B-19. NSAIDs, except ASA. Non-opioid analgesics. Drugs for gout

Question 1

Non-Selective NSAIDs

Answer 1

(numbers denote affinity for COX1 vs. COX2)

1. Acetic Acid Derivatives:
   a. Indomethacin - 1 > 2
   b. Diclofenac, ketorolac - 1 = 2
2. Aryl Propionic Acid Derivatives:
   a. Ibuprofen - 1 > 2
   b. Tiaprofenic acid
   c. Naproxen
   d. Flurbiprofen
3. Oxicams: (Long-acting enolic acid derivatives)
   a. Piroxicam - 1 > 2
   b. Meloxicam - 2 > 1
4. Fenamates:
   a. Meclofenamic acid
   b. Flufenamic acid
   c. Mefenamic acid
5. Pyrazolone Derivatives:
   a. Phenylbutazone
   b. Phenazone
   c. Nor-/aminophenazone
6. Alkanone Derivatives:
   a. Nabumetone - 2&raquo_space; 1
7. Others:
   a. Nimesulide - 2&raquo_space; 1

Question 2

Selective NSAIDs

Answer 2

(COX2 only)

1. Celecoxib
2. Parecoxib
3. Valdecoxib
4. Rofecoxib - withdrawn

Question 3

Non-opioid analgesics

Answer 3

1. Acetaminophen

2. Paracetamol

Question 4

Indomethacin (MOA, SE, indications)

Answer 4

MOA:
1. COX1 > COX2; also inhibits PLA2 + inhibits neutrophil migration.

Side Effects:
(severe, drug rarely used)
1. Highly ulcerogenic - used experimentally to induce ulcers.
2. Aplastic anemia + agranulocytosis - high risk.
3. Severe headache.

Indications:
(normal NSAID indications, plus…)
1. Hodgkin lymphoma - for decreasing refractory fever
2. Patent DA - especially useful for this
3. Severe RA pain
4. Gout

Question 5

Diclofenac + Ketorolac (MOA, kinetics, SE)

Answer 5

MOA:
COX1 = COX2

Kinetics:
short DOA, longer effect in joints (↑ conc. in synovium).

Side Effects:

1. Cardiotoxicity
2. ↑ fluid retention (caution in htn pts)
3. gastric bleeding (even w/ 1 dose)

Question 6

Ibuprofen (MOA, kinetics, indications, SE)

Answer 6

MOA:
COX1 > COX2

Kinetics:
1-2 h DOA, accumulates in joints

Indications:
(normal NSAID indications + )
1. patent DA treatment

Side effects:
1. aseptic meningitis

Question 7

Naproxen (MOA, kinetics)

Answer 7

MOA:
inhibits neutrophil migration. (Naproxen inhibits neutros).

Kinetics:
14 hr DOA, 1x/day

• Proven to be NOT cardiotoxic

Question 8

Flurbiprofen (MOA, indications)

Answer 8

MOA:
inhibits TNFα as well (good for RA).

Indications:

1. as an ophthalmological pre-op anti-miotic (solution).
2. arthritis (incl. RA).
3. dental pain (oral).

Question 9

Tiaprofenic Acid (indications, SE)

Answer 9

Indications:
mainly arthritis

Side effects:

1. less cartilage / kidney damage than others
2. high risk of severe cystitis w/ long-term use

Question 10

Piroxicam (MOA -> cox activity)

Answer 10

MOA:

COX1 > COX2

Question 11

Meloxicam (MOA, SE)

Answer 11

MOA:
COX2 > COX1 → anti-inflammatory effect before ulcerogenic effect.

Side Effects:
1. higher risk of edema (stronger kidney effects).

Question 12

Mefenamic acid (indications, SE)

Answer 12

Indications:

1. menstrual pain
2. perimenstrual migraine prophylaxis

Side Effects:
can cause SJS

Question 13

Flufenamic and Meclofenamic acid (SE)

Answer 13

SE:

1. high rate of GI SE (diarrhea) -> less in use.

Question 14

Phenylbutazone (MOA, SE, indications)

Answer 14

(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:
1. Thrombophlebitis - as a local cream

Question 15

Phenazone and amino-/noraminophenazone

Answer 15

• 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.

Question 16

Nabumetone (MOA, kinetics, SE)

Answer 16

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

Question 17

Nimesulide (MOA, SE)

Answer 17

MOA:
COX2&raquo_space; COX1 and PLA2 inhibition (strong anti-inflammatory, no ulcers).

Side Effect:
Hepatotoxicity

Question 18

Selective NSAIDs - MOA

Answer 18

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)

Question 19

Selective NSAIDs (indications, CI)

Answer 19

Indications:

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

Contraindications:

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

Question 20

Paracetamol / Acetaminophen (properties)

Answer 20

• 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

Question 21

Paracetamol / Acetaminophen (indications, SE)

Answer 21

Indications:
Pain / fever (mild-moderate pain, as in osteoarthritis).

Side Effects:

1. 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.

Question 22

Gout - hyperuricemia (definition)

Answer 22

1. 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.
2. renal calculi and interstitial nephritis may also result from hyperuricemia.

Question 23

Gout (Physiology)

Answer 23

• uric acid is a byproduct of purine metabolism.
  1. in the liver, nucleic acids are broken down into nucleotide monomers and individual purine nucleosides.
  2. purine intermediate hypoxanthine is converted to xanthine by xanthine oxidase; xanthine oxidase further catalyzes conversion of xanthine to uric acid.

Question 24

Gout (Pathogenesis)

Answer 24

• can be due to overproduction or underexcretion (more common) of uric acid.

1. 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.
2. Other Diseases - metabolic syndrome, kidney failure, hemolytic anemia, obesity, enzyme deficiencies (such as the HGPRT deficiency in Lesch-Nyhan syndrome).
3. Medications - many drugs decrease urate excretion: ASA, ACE-Is, ARBs, BBs, ritonavir, pyrazinamide, thiazide diuretics, niacin, etc.
4. Tophi formation is cyclical: ↑ urate level in joints → precipitation of Na-Urate crystals → phagocytosis of crystals by synoviocytes → chemokines released + pH ↓ → neutrophils attracted to joint + further precipitation occurs.

Question 25

Gout- drugs for acute attacks

Answer 25

1. NSAIDs - Indomethacin
   (* high dose ASA ↑ urate excretion but is not used due to sfx).
2. Corticosteroids - Prednisolone
   (* oral 40 mg / can also be intra-articular or s.c.)
3. Tubulin inhibitor - Colchicine

• 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).

Question 26

Colchicine (MOA, SE)

Answer 26

(toxic plant alkaloid)

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

Side Effects:

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

Question 27

Gout - drugs for chronic prophylaxis

Answer 27

1. XO inhibitors:
   a. Allopurinol
   b. Febuxostat
2. Uricases:
   a. Rasburicase
   b. Pegloticase
3. Uricosurics:
   (urate excretion enhancers; 2nd line for underexcretion)
   a. Probenecid
   b. Sulfinpyrazone

Question 28

Allopurinol (MOA, kinetics, indications, SE, interactions)

Answer 28

MOA:
competitive xanthine oxidase inhibition via an active metabolite.

Kinetics:
oral absorption, 1x/day.

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.

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

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

Question 29

Febuxostat (MOA, SE)

Answer 29

MOA:
XO inhibitor

Side Effects:

1. Hepatic effects
2. nausea

Question 30

Rasburicase and Pegloticase (MOA, indications, SE)

Answer 30

MOA:
recombinant uric oxidase (uricase) → transforms urate to allantoin (more water-soluble).

Indication:
1. used if allopurinol causes HS rxn.

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.

Question 31

Probenecid and Sulfinpyrazone (MOA, SE)

Answer 31

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

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.