in psoriasis, ankylosing spondylitis (inflamm of spine), polymyositis (inflamm of muscle) and vaculitis (inflamm of blood vessel)

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12
Q

synthetic DMARD
methotrexate

AE? (3)

dosage form, half-life

A
  • Gastrointestinal disturbances, dose-related liver toxicity.
  • Bone marrow depression and pneumonitis can occur
  • anemia due to bone marrow supp (give folic acid)

Given orally; has active metabolite. Half-life 6–9h

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13
Q

synthetic DMARD
sulfasalazine

MOA?

indication (3)

A

MOA
In the colon the salicylic acid moiety is released, is absorbed and has anti-inflammatory action.

Indication
Rheumatoid arthritis, juvenile arthritis, inflammatory bowel disease.

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14
Q

synthetic DMARD
sulfasalazine

AE? (4)

dosage form, half-life

A

Nausea & vomiting, headaches, rashes. About a third of patients discontinue the drug because of side effect

Given orally; only ~15% is absorbed in the GIT. Half-life 6–16h.

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15
Q

synthetic DMARD
Leflunomide

MOA?

indication (1)

A

Gives rise to a metabolite that inhibits dihydrooratate
dehydrogenase; this results in inhibition of T-cell proliferation and decreased production of autoantibodies by B cells.
- inhibits immunity

indication: RA

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16
Q

synthetic DMARD
Leflunomide

AE? (3)

dosage form, half-life

A
  • ~25% of patients get diarrhoea. Increased BP, weight gain can occur

Absorbed orally. The metabolite undergoes enterohepatic cycling, half-life thus ~18 days

17
Q

synthetic DMARD

Targeted synthetic DMARD

for RA (name 2)
for psoriatic arthritis (name 2)
A

– RA: tofacitinib, baricitinib
• They Inhibit Janus Kinase (JAK)

– Psoriatic arthritis (PsA): apremilast, tofacitinib
• Apremilast: The drug acts as a selective inhibitor of
the enzyme phosphodiesterase 4 (PDE4) and
inhibits spontaneous production of TNF-alpha from
human rheumatoid synovial cells.
• Tofacitinib: JAK inhibitor

newly made drugs, for alopecia

18
Q

biologic DMARD

name 2

MOA

A

Biologic - mostly antibodies and against inflamm cytokines like interleukin and TNFa
An anticytokine antirheumatoid drug. Reduces joint inflammation and symptoms of rheumatoid arthritis. Reduces symptoms of Crohn’s disease.

Infliximab

  • Adalimumab is also an anti-TNFalpha antibody (half-life 10– 20 days).
  • Etanercept another anti-TNF-alpha antibody (given
    subcut. twice a week; half-life ~5 days).

It is a monoclonal antibody against TNF- that binds with the TNF-alpha and prevents its interaction with cell surface receptors in inflammatory cells

19
Q

biologic DMARD

infliximab
indication

A

Active rheumatoid arthritis – usually combined with
methotrexate if other DMARDs haven’t worked. Ankylosing spondylitis and psoriatic arthritis – if other therapy hasn’t worked.
- Start out with NSAID, then synth DMARD, then biologic

Crohn’s disease (inflamm bowel disease)

20
Q

biologic DMARD

infliximab
dosage form, half-life
AE (4)

A

Given by i.v. infusion every 4 weeks. Half-life 9–12 days

Nausea, vomiting, headache, upper respiratory tract
infections with cough

21
Q

glucocorticoids role

A

inhibit macrophage and release of IL-1 and TNFa

22
Q

Drugs Used in Gout

name prototype

indications

A

Colchicine is used to treat crystal-associated arthritis, most commonly gout (a disease caused by uric acid crystal deposition in joints).

Ppl who eat red meat have high level of uric acid
Deposits in joints like leg joints

indications
• Gout
• Acute attacks
• Long-term prevention of recurrent attacks as an adjuvant
to uric acid–lowering therapies
23
Q

Drugs Used in Gout
Colchicine

MOA?

A

Inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators by following mechanisms;

  • inhibits microtubule polymerization by binding to its constitutive protein, tubulin, which is essential to mitosis.
  • inhibits activation and migration of neutrophils to sites of inflammation
  • interferes with the inflammasome complex found in neutrophils and monocytes that mediate interleukin-1β activation, a component of inflammation
  • inhibits superoxide anion production in response to urate crystals
  • interrupts mast cell degranulation
24
Q

Drugs Used in Gout
Colchicine

PK
Contraindication

A

The half-life of the tubulin-colchicine complex is 20 to 30 hours.
• Although clearance is primarily via the liver, renal
clearance accounts for about 20%, and renal
insufficiency is a very strong risk factor for toxicity

contra
• Renal failure: increased risk of toxicity

25
Q

Drugs Used in Gout
Colchicine

AE (5)

A

• Colchicine has a narrow therapeutic index. Narrow window of therapetuic and toxic fx, small increase in dose can be toxic
• Gastrointestinal: Diarrhea is virtually a guaranteed side
effect when colchicine is given in doses suitable for acute attacks of gout.
• Bone marrow suppression: Antimitotics preferentially
target rapidly dividing cells, such as those found in the bone marrow.
• Myopathy may occur. (weak muscle)
• Neuropathy may occur

26
Q

Uricosurics

name prototye and other drug

indication

A

Uricosurics lower uric acid levels in blood as a treatment for gout.

Prototype and Common Drugs
Prototype: Probenecid
Others: Sulfinpyrazone

gout

27
Q

Uricosurics

MOA

PK

A

Uric acid levels in the blood are elevated in gout, and one treatment strategy is to lower uric acid levels by enhancing uric acid excretion. Probenecid is completely reabsorbed by the proximal tubule and prevent uric acid reabsorption.

PK
• One uricosuric drug may either add to or inhibit the action of another. The biphasic effect may be seen within the normal dosage range with some drugs such as salicylates.
• Twice-a-day and up to four-times-a-day administration has resulted in probenecid being used by fewer patients compared with another class of gout therapies, the xanthine oxidase inhibitors, which decrease uric acid synthesis.
28
Q

Uricosurics

contra (3)
AE (3)

A

contra
• Renal insufficiency.
• Urolithiasis (renal stones or calculi).
• Peptic ulcer

AE
• Probenecid is well tolerated.
• Gastrointestinal irritation is usually mild.
• Allergic reactions usually are mild and occur in 2% to 4% of patients.

29
Q

Uricosurics
Xanthine oxidase inhibitors

name prototye and other drug

indication

A

Prototype and Common Drugs
Prototype: Allopurinol
Others: Febuxostat

decrease uric acid synthesis and
are used in gout

  • Gout
  • Renal stones composed of uric acid
  • Complicated hyperuricemia
30
Q

Uricosurics
Xanthine oxidase inhibitors

MOA

  • allopurinol
  • febuxostat
A
  • Allopurinol is a purine analogue of hypoxanthine and is a substrate for, and inhibitor of, the enzyme xanthine
    oxidase. Xanthine oxidase converts hypoxanthine to
    xanthine to uric acid; inhibition therefore reduces the
    production of uric acid
  • Febuxostat is a new nonpurine inhibitor of xanthine oxidase. A significant difference from allopurinol is that being a nonpurine, it does not inhibit purine or pyrimidine synthesis, while allopurinol does
31
Q

Uricosurics
Xanthine oxidase inhibitors

contra (1)
PK

A

contra: Previous hypersensitivity reactions to allopurinol

• Allopurinol increases the half-life of probenecid and
enhances its uricosuric effect.
• Mercaptopurine, azathioprine, and theophylline are
metabolized by xanthine oxidase, and coadministration
with allopurinol will dramatically increase levels of these drugs.

32
Q

Uricosurics
Xanthine oxidase inhibitors

AE

  • allopurinol (4)
  • febuxostat (2)
A

Allopurinol
• Skin reactions: Both mild and severe reactions can occur.
• Rarely, toxic epidermal necrolysis or Stevens-Johnson
syndrome occurs, which can be fatal.
• Liver reactions: Severe hepatic reactions including elevations of liver enzymes, fever, eosinophilia, and rash may occur.
• Renal insufficiency.

Febuxostat
• Febuxostat appears to not produce the hypersensitivity reactions that occur with allopurinol.
• Increase in the risk of myocardial infarction, stroke, and cardiovascular death with febuxostat.

233 2nd midterm (13 decks)

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