NSAIDs Flashcards
Name the 3 Groups of NSAIDs
- Aspirin/Salicylates
- Traditional Non-Selective NSAIDs (ibuprofen)
- Coxibs (COX inhibitors)
A: How does Cell/Tissue Damage lead to Pain/Inflammation/Fever?
1: Damage induces ________ to produce ________
2: ________ binds to Cyclooxygenase and is converted into ________
3: ________ is then modified by multiple syntheses into
what 3 major compounds?
4: ________ can then go to induce pain/inflammation/fever.
B: What is the rate limiting step for this reaction?
A: How does Cell/Tissue Damage lead to Pain/Inflammation/Fever?
1: Damage induces [Phospholipase A2] to produce [Arachidonic Acid]
2: [Arachidonic Acid] binds to Cyclooxygenase and is converted into [Prostaglandin H2] = RATE LIMITING STEP!
3: [Prostaglandin H2] is then modified by multiple syntheses into
- [Prostacyclin]
- [Prostaglandin E2]
- [Thromboxane TXA2]
4: [Prostaglandins] can then go to induce pain/inflammation/fever.
B: What is the rate limiting step for this reaction?
[Arachidonic Acid] conversation into [PGH2] by Cyclooxygenase
Aspirin
MOA
IRREVERSIBLE NON-Competitive COX inhibitor
A: COX1 Expression
B: COX1 Location
A: Expressed constitutively and does NOT need to be induced
B: COX1 is UBIQUITOUSLY EXPRESSED IN MOST TISSUE
A: COX-TWO Expression
B: COX-TWO Location
- Where can it be Induced? (4)
- Where is it constitutively expressed? (2)
A: INDUCIBLE in many cell types in response to [pro-inflammatory]/mitogenic stimuli
B:
-INDUCED in [macrophages/monocytes], [Dorsal Horn Neurons], osteoblast and Fibroblast
-has low level constitutive expression in KIDNEY AND ENDOTHELIUM
COX1
A: Physiological Role (4)
B: What compounds do COX1 produce that facilitate these roles?
HOUSEKEEPING:
1. Platelet Regulation (monitors blood clotting)
- Kidney Function
- Cytoprotection of Stomach by regulating Acid/Mucus production & [gastric blood flow]
- Maintains Patent Ductus Arteriosus for Fetus and stimulates [Uterine contractions during labor (involves PGF2a) ]
(COX1 is NOT inhibited by Celecoxib)
B: [PGE2/PGi2]
COX-TWO
Physiological Role
PRO-INFLAMMATORY RESPONSE (Mitogenesis and Signaling)
How do Prostaglandins cause Peripheral Pain Sensitization?
[Prostaglandin E2] produced by a [COXTWO inflammatory cell] DEC PAIN THRESHOLD for [Primary afferent neurons]—> [Peripheral Pain Sensitization]
How do Prostaglandins cause CENTRAL Pain Sensitization
1st: [B.I.T.] produced by a [COXTWO inflammatory cell] travels to [Dorsal Horn Neurons] and induces COXTWO expression there.
2nd: [Dorsal Horn Neurons] now produce Prostaglandins which bind to PGE2 Receptors in the [Dorsal Horn Neurons] to ENHANCE the depolarization of [Secondary Afferent neurons]
[B.I.T.] = [Bradykinin/ IL-1 / TNFa]
Elucidate the steps of Fever Production starting with Tissue Damage
- Damaged Tissue produces [____ and ______] which travels to the CNS
- [____ and ______] stimulate endothelial cells of the [_______ blood vessels] to express _______ and [____ synthase]
- _____ and _____ in the endothelial cells of the [_____ blood vessel] produce [______] which goes to stimulate hypOthalamus to INC body temperature
Elucidate the steps of Fever Production starting with Tissue Damage
- Damaged Tissue produces [IL-1 and TNFa] which travels to the CNS
- [IL-1 and TNFa] stimulate endothelial cells of the [hypOthalamus blood vessels] to express COXTWO and [PGE synthase]
- [COXTWO/PGEsynthase] in the endothelial cells of the [hypOthalamus blood vessel] produce [Prostaglandin E2] which goes to stimulate hypOthalamus to INC body temperature
A: What is another name for PGi2?
B: What are its roles? (2)
C: Endothelial cells express COX1 or COXTWO? What are the primary compounds produced from Endothelial cells?
A: Prostacyclin!
B:
1) VasoDilates
2) INHIBITS Clotting
C: Endothelial cells express BOTH COX1 and COXTWO! They primarily produce [PGi2/PGE2] because they do NOT contain the [Thromboxane synthase]
“(PGi2 Prostacyclin) | (PGE2) “
A: Platelets express ONLY _____[COX⬜] but primarily produce ________.
B: What are the roles of the compound produced? (2)
A: Platelets express ONLY COX1 but primarily produce [Thromboxane].
B: What are the roles of the compound produced? (2)
1) vasoconstricts
2) promotes clotting
A: Why is PGi2 particularly important in Pt with Renal Dz or Heart Failure? (3)
B: Is [ ______-medicated acute renal failure] caused by taking NSAIDs in a diseased state, reversible?
A: [Renal Dz and Heart Failure]—> INC Renal VasoCONSTRICTORS. [PGi2] is a vasodilator that will
- INC Renal Blood flow to prevent Renal ischemia
- INC GFR
- INC water and Na+ excretion
B: Is [ HEMODYNAMICALLY-medicated acute renal failure] caused by taking NSAIDs in a diseased state, reversible?
->YES! JUST TAKE THEM OFF OF THE NSAIDS!
A: Why is Aspirin READILY absorbed in the stomach and [upper small intestine]?
ASA (AcetylSalicylicAcid) is a weak acid and in the acidic environment of the stomach it will be in a [NEUTRAL PROTONATED FORM]—> Allows EASY ABSORPTION!
Aspirin Recommended Dosing
- Anti-Platelet activity = ⬜ dose
- Anti-Pyretic = ⬜ dose
- Analgesic = ⬜ dose
- Anti-Inflammation= ⬜ dose
Aspirin Recommended Dosing
- Anti-Platelet activity = [81mg qD]
_________________ - Anti-Pyretic(must cross BBB) = [400mg BID]
_________________ - ]Anti-Pain (Analgesic)] = [400mg BID]
_________________ - [Anti-Puff (anti-Inflammation)= [4,000mg - 6,000mg qD]
A: Why is concurrently taking [Salicylates/Aspirin] and Warfarin OR Sulfonylureas contraindicated?
B: Sulfonylurea Toxicity —> ⬜
[Salicylates/Aspirin] are 50-90% Protein bound once they enter the serum. This will DISPLACE other very protein bound drugs like WARFARIN OR Sulfonylureas—-> Warfarin/Sulfonylurea Toxicity!
B: Sulfonylurea toxicity —-> hypOglycemia
A: What is the Difference between Diflusinal and Aspirin? (2)
B: When would you use [Diflusinal or other Salicylates] and not Aspirin? (2)
- Diflusinal can NOT cross BBB which means it is NOT an Anti-Pyretic
- ## Diflusinal (and all other Salicylates) does not IRREVERSIBLY inhibit COX –> they are less potent than ASAB: Use Salicylates when:
1) Pt is at risk for GI Complications (gastric ulcers)
2) Pt is at risk for Bleeding (hemophiliac)
How do you treat Salicylate OVERDOSE and why?
Alkalinize the Urine (make urine more basic) —>cause Salicylate to convert into its [DeProtonated CHARGED Form] —> Trap it in the urine—> INC Excretion and prevents renal Absorption
Between which of the 3 NSAID groups would you use to treat GOUT?
Traditional NSAIDs
A: Ibuprofen has a _____[slow/rapid] onset of ____ min and is _____[better/least] tolerated than Aspirin even though it is just as _____.
B: INDICATIONS (2)
Ibuprofen has a RAPID onset of [15-30 min] and is BETTER tolerated than Aspirin even though it is just as potent.
INDICATIONS:
- Fever
- Acute Pain
A: Naproxen is ___ times more potent than aspirin and has a RAPID onset of ____ min.
B: Naproxen has a serum half life of ___ hours which allows for _____ dosing
C: Naproxen is an extremely ideal _______
A: Naproxen is 20 x more potent than aspirin and has a RAPID onset of 60 min.
B: Naproxen has a serum half life of 14 hours which allows for twice/day dosing
C: Naproxen is an extremely ideal Anti-Pyretic
What’s special about OXAPROZIN?
[Traditional NSAID] with LONG HALF-LIFE OF 50-60 HOURS —> allows for once/day dosing
INDOMETHACIN
A: Primary Indications (3)
B: Cons
A: Indication
1) NSAID Used to promote closure of [Fetal Ductus Arteriosus]
2) 10-40 x more potent than Aspirin at anti-inflammation
3) Inhibits neutrophil mobility
B: Cons
(x) NOT TOLERATED AS WELL AS IBUPROFEN-Toxicity limits usage
KETOLORAC
A: Primary Indication
B: What can this NSAID replace?
A: Indication:
[Intravenous NSAID] that treats post-surgical pain
B: Can be used as an Opioid Replacement Drug
DICLOFENAC
B: What’s the cons of this drug and its class?
A: DICLOFENAC= Relatively Selective COXTWO Inhibitor
B: [COXTWO Inhibitors] INC chances of Stroke/Heart Dz!!
What are 2 ASPIRIN-Specific Adverse Effects?
- Reye’s syndrome (occurs in genetic subset of children/teens who take Aspirin during a viral infection) = FATAL degenerative liver dz associated w/encephalitis
- INC Risk of Gout
A: What is the most common adverse effect reported for [tNSAIDs & (Aspirin/Salicylates) ] ?
B: How do [tNSAIDs & (Aspirin/Salicylates) ] cause Gastric damage? (2)
C: How do you treat [tNSAIDs & (Aspirin/Salicylates) ] induced Gastric damage? (2)
B:
1) DIRECTLY damage gastric epithelium from being ion trapped in the compartment sometimes
C: Treatment:
-Misoprostol = PGE1 in a pill [CAN NOT GIVE TO PREGNANT WOMAN SINCE IT INDUCES ABORTION]
-Omeprazole
A: [Acute interstitial nephritis and Nephrotic Syndrome]
B: Who does this occur most in/
A: RARE but important clinical syndrome associated with IDIOPATHIC Glomerular [inflammatory cell infiltration] / proteinuria and NV. Caused by month exposure to NSAIDs!
-Pt recovers once NSAIDs are discontinued
B: Occur most in Women and Elderly
[CHRONIC interstitial nephritis and Analgesic Nephropathy]
A: Caused by CHRONIC Daily OVER USE of NSAIDs which leads to Chronic Renal Ischemia—> ESRD
ESRD= End Stage Renal Dz
A: What is [NSAID Hypersensitivity]?
B: What are the sx and what is the onset?
A: NON-IMMUNE inflammatory attack that occurs when pt takes [Aspirin / tNSAIDs/ COXTWO inhibitors]. Arachidonic acid accumulation–> Leukotriene production–> [airway hypersensitivity rxn]
B: Rapid Severe asthma attack that onsets 30-60 min after intake
NSAIDs taken in pregnant women after ____ weeks gestation can cause [Premature Ductus Arteriosus ____] in the fetus
NSAIDs taken in pregnant women after 30 weeks gestation can cause [Premature Ductus Arteriosus CLOSURE] in the fetus
A: COXTWO inhibitors such as Celecoxib are BEST used for what 3 circumstances?
B: What type of effect does [COXTWO inhibitors] have on Kidneys?
C: Why is Celecoxib NOT a first-choice NSAID?
A: COXTWO inhibitors such as Celecoxib are BEST used for
- [Rheumatoid Arthritis]
- Osteoarthritis
- Pt who are at higher risk for GI bleeds
B: [COXTWO inhibitors] have SAME NEPHROTOXICITY as tNSAIDS and [Aspirin/Salicylates] because Kidneys constitutively express COXTWO and need it
C: Celecoxib significantly Increases Stroke/Heart Dz probability and so is NOT a 1st choice NSAID
Which 3 Drugs have Dangerous impaired Renal Clearance due to NSAID usage?
- Lithium
- Methotrexate
- [Gentamicin-Aminoglycoside]
A: Acetaminophen is metabolized into its active metabolite (______) which inhibits ______ AND activates the ______ system—> DEC Fever & Pain
B: Acetaminophen is not a good anti-______ or anti-______ because it does not inhibit ________. This is due to [peripheral ______] that quickly degrade it in the periphery only
C: How does Acetaminophen affect the Kidneys and GI system?
A: Acetaminophen is metabolized into its active metabolite (AM404) which inhibits CNS COXTWO AND activates the cannabinoid system—> DEC Fever & Pain
B: Acetaminophen is not a good anti-inflammatory or anti-platelet because it does not inhibit [Peripheral COX1 or COXTWO]. This is due to [peripheral HydroPerOxides] that quickly degrade it
C: How does Acetaminophen affect the Kidneys and GI system?
:-) It safe for both due to inability to act on [Peripheral COX1 and COXTWO]
