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Pharma 2- Semmelweis > B-18. NSAIDs, except ASA. Non-opioid analgesics. Drugs for gout. > Flashcards

B-18. NSAIDs, except ASA. Non-opioid analgesics. Drugs for gout. Flashcards

1
Q

Acetic Acid Derivative Drugs (2)? COX effect?

A
  1. ) Indomethacin - COX1 > COX2

2. ) Diclofenac, ketorolac - COX1 = COX2

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2
Q

Indomethacin MOA

A

COX1 > COX2; also inhibits PLA2 + inhibits neutrophil migration

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3
Q

Indomethacin side effects

A

Side Effects: severe, drug rarely used
o Highly ulcerogenic - used experimentally to induce ulcers
o Aplastic anemia + agranulocytosis - high risk
o Severe headache

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4
Q

Indomethacin indications

A

Indications: normal NSAID indications, plus…
o Hodgkin lymphoma - for decreasing refractory fever
o Patent DA - especially useful for this
o Severe RA pain
o Gout

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5
Q

Diclofenac + ketorolac
MOA?
Kinetics?

A

MOA: COX1 = COX2
Kinetics: short DOA, longer effect in joints (↑ conc. in synovium)

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6
Q

Diclofenac + ketorolac sIDE EFFECTS

A
  1. ) Cardiotoxicity
  2. ) ↑ fluid retention (caution in hypertension patients)
  3. ) Gastric bleeding (even w/ 1 dose)
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7
Q

Aryl Propionic Acid Derivative Drugs (4)

A
  1. ) Ibuprofen - COX1 > COX2
  2. ) Tiaprofenic acid
  3. ) Naproxen
  4. ) Flurbiprofen
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8
Q

Ibuprofen

● MOA:?
● Kinetics:?
● Indications:?
● Side effects:?

A

Ibuprofen

● MOA: COX1 > COX2
● Kinetics: 1-2 h DOA, accumulates in joints
● Indications: normal NSAID indications + patent DA treatment
● Side effects: aseptic meningitis

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9
Q

Naproxen
● MOA:?
● Kinetics:?
● Proven to be?

A

Naproxen
● MOA: inhibits neutrophil migration
● Kinetics: 14 hr DOA, 1x/day
● Proven to be NOT cardiotoxic

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10
Q

Flurbiprofen
● MOA:?
● Indications:?

A

Flurbiprofen
● MOA: inhibits TNFα as well (good for RA)
● Indications: as an ophthalmological pre-op anti-miotic (solution); arthritis, incl. RA, and dental pain (oral)

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11
Q

Tiaprofenic Acid
● Indications:?
● Side effects:?

A

Tiaprofenic Acid
● Indications: mainly arthritis
● Side effects: less cartilage / kidney damage than others, but high risk of severe cystitis w/ long-term use

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12
Q

Oxicams drugs (2)

A
  1. ) Piroxicam - COX1 > 2

2. ) Meloxicam - COX2 > 1

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13
Q 
Piroxicam
● MOA:?
Meloxicam
● MOA:?
● Side Effects:?
A

Piroxicam
● MOA: COX1 > COX2
Meloxicam
● MOA: COX2 > COX1 → anti-inflammatory effect before ulcerogenic effect
● Side Effects: higher risk of edema (stronger kidney effects)

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14
Q

Fenamates drugs (3)

A
  1. ) Meclofenamic acid
  2. ) Flufenamic acid
  3. ) Mefenamic acid
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15
Q

Mefenamic acid
● Indications:?
● Side Effects:?

Flufenamic and Meclofenamic acid
● Are they still in use? Side effect?

A

Mefenamic acid
● Indications: menstrual pain and perimenstrual migraine prophylaxis
● Side Effects: can cause SJS

Flufenamic and Meclofenamic acid
● less used, high rate of GI sfx (diarrhea)

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16
Q

Pyrazolone Derivatives Drugs (3)

A

Pyrazolone Derivatives

  1. ) Phenylbutazone
  2. ) Phenazone
  3. ) Nor-/aminophenazone
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17
Q

Phenylbutazone
Still in use?

● MOA:?
● Side Effects:?
● Indication:?

A

Phenylbutazone - strong anti-inflammatory, less anti-fever/pain effects; withdrawn in US

● MOA: also increases urate elimination (helpful in gout)
● Side Effects: severe; use longer than 1 wk is CI (is used longer in ankylosing spondylitis)
1.) Fluid retention
2.) Myelosuppression - dose-dependent/reversible and irreversible/idiosyncratic forms
● Indication: Thrombophlebitis - as a local cream

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18
Q

Phenazone and amino-/noraminophenazone

● Anti-inflammatory effect? Anti-fever/pain indications?
● Aminophenazone side effect?
● Noraminophenazone extra benefit?

A

Phenazone and amino-/noraminophenazone

● Anti-inflammatory effect is weak, better for anti-fever/pain indications
● Aminophenazone has higher marrow toxicity risk
● Noraminophenazone (aka Metamizol, trade name Algopyrin) is less ulcerogenic

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19
Q

Alkanone Derivative Drug?

Others Drug?

A

Alkanone Derivative is Nabumetone - COX2&raquo_space; 1

Other - Nimesulide - COX2&raquo_space; 1

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20
Q

Nabumetone
● MOA:?
● Kinetics:?
● Side Effects:?

A

Nabumetone
● MOA: prodrug w/ COX2&raquo_space; COX1 effect → anti-inflamm. w/out ulcerogenic effects (is also non-acidic)
● Kinetics: long DOA (24 hrs); 1x/day
● Side Effects: ↑ stroke / MI risk - similar to selective NSAIDs

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21
Q

Nimesulide
● MOA:?
● Side Effect:?

A

Nimesulide
● MOA: COX2&raquo_space; COX1 and PLA2 inhibition (strong anti-inflammatory, no ulcers)
● Side Effect: Hepatotoxicity

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22
Q

Selective NSAID drugs (4)

A

Selective NSAIDs - COX2 only

Celecoxib, parecoxib, valdecoxib (rofecoxib - withdrawn)

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23
Q

Selective NSAID differences

A
  1. ) only inhibit COX2 → no platelet aggregation inhibition via COX-1 synth’d TXA
  2. ) Less ulcerogenic (COX1 makes gastroprotective PGs), but ↑ TXA2 / ↓ PGI2 → ↑ thromboembolism
  3. ) Can ↓ Alzheimer progression and have anti-cancer effects (COX2 ↑ is oncogenic)
24
Q

Which of the selective NSAIDs are in use?

A

Celecoxib and parecoxib mostly in use; valdecoxib less so + rofecoxib withdrawn

25
Q

Celecoxib and parecoxib indications

A

○ Arthritis - osteoarthritis, RA and juvenile RA
○ Ankylosing spondylitis
○ Pain - acute pain and menstrual pain
(Has also been used to reduce polyps in FAP)

26
Q

Celecoxib and parecoxib contraindications

A

○ Acute MI / unstable angina / prior MI - due to thromboembolic side effects
○ Sulfa allergy - celecoxib is a sulfa drug

27
Q

Non-Opioid Analgesics

A

Paracetamol / Acetaminophen

28
Q

Paracetamol / Acetaminophen effects?

A

● Was classified as an NSAID; now is known to NOT be anti-inflammatory; only painkiller / anti-fever effects
● Inhibits COX only in CNS (“COX3”, sketchy says some COX2 as well); not ulcerogenic
● May modulate the endogenous cannabinoid system + activate TRPV1 receptors → analgesic effects

29
Q

Paracetamol / Acetaminophen indication

A

○ Pain / fever - mild-moderate pain, as in osteoarthritis

30
Q

Paracetamol / Acetaminophen side effects? What is the formula side effect?

A

Hepatotoxic at high dose

  • Toxic metabolite NAPQI needs sulfhydryl groups of glutathione for inactivation
  • At >4 g dose, glutathione can not fully neutralize NAPQI; can give NAC to restore glutathione and/or oral activated charcoal within 4 hours of ingestion
31
Q

What is gout?

A

● A metabolic disease with recurrent episodes of acute arthritis due to elevated serum uric acid → urate deposition in skin + joints → crystal precipitation and tophi formation
● Renal calculi and interstitial nephritis may also result from hyperuricemia

32
Q

Uric acid is a byproduct of?

A

purine metabolism

33
Q

How are nucleic acids and purines metabolized to form uric acid?

A

○ In the liver, nucleic acids are broken down into nucleotide monomers and individual purine nucleosides
○ Purine intermediate hypoxanthine is converted to xanthine by xanthine oxidase; xanthine oxidase further catalyzes conversion of xanthine to uric acid

34
Q

Pathogenesis of uric acid

A

Can be due to overproduction or underexcretion (more common) of uric acid

35
Q

Causes of uric acid production

A

○ Lifestyle - purine-rich foods such as seafood, organ meat, beer yeast ↑ urate levels
○ Genetics - variations in genes encoding for urate transport proteins in kidney ↑ gout risk

○ Other Diseases - metabolic syndrome, kidney failure, hemolytic anemia, obesity, enzyme deficiencies (such as the HGPRT deficiency in Lesch-Nyhan syndrome)

○ Medications - many drugs decrease urate excretion: ASA, ACE-Is, ARBs, BBs, ritonavir, pyrazinamide, thiazide diuretics, niacin, etc.

36
Q

How is tophi formation cyclical?

A

↑ urate level in joints → precipitation of Na-Urate crystals → phagocytosis of crystals by synoviocytes → chemokines released + pH ↓ → neutrophils attracted to joint + further precipitation occurs

37
Q

Gout drugs for acute attacks (3)

A

Gout drugs for acute attacks:

a) NSAIDs - indomethacin
b) Corticosteroids - prednisolone
c) Tubulin inhibitor - colchicine

38
Q

When can acute gout drugs be used?

A

● These drugs can also be used to treat calcium pyrophosphate dihydrate crystal deposition disease (“pseudogout”)
● Diff dx is performed by synovial fluid microscopy → gout = non-birefringent needle crystals; CPPD = birifringent, rhomboid crystals)

39
Q

Acute gout NSAIDs MOA

A

NSAIDs - especially indomethacin; high dose ASA ↑ urate excretion but is not used due to sfx

40
Q

Acute gout corticosteroid drug, dose, kinetics

A

Glucocorticoids - oral prednisolone (40 mg); can also be intra-articular or s.c.

41
Q

Colchicine is?

MOA?

A

Colchicine - toxic plant alkaloid

● MOA: binds intracellular tubulin → inhibits polymerization to microtubules → inhibits neutrophil migration, phagocytosis + degranulation

42
Q

Cochicine side effects?

A

● GI effects - diarrhea / nausea / vomiting due to tubulin disruption in enteric epithelial cells
● Liver/kidney damage - including hepatic necrosis and ARF
● Myelosuppression - via ↓ mitosis due to microtubule effects
● Peripheral neuritis

43
Q

For chronic gout prophylaxis

drug classes?

A

a) XO inhibitors
b) Uricases
c) Uricosurics

44
Q

For chronic gout Uricases

A
  1. ) Rasburicase

2. ) Pegloticase

45
Q

For chronic gout Uricosurics

A
  1. ) Probenecid

2. ) Sulfinpyrazone

46
Q

For chronic gout XO inhibitors

A
  1. ) Allopurinol

2. ) Febuxostat

47
Q

Allopurinol
● MOA:?
● Kinetics:?

A

Allopurinol
● MOA: competitive xanthine oxidase inhibition via an active metabolite
● Kinetics: oral absorption, 1x/day

48
Q

Allopurinol

● Indications:?

A

Allopurinol
● Indications:
1.) Gout prophylaxis - taken life-long in patients with recurrent episodes
2.) Chemotherapy - as in tumor lysis syndrome (↑ K+, Pi, urate + BUN; ↓ Ca++)
3.) Lesch-Nyhan syndrome - X-linked defic. of HGPRT; children pick at skin / bite lips where urate deposits

49
Q

Allopurinol

● Side Effects:?

A

Allopurinol
● Side Effects:
1.) Hypersensitivity - most common side effect, “allopurinol rashes”; common cause of SJS
2.) DRESS syndrome - fever, general LAP, facial edema, morbilliform rash
3.) Rarely, myelosuppression

50
Q

Allopurinol

● Interaction:?

A

Allopurinol
● Interaction: If given with azathioprine + 6-mercaptopurine (purine analogs), allopurinol inhibits their metabolism via xanthine oxidase → ↑ toxicity of cytotoxic agents

51
Q

Febuxostat
● MOA:?
●Side Effects:?

A

Febuxostat
● MOA: XO inhibitor
● Side Effects: Hepatic effects and nausea

52
Q

Rasburicase and pegloticase
● MOA:?
● Indication:?

A

Rasburicase and pegloticase
● MOA: recombinant uric oxidase (uricase) → transforms urate to allantoin (more water-soluble)
● Indication: used if allopurinol causes HS rxn

53
Q

Rasburicase and pegloticase

● Side Effects:?

A

Rasburicase and pegloticase
● Side Effects:
1.) Hemolytic anemia - can precipitate anemia in G6PD deficiency patients
2.) Anaphylaxis - in ~10% pts → must be given in-patient i.v. by rheumatologist

54
Q

Uricosurics are?

A

Uricosurics - urate excretion enhancers; 2nd line for underexcretion

55
Q

Probenecid and Sulfinpyrazone

● MOA:?

A

Probenecid and Sulfinpyrazone

● MOA: competitively inhibits reabsorption of urate by OAT (organic anion transporter) in PCT

56
Q

Probenecid and Sulfinpyrazone

●Side Effects:?

A

Probenecid and Sulfinpyrazone
●Side Effects:
1.) Kidney stones - ↑ urate in urine; prevent with hydration and adequate urination
2.) Also inhibits penicillin elimination → ↑ toxicity
3.)Sulfa allergy - rare, but is a sulfa drug
4.) Can worsen / precipitate an acute attack; start drug 2-3 weeks after last attack

Pharma 2- Semmelweis (43 decks)

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