NSAIDS

Question 1

DRUG LIST

Answer 1

Aspirin and friends
– Aspirin
– Salicylate

NSAID’s
– Ibuprofen
– Naproxen
– Acetaminophen 
– Celecoxib

GI protective Drugs
– Omeprazole
– Misoprostol

Question 2

NSAID Excretion

Answer 2

RENAL

Question 3

NSAID pharmacokinetics

Answer 3

Competitive inhibitors of COX enzymes via reversible active site inhibition (note: aspirin is IRREVERSIBLE)

Major biological effect is related to inhibition of prostaglandin synthesis

Question 4

NSAID’s‐ Therapeutic Effects

Answer 4

At lower doses:
• Analgesia (can be additive with opioids)
• Antipyretic

At HIGHER doses
• Anti‐inflammatory
– Musculoskeletal disorders: Arthritis
– Symptomatic relief

Question 5

Arachidonic Acid Pathway

Answer 5

Stimulus (chemical/physical stress) >>
Phospholipase A2 >>
Phospholipids >>
Arachidonic acid >>
EICOSANOIDS

Question 6

Eicosanoids

Answer 6

Oxygenated polyunsaturated fatty acids

Act in paracrine/autocrine manner

Bind to specific receptors on cell membranes
– Arachidonic acid (precursor)
• Prostaglandins
• Thromboxanes
• Leukotrienes (Dr. Ceryak)

Question 7

Prostanoid pathway

Answer 7

Cyclooxygenase (COX) >>
prostaglandins
prostacyclin
thromboxane
(all prostanoids)

Question 8

Prostanoids: Prostacyclin

Answer 8

PGI2: (Prostacyclin)
• Synthesized by vascular endothelium
• Vasodilation
• Inhibits platelet aggregation (counteracts TXA2)

Question 9

Prostanoids: Thromboxane

Answer 9

TXA2: (Thromboxane)
• Platelet aggregation (made from platelet COX‐1)
• Vasoconstriction/Bronchoconstriction

Question 10

Prostanoids: PGE1

Answer 10

PGE1:
• Misoprostol: PGE1 analog, prevents peptic ulcer by preventing acid secretion, termination of early pregnancy (in combo with mifepristone)

Question 11

Prostanoids: PGE2

Answer 11

PGE2:
• Increases body temperature (produced by COX‐2 after interleukin‐ 1 stimulation)

• Inflammation (via  blood flow, vasodilation/leukocyte infiltration, edema)
– Suppresses humoral antibody response

• Protective against peptic ulcers

Question 12

Eicosanoid Receptors

Answer 12

Increase cAMP or cytosolic Ca++

Question 13

Cyclooxygenase (COX)

Answer 13

Two isoforms:
• COX‐1 (PGH synthase‐1)
– Constitutive expression in most tissues (ALWAYS)
• Inhibition leads to GI‐related side effects

• COX‐2 (PGH synthase‐2)
– Expression is induced by ‘stress’, growth factors, cytokines and inflammatory mediators .
• Major source of prostanoids at sites of inflammation (cancer)

Question 14

NSAIDS and COX inhibition

Answer 14

All NSAIDS are nonselective, EXCEPT celecoxib (note: blackbox warning for CV risk)

Question 15

NSAID use

Answer 15

Analgesic

• Particularly effective when pain is due to an inflammatory process

Question 16

NSAID use

Answer 16

Antipyretic‐ lowers fever
**PGE2 is elevated by cytokine release in and adjacent to the pre optic hypothalamus triggering an elevation of body temp and decrease in heat lost (NSAIDs inhibit prostaglandin synthesis)

Question 17

NSAID use

Answer 17

Anti‐inflammatory
• Generally need larger doses
• ONLY SYMPTOMATIC RELIEF

Question 18

NSAIDS and Cancer

Answer 18

Increasingly apparent relationship between chronic inflammation and cancer

Question 19

Common Adverse Effects for NSAID’s: GI

Answer 19

Pain, nausea, diarrhea, gastric ulcers/erosions, GI hemorrhage, perforation (other NSAIDs less than aspirin)

Question 20

Common Adverse Effects for NSAID’s: Renal

Answer 20

• Renal insufficiency, renal failure, hyperkalemia, proteinuria
• decrease effectiveness of antihypertensive meds
• Analgesic nephropathy: slowly progressive renal failure, decreased concentrating capacity; associated with high doses of combinations of NSAID’s and frequent urinary tract infections – Decreased PGE2 = less renal blood flow?

Recall PGE2 is involved in blood flow.

Question 21

NSAID and pregnancy

Answer 21

CONTRAINDICATED (only tylenol ok)

Question 22

Common Adverse Effects for NSAID’s: Hypersensitivity

Answer 22

Hypersensitivity reactions – not IgE‐meditaed

• Aspirin intolerance/allergy is contraindication for therapy with any other NSAID

RED FLAG for aspirin = nasal polyps

Question 23

Common Drug Interactions Associated with NSAID’s

Answer 23

1) Use of NSAID’s concomitantly with low dose aspirin (cardioprotective)
• Ibuprofen impairs aspirin’s ability to acetylate the active site of COX and therefore entire anti platelet effect goes away

2) With ACE inhibitors
• ACE inhibitors + NSAID’s = hyperkalemia, (elderly, HTN, DM, ischemic heart disease)

• May decrease EFFICACY of ACE inhibitors (due to inhibition of vasodilatory PGs?), renal toxicity (NSAIDs decrease renal EXCRETION of ACE inhibitors)

Question 24

DI: Warfarin

Answer 24

NSAIDs and aspirin all inhibit platelet function: increased bleeding

Metabolized by CYP2C9 (inhibits metabolism of warfarin)

Question 25

Aspirin MOA

Answer 25

``` Analgesic Antipyretic (lo dose) Anti‐inflammatory‐ non‐selective irreversible inhibitor of both COX‐1 and COX‐2 – At higher doses than the analgesic/antipyretic dose ```

Question 26

Aspirin Metabolism

Answer 26

Acetylates Cox 1 and 2 | Liver breaks down to acetic acid and salicylate (salicylate = competitive and reversible inhibitor of COX)

Question 27

Aspirin: cardiovascular use

Answer 27

Cardiovascular‐Cardioprotective (low doses) (decreases platelet aggregation) * Platelet effects last 4‐7 days due to permanent inactivation of platelet COX’s; thromboxane (TXA2) synthesis prevented * Increased bleeding times • Decreased MI – 20‐25% aspirin (low dose) – 10% naproxen – Evidence does not support low‐dose aspirin in healthy individuals without CV risk factors (only in people with MI)

Question 28

Aspirin Adverse effects

Answer 28

Gastrointestinal Effects • Prevents synthesis of protective PGE1/2 for GI epithelial cells in stomach lining (increase acid secretion) • Co‐adm with PPI ``` Hypersensitivity (0.5‐2.5%) • Often nasal polyps • Reaction is not immunologically mediated • PROVOKED BY LOW DOSES • Probably due to diversion of AA to the leukotriene pathways (Cox‐1) • Mast cell and eosinophil involvement CROSS SENSITIVITY with all NSAIDS ```

Question 29

Aspirin Adverse effects 2

Answer 29

Acid‐base balance – at therapeutic dose: respiratory alkalosis (stimulation of respiratory center/medulla), increase CO2 production – at toxic doses: get a respiratory and metabolic acidosis due to accumulation of (lactic) acid products

Question 30

Aspirin Adverse effects 3

Answer 30

Renal Effects • Analgesic nephropathy – Slowly progressive renal failure, decreased renal perfusion Ototoxicity • Tinnitus, high frequency hearing loss

Question 31

Ibuprofen facts

Answer 31

- recently approve for IV | - short 1/2 life (2 hrs)

Question 32

Naproxen

Answer 32

- LONG 1/2 life (14 hrs)

Question 33

Celecoxib (Celebrex)

Answer 33

Preferentially inhibits COX2, therefore less GI side effects!! Risk of thrombosis, hypertension, atherogenesis —avoid in patients prone to cardiovascular or cerebrovascular disease.

Question 34

Celecoxib (Celebrex): CV risk

Answer 34

Inhibits PG12 which is a prostacylcin, therefore inhibits macrophage activation that releases Cox 2 (decrease platelet aggregation) and increased leukotrienes

Question 35

GI Protective Agents for Use with NSAIDs

Answer 35

``` Misoprostol • PGE1 analog • Inhibits gastric acid, prevents ulcers • Induces labor/Uterine contractions • Abortifacient ``` Omeprazole • Better tolerated than misoprostol • Proton pump inhibitor • Prodrug/enteric coating

Question 36

Acetaminophen Administration

Answer 36

PO, IV Analgesic and antipyretic activity – NO STRONG ANTI‐INFLAMMATORY ACTIVITY

Question 37

Acetaminophen Metabolism

Answer 37

Reversible inhibitor of Cox 1/2 Gets metabolized by glucuronidation and sulfation. If you saturate the enzyme, it goes down a third pathway. Forms a reactive toxic intermediate that binds to proteins in the liver. (the enzyme CYP2E1 involved can be increased by ethanol)

Question 38

Acetaminophen‐ Hepatotoxicity

Answer 38

* Single doses of 10‐15 g‐serious hepatotoxicity; 20‐25g are potentially fatal * Induction of CYP2E1 increases risk of toxicity * Symptoms‐ nausea, abdominal pain and anorexia * Plasma transaminases elevated 12‐36 h after ingestion * Clinical indication of hepatic damage 2‐4 d; liver enzymes peak 72‐96 h after drug

Question 39

Acetaminophen‐ Hepatotoxicity Tx

Answer 39

* Activated charcoal to reduce absorption | * N‐acetylcysteine (Mucomyst), detoxifies NAPQI