L38- NSAIDs Flashcards
define NSAIDs and indicate prototype
group of drugs involved in antipyretic, analgesic, anti-inflammatory activity
ASA / aspirin is prototype
(1) is the main source of eicosanoids, with (2) as the structural elements. It is converted from cell membrane to (1) by (3), which can be inhibited by (4) drugs.
1- arachidonic acid
2- 20C unsaturated FA with 4 double bonds
3- PLA2
4- steroids (inhibition, downregulation)
NSAIDs generally inhibit ______ reaction / cascade- include all components
COX-1/2 = cyclooxygenase
-arachidonic acid —-> Prostaglandins: prostacyclin, thromboxanes
arachidonic acid is converted to LTs via ______
lipoxygenases
(1) = prostacyclin
(2) is the main thromboxane
1- PG-I2
2- TX-A2
______ is mainly responsible for fever and pain responses, include brief mechanism
PG-E2:
- Fever via hypothalamus / anterior pituitary pathway
- Pain via sensitization of peripheral nerves to pain stimulation
COX-1:
- (constitutive/inducible) enzyme
- (2) main location
- (3) main function
- major source of (4)
1- constitutive
2- gastric epithelium, platelets
3- tissue homeostasis
4- cytoprotective PG formation
COX-2:
- (constitutive/inducible) enzyme, (2) is the exception
- major source of (3) and (4)
1- inducible via GFs, tumor promoters, CKs
2- constitutive in brain, kidneys
3- eiconasoids in cancer / inflammation
4- prostacyclin (PG-I2)
anti-inflammatory of NSAIDs mostly results from action on COX-(1/2) inhibition
COX-2
gastric damage from NSAIDs results from ______ actions
COX-1 inhibition + direct irritation
list the all the NSAIDs
Selectives (for COX-2): celecoxib, meloxicam
Non-Selectives (PAINKID): piroxicam, aspirin, ibuprofen, naproxen, ketorolac, indomethacin, diclofenac
______ is the main specific use for NSAIDs
mild-to-moderate pain: especially inflammatory pain, eg. MSK disorders (RA, OA)
list the two main uses of aspirin beyond its NSAID activity, explain (hint- not post-MI use)
1) 50% dec in colon cancer risk
2) adjunct with Niacin (anti-dyslipidemia, lows serum cholesterol) in order to prevent PG mediated intense flushing
______ can be used to close persistent PDA in neonatal life (drug of choice)
indomethacin
note- ibuprofen has shown to have equal efficacy and safety
list the main systems that NSAID AEs mostly affect
- GI
- renal
- CVS
- respiratory (NERD)
describe the main GI AE with NSAID use, include mechanism
Ulceration:
1) inhibition of COX-1 –> dec in protective components for GI lining (seen in non-selective NSAIDs)
2) direct local irritation of gastric mucosa
to prevent GI AEs, NSAIDs can be co-administered with….
misoprostol (PG-E1)
PPIs
H2R blockers
______ has highest risk for GI AEs with NSAID use, ______ has the lowest risk
high- Piroxicam (non-selective)
low- celecoxib (COX-2 selective)
describe the main CVS AE with NSAID use, include mechanism and if more in selective or non-selective NSAIDs
Mostly selective NSAIDs, celecoxib > meloxicam in terms of COX-2 selectivity:
- Platelets (COX-1) –> inc TX-A2 (selective) –> vasoconstriction, platelet aggregation
- Endothelial cells can replenish COX-2, but still overall –> dec PG-I2 –> dec vasodilation, dec inhibition of platelet aggregation
=> thrombosis formation —> inc risk of MI, CVA, death
compare GI and CVS AEs between selective and non-selective NSAIDs
selective: mostly GI issues via COX-1 inhibition
non-selective / coxibs: mostly CVS via only COX-2 inhibition
list the two major adverse renal effects from NSAIDs
- dec renal blood flow
- analgesic nephropathy
describe mechanism of decreased renal blood flow from using NSAIDs
Normal Situations:
- PGs dilate afferent arterioles => inc RBF
- Angiotensin II (AGII) constricts efferent arterioles –> inc RBF
CHF / CKD Pts:
- inc PGs are more important than AGII at maintaining RBF/GFR
- *-if given NSAID –> dec PGs => dec RBF
prolonged and excessive use of NSAIDs may lead to….
chronic interstitial nephritis —- papillary necrosis
**use acetaminophen
______ is the NSAID that most commonly causes hypersensitivity reactions, explain
Celecoxib- contains Sulfonamide –> rxn via allergy
NSAID effects on respiratory system:
- inc in (1) causes (2) response in lungs and (3) symptoms
- inc in (4) causes (5) response in lungs and (6) symptoms
NERD: NSAID exacerbated respiratory disease
1/2/3- inc LT-C4, LT-B4 –> bronchoconstriction:
-wheezing, dyspnea
4/5/6- inc LT-C4, LT-B4 –> vasodilation:
- flushing, hypotension, shock
- vasomotor rhiniti, angioedema, urticaria
list the drugs that are most concerning when used with NSAIDs
ACE inhibitors
corticosteroids
warfarin
describe the effect of ACE inhibitors and NSAIDs when co-administered
ACEI alone:
- dec angiotensin II
- dec inactivation of bradykinin => inc PGs –> vasodilation + dec BP
ACEI w/ NSAID –> dec PG production –> diminishes effects of ACEIs
describe ‘triple whammy’ drug interactions
Triple Whammy: ACEI + diuretic + NSAID => acute renal injury
- NSAID –> dec PG => afferent vasoconstriction –> dec GFR
- ACEI –> dec AG II => efferent vasodilation –> dec GFR
- diuretic –> dec plasma volume –> dec GFR
______ is the main risk with using NSAIDs + corticosteroids
inc risk of GI ulceration:
-do not take on empty stomach if they must be taken together
______ is the main risk with using NSAIDs + warfarin
inc risk of bleeding- especially in susceptible patients (von Willebrand’s, hemophilia)
list and explain the contraindications for NSAIDs (hint- 2)
1) children/young adults (no ASA or salicylate derivatives):
-Reye’s syndrome = fever + viral-like illness
(use acetaminophen)
2) pregnancy, especially near term
- may cause premature PDA closure
list the salicyclates
ASA
magnesium choline salicylate
sodium salicylate
salicyl salicylate
______ is the major unique feature of ASA compared to other salicylates
irreversible inhibition of COX-1/2
ASA is metabolized into (1), which may cause (2) casade depending on dosage
1- ASA –> **salicylate + acetic acid
2- salicyclare is oxidative phosphorylation uncoupler:
i) inc CO2
ii) at high doses, inc CO2 => hyperventilation
iii) at toxic doses, over stimulation of ventilation => desensitization –> hypoventilation
ASA has a (1) effect on platelets, lasting for (2) duration and having (3) as main result
1- irreversible inhibition of COX-1
2- 5-7 days = platelet lifespan
3- dec TX-A2 (usually vasoconstriction + platelet aggregation) => prolonged bleeding time
Note- endothelial cells are not as affected at low doses b/c they can make their own COX enzymes
describe the relative effects of each of the following on PG-I2/prostacyclin levels and TX-A2 levels:
- (1) low dose ASA
- (2) convention NSAIDs
- (3) COX-2 inhibitors
1- slight dec PG-I2, major dec TX-A2
2- major dec in PG-I2 and TX-A2
3- major dec PG-I2, no effect TX-A2
ASA:
- (1) major clinical use
- (2) CVS use
1- mild to moderate pain: RA and other anti-inflammatory + antipyretic
2- cardioprotective –> inhibits platelet aggregation at low doses
list the effects of ASA as dose increases
- low dose 81mg, antiplatelet
- moderate dose 650-1000mg, antipyretic + analgesic
- high doses 1-6g, anti-inflammatory + tinnitus
- 6-10g, hyperventilation / respiratory alkalosis
- 10-20g, fever, dehydration, metabolic acidosis
- 20-30g, shock, coma, respiratory / renal failure, death
describe the metabolism of ASA
<1g, first-order kinetics; half-life 3.5hrs
>1g, zero-order kinetics
metabolized by liver –> metabolites excreted by urine
list the many AEs of ASA
- GI distress (ulceration)
- prolonged bleeding time
- Reye’s syndrome (young people)
- hypersensitivity
- hepatic injury at high doses
- anti-uricosuric effect (inc serum uric acid)
- salicylism
describe the anti-uricosuric effect
with use of ASA:
- uric acid is excreted into renal tubule via OAT (organic acid transporter)
- ASA competes with uric acid for OAT
- dec uric acid secretion
- hyperuricemia
(avoid use in gout Pts)
(1) describe salicylism
(2) describe acute salicylate intoxication
1- (mild chronic salicylate intoxication) HA, dizziness, tinnitus, mental confusion, hyperventilation
2:
- mixed respiratory alkalosis and metabolic acidosis
- respiratory failure is usual cause of death
- circulatory collapse may occur
Acetaminophen is a metabolite of (1) and its MOA is (2), giving it (3) activity in terms of clinical use, but not (4).
1- phenacetin
2- weak COX-1/2 inhibitor
3- analgesic, antipyretic
4- anti-inflammatory
______ may accumulate in acetaminophen overdose
NAPQI = N-acetyl-p-benzoquinone imine
