NSAIDS Flashcards
Metabolism of Aspirin
Aspirin is deacetylated to salicylic acid then phase 2 metabolism leads to renal elimination
Aspirin has short half life but salicylic acid has much longer half life
Uses of aspirin
Uricosuric effect- Uric acid is filtered in kidney and then reabsorbed by URAT transporter and if block this transporter at high doses (increase Uric acid excretion) and at low doses then block secretory mechanisms (increased Uric acid in plasma)
CNS effects: especially at high doses and toxicity get stimulation followed by depression, tinnitus, high tone deafness, confusion, dizziness, delirium, psychosis, coma, nausea, vomiting
General: anti-inflammatory, analgesic, anti-pyretic
Use in cancer and CV disease
Toxicity or Adverse Effects of Aspirin/NSAIDs
NSAID and GI: block production of cytoprotective PGs so cause ulceration and irritiation and blood loss with chronic use three times more risk
Platelet: increase bleeding time by inhibiting the TXA2 which is part of clotting mechanism
Dose effect- single dose inhibits bleeding time for one week because platelets lack nucleus so new COX with new platelets after a week
Hypersensitivity:: intolerance and characterized by respiratory related and happens with all NSAIDs but less likely with no acetylated salicylates and treated with anaphylactic shock
Kidney: decrease renal blood flow and promote salt and water retention but only important with people dependent on vasodilatory effects so not important in normal people
Uterus: prolongation of gestation, labor, and increased risk of postpartum hemorrhage and intrauterine closure of PDA and avoid during third trimester
Aspirin Overdose
Reyes Syndrome common in children after viral disease (liver degeneration
Half life of salicylic acid increase to 15-30 hours because all enzymes saturated
Dose dependent effects in aspirin
Low dose- CV disease
Intermediate dose- low intensity pain/ fever
High dose- chronic inflammatory disease/ arthritis
Side effects of non selective NSAIDs
GI irritation
Inhibition of platelet aggregation/risk of bleeding
Decrease in RBF in patients dependent on vasodilation of PG
Hypersensitivity
Propionic derivatives
Ibuprofen
Naproxen (longer half life so dose once/day)
Less GI effects
Reversible inhibition of COX 1 and COX 2
Uses: inflammatory disease, mild to moderate pain, fever
Dysmenorrhea, osteoarthritis, IV to close patent ductus arteriosus (Ibuprofen), acute gout, tendinitis, fever
Indole derivatives
Indomethacin
Reverse inhibition of COX1 and COX2
Oral and IV, 90% bound to plasma proteins
Therapeutic use: gout, preterm labor, close patent ductus arteriosus, not routinely used for fever and pain
Anti-inflammatory, analgesic, Anti-pyretic
Adverse effects: GI toxicity, CNS effect of severe frontal headache
Pyrole derivative
Ketorolac
Reverse inhibitor of COX 1 and 2
Oral and IV and IM administration( rapid onset and short duration)
Adverse effects- adverse GI, bleeding, renal and hypersensitivity
Use for post operative pain as alternative of opioid analgesics (short term) and much more effective for pain than inflammation
Oxicam derivative
Piroxicam and Nabumetone
Sulfasalazine
In ulcerative colitis and rheumatoid arthritis
MOA: independent of COX and inhibit cytokine production and lipoxygenase inhibition and free radical scavenger
Local effects in GI to inhibit inflammation
When exposed to bacteria in colon then cleaved to salicylic acid and sulfa antibiotic
Adverse effects: headache, nausea, fatigue, allergic reaction, male sperm motility and inhibit intestinal folate absorption
Celecoxib
Contains a sulfonamide side chain and important for allergic reaction (to sulfa drugs)
MOA: bind tightly to a distinct hydrophilic side pocket of COX2 (close proximity of active site) and specific to COX 2 because not present in COX 1
Oral administration and highly bound to plasma proteins and metabolized by CYP2c9 to inactive metabolites
Adverse effects: hypersensitivity, GI irritation, CV thrombotic effects, anemia (rare)
Contraindication: patients with sulfonamide toxicity, prior NSAID hypersensitivity, deficiency CYP, pre exisiting CV risk factors, GI bleeding history, following coronary artery bypass graft surgery
Use: rheumatoid arthritis and osteoarthritis, primary dysmenorrhea, acute pain, colorectal polyps (COX 2 contribute to some cancers)
Pharmacological effects: anti-pyretic, analgesic, anti-inflammatory
Acetaminophen
MOA: no affinity for active site of COX but increased selectivity for brain COX. Also may prevent reduction of COX to peroxidase form (no PG production)
Oral administration with minimal plasma protein binding
Half life= 2 hours
Metabolism- partially by liver microsomes system (CYP 2E1, CYP1A2, CYP 3A4) and contribute to toxicity
Main metabolism through glucuronidation and sulfation (95%)
Usually really excreted
Analgesic and anti-pyretic BUT not anti-inflammatory
Adverse effects: well tolerated at normal doses, little to no GI issues, most serious is hepatic toxicity
Hepatic toxicity: initial and mild and nonspecific but after 24-36 hours then evidence of liver injury (elevated liver enzymes) and in severe cases liver failure, hepatic encephalopathy
Manage toxicity: N-acetyl cysteine replenish glutathione stores
Therapeutic use: Acute pain and fever, no anti-inflammatory effects
Nabumetone
MOA: active metabolite reverse inhibitor of COX 2> COX 1 inhibition
Converted to metabolite
Long half life
Anti-inflammatory and analgesic
Therapeutic: osteoarthritis and rheumatoid arthritis
Piroxicam
MOA: reversible inhibition of COX 1 and 2
Plasma half life is 50 hours with 99% bound plasma proteins
Anti-inflammatory, anti-pyre tic, analgesic
Adverse effect: GI toxicity
Therapeutics: symptoms of acute and chronic rheumatoid arthritis and osteoarthritis
