Lecture 5: NSAIDs Flashcards
NSAIDS in general
Mechanism: Inhibit cyclooxygenase
Uses: 1. Anti-inflammatory, 2. Analgesia, 3. Antipyretic
SE:
GI irritation (COX-1 produces prostaglandins PGE2 and PGI2, inhibiting acid secretion and promoting secretion of cytoprotective mucus in intestine)
Increased bleeding time (COX-1 in platelet produces thromboxane TXA2 which increases platelet aggregation)
Hypersensitivity (shunting to leukotrienes)
Decreased renal blood flow and GFR (COX-1 and COX-2[upreg in vol depleted] increase PGE2 and PGI2 which increase renal blood flow and increase Na+ and H2O excretion)
Pregnancy (COX->Pg-> Increase uterine contractions and maintain patent Ductus arteriosus),
Drug interactions (alcohol/GI irritation and bleeding, NSAIDs/Increased risk of bleeding, decreased renal function, Steroids/Increased risk of GI toxicity, Anticoagulants/warfarin, increased bleeding, Methotrexate/Impaired renal excretion, aspirin and salicylates/salicylate poisoning)
Acetylsalicylic Acid/Aspirin
Mechanism: Irreversible inhibitor of cyclooxygenase 1 and 2.
Uses: Cancer? CV disease (low dose) Fever, pain, (intermediate dose) Chronic inflammatory disease/rheumatoid arthritis (high dose)
SE: Typical NSAIDs side effects + Salicylism + Reye’s Syndrome
Pharmacology:
Non COX inhibition effects (1. Uric acid excretion 2. CNS 3. Respiration)
- At low dose decrease uric acid secretion. at high dose increase uric acid excretion.
- CNS (b/c crosses BBB) delirium psychoses, nausea, vomiting.
- Respiration (Direct stim of respiratory center to increase RR, leading to respiratory alkalosis, compensated by a renal excretion of bicarbonate.
- Salicylism
- Reye’s syndrome (liver failure and death related to viral epidemics
Ibuprofen and Naproxen
Mechanism: Reversible inhibitor of COX 1 and COX 2. Naproxen has a much longer plasma half life (14 hr vs. 2) than ibuprofen
Uses:
Both: Rheumatoid disorders (including juvenile rheumatoid arthritis), osteoarthritis, mild-to-moderate pain, dysmenorrhea, fever,
Ibuprofen: Inflammatory diseases, IV preparation to induce closure of PDA in premature infants less than 32 wk gestational age when usual treatments ineffective.
Naproxen: manage ankylosing spondylitis, acute gout/bursitis/tendonitis,
SE: Less GI effects than Aspirin
Indomethacin
Mechanism: Reversible inhibitor of COX 1 and COX 2
Uses:
gout
preterm labor (investigational)
IV form used for closure of patent ductus arteriosus in neonates
Ankylosing spondylitis
not routinely used to treat pain or fever.
SE: Frequent adverse rxns, CNS severe frontal headache, better tolerated if given at night
Ketorolac
Mechanism: Reversible inhibitor of COX 1 and COX 2
Uses:
Alternative for opioid analgesics in treatment of post-operative pain (short term, and much more effective for pain than inflammation)
SE: Serious adverse effects
Nabumetone
Mechanism: Active metabolite (6methoxy2naphthylacetic acid) is reversible inhibitor of COX2 moreso than COX-1.
Uses:
Osteoarthritis
Rheumatoid arthritis
SE: Well tolerated with less GI effects
Piroxicam
Mechanism: Reversible inhibitor of COX 1 and COX 2. SUPER LONG HALF LIFE plasma T1/2 50 hours
Uses:
Symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis, advantage in osteoarthritis treatment because of LONG HALF LIFE.
SE: GI toxicity
Sulfasalazine
Mechanism: 5-aminosalicylic acid (mesalamine) active component linked to sulfapyridine (a sulfa antibiotic) by azo bond (which prevents absorption in upper GI tract). NOT CYCLOOXYGENASE INHIBITION. Possibly inhibition of IL-1, TNFalpha, lipoxygenase pathway, scavenging of free radicals oxidants, inhibition of NF-kappaB.
Uses:
Mild or moderately active ulcerative colitis (b/c of mesalamine)
Rheumatoid arthritis and ankylosing spondylitis (b/c of sulfapyridine)
SE:
High % for b/c sulfa moiety
Allergic rxns (rash, fever, hepatitis, pneumonitis, hemolytic anemia, bone marrow suppression)
Decreases number and motility of sperm
Therapeutic application: mild or moderately active ulcerative colitis, rheumatoid arthritis, and ankylosing spondylitis
Celecoxib
Mechanism: COX-2 selective inhibition. Metabolized by CYP450 2C9
Uses: Rheumatoid arthritis and osteoarthritis Primary dysmenorrheal Management of acute pain reduce # of intestinal polyps in familial adenomatous polyposis (COX2 contributory to certain cancers)
SE:
Hypersensitivity
Increase risk in GI irritation, ulceration, bleeding
Increased risk of adverse CV thrombotic events
Anemia (rare)
Contraindications: Sulfonamide toxicity Prior NSAID hypersensitivity CV risk factors/disease GI disease Coronary artery bypass graft surgery CYP2C9 deficiency
Acetaminophen
Mechanism: No aff for COX1 or COX2 active site. inhibits reduction of COX to peroxidase form, brain selective? COX3?
Metabolized partially by liver microsomal system (CYP2E1, CYP1A2, CYP3A4), but mostly by glucoronidation and sulfation (95%)
Uses:
Treatment of mild-to-moderate pain and fever; does not have antirheumatic or anti-inflammatory effects
SE:
Well tolerated with little to no GI issues at normal doses. But with excessive use results in hepatic toxicity… evidenced by elevated liver enzymes like aminotransferase.
NAPQI (N-acetyl-p-benzoquinoneimine toxicity if glutathione reduced), covalently binds amino acids in proteins and enzymes.
N-acetylcysteine used to replenish glutathione stores to manage toxicity.
Contraindication:
Ethanol use, as alcohol induces CYP450 (producing NAPQI) and depletes glutathione.
Describe the metabolism of and mechanism of toxicity of acetaminophen
NAPQI toxicity when glutathione depleted leading to tissue adducts and hepatotoxicity.
Acetaminophen–>1. Unmodified to urine/2. Sulfate or glucuronide to urine/3. CYP450 to NAPQI to either adq glutathione and urine OR depleted glutathione and toxicity
Describe the metabolism and mechanism of toxicity of Acetylsalicylic Acid/Aspirin
Long half life of salicylic acid.
Acetylsalicylic acid–>hydrolysis to salicylic acid–>1. Oxidation/2. Glucuronidation/3. Glycination
