NSAIDs Flashcards
3 general properties of NSAIDs
- anti-inflammatory
- anti-pyretic
- analgesic
In general, when you think about PGs and inflammation,
think about________
(is it COX 1 or COX2)
COX2
Does acetaminophen have anti-inflammatory properties
NO
What is the general mechanism of all NSAIDs
inhibition of cyclooxygenase however not all inhibit COX1 and or COX2 some are specific
Mechanism of Action of Aspirin
- it is an IRREVERSIBLE inhibitor of COX1 and COX2
- It does this by acetylating a serine moiety
How many NSAIDs are irreversible inhibitors of COX1 and COX2
ONLY ASPIRIN
then rest are reversible inhibitors
Therapeutic implications of irreversible inhibition of COX1 and COX2
the only way to overcome irreversible inhibition is to synthesize new COX enzymes.
Platelets don’t have a nucleus so they cant synthesize new COX enzymes so once they are knocked out that platelet is done. Fortunately platelets regenerate in about 7 days. So when new platelts are formed those new platelets will have OCX function
- this is why you only need a low dose of aspirin in CV disease.
- whereas in endothelial cells they have a nucleus so they can re-synthesize COX quickly
describe the pharmacokinetics of aspirin
-how is it absorbed and what limits the absorption
- oral absorption that is limited by dissolution rate. therefore if you chew the aspirin you can increase the absorption rate
- It is hard on the stomach so it can have an enteric coating or buffer to help make is dissolve in the intestines instead of the stomach
- highly bound to plasma proteins
- crosses the BBB
Does aspirin cross the BBB
YES
Describe the metabolism of Aspirin
- It is deacetylated into Salicylic acid
- Salicyclic acid is then broken down via
- Phase I oxidation (4%)
- Phase II glucuronidation (34%)
- hase II glycination (49%)
How is aspirin eliminated
renal and it is dose dependent. Normally it is about 2-3 hours, but can be up to 30 hours when the dose is high enough because the metabolism enzymes saturate and there is a build up of Salicylic acid
unique effects specific to aspirin that are unrelated to COX inhibition
- Uric acid excretion
- CNS effect (bc crosses BBB)
- Respiratory effect
Explain why gout is a contraindication for aspirin
- gout is a build up on uric acid
- low dose aspirin: decrease uric acid excretion
- small secretory component for urate that is sensitive to low concentrations of salicyclates
- large dose aspirin- increase uric acid secretion
-usually people take low dose aspirin so if someone ahs gout and they take a low dose aspriing they already have ab build up of uric acid and now they will decrease uric acid excretion, further increasing th build up of uric acid
Effect of PGs on Uric acid excretion
PGs have no effect on uric acid excretion, but aspirin does.
CNS effects of Aspirin
tinnitus, high-tone deafness, confusion, dizziness, delirium, psychosis, coma
What is the major limitation to long term therapy with NSAIDs (especially aspirin)
GI side effects
Effects of PGs on GI system
- major PGs that effect the GI system are PGE2 and PGI2 (which are formed by COX1 bc that is the constitutive one and COX2 is the inducible one that is associated with injury and inflammation )
- PGE2 and PGI2 promote secretion of the cytoprotective mucus in the intestine and inhibit acid secretion by the stomach
NSAID GI side effects
block the production of cytoprotective PGs
- GI ulceration and irritation
- chronic use of NSAIDs increases risk by 3x
PGs and platelets
- PGI2 inhibits platelet aggregation
- TXA2 stimulates platelet aggregation
NSAID effects on platelets
ALL NSAIDs increase bleeding time by inhibiting platelet TXA2
a single dose of 80 mg aspirin inhibits bleeding time for one week bc platelets lack a nucleus and will only get a new COX with new platelets bc ASA irreversible inhibition of COX
NSAID hypersensitivity
- intolerance to aspirin and other NSAIDS
- NOT an IgE-mediated mechanism
- proposed mechanism: Blocking COX causes all Arachidonic acid to be shuttled in the leukotriene pathway. these are responsible for allergy bronchoconstriction and mucus production
PGs and the KIdney
- COX-1
- Role for COX-2 as well especially in disease states
- PGE2 and PGI2 increase renal blood flow
- increase Na and water excretion
NSAID renal side effect
- decrease renal blood flow
- promote salt and water retention
- effects more prominent in individuals dependent on vasodilatory PGs (ie people who have CHF, renal disease and ELDERLY)
PGs and the uterus
- pregnant uterus
- PGF2a=contraction
- PGE2=contraction
- PGI2=dilation (early pregnancy) - maintina patent ductus arteriosus (PDA) in fetus
- Non pregnant uterus
- PG mediated effects on contraction
- hyperalgesia
NSADIs and pregnancy
- prolongation of gestation
- prolonged labor
- increased risk of postpartum hemorrhage: TXA2/platelets/clotting
- intratuterine closure of PDA
-but thought that low doses don’t case harm to fetus
NSAIDs and the non-pregnant uterus
decrease pain associated with primary dysmennorhea
Salicyclism
aspirin poisoning
-symptoms are a lot of the CNS toxicity bc at high doses more will cross the BBB
Reye Syndrome
-specific to aspirin use in children (6-11 years) and often follows a virus like chicken pox or influenza B
- clinical characteristics:
- acute encephalopathy
- liver degeneration
-mandates warning that all children under the age of 19 are at risk of reye syndrome
Therapeutic uses of aspirin
- fever, pain, inflammatory disorders
- CV disease
- low dose: CV disease
- intermediate dose: low intensity pain/fever
- high dose: chronic inflammatory disease/rheumatoid arthritis
low dose aspirin
CV disease
intermediate dose aspriin
low intensity pain/fever
high dose aspirin
chronic inflammatory disease/rheumatoid arthritis
Side effects associated with ALL NON- SELECTIVE (COX-1 AND COX-2) NSAIDS
- GI irritation
- Inhibition of platelet aggregation/increased risk of bleeding
- Decrease in RBF in patients dependent of vasodilatory PGs
- hypersensitivity
COX 2 is the major isoform associated with
inflammation
Theory behind development of COX-2 inhibitors
_Cox2 is the isoform associated with inflammation
- Major limitation of conventional NSAIDd was GI-related side effects
- COX1 responsible for synthesis of cytoprotective
- so if we only block COX-2 then we can treat inflammation whiheout risk of GI side effects
-unfortunately this didn’t pan out and we still get GI side effects for an unknown reason
What is the only selective COX-2 inhibitor
Celecoxib
Celecoxib and allergies
- contains a sulfonamide side chain
- this is important for allergic reactions bc some people are allergic to sulfa drugs. this is a true antigen antibody allergic reaction unlike the NSAID hypersensitivity we previously talked about
Celecoxib mechanism of action
- reversible inhibitor of COX2
- COX 2 specific bc the binding site that it binds to does not exist in COX 1
Celecoxib is metabolized by what?
CYP2C9
Adverse effects of Celecoxib
-hypersensitivity Increased risk of adverse CV thrombotic events, like MI/stroke - Increase risk of GI irritation, ulceration, bleeding
Contraindications
-Pre-existing CV risk factors or disease -Patients with a sulfonamide toxicity -Prior NSAID hypersensitivity -Following coronary artery bypass graft surgery -Deficiency of CYP2C9
FDA recommendations for NSAIDs
-package insert for all NSAIDs, including Celecoxib
• Exception is aspirin
-risk of serious, and potentially life-threatening, gastrointestinal bleeding.
What are the 2 reversible COX inhibitors that can be orally administered and what are their major differences
Ibuprofen and Naproxen
-the major difference is half life, naproxen is taken once a day and ibuprofen is take 3-4 times a day
-they have less GI effects than aspirin
What is the NSAID that can be given . orally or via IV and what is it used for
Indomethacin
- reversible inhibition of COX1 and COX2
- used for gout, preterm labor, to close patent ductusarteriosus (IV)
- not routinely used to treat pain or fever
Ketorolac
- reversible inhibitor of COX1 and COX2
- oral, IV and IM administration
- rapid onset short duration
- **-used as alternative for opioid analgesics in the treatment of post-operative pain*****
- oral or injection
- short term aka less than 5 days
- much more effective for pain than inflammation-important!!!!!!!
Piroxicam
-Reversible inhibitor of COX1 and COX2
-oral administration once a day
-metabolized by CYP2C9
-EXTREMELY LONG HALF LIFE
-and osteoarthritis
Therapeutic use
*Symptomatic treatment of acute and chronic rheumatoid arthritis
Acetaminophen
reversible COX inhibitor not NSAID
Acetaminophen may not work in cells or tissues that ______
have high levels of peroxide
Metabolism of acetaminophen
-partially metabolized by liver microsomal system (phase I)
*CYP2E1, CYP1a2, CYP3A4
- Mainly undergoes (phase II) glucoronidation and sulfation (95%
of total)
How is acetaminophen excreted
renal excretion
What is the plasma half life
about 2 hours
Adverse effect/toxicity of acetaminophen
- None to little GI issues
- Most serious is hepatic toxicity
Toxicity of acetaminophen explanation and treatment
how does alcohol play a role
-too much acetaminophen leads to more acetaminophen being metabolized by CYP2E1 into NAPQI which leads to hepatotoxicity
- Treatment is N-acetylcysteine (replenishes
glutathione stores) preferably within 36 hours
-Alcohol induces the enzyme CYP2E1 so that more acetaminophen in converted to NAPQI which leads to hepatotoxicity
therapeutic uses of acetaminophen
- acute pain and fever
- NO ANTI-INFLAMMATORY EFFECTS
