B-17. General properties of NSAIDs. Acetylsalicylic acid.

Question 1

Which part of inflammation does NSAIDS affect?

Answer 1

The vascular phase, not the cellular inflammatory functions

Question 2

Mechanism of eicosanoid synthesis

Answer 2

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

Question 3

COX1 is found in? Is it constitutive or inducible?

Answer 3

COX1 is found in the stomach, platelets, kidney, vessels.

It is somewhat inducible but mostly known as constitutively active.

Question 4

COX2 is found in? Is it constitutive or inducible?

Answer 4

COX2 is found in the kidney, uterus, stomach, vessels, CNS.

COX2 in the endothelium is constitutive but typically inducible in inflammation

Question 5

COX enzymes synthesize what? What is this made up of?

Answer 5

Prostanoids made up of…

1. ) Prostaglandins
2. ) Thromboxane
3. ) Prostacyclin

Question 6

Prostaglandins (PGE1 and 2) cause? Created by which COX enzyme?

Answer 6

↑ pain sensation, fever, inflammation, vascular permeability (mostly COX2)

Question 7

Prostacyclin (PGI2) cause? Created by which COX enzyme?

Answer 7

From endothelial COX2

Prostacyclins cause vasodilation, platelet aggregation inhibition

Question 8

Thromboxanes (TXA2) cause? Created by which COX enzyme?

Answer 8

COX1 from platelets

Thromboxanes cause vasoconstriction and platelet aggregation

Question 9

What do PGs in the stomach do?

Answer 9

Inhibit HCl secretion, stimulate mucus secretion and bicarbonate production (protects stomach mucosal lining)

Question 10

What is the effect of PGs on idney arterioles?

Answer 10

PGs from both COX1 + 2 in glomerular endothelium dilate afferent arterioles in kidney

Question 11

What is leukotriene pathway and what do they cause? What causes an increased leukotriene effect?

Answer 11

AA → LOX → leukotrienes → leading to bronchoconstriction, ↑ chemotaxis and vessel permeability (edema)
COX inhibition by NSAIDs shifts eicosanoid production to the LOX pathway → increased leukotriene effects

Question 12

Non-selective COX inhibitor + derivatives

Answer 12

Salicylic acid derivatives

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

Question 13

NSAID general effects/indications

Answer 13

1. ) Analgesia
2. ) Anti-Inflammatory
3. ) Antipyretic
   4) Uterine Relaxation
   5) Platelet Aggregation Inhibition

Question 14

NSAID Analgesic effect

Answer 14

Analgesia - mild/moderate effect; esp. for joint/muscle pain, headache, toothache, bone metastatic pain
● PGE1/2 have hyperalgesic effects; NSAIDs decrease sensitivity of nociceptors

Question 15

NSAID Anti-Inflammatory effect

Answer 15

Anti-Inflammatory - COX2 inhibition → decreased PGEs; esp. effective for joint inflammation, RA, osteoarthritis

Question 16

NSAID Antipyretic effect

Answer 16

Antipyretic - decreased fever via decreased PGE

● Mechanism: IL-1 → increased PGE2 in preoptic region of hypothalamus → increased cAMP → increased temp

Question 17

NSAID Uterine Relaxation and effect on fetus

Answer 17

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 since they can cause a premature closure of ductus arteriosus
● Child born with patent DA → use NSAIDs (esp. indomethacin) before surgery to try to close DA
● Good for menstrual cramps in non-pregnant women

Question 18

NSAID Platelet Aggregation Inhibition effect

Answer 18

Platelet Aggregation Inhibition - via decreased TXA2 and increased prostacyclin; only non-selectives

Question 19

NSAID general acute side effects

Answer 19

generally worse for non-selective NSAIDs

1. ) Marrow effects
2. ) Gastritis / erosion / ulceration
3. ) Bleeding
4. ) Renal Effects
5. ) Hyperkalemia
6. ) CNS Effects
7. ) Allergy
8. ) Bronchoconstriction
9. ) Thromboembolism

Question 20

NSAID marrow side effects? Which drugs at risk of this?

Answer 20

Marrow effects - aplastic anemia and agranulocytosis; most NSAIDs have low risk for this
● indomethacin, phenylbutazone + aminophenazone are high risk

Question 21

NSAIDs gastritis/erosion/ulceration side effects? How do we avoid these effects?

Answer 21

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)

Question 22

NSAIDs bleeding side effects? What happens to bleeding time tests?

Answer 22

Bleeding - via platelet aggregation inhibition; from mild GI bleeding to hemorrhagic stroke; prolong bleeding time tests

Question 23

NSAIDs renal side effects

Answer 23

Renal Effects - for both selective + non-selective
● acute kidney injury - PGs dilate afferent arteriole; decreased PGs → decreased RBF/GFR → risk of acute renal failure
(renal papillary necrosis - specific form of AKI; due to papillary ischemia)
● acute interstitial nephritis due to HS rxn - increased creatinine, eosinophilia, urine casts, rash/fever
● decreased drug clearance - ex: lithium reabsorption increased with renal impairment
● can cause increased blood pressure and decreased Na excretion in normo- and hypertensive patients

Question 24

NSAIDs Hyperkalemia side effects

Answer 24

Hyperkalemia - decreased renal PGs → impaired renin / aldo secretion (type 4 RTA)

Question 25

NSAID CNS side effects

Answer 25

CNS Effects - for both selective and non

● can cause HA, tinnitus, dizziness

Question 26

NSAID allergy side effects

Answer 26

Allergy - HS rxn, urticaria, rashes, exfoliative dermatitis (SJS)

Question 27

NSAID bronchoconstriction side effects

Answer 27

Bronchoconstriction - COX inhibition → LOX pathway increased → LTC4 causes bronchoconstriction

Question 28

NSAID thromboembolism side effects

Answer 28

Thromboembolism - only for COX2-selective drugs, due to TXA2 increased / prostacyclin decreased

Question 29

Chronic side effect of NSAID use

Answer 29

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

Question 30

Acetylsalicylic Acid (ASA) MOA

Answer 30

irreversible inhibition of COX 1 + 2 via covalent acetylation

Question 31

Acetylsalicylic Acid effect on prostanoids

Answer 31

○ Decreases synthesis of both TXA2 (platelet activator/aggregator) and prostacyclin (platelet inhibitor /vasodilator)
○ 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 where they bind platelets more readily as they pass, but lower concentrations in systemic circulation
- Affecting endothelial prostacyclin production less
- Low doses also affect TXA2 (via COX1) more than prostacyclin (COX1 and 2)

Question 32

Acetylsalicylic Acid dosing

Answer 32

○ Higher affinity for COX1 → smaller dose (75-100 mg/day) → mainly antithrombotic effect
○ 500-600 mg = fever/pain dose
○ > 4 g = COX2 anti-inflammatory dose (severe side fx, rarely used)

Question 33

Acetylsalicylic Acid Indications

Answer 33

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 34

Acetylsalicylic Acid Side effects

Answer 34

1.) ↑ uric acid reabsorption at low dose; ↑ excretion at high dose

2. ) Respiratory effects:
   - Hyperventilation via direct resp. center stimulation but 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 35

How can Acetylsalicylic acid toxicity be treated?

Answer 35

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)

Question 36

Contraindications for Acetylsalicylic acid

Answer 36

1. ) CKD or AKI-risk patients
2. ) G6PDh deficiency (can cause hemolytic anemia in high dose)
3. ) Hemophilia
4. ) Hyperuricemia
5. ) Use w/ caution in asthmatics and patients with Diabetes Mellitus, gastritis / ulcers