B-18. General properties of NSAIDs. Acetylsalicylic acid

Question 1

Eicosanoid synthesis

Answer 1

Chem/physical stim → ↑ IC Ca++ → PLA2 translocation to membrane → AA release → COX.

Question 2

COX1 (locations)

Answer 2

1. stomach
2. platelets
3. kidney
4. vessels constitutively
   * somewhat inducible

Question 3

COX2 (locations)

Answer 3

1. kidney
2. uterus
3. stomach
4. vessels
5. CNS constitutively;
   * * inducible elsewhere in inflammation

Question 4

what are prostanoids? (list, synthesis and functions)

Answer 4

synthesized by COX enzymes.

1. PGE1 + 2 - ↑ pain sensation, fever, inflammation, vasc. permeability (mostly COX2).
2. PGI2 (prostacyclin) - from endothelial COX2, vasodilation, platelet agg. inhibition.
3. TXA2 - COX1 from platelets, vasoconstriction + platelet agg.
4. PGs in stomach inhibit HCl secretion + stimulate mucus secretion.
5. PGs from both COX1 + 2 in glomerular endothelium dilate afferent arterioles in kidney.

Question 5

leukotrienes (production and functions)

Answer 5

production: AA → LOX → leukotrienes.
functions: bronchoconstriction, ↑ chemotaxis + vessel permeability (edema).

Question 6

COX inhibition by NSAIDs shifts eicosanoid production to?

Answer 6

LOX pathway → ↑ leukotriene effects.

Question 7

Non-Selective NSAIDs

Answer 7

Salicylic acid derivatives:

1. ASA - acetylsalicylic acid / Aspirin.
2. Sodium Salicylate - potential ASA replacement for ASA-sensitive pts.
3. ASA-CaCO3 - “buffered” with Ca carbonate to reduce gastric bleeding.

Question 8

Effects of NSAIDs

Answer 8

1. Analgesia - mild/moderate effect; esp. for joint/muscle pain, HA, toothache, bone metastatic pain
   PGE1/2 have hyperalgesic effects; NSAIDs ↓ sensitivity of nociceptors
2. Anti-Inflammatory - COX2 inhibition → ↓ PGEs; esp. effective for joint inflammation, RA, osteoarthritis
3. Antipyretic - ↓ fever via ↓ PGE
   Mechanism: IL-1 → ↑ PGE2 in preoptic region of hypothalamus → ↑ cAMP → ↑ temp
4. Uterine Relaxation - via ↓ PGs; would be good for premature labor, but PGs keep ductus arteriosus open, so NSAIDs (esp. indomethacin + ibuprofen) are CI in pregnancy
   * Child born with patent DA → use NSAIDs (esp. indomethacin) before surgery to try to close DA
   * Good for menstrual cramps in non-pregnant women
5. Platelet Aggregation Inhibition - via ↓ TXA2 and ↑ prostacyclin; (only non-selectives).

Question 9

SE of NSAIDs

Answer 9

1. Marrow effects - aplastic anemia and agranulocytosis; most NSAIDs have low risk for this
   * indomethacin, phenylbutazone + aminophenazone are high risk.
2. Gastritis / erosion / ulceration - non-selectives only
   * NSAIDs are weak acids (exc. nabumetone) - non-ionized and absorbed well from stomach due to acidity of lumen; once they enter mucosal cells, ↑ cytoplasmic pH → ionize and are “trapped”.
   * Decrease PGs - ↓ gastroprotective effects.
   * Avoid these effects with co-admin of pantoprazole (PPI) or famotidine (weaker, H2 atg) or synthetic PG analog misoprostol (4x/day, diarrhea sfx).
3. Bleeding - via plt aggregation inhibition; from mild GI bleeding to hemorrhagic stroke; prolong bleeding time tests.
4. Renal Effects - for both selective + non-selective
   * acute kidney injury - PGs dilate afferent arteriole; ↓ PGs → ↓ RBF/GFR → risk of ARF
   (renal papillary necrosis - specific form of AKI; due to papillary ischemia).
   * acute interstitial nephritis due to HS rxn - ↑ creatinine, eosinophilia, urine casts, rash/fever.
   * decreased drug clearance - ex: lithium reabsorption ↑ with renal impairment.
   * can cause ↑ BP and ↓ Na excretion in normo- and hypertensive pts.
5. Hyperkalemia - ↓ renal PGs → impaired renin / aldo secretion (type 4 RTA).
6. CNS Effects - for both selective and non
   * can cause HA, tinnitus, dizziness
7. Allergy - HS rxn, urticaria, rashes, exfoliative dermatitis (SJS)
8. Bronchoconstriction - COX inhibition → LOX pathway ↑ → LTC4 causes bronchoconstriction
9. Thromboembolism - only for COX2-selective drugs, due to TXA2 ↑ / prostacyclin ↓

With chronic use:

1. May damage cartilage (research: via ↓ glycosaminoglycan synth; reversible with misoprostol).
2. Cardiotoxicity - especially diclofenac; may be free radical related; ↑ risk of HF / MI.
   (naproxen is proven totally non-cardiotoxic).

Question 10

Acetylsalicylic Acid (ASA) - MOA

Answer 10

irreversible inhibition of COX 1 + 2 via covalent acetylation.

1. ↓ synthesis of both TXA2 (plt activator/aggregator) and prostacyclin (plt ihibitor / vasodilator).
2. TXA2 is formed in platelets, which are anuclear and don’t synth new COX once it is inhibited → inhibition lasts lifetime (~ 8 days) of platelet; prostacyclin is formed by endothelium, which synthesizes new COX → ↑ prostacyclin/TXA2 ratio.
   * lower doses provide high concentrations in portal circulation, but lower concentrations in systemic circulation, affecting endothelial prostacyclin production less; low doses also affect TXA2 (via COX1) more than prostacyclin (COX1 and 2).
3. higher affinity for COX1 → smaller dose (75-100 mg/day) → mainly antithrombotic effect.
4. 500-600 mg = fever/pain dose; > 4 g = COX2 anti-inflammatory dose (severe side fx, rarely used).

Question 11

Acetylsalicylic Acid (ASA) - Indications

Answer 11

1. 1° + 2° thromboembolic prophylaxis - as in post-MI, unstable angina, angioplasty, cerebrovascular issues; large loading dose followed by 75-100 mg/day.
2. Kawasaki disease - #1 childhood vasculitis; fever, oral erythema, rash, conjunctivitis, cervical LAP; high dose ASA used acutely → low dose later.
3. Pain, fever, inflammation.

Question 12

Acetylsalicylic Acid (ASA) - SE

Answer 12

toxicity can be treated with activated charcoal within 2 hrs of ingestion and alkalization of serum / urine with sodium bicarbonate (alkalinization draws weak acids like ASA out of tissues).

1. ↑ uric acid reabsorption at low dose; ↑ excretion at high dose.
2. Respiratory effects:
   * Hyperventilation via direct resp. center stimulation
   (at high dose - inhibits resp/CV centers - lethal
   dose 10-30 g).
   * Increases oxygen use via uncoupling of oxidative phosphorylation.
   * Bronchoconstriction - higher risk than other non-selectives.
3. Reye’s Syndrome - rapid encephalopathy + hepatic dysfunction; mostly in kids, especially when given during flu / varicella infection; see steatosis + hepatomegaly w/ seizure, vomiting, coma.
4. Euphoria / seizure / tinnitus - at high dose / in toxicity.
5. Anion Gap Metabolic Acidosis - after initial respiratory alkalosis via respiratory stimulation.

Question 13

Acetylsalicylic Acid (ASA) - Contraindications

Answer 13

1. CKD or AKI in risk patients.
2. G6PDh deficiency (can cause hemolytic anemia in high dose).
3. hemophilia.
4. hyperuricemia.

(use w/ caution in asthmatics + pts w/ DM, gastritis / ulcers).