NSAIDS Flashcards
DRUG LIST
Aspirin and friends
– Aspirin
– Salicylate
NSAID’s – Ibuprofen – Naproxen – Acetaminophen – Celecoxib
GI protective Drugs
– Omeprazole
– Misoprostol
NSAID Excretion
RENAL
NSAID pharmacokinetics
Competitive inhibitors of COX enzymes via reversible active site inhibition (note: aspirin is IRREVERSIBLE)
Major biological effect is related to inhibition of prostaglandin synthesis
NSAID’s‐ Therapeutic Effects
At lower doses:
• Analgesia (can be additive with opioids)
• Antipyretic
At HIGHER doses
• Anti‐inflammatory
– Musculoskeletal disorders: Arthritis
– Symptomatic relief
Arachidonic Acid Pathway
Stimulus (chemical/physical stress) >> Phospholipase A2 >> Phospholipids >> Arachidonic acid >> EICOSANOIDS
Eicosanoids
Oxygenated polyunsaturated fatty acids
Act in paracrine/autocrine manner
Bind to specific receptors on cell membranes – Arachidonic acid (precursor) • Prostaglandins • Thromboxanes • Leukotrienes (Dr. Ceryak)
Prostanoid pathway
Cyclooxygenase (COX) >> prostaglandins prostacyclin thromboxane (all prostanoids)
Prostanoids: Prostacyclin
PGI2: (Prostacyclin)
• Synthesized by vascular endothelium
• Vasodilation
• Inhibits platelet aggregation (counteracts TXA2)
Prostanoids: Thromboxane
TXA2: (Thromboxane)
• Platelet aggregation (made from platelet COX‐1)
• Vasoconstriction/Bronchoconstriction
Prostanoids: PGE1
PGE1:
• Misoprostol: PGE1 analog, prevents peptic ulcer by preventing acid secretion, termination of early pregnancy (in combo with mifepristone)
Prostanoids: PGE2
PGE2:
• Increases body temperature (produced by COX‐2 after interleukin‐ 1 stimulation)
• Inflammation (via blood flow, vasodilation/leukocyte infiltration, edema)
– Suppresses humoral antibody response
• Protective against peptic ulcers
Eicosanoid Receptors
Increase cAMP or cytosolic Ca++
Cyclooxygenase (COX)
Two isoforms:
• COX‐1 (PGH synthase‐1)
– Constitutive expression in most tissues (ALWAYS)
• Inhibition leads to GI‐related side effects
• COX‐2 (PGH synthase‐2)
– Expression is induced by ‘stress’, growth factors, cytokines and inflammatory mediators .
• Major source of prostanoids at sites of inflammation (cancer)
NSAIDS and COX inhibition
All NSAIDS are nonselective, EXCEPT celecoxib (note: blackbox warning for CV risk)
NSAID use
Analgesic
• Particularly effective when pain is due to an inflammatory process
NSAID use
Antipyretic‐ lowers fever
**PGE2 is elevated by cytokine release in and adjacent to the pre optic hypothalamus triggering an elevation of body temp and decrease in heat lost (NSAIDs inhibit prostaglandin synthesis)
NSAID use
Anti‐inflammatory
• Generally need larger doses
• ONLY SYMPTOMATIC RELIEF
NSAIDS and Cancer
Increasingly apparent relationship between chronic inflammation and cancer
Common Adverse Effects for NSAID’s: GI
Pain, nausea, diarrhea, gastric ulcers/erosions, GI hemorrhage, perforation (other NSAIDs less than aspirin)
Common Adverse Effects for NSAID’s: Renal
- Renal insufficiency, renal failure, hyperkalemia, proteinuria
- decrease effectiveness of antihypertensive meds
- Analgesic nephropathy: slowly progressive renal failure, decreased concentrating capacity; associated with high doses of combinations of NSAID’s and frequent urinary tract infections – Decreased PGE2 = less renal blood flow?
Recall PGE2 is involved in blood flow.
NSAID and pregnancy
CONTRAINDICATED (only tylenol ok)
Common Adverse Effects for NSAID’s: Hypersensitivity
Hypersensitivity reactions – not IgE‐meditaed
• Aspirin intolerance/allergy is contraindication for therapy with any other NSAID
RED FLAG for aspirin = nasal polyps
Common Drug Interactions Associated with NSAID’s
1) Use of NSAID’s concomitantly with low dose aspirin (cardioprotective)
• Ibuprofen impairs aspirin’s ability to acetylate the active site of COX and therefore entire anti platelet effect goes away
2) With ACE inhibitors
• ACE inhibitors + NSAID’s = hyperkalemia, (elderly, HTN, DM, ischemic heart disease)
• May decrease EFFICACY of ACE inhibitors (due to inhibition of vasodilatory PGs?), renal toxicity (NSAIDs decrease renal EXCRETION of ACE inhibitors)
DI: Warfarin
NSAIDs and aspirin all inhibit platelet function: increased bleeding
Metabolized by CYP2C9 (inhibits metabolism of warfarin)
Aspirin MOA
Analgesic Antipyretic (lo dose) Anti‐inflammatory‐ non‐selective irreversible inhibitor of both COX‐1 and COX‐2 – At higher doses than the analgesic/antipyretic dose
Aspirin Metabolism
Acetylates Cox 1 and 2
Liver breaks down to acetic acid and salicylate (salicylate = competitive and reversible inhibitor of COX)
Aspirin: cardiovascular use
Cardiovascular‐Cardioprotective (low doses)
(decreases platelet aggregation)
- Platelet effects last 4‐7 days due to permanent inactivation of platelet COX’s; thromboxane (TXA2) synthesis prevented
- Increased bleeding times
• Decreased MI
– 20‐25% aspirin (low dose)
– 10% naproxen
– Evidence does not support low‐dose aspirin in healthy individuals without CV risk factors (only in people with MI)
Aspirin Adverse effects
Gastrointestinal Effects
• Prevents synthesis of protective PGE1/2 for GI epithelial cells in stomach lining (increase acid secretion)
• Co‐adm with PPI
Hypersensitivity (0.5‐2.5%) • Often nasal polyps • Reaction is not immunologically mediated • PROVOKED BY LOW DOSES • Probably due to diversion of AA to the leukotriene pathways (Cox‐1) • Mast cell and eosinophil involvement CROSS SENSITIVITY with all NSAIDS
Aspirin Adverse effects 2
Acid‐base balance
– at therapeutic dose: respiratory alkalosis (stimulation of respiratory center/medulla), increase CO2 production
– at toxic doses: get a respiratory and metabolic acidosis due to accumulation of (lactic) acid products
Aspirin Adverse effects 3
Renal Effects
• Analgesic nephropathy – Slowly progressive renal failure, decreased renal perfusion
Ototoxicity
• Tinnitus, high frequency hearing loss
Ibuprofen facts
- recently approve for IV
- short 1/2 life (2 hrs)
Naproxen
- LONG 1/2 life (14 hrs)
Celecoxib (Celebrex)
Preferentially inhibits COX2, therefore less GI side effects!!
Risk of thrombosis, hypertension, atherogenesis —avoid in patients prone to cardiovascular or cerebrovascular disease.
Celecoxib (Celebrex): CV risk
Inhibits PG12 which is a prostacylcin, therefore inhibits macrophage activation that releases Cox 2 (decrease platelet aggregation) and increased leukotrienes
GI Protective Agents for Use with NSAIDs
Misoprostol • PGE1 analog • Inhibits gastric acid, prevents ulcers • Induces labor/Uterine contractions • Abortifacient
Omeprazole
• Better tolerated than misoprostol
• Proton pump inhibitor
• Prodrug/enteric coating
Acetaminophen Administration
PO, IV
Analgesic and antipyretic activity
– NO STRONG ANTI‐INFLAMMATORY ACTIVITY
Acetaminophen Metabolism
Reversible inhibitor of Cox 1/2
Gets metabolized by glucuronidation and sulfation. If you saturate the enzyme, it goes down a third pathway. Forms a reactive toxic intermediate that binds to proteins in the liver. (the enzyme CYP2E1 involved can be increased by ethanol)
Acetaminophen‐ Hepatotoxicity
- Single doses of 10‐15 g‐serious hepatotoxicity; 20‐25g are potentially fatal
- Induction of CYP2E1 increases risk of toxicity
- Symptoms‐ nausea, abdominal pain and anorexia
- Plasma transaminases elevated 12‐36 h after ingestion
- Clinical indication of hepatic damage 2‐4 d; liver enzymes peak 72‐96 h after drug
Acetaminophen‐ Hepatotoxicity Tx
- Activated charcoal to reduce absorption
* N‐acetylcysteine (Mucomyst), detoxifies NAPQI
