L38- NSAIDs Flashcards by Connor Patrick

define NSAIDs and indicate prototype

group of drugs involved in antipyretic, analgesic, anti-inflammatory activity

ASA / aspirin is prototype

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(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)

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NSAIDs generally inhibit ______ reaction / cascade- include all components

COX-1/2 = cyclooxygenase

-arachidonic acid —-> Prostaglandins: prostacyclin, thromboxanes

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arachidonic acid is converted to LTs via ______

lipoxygenases

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(1) = prostacyclin

(2) is the main thromboxane

1- PG-I2

2- TX-A2

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______ 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

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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

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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)

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anti-inflammatory of NSAIDs mostly results from action on COX-(1/2) inhibition

COX-2

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gastric damage from NSAIDs results from ______ actions

COX-1 inhibition + direct irritation

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list the all the NSAIDs

Selectives (for COX-2): celecoxib, meloxicam

Non-Selectives (PAINKID): piroxicam, aspirin, ibuprofen, naproxen, ketorolac, indomethacin, diclofenac

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______ is the main specific use for NSAIDs

mild-to-moderate pain: especially inflammatory pain, eg. MSK disorders (RA, OA)

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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

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______ can be used to close persistent PDA in neonatal life (drug of choice)

indomethacin

note- ibuprofen has shown to have equal efficacy and safety

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list the main systems that NSAID AEs mostly affect

GI
renal
CVS
respiratory (NERD)

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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

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to prevent GI AEs, NSAIDs can be co-administered with….

misoprostol (PG-E1)
PPIs
H2R blockers

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______ 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