NSAIDs - 20,21 Flashcards
Inflammation
- initiates ___ process
- may injure normal tissues
- too strong of a response ( ___ infection)
- prolonged response ( ___ infection)
- inappropriate response ( ___-antigens, ___ disease)
- 5 signs
- healing
- severe
- persistent/recurrent
- self-antigens, autoimmune
- heat (calor), redness (rubor), swelling (tumor), pain (dolor), loss of function (functio laesa)
Chemical mediators of inflammation
- vasoactive ___ (histamine and ___ )
- Eicosanoids (prostaglandins, ___, and lipoxins)
- ___ activating factor (PAF)
- Cytokines (TNF, IL-___, chemokines → ___ inflammation) (IFN-y → ___ inflammation)
- complement components (C3a and C5a)
- Coagulation and kinin systems (bradykin, thrombin, fibrinopeptides)
- amines, serotonin
- leukotrienes
- platelet
- 1, acute
- chronic
What is this?
PAF
T or F: Eicosa means 30
False; 20, eicosanoids will have 20 or more carbons
Eicosanoids
4 types
PGE2- Blood vessel ___ , brochi ___ , uterus ___
PGF2a - blood vessels ___ , bronchi ___ , uterus ___
PGI2 - blood vessels ___ , platelets ___
TXA2 - blood vessles ___ , platelets ___
- dilation, dilation oxytocic dilation
- constriction, contriction, oxytocic constriction
- dialtion, inhibits aggregation
- constriction, aggregation (clotting)
prostaglandin = ___
leukotrienes = ___
lipoxin = ___
- inflammation
- allergies
- anti-inflammatory
Eicosanoids
- ___-lived mediators (seconds to minutes)
- ___ and paracrine signaling
- bind GPCRs in target cells (Gs and Gq)
- Gs = ___
- Gq = ___
- short
- autocrine
- dilation
- constriction
Arachidonic acid
- 20-carbon polyunsaturated fatty acids
- ___ fatty acids
- most abundant and important ___ of eicosanoids
- Released from membrane phospholipids by ___ (PLA2)
- corticosteroids ___ the production of phospholipase A2
- essential
- precursor
- phospholipase A2
- suppress
Oxygenation of arachidonic acid
- PGH synthase ( ___ ) pathway
- Lipoxygenase pathway
- Epoxygenase ( ___ ) pathway
- Isoprostane pathway (free radical reaction)
- COX
- CYP450
PGH synthase
- both COX and ___ activities
- COX reaction: radical-mediated oxidation
- ___ reaction: hydroperoxyl group (-OOH) to a hydroxyl group (-OH)
Hydroperoxidase
Isoforms of PGH synthase
PGH synthase-1
* COX-1: housekeeping ( ___ cytoprotection)
PGH synthase 2
* COX-2: expressed upon stimulus in inflammatory and immune cells.
* Stimulated by ___ , tumor promoters, and ___ .
Inhibited by ___
- gastric
- growth factors, cytokines
- NSAIDs
Prostaglandins vs. thromboxanes
platelets = ___
vascular endothelia = ___
- TXA2
- PGI2
Eicosanoid drugs
Alprostadil
* type: ___
* relaxes smooth muscles and ___ blood vessels
* used for ___ by injection or suppository
- PGE1
- expands
- ED
ouch, make sure they pee before
Eicosanoid drugs
Misoprostol
* ___ derivative
* Prevents ___
* when combined with ___ , terminates early pregnancy
- PGE1
- peptic ulcer
- mifepristone
Eicosanoid drugs
Latanoprost
* topically active ___ derivative (prodrug)
* ___ blood vessels
* used for glaucoma
- PGF2a
- constrict
Eicosanoid drugs
Prostacyclin
* type: ___
* powerful ___
* inhibitor of ___
* used to treat pulmonary arterial hypertension by ___ injection or ___
* should not be used with ___
- PGI2
- vasodilator
- platelet aggregation
- IV, inhalation
- anticoagulants
NSAID uses
- Treatment of moderate pain, ____ , and inflammation from acute
inflammation
Treatment of early-stage rheumatoid arthritis and osteoarthritis - ___ prevention
- fever
- cancer
NSAID mechanism of action
Inhibition of prostaglandin endoperoxide H synthase (PGHS or COX), which catalyzes the formation of prostaglandins.
* Many NSAIDs ___ both COX-1 and COX-2.
inhibit
Classes of NSAIDs
- Salicylates
- Arylacetic acids
- Arylpropionic acids
- Non-carboxylate NSAIDs
- COX-2 selective NSAIDs
Example of a salicylate NSAID?
aspirin
Example of aryl propionic acid NSAID?
ibuprofen
Example of aryl acetic acid NSAID?
Indomethacin
Example is non-carboxylate NSAID?
meloxicam
Example of COX-2 Selective NSAID?
Celecoxib
Side effects of NSAIDs
Gastrointestinal
* mild: dyspepsia, N/V
* severe: ulcer, blood loss
* the ___ of NSAIDs is the primary insult
* inhibition of ___ secondary insult
* inhibition of ___ (increased tendency of bleeding)
- acidicty
- PGEs
- platelet aggregation
Side effects of NSAIDs
Blood coagulation
* ____ prolongs bleeding by irreverible inhibition of platelet COX - ___
* can be used in some patients with ___ disease to prevent blood coagulation
- aspirin, 1
- cardiovascular
T or F: aspirin before surgery or tooth extraction is recommended
‘FALSE; youll bleed like crazy.
contraindicated
Side effects of NSAIDs
renal
* renal failure in patients with cardiovascular, ___, and ___ diseases
heptic, renal
Side effects of NSAIDs
Hypersensitivity
* Characterized by skin rashes, hives, angioedema, and an asthma-like
syndrome (blocked by ___ inhibitors).
* Occurs in 0.3% of the population (___ % in asthmatics).
- 5-lipoxygenase
- 10%
theory: higher in asthmatics due to higher baseline leukotriene levels
Side effects of NSAIDs
Reye’s syndrome
* specific to ___
* ___ damage common in survivors
* occurs in children who have had the ___ or ___
* ___ should not be given to anyone under the age of ___ who has a ___
- salicylates
- brain
- flu, chicken pox
- aspirin 12, fever
Side effects of NSAIDs
CNS
- tinnitus
- dizziness
- headache
tinnitus is ringing of the ears
Prevention of GI side effects
- misoprostol __ analog (prevents ulcers)
- esomeprazole ___ inhibitor (reduced acid secretion even in the absense of COX-1 activity)
- combo products: naproxen/esomeprazole, naproxen/misoprostol, diclofenac/misoprostol
Misoprostol
- PGE1
- proton pump
Drug interactions of NSAIDs
- ___ % of NSAIDs are bound to ___
- NSAIDs may ___ for serum albumin binding sites with other drugs
Example – combination with oral anticoagulants
* Increases the plasma concentration of free ___.
* The ability of salicylate to produce GI bleeding and inhibit the clotting
mechanism aggravates the problem.
* Necessitates a possible ___ in the dosage of anticoagulant.
- 90-99%, albumin
- compete
- anticoagulant
- decrease
Structure-activity relationships in NSAIDs
- commonly contains a __ group
- acidic group located one carbon away from ___ or heteroaromatic ring
- a methyl group on the carbon atom separating the acidic group from the aromatic ring tends to increase activity for “ ___ “
A second area of lipophilicity (aromatic or alkyl) that
is noncoplanar with the aromatic or heteroaromatic
ring generally ___ activity.
- acidic/carboxyl
- “profens”
- enhaces
Salicylates
- Absorbed as an ionic form from the small intestine and, to lesser extent, from the stomach as an ___ form.
- Inhibits COX-1 and COX-2 ___.
- May suppress COX-2 induction.
- acid
- reversibly
Salicylates - aspirin
- The only NSAID that ___ inhibits COX by acetylating a ___
residue in the active site. - Absorbed largely as the intact form but hydrolyzed rapidly to salicylate by
plasma ___. - Blocks platelet-aggregating factor TXA2 effectively; increases the risk of
bleeding but also reduces the risk of myocardial infarction. - not ___ in solutions due to esters being sensitive to ___
- irreversibly, serine
- esterase
- TXA2
- stable
- hydrolyzing
Salicylates
Salsalate (Disalcid®)
* ___ of salicylic acid (prodrug)
* hydrolyzed into 2 ___ in the small intestine and ___
* does not cause ___
- dimer
- salicylates, absorbed
- GI bleeding
Salicylates
Diflunisal (Dolobid®)
* More ___ analgesic than
aspirin, but produces ___ side effects.
less ___ activity than aspirin
3-4 fold longer t1/2 than aspirin
- potent
- less
Arylacetic acids
Indomethacin
* one of the most ___ NSAIDs
* high incidence of side effects
* not suitable for ___ use
* not stable in solution due to hydrolysis of ___
- potent
- long term
- amide bond
Arylacetic acids
Sulindac
* prodrug; the ___ group is reduced to the active sulfide intermediate in the circulatory system
* less ___ side effects
* suitable for ___ use to treat ___ inflammation
- sulfoxide
- GI
- long term, chronic
Arylacetic acids
Etodolac
* ___ acid
* As potent as ___.
* Somewhat selective for ___.
* Less ___ bleeding
* Suitable for ___ use to manage ___.
- Pyranocarboxylic
- indomethacin
- COX-2
- GI
- long-term, osteoarthritis
Arylacetic acids
Diclofenac
* The most widely used NSAID in the world.
* As potent as ___
* Somewhat selective for ___.
* Inhibits both COX and ___ pathways.
* good for long term
- indomethacin
- COX-2
- lipoxygenase
Arylpropionic acids
Ibuprofen (Advil® or Mortrin®)
* more potent than aspirin but less than indomethacon
* moderate gastric irritation
* ___ group enhances it activity and reduces many side effects.
Bioequivalent racemic mixture
* S-(+)-enantiomer possesses ___ activity in vitro.
* R-(-)-enantiomer is converted to S-(+)-enantiomer enzymatically in vivo.
- α-Methyl
- greater
Arylpropionic acids
Naproxen (Aleve®)
* ___ (+) - enantiomer
* more potent than ibuprofen
* moderate ___
* used to treat ___ arthritis and osteoarthritis
- S
- gastric irritation
- rheumatoid
Arylpropionic
Ketorolac
* Cyclized heteroarylpropionic acid
derivative
* ___ management of
moderate to severe pain.
* Analgesic activity similar to
___ acting analgesics.
* Widely accepted alternative to
narcotic analgesics.
- short term
- centraly (like opiates)
Non-carboxylates
Nabumetone
* nonacidic prodrug
* metabolized quickly to ___ which is a ___ inhibitor
* minimum ___ side effects
* Potent anti-inflammatory, but weak ___ activity.
- 6-MNA, COX
- gastric
- analgesic
Non-carboxylates
Meloxicam
* Belongs to the oxicam class,
which resembles the ___ intermediate in COX.
* Enolic acid
* ___ acting ; single daily dose.
* As potent as ___.
* Somewhat selective for ____.
* good more longe term use
- peroxy radical intermediate
- long
- indomethacin
- COX-2
Consequences of COX-1 inhibition
- Stomach irritation and ___
- Blockade of platelet ___
- Inhibition of uterine ___
- Inhibition of ___ mediated renal function
- ___ reactions
Preferential inhibition of COX-2 gives anti-inflammatory effects with
lower incidence of gastric ulceration.
- ulceration
- aggregation
- motility
- prostaglandin
- hypsersensitivity
What NSAIDs are good for long term use?
- Etodolac
- meloxicam
- celecoxib
- nimesulide
What NSAIDs are good for long term use?
- Etodolac
- meloxicam
- celecoxib
- nimesulide
Selective COX-2 Inhibitors
- ___ in the NSAID binding site of COX-2 is substituted for ___ in that of COX-1.
- Selective COX-2 inhibitors exploit the ___ NSAID binding site in COX-2 with larger and relatively rigid substituents.
- “coxib”
- valine, isoleucine
- larger
Side effects of selective COX-2 inhibitors
- elevated ___ and atherogenesis
- expression of COX-2 in endothelium is critical for ___ production
- selective COX-2 inhibitors do not affect the production of ___ by COX-1 (heightedned thrombotic response on the rupture of artherosclerotic plaque)
- increased risk for heart attack and ___
- blood pressure
- PGI2 (prostacyclin)
- TXA2
- stroke
Celecoxib
Celebrex®
* First NSAID to be marketed as selective COX-2 inhibitor.
* Used for osteoarthritis and rheumatoid arthritis.
* Good efficacy against pain, inflammation, and fever.
* As potent as ___.
* Less risk of ___ side effects.
* No ___ activity.
- naproxen
- GI
- antiplatelet
Celecoxib
Celebrex®
* First NSAID to be marketed as selective COX-2 inhibitor.
* Used for osteoarthritis and rheumatoid arthritis.
* Good efficacy against pain, inflammation, and fever.
* As potent as ___.
* Less risk of ___ side effects.
* No ___ activity.
- naproxen
- GI
- antiplatelet
Acetaminophen
- Analgesic and antipyretic effects similar to ___
- Much weaker as an ___ agent.
- mechanism of action: Does not inhibit ___ acid binding to ___.
- Scavenges ___ required for PGH synthase activity
- Peroxynitrite is the major oxidant for ___ synthase activity in the ___.
- In inflammation, high concentrations of ___ are present, and acetaminophen scavenging is overwhelmed.
- aspirin
- anti-inflammatory
- arachidonic, PGHS
- peroxynitrite
- PGH, CNS
- peroxides
Acetaminophen
- Lower incidence of ___ and ___
- Tolerated in patients with blood ___ disorders.
- Not associated with ___ syndrome.
- Does not cross-react with ___
- Hepatotoxicity at toxic doses (CYP 450 mediated N-hydroxylation to form N-acetylimidoquinone
which reacts with ___ ) . - Toxic doses overload the glutathione, and cell damage occurs in the liver.
- GI disturbance and hypersensitivity
- Reye’s
- aspirin
- glutathione
glutathione is a reducing agent in cells (detoxifying in liver)
What is this?
Arachidonic acid
precursor of eicosanoids
What is this?
Arachidonic acid
What is this?
TXA2
What is this?
PGI2 (prostacyclin)
What is this?
What is this?
PGF2
What is this?
Alprostadil
PGE1
What is this?
Misoprostol
PGE1 derivative
What is this?
Latanoprost
PGF2a
derivative (prodrug)
What is this?
Aspirin (ASA)
What is this?
Salsalate
Salicylates
What is this?
Diflunisal (Dolobid®)
Salicylates
What is this?
Indomethacin
Arylacetic acids
What is this?
Sulindac
Arylacetic acids
What is this?
Etodolac
Arylacetic acids
What is this?
Diclofenac
Arylacetic acids
What is this?
Ibuprofen
Arylpropionic acids
What is this?
Naproxen (Aleve®)
Arylpropionic acids
What is this?
Ketorolac
Arylpropionic acids
What is this?
Nabumetone
Non-carboxylates
What is this?
meloxicam
Non-carboxylates
What is this?
Celecoxib
Selective COX-2 Inhibitors
What is this?
