B-17. General properties of NSAIDs. Acetylsalicylic acid. Flashcards
Which part of inflammation does NSAIDS affect?
The vascular phase, not the cellular inflammatory functions
Mechanism of eicosanoid synthesis
Chemical/physical stim → ↑ IC Ca++ → PLA2 translocation to membrane → AA release → COX
COX1 is found in? Is it constitutive or inducible?
COX1 is found in the stomach, platelets, kidney, vessels.
It is somewhat inducible but mostly known as constitutively active.
COX2 is found in? Is it constitutive or inducible?
COX2 is found in the kidney, uterus, stomach, vessels, CNS.
COX2 in the endothelium is constitutive but typically inducible in inflammation
COX enzymes synthesize what? What is this made up of?
Prostanoids made up of…
- ) Prostaglandins
- ) Thromboxane
- ) Prostacyclin
Prostaglandins (PGE1 and 2) cause? Created by which COX enzyme?
↑ pain sensation, fever, inflammation, vascular permeability (mostly COX2)
Prostacyclin (PGI2) cause? Created by which COX enzyme?
From endothelial COX2
Prostacyclins cause vasodilation, platelet aggregation inhibition
Thromboxanes (TXA2) cause? Created by which COX enzyme?
COX1 from platelets
Thromboxanes cause vasoconstriction and platelet aggregation
What do PGs in the stomach do?
Inhibit HCl secretion, stimulate mucus secretion and bicarbonate production (protects stomach mucosal lining)
What is the effect of PGs on idney arterioles?
PGs from both COX1 + 2 in glomerular endothelium dilate afferent arterioles in kidney
What is leukotriene pathway and what do they cause? What causes an increased leukotriene effect?
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
Non-selective COX inhibitor + derivatives
Salicylic acid derivatives
- ) Acetylsalicylic acid / Aspirin
- ) Sodium Salicylate - potential ASA replacement for ASA-sensitive patients
- ) ASA-CaCO3 - “buffered” with Ca carbonate to reduce gastric bleeding
NSAID general effects/indications
- ) Analgesia
- ) Anti-Inflammatory
- ) Antipyretic
4) Uterine Relaxation
5) Platelet Aggregation Inhibition
NSAID Analgesic effect
Analgesia - mild/moderate effect; esp. for joint/muscle pain, headache, toothache, bone metastatic pain
● PGE1/2 have hyperalgesic effects; NSAIDs decrease sensitivity of nociceptors
NSAID Anti-Inflammatory effect
Anti-Inflammatory - COX2 inhibition → decreased PGEs; esp. effective for joint inflammation, RA, osteoarthritis
NSAID Antipyretic effect
Antipyretic - decreased fever via decreased PGE
● Mechanism: IL-1 → increased PGE2 in preoptic region of hypothalamus → increased cAMP → increased temp
NSAID Uterine Relaxation and effect on fetus
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
NSAID Platelet Aggregation Inhibition effect
Platelet Aggregation Inhibition - via decreased TXA2 and increased prostacyclin; only non-selectives
NSAID general acute side effects
generally worse for non-selective NSAIDs
- ) Marrow effects
- ) Gastritis / erosion / ulceration
- ) Bleeding
- ) Renal Effects
- ) Hyperkalemia
- ) CNS Effects
- ) Allergy
- ) Bronchoconstriction
- ) Thromboembolism
NSAID marrow side effects? Which drugs at risk of this?
Marrow effects - aplastic anemia and agranulocytosis; most NSAIDs have low risk for this
● indomethacin, phenylbutazone + aminophenazone are high risk
NSAIDs gastritis/erosion/ulceration side effects? How do we avoid these effects?
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)
NSAIDs bleeding side effects? What happens to bleeding time tests?
Bleeding - via platelet aggregation inhibition; from mild GI bleeding to hemorrhagic stroke; prolong bleeding time tests
NSAIDs renal side effects
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
NSAIDs Hyperkalemia side effects
Hyperkalemia - decreased renal PGs → impaired renin / aldo secretion (type 4 RTA)
NSAID CNS side effects
CNS Effects - for both selective and non
● can cause HA, tinnitus, dizziness
NSAID allergy side effects
Allergy - HS rxn, urticaria, rashes, exfoliative dermatitis (SJS)
NSAID bronchoconstriction side effects
Bronchoconstriction - COX inhibition → LOX pathway increased → LTC4 causes bronchoconstriction
NSAID thromboembolism side effects
Thromboembolism - only for COX2-selective drugs, due to TXA2 increased / prostacyclin decreased
Chronic side effect of NSAID use
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)
Acetylsalicylic Acid (ASA) MOA
irreversible inhibition of COX 1 + 2 via covalent acetylation
Acetylsalicylic Acid effect on prostanoids
○ 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)
Acetylsalicylic Acid dosing
○ 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)
Acetylsalicylic Acid Indications
- ) 1° + 2° thromboembolic prophylaxis
- as in post-MI, unstable angina, angioplasty, cerebrovascular issues; large loading dose followed by 75-100 mg/day - ) Kawasaki disease
- #1 childhood vasculitis; fever, oral erythema, rash, conjunctivitis, cervical LAP; high dose ASA used acutely → low dose later - ) Pain, fever, inflammation
Acetylsalicylic Acid Side effects
1.) ↑ uric acid reabsorption at low dose; ↑ excretion at high dose
- ) 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
- ) Euphoria / seizure / tinnitus - at high dose / in toxicity
- ) Anion Gap Metabolic Acidosis - after initial respiratory alkalosis via respiratory stimulation
How can Acetylsalicylic acid toxicity be treated?
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)
Contraindications for Acetylsalicylic acid
- ) CKD or AKI-risk patients
- ) G6PDh deficiency (can cause hemolytic anemia in high dose)
- ) Hemophilia
- ) Hyperuricemia
- ) Use w/ caution in asthmatics and patients with Diabetes Mellitus, gastritis / ulcers
