NSAIDS

Question 1

What explains the GI complaints associated with aspirin use?

Answer 1

Decreased production of PGs that promote mucus secretion

Question 2

Why does aspirin increase bleeding time

Answer 2

TXA₂ production in platelet decreases

Question 3

General properties of NSAIDS

Answer 3

• Anti-inflammatory
• Anti-pyretic
• Analgesic

Question 4

Mechanism of action of all NSAIDS

Answer 4

Inhibition of cyclooxygenase

Question 5

Acetylsalicylic Acid/Aspirin mechanism of action

Answer 5

Irreversible inhibitor of Cox 1 and 2

Acetylation of a serine moiety - Serine 230

Question 6

Why doesn’t protein synthesis occur in both Endothelial cells AND platelets

Answer 6

Platelets have no nucleus - once inhibited, cannot create more protein

Question 7

Aspirin

Absorption:

Distribution:

Answer 7

Absorption: Oral absorption

• Rapidly absorbed from stomach and small intestine
• limited by dissolution rate (chewing increases)
• Buffered (substances which neutralize acid) vs. enteric coated (dissolves in intestines)

Distribution:

• Highly bound to plasma proteins
• Crosses BBB and placental barrier

Question 8

Aspirin Metabolism

Answer 8

Renal Elimination

Plasma half life is dose-dependent

Question 9

Unique effects specific to Aspirin/Salicylates

Answer 9

Uric Acid Excretion

CNS

Respiration

Question 10

Uricosuric Effects

Answer 10

• Any agent that increases rate of excretion of uric acid
• Uptake of uric acid from renal tubules via a transporter that acts as an anion exchanger
• Uriosuric agents compete with the urate transporter

Question 11

What is the dose dependent Uricosuric effect of Aspirin?

Answer 11

Low doses - decrease uric acid exretion

• Secretory component for urate sensitive to low concentrations of salicylates

Large doses - Increase uric acid excretion

• Normal mechanism to block reabsorption via interaction with transpoter (OAT)

Question 12

CNS effects of high doses of Salicylates (Toxicity)

Answer 12

• Stimulation followed by depression
• Tinnitus, high tone deafness, confusion, dizziness, delirium, psychosis, coma
• Nausea and vomiting

Question 13

_________ are a major limitation to long term therapy with NSAIDs

Answer 13

GI side effects

Question 14

PGs and their function in the GI

Answer 14

• Inhibit acid secretion by the stomach
• Promote secretion of cytoprotective mucus in the intestine

Question 15

NSAID GI Side Effects

Answer 15

Block the production of cytoprotective PGs

• GI ulceration and irritation

Question 16

NSAIDs and Platelets

Answer 16

• All NSAIDs increase bleeding time by inhibiting platelet TXA₂
• Platelets lack nucleus so new COX only with new platelets since ASA irreversible inhibition of COX

Question 17

Aspirin Hypersensitivity

Answer 17

Blocking COX forces arachidonic acid to follow other pathways leading to products which promote allergy, bronchoconstriction. inflammation and mucus production

• Treated as analphylactic shock (epinephrine)

Question 18

NSAID renal side effects

Answer 18

• Decrease renal blood flow
• Promote salt and water retention
• Effects more prominant in individuals dependent on vasodilatory PGs
  
  • Elderly

Question 19

NSAIDs and pregnancy

Answer 19

• Prolongation of gestation
• Prolonged labor
• Increased risk of postpartum hemorrhage
• Intrauterine closure of the Patent Ductus Arteriosus
  
  • NSAIDS still used

Question 20

Dose needed for Salicylate poisoning

Asprin:

Methyl Salicylate:

Answer 20

Aspirin: dose 10 to 30 grams

Methyl Salicylate: dose of 4.7 grams in children

Question 21

Aspirin Half Life During Over Dose

Answer 21

15-30 hours

Question 22

Reye’s Syndrome

Answer 22

• Specific to aspirin
• Most often in children (6-11)
• Acute encephalopathy; Liver degeneration
• Often follows a viral illness
• Mechanism unknown (Mitochondrial damage?)

Question 23

Drug Interactions for NSAIDs

Answer 23

1. Alcohol
2. NSAIDS
3. Steroids
4. Anticoagulants
5. Methotrexate

Question 24

NSAID therapeutic uses:

• Low Dose:
• Intermediate Dose:
• High Dose:

Answer 24

Low Dose (80 mg/day): CV disease

Intermediate Dose (325 mg to 1g/day): Low intensity pain/fever

High Dose (5-8 grams/day): Chronic inflammatory disease/ rheumatoid arthritis

Question 25

Side Effects Associated with all Non-Selective NSAIDs

Answer 25

* GI irritation * Inhibition of platelet aggregation/ bleeding * Decrease in RBF in patients dependent on vasodilatory PGs * Hypersensitivity

Question 26

Propionic Derivatives

Answer 26

1. Ibuprofen 2. Naproxen

Question 27

Indomethacin Function: Administration: Therapeutic Uses: Side Effects:

Answer 27

Function: Reversible inhibition of COX1 and COX2 Administration: Both oral and IV Therapeutic Uses: Gout; preterm labor; close PDA Side Effects: Severe frontal headache * Better tolerated if given at night

Question 28

Ketorolac Function: Administration: Therapeutic Uses: Side Effects:

Answer 28

Function: Reversible inhibitor of COX1 and COX2 Administration: Oral, IV, and IM administration Therapeutic Uses: Used as alternative for opioid analgesics in the treatment of post-operative pain Side Effects: Possibility of serious adverse GI, renal, bleeding, and hypersensitivity

Question 29

Piroxicam Metabolism: Administration (per day): Therapeutic Uses:

Answer 29

Metabolism: Metabolized by CYP2C9 (extremetly long t½) Administration (per day): Oral administration/ once a day Therapeutic Uses: Symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis

Question 30

Nabumetone (pro-drug) Administration (per day): Function: Therapeutic Use:

Answer 30

Administration (per day): Oral administration/ once a day Function: Active metabolite that may be more COX2 specific Therapeutic Use: Management of osteoarthritis and rheumatoid arthritis

Question 31

Sulfasalazine - Mechanism of Action

Answer 31

* Effect is independent of COX inhibition * Inhibition of cytokine production * Inhibition of lipoxygenase * Free radical scavenger

Question 32

Sulfasalazine Pharmacokinetics: Pharmacological effects: Adverse effects: Therapeutic Uses:

Answer 32

Pharmacokinetics: Azo bond prevents absorption in upper GI tract Pharmacological effects: Local effect in GI to inhibit inflammation Adverse effects: Occur in high % of patients (sulfa moiety) Therapeutic Uses: Ulcerative colitis; Rheumatoid arthritis

Question 33

Benefit of developing COX2 specific inhibitors

Answer 33

If only block COX2, can treat inflammation without risk of GI side effects

Question 34

What does Celecoxib (Celebrex) inhibit?

Answer 34

COX-2 selectively

Question 35

Celecoxib mechanism of action

Answer 35

* Binds tightly to a distinct hydrophilic side pocket region of COX-2 * Close proximity to COX2 binding site * COX 2 specific because this site is not present in COX1

Question 36

Celecoxib Administration: Absorption: Metabolism:

Answer 36

Administration: Oral administration Absorption: Highly bound to plasma proteins Metabolism: Metabolized via CYP2C9 to inactive metabolites

Question 37

Celecoxib Major adverse effects: Major Contraindications:

Answer 37

Major adverse effects: Increase risk of GI irritation, ulceration, bleeding Major Contraindications: History of GI bleeding; deficiency of CYP2C9

Question 38

Celecoxib Therapeutic Uses

Answer 38

* Signs/symptoms of rheumatoid arthritis and osetoarthritis * Primary dysmenorrhea * Acute pain * Colorectal polyps

Question 39

Acetaminophen Mechanism of Action

Answer 39

Not fully understood No affinity for active site of COX (may be selective for brain COX) May prevent reduction of COX to peroxidase form * inhibition by acetaminophen would be more effective under reducing conditions of low peroxide concentration * High levels of peroxide (inflammatory sites) are resistant to the action of acetaminophen

Question 40

Acetaminophen Administration: Metabolism: Excretion:

Answer 40

Administration: Oral administration Metabolism: Partially by liver microsomal system * CYP2E1, CYP1A2, CYP3A4 - half life is 2 hours * Mainly undergoes glucoronidation and sulfation Excretion: Renal excretion

Question 41

Acetaminophen: Toxicity

Answer 41

* Well tolerated at normal doses * Little to no GI issues * Most serious is hepatic toxicity

Question 42

Hepatic Toxicity with Acetaminophen Symptoms? Management?

Answer 42

* Symptoms * Liver injury - elevated liver enzymes * Severe cases: liver failure; death * Management * N-Acetylcysteine (replenishes gluathione stores) * Earlier is better \< 36 hours

Question 43

Role of alcohol in acetaminophen toxicity

Answer 43

* Alcohol induces the P450 involved in production of toxic metabolite * Alcohol depletes glutathione

Question 44

Therapeutic use of Acetaminophen

Answer 44

1. Acute pain and fever 2. No anti inflammatory effects