NSAIDs and Anti-Gout Drugs | Summaries Pharmacology

PHARMACOLOGY

NSAIDs

Pharmacokinetics

• Weak acids

• Taken after a meal

• Metabolized by the

LIVER— Cytochrome

enzyme system

(CYP3A or CYP2C

P450)

• Excretion: RENAL

(main)> Enterohepatic

circulation

• Albumin-bound

(inactive)

MOA

• Phospholipase A2 acts

on arachidonic acid

to produce

cyclooxygenases.

• COX-1: GI mucosal

integrity, platelet and

renal function

• COX-2: Pain, fever,

inflammation

• Non-selectively block

COX enzymes

COX-1 Stimulation

• GI mucosal integrity:

PGE1

• Platelet aggregation:

TXA2

• Platelet

disaggregation: PGI2

• Renal function: PGE

and PGI

COX-2 Stimulation

• Inflammation: PGE2

and PGI2

• Fever: PGE2

• Pain:

NON-SELECTIVE COX INHIBITORS

Diclofenac

• Greatest hepatotoxic

and CV risk

• Highest risk for MI in

susceptible px

• Nephrotoxic (150

mg/day)

Diflunisal

• Cancer pain with

bone metastasis

Flurbiprofen

• Affects TNF-ą and NO

synthesis to prevent

inflammation

Ibuprofen

• Closes PDA

• Limits anti-platelet

effect of aspirin

• Reduced anti-

inflammatory effect

when used with aspirin

(neutralize each

other’s effects)

Indomethacin

• Closes PDA

• Inhibits phospholipase

Ketoprofen

• Topical

• Inhibits both COX and

LOX

• Indicated for px with

bronchial asthma

Nabumetone

• Only non-acid NSAID

Naproxen

• Only single

enantiomer NSAID

Oxaprozin

• Mildly uricosuric

(gouty arthritis)

• Very long-half-life (50-

60 hrs)

Sulindac

• Suppresses familial

intestinal polyposis

• Inhibits development

of colon cancer

Tolmetin

• Ineffective for gout

SELECTIVE COX-2 INHIBITORS (COXIB & XICAM)

CELECOXIB, MELOXICAM,

ETORICOXIB

• Same efficacy with

traditional NSAIDs

• Less GI effects

• No effect on platelet

aggregation

NON-ACETYLATED SALICYLATES

Magnesium choline,

Sodium, Salicyl SALICYLATES

• Anti-inflammatory >

analgesic

• Weak COX inhibitors

(less pain relief)

• Indicated for px with

asthma, bleeding

tendencies, and renal

dysfunction

ADVERSE EFFECTS (NSAIDs)

Gastrointestinal

• Inhibition of COX-1–

reduces

cytoprotective PGE1

• Abdominal pain,

ulcers, bleeding

Cardiovascular

• Inhibits COX-2–

reducing PGI2 and

PGE2

• Na+ retention,

vasoconstriction and

pro-thrombotic

• Edema, hypertension,

MI, CHF

Liver

• NSAIDs are

metabolized in the

liver (CYP450)

• Elevated AST/ALT,

drug-induced hepatitis

Lungs

• Inhibition of COX >

stimulates LOX>

increase production of

• Bronchoconstriction

(exacerbation of

asthma)

Kidneys

• Inhibition of COX-1>

reduces PGE and PGI

formation>

decreasing renal

blood flow and

sodium excretion

• Renal

insufficiency/failure

Skin

• Allergies (ibuprofen)

• Anaphylaxis

CARDIOVASCULAR RISKS

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PHARMACOLOGY

NSAIDs Pharmacokinetics

Weak acids
Taken after a meal
Metabolized by the LIVER— Cytochrome enzyme system (CYP3A or CYP2C P450)
Excretion: RENAL (main)> Enterohepatic circulation
Albumin-bound (inactive) MOA
Phospholipase A2 acts on arachidonic acid to produce cyclooxygenases.
COX-1: GI mucosal integrity, platelet and renal function
COX-2: Pain, fever, inflammation
Non-selectively block COX enzymes COX-1 Stimulation
GI mucosal integrity: PGE 1
Platelet aggregation: TXA
Platelet disaggregation: PGI
Renal function: PGE and PGI COX-2 Stimulation
Inflammation: PGE and PGI
Fever: PGE 2
Pain: NON-SELECTIVE COX INHIBITORS Diclofenac
Greatest hepatotoxic and CV risk
Highest risk for MI in susceptible px
Nephrotoxic ( mg/day) Diflunisal •^ Cancer pain bone metastasis^ with Flurbiprofen
Affects TNF-ą and NO synthesis to prevent inflammation Ibuprofen
Closes PDA
Limits anti-platelet effect of aspirin
Reduced anti- inflammatory effect when used with aspirin (neutralize each other’s effects) Indomethacin
Closes PDA
Inhibits phospholipase A Ketoprofen
Topical
Inhibits both COX and LOX
Indicated for px with bronchial asthma Nabumetone • Only non-acid NSAID Naproxen •^ Only single enantiomer NSAID Oxaprozin
Mildly uricosuric (gouty arthritis)
Very long-half-life (50- 60 hrs) Sulindac
Suppresses familial intestinal polyposis
Inhibits development of colon cancer Tolmetin • Ineffective for gout SELECTIVE COX-2 INHIBITORS (COXIB & XICAM) CELECOXIB, MELOXICAM, ETORICOXIB
Same efficacy with traditional NSAIDs
Less GI effects
No effect on platelet aggregation NON-ACETYLATED SALICYLATES Magnesium choline, Sodium, Salicyl SALICYLATES
Anti-inflammatory > analgesic
Weak COX inhibitors (less pain relief)
Indicated for px with asthma, bleeding tendencies, and renal dysfunction ADVERSE EFFECTS (NSAIDs) Gastrointestinal
Inhibition of COX- 1 – reduces cytoprotective PGE
Abdominal pain, ulcers, bleeding Cardiovascular
Inhibits COX- 2 – reducing PGI2 and PGE
Na+ retention, vasoconstriction and pro-thrombotic
Edema, hypertension, MI, CHF Liver
NSAIDs are metabolized in the liver (CYP450)
Elevated AST/ALT, drug-induced hepatitis Lungs
Inhibition of COX > stimulates LOX> increase production of LT
Bronchoconstriction (exacerbation of asthma) Kidneys
Inhibition of COX-1> reduces PGE and PGI formation> decreasing renal blood flow and sodium excretion
Renal insufficiency/failure Skin • Allergies (ibuprofen)
Anaphylaxis CARDIOVASCULAR RISKS

COX- 2

Inhibition causes: vasoconstriction (low PGI) and platelet aggregation (high TXA)
Increased risk for MI and hypertension COX- 1
Inhibition causes: vasodilation (high PGI) and inhibition of platelet aggregation (low TXA) NSAID SELECTIVITY AND CV RISK (The more selective, the higher CV risk) COX-2 Selective
Celecoxib
Completely inhibits COX-2; increase COX- 1
Less PGI 2 ; More TXA
Increased CV; decreased GI effects Semi-selective
Meloxicam, Diclofenac, Etodolac, Indomethacin, Piroxicam, Nabumetone, Sulindac
Inhibit COX-2; retain COX- 1
More TXA
Increased MI and hypertension Non-selective
Ibuprofen, Naproxen
Inhibits COX
Less PGI and TXA
Decreased CV events Irreversible, Nonselective
Aspirin
Cardioprotective at low doses; increased GI risk Drugs Used for Gout Colchicine
Anti-inflammatory
Route: Oral
Metabolism: Liver
Elimination: Intestinal and Renal
MOA: Inhibits microtubule polymerization to prevent chemotaxis of neutrophils and phagocytosis to the site of inflammation.
Also inhibits LT-B4 and IL- 1 ß
Diarrhea
Indications: Acute gout flares, intercritical gout pain, initiation therapy w/ xanthine oxidase, cirrhosis, CAD, pericarditis prevention Glucocorticoids
NSAIDs
Route: Oral, IV, Intra- articular
Metabolism: Liver
Elimination: Renal
MOA: Inhibits phospholipase A
Gastritis, Gastric ulcer, GI bleeding
Indications: Severe symptomatic gout Allopurinol
Urate-lowering drugs
Route: Oral
Elimination: 1/ unchanged in urine
MOA: Inhibits xanthine oxidase
Gout flares (gout attack), exfoliative dermatitis
Indications: Chronic gout, hyperuricemia in px with CKD, Chemotherapy prophylaxis Febuxostat
Urate-lowering drugs
Route: Oral (80% bioavailability)
Metabolism: Hepatic
Elimination: Renal
MOA: Non-purine xanthine inhibitor
Liver fxn abnormalities, diarrhea, headache, nausea
Indications: Chronic gout Pegloticase (Recombinant Mammalian Uricase)
Uricosurics (tophaceous gout)
Route: IV infusion ( wks)
MOA: Converts uric acid to allantoin
Gout flares, anti- pegloticase antibodies, hemolytic anemia
Indication: Chronic gout

NSAIDs and Anti-Gout Drugs, Summaries of Pharmacology

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PHARMACOLOGY

COX- 2