NSAIDs Flashcards
What are eicosanoids?
Eicosanoids are potent and bioactive lipid signals that are generated from the essential Polyunsaturated Fatty Acid (PUFA) arachidonic acid. Every cell in your body can generate these lipid signals.
NSAIDs - Mechanism of Action
- inhibit cyclooxygenase (synthesis PGs & TXA)
- two cyclooxygenase enzymes (COX-1, COX-2)
- COX-1 and COX-2 selectivity of NSAIDS - free radial scavengers (e.g. salicylate anti- oxidant), indirect effect inhibition of general eicosanoid formation
- Aspirin covalent modification of enzyme
– irreversible inhibition
steroids inhibit…
phospholipases
cox1 and cox2 inhibitors, aspirin, indomethacin inhibit
cyclooxygenase
prostacylin PGI2 causes
vasodilation, inhibits platelet aggregation
thromboxane A2, TXA2 causes
vasoconstriction, promotes platelet aggregation
Leukotriene causes
vasoconstriction, bronchospasm increased permeability
Lipoxin causes
vasodilation, inhibit neutrophil chemotaxis, stimulate monocyte adhesion
PGE causes
vasodilation, potentiate edema
NSAID general actions
anti-inflammatory, analgesic, antipyretic, platelet function
-analgesic: PG related, direct action on nerves pain amplification dorsal horn, inflammatory pain, analgesia superior to opioids for inflammation associated pain
cox1 vs cox2 structures
-both have different sized substrate channels
-cox2 has solvent accessible pocket which led to design of cox2 selective inhibitors
Common Systemic OTC NSAID drugs
aspirin, ibuprofen, naproxen
-tylenol not NSAID but analgesic, its MOA is not inhibition of cox and has no anti-inflammatory actions
NSAID Ophthalmic Use and drugs
initial use maintain pupil dilation post surgery
-flubiprofen: inoperative miosis, OL- postop inflammation, uveitis
-Ketorolac: pain, allergies, inflammation post-op OL: cystoid macular edema
-Suprofen (1%): intraoperative miosis OL: contact lens GPS
-Diclofenac (0.1%): intraoperative miosis, inflammation post-op, pain; OL: allergies
Nepafenac (0.1%): post-op pain & inflammation
Bromfenac (0.09%): post-op pain & inflammation
Applications of Ophthalmic Formulations
- prevent intraoperative miosis (often coadministered with mydriatic)
* effect small when used alone
* effect slightly greater in light irides - prevent/treat cystoid macular edema
- control post-operative inflammation &/or pain
- prevent breakdown & re-establishing BAB (some equi-effective to corticosteroids)
- allergies, ocular itching (seasonal, GPC)
Systemic NSAID’s
* adjunct to ophthalmic therapy
* more generalized effect (no benefit to ocular pain)
NSAIDs - Side Effects of Ophthalmic NSAIDs
- rebound inflammation not seen
- transient ocular irritation (stinging, burning, conjunctival hyperemia)
* 15%, diclofenac to 40%, ketorolac - delayed wound healing, corneal melts (diclofenac, ketorolac, bromfenac, flurbiprofen?)
- allergies
- soft contact lens, ocular irritation (diclofenac, ketorolac)
- Dry Eye complaints (12%)
NSAID Precaution & Drug Interactions
- product-dependent (ophthalmic vs. systemic)
- soft contact lenses (irritation/preservative issues)
- older eyes + intraocular surgery
- children?
- pregnant women?
- drug interactions (endogenous role of PG? cAMP?)
* brimonidine, carbachol & NSAIDs (?)
* PG analogs & NSAIDs (?)
Additional Actions & Effects
- aspirin irreversibly inhibits COX activity
* low dose analgesic & “blood thinning”, reduced risk stroke & heart disease
* high dose (12-20 tablets/per day) anti-inflammatory
* reduced cancer risk (colon, prostate) - acetaminophen not anti-inflammatory
* good antipyretic/analgesic activity - diflusinal no antipyretic activity (salicylate derivative)
- diclofenac & indomethacin high potency anti-inflammatory drugs, not well tolerated
- COX-2 inhibitors (celecoxib & meloxicam) more selectively anti-inflammatory? (no direct platelet effect-but COX-2 is constitutively expressed in the healthykidney, heart and some blood vessels)
- interdrug variability in duration of action (hrs to weeks)
Systemic Uses
symptomatic &/or anti-inflammatory
* analgesia (headache, dental, dysmenorrhea)
* fever
* corns, muscle sprains etc (topical salicylates)
* auto-immune diseases (e.g. rheumatoid arthritis)
* gout
* post surgery (pain control+)
* prophylaxis for colon cancer (aspirin, rofecoxib-vioxx)
* Cardiovascular uses (aspirin)
- most administered orally
(exceptions: topically for eyes & skin; intramuscular injections)
OTC Drug Selection for Acute Conditions
short term analgesia
* acetaminophen
* ibuprofen/naproxen
* aspirin
Fever
* acetaminophen
* aspirin (low potency, blood brain barrier)
* Ibuprofen/naproxen
inflammatory pain and inflammation (cold, sprains, flu, etc)
* aspirin
* ibuprofen/naproxen
external applications (corns, muscle sprains etc)
* aspirin/salicylates (oil of wintergreen)
* salicylate – Acne cream/facial washes
NSAIDs & Chronic Pain/Inflammation
chronic pain/inflammation/arthritis
* high dose aspirin
* naproxen
* piroxicam
* diflunisal
* celecoxib! [rofecoxib-Vioxx removed due to CV risk]
* meloxicam
special application of aspirin
* colon cancer (prophylaxis)
* cardioprotection, stroke
role for COX-II inhibitors?
* rheumatoid arthritis (platelet sparing, limit GI irritation)
* cancer [unacceptable CV risk]
* expensive and no better than aspirin for cancer prophylaxis
NSAIDs Side-Effects & Drug Interactions
- Side effects (virtually all cells have COX enzymes, fetal development)
* problem of high doses, chronic use &/or potent drugs
* numerous for most
* reduced with selectivity? (COX-2 vs. 1- & 2- inhibitors)
* even acetaminophen rel. dangerous (alcohol-hepatitis) - Drug interactions (PG regulate renal function)
* problematic for most (clearance issues)
Systemic SEs of Aspirin
- GI distress/bleeding
- prolongation of bleeding
- hypersensitivity
- Reye’s syndrome
- indoleacetic acids generally high intolerance
- less GI effects with proprionic acid derivatives
& COX-2 selective inhibitors compared to aspirin - CNS effects
- toxic doses (salicylism) can be deadly
Salicylate toxicity symptom
tinnitus- ringing in the ears is first sign of poisoning
Acetaminophen/Paracetamol Side Effects
- acetaminophen hepatotoxicity
- acetaminophen extremely toxic to cats and lethal to snakes
- Post Hoc analysis of concluded that use of acetaminophen in the first years of life is associated with risk of severe asthma symptoms, rhinoconjunctivitis and eczema.
NSAID Ocular Side-Effects
- corneal erosion
- corneal deposits
- keratitis
- corneal ulceration
- retinal hemorrhage
- epithelial breakdown
