NSAIDs

Question 1

Nociceptive Pain

Answer 1

• Early warning system for a potentially damaging stimulus
• Includes inflammatory pain
  
  • Ideally promotes healing of injured tissue

Question 2

Neuropathic Pain

Answer 2

• Maladaptive, persistent, and recurrent
• PNS or CNS damage ⇒ abnormal sensory processing
• Pain is real but no anatomic lesion present

Question 3

NSAIDs

Indications

Answer 3

• Acutely for nociceptive pain
  
  • Provide pain relief
  • Reduce inflammation and feve
• Chronically for inflammatory pain
  
  • Reduce inflammation caused by osteoarthritis, rheumatoid arthritis, ankylosing spondylitis
  • Do not stop the progression of the disease

Question 4

NSAIDs

MOA

Answer 4

⊗ Cyclo-oxygenase

Responsible for the production of inflammatory mediators

COX converts arachidonic acid → prostaglandins

Two isozymes ⇒ COX I and COX II

Question 5

COX Products

Effects

Answer 5

• COX I is constitutively active
  
  • GI protection
    
    • PGI₂ ⇒ ⊗ acid secretion
    • PGE₂ & PGF_2α ⇒ ⊕ mucus synthesis
  • Platelet function
    
    • TXA₂ ⇒ ⊕ aggregation
  • Regulates renal blood flow
    
    • Prostaglandins ⇒ vasodilation
      
      • Balances the effect of vasoconstrictors
• COX II is an inducible enzyme
  
  • Responsible for producing prostaglandins that mediate pain, inflammation, and fever

Question 6

NSAIDs

Actions

Answer 6

3 main pharmacological actions:

1. Analgesia for mild to moderate pain
   
   • PGE₂ ⇒ ↑ terminal membrane excitability @ site inflammation ⇒ sensitization of nerve endings to chemical mediators
   • NSAID’s ⊗ peripheral PGE₂ production ⇒ ↓ sensation of pain
   • May be used in combo with opioids
2. Anti-inflammatory
   
   • Infection or injury ⇒ WBC infiltration ⇒ prostaglandin production ⇒ vasodilation & ↑ permeability of post-capillary venules ⇒ edema
   • NSAIDS ⊗ COX ⇒ ↓ production
3. Antipyretic
   
   • Inflammation ⇒ pyrogens ⇒ ↑ PGE₂ in the hypothalamus
   • ↓ PGE₂ ⇒ ↓ fever when hypothalamic set point is elevated
   • Do not affect temperature in healthy individuals

Question 7

NSAIDS

Selectivity

Answer 7

COX II ⊗ most important for therapeutic effect

Always used @ concentration that will ⊗ COX II

Question 8

Renal

Adverse Effects

Answer 8

• Hypovolemia, cirrhosis, heart failure, diuretics, renal and CV disease ⇒ ↑ vasoconstrictors such as Ang II and catecholamines
• Prostaglandins antagonize the intrarenal effects of vasoconstrictors ⇒ maintains blood flow
• NSAIDs ⊗ prostaglandin synthesis ⇒ allows vasoconstriction to predominate
• Can lead to acute renal failure

Question 9

Gastrointestinal

Adverse Effects

Answer 9

GI bleeding and ulcers

NSAIDs irritate the lining of the GI tract via several mechanisms:

Many are weak acids ⇒ traps H+ inside gastric mucosal cells ⇒ topical effect on stomach lining

⊗ of prostaglandin synthesis ⇒ ↓ gastric mucous synthesis & ↑ acid secretion

↓ TXA2 ⇒ ↓ platelet aggregation ⇒ ↑ risk of GI bleeds

Prevention of GI irritation

Misoprostol is prostaglandin agonist which reduced the risk of gastric

and duodenal ulcers

It may also cause diarrhea. It induce abortions in

women.

Proton pump inhibitors reduce acid secretion. Generally, they have few

adverse effects but they can cause diarrhea, constipation, abdominal pain, headache, and long-term use may lead to stomach infections. They can also inhibit the absorption of vitamins and ions that are dependent on an acid environment.

Question 10

GI Adverse Effects

Prevention

Answer 10

• Misoprostol ⇒ prostaglandin agonist
  
  • ↓ Risk of gastric and duodenal ulcers
  • May also cause diarrhea
  • Induce abortions in women
• Proton pump inhibitors ⇒ ↓ acid secretion
  
  • Can cause diarrhea, constipation, abdominal pain, headache,
  • Long-term use may lead to stomach infections
  • ⊗ Absorption of vitamins and ions that are dependent on an acid environment

Question 11

Platelet Function

Adverse Effects

Answer 11

Inhibition of platelet function

• COX-1 in platelets ⇒ TXA₂ production ⇒ ↑ platelet aggregation
• COX-2 in endothelial ⇒ PGI₂ production ⇒ ↓ platelet aggregation
• Platelets cannot make more COX but endothelial cells can
• Aspirin irreversibly ⊗ in platelets
  
  • Prevents MI by causing a long-lasting ⊗ of platelet aggregation
• Other NSAIDs ⇒ transient ⊗ of COX
  
  • Can ⊗ antiplatelet action of ASA by blocking access to COX

Question 12

Cardiovascular

Adverse Effects

Answer 12

• All NSAIDS except ASA
  
  • Low-dose ASA platelet specific
• ↑ risk of serious CV thrombotic events, MI and stroke
  
  • Risk ↑ w/ duration of use & underlying CV disease
• Due to an imbalance between actions of TXA₂ and PGI₂
• COX-II selective inhibitors ⇒ ⊗ PGI₂ production in endothelial cells w/o sign. ⊗ of TXA₂ in platelets ⇒ ⊕ platelet aggregation and clot formation
  
  • Rofecoxib & Valdecoxib removed from market d/t cardiotoxicity
• May also be related to ∆ endothelial function, oxidative stress, and renal effects

Question 13

Aspirin

(Acetylsalicylic acid)

Indications

Answer 13

• Low-dose (80 mg/day) used prophylactically to ↓ risk of MI & CVA
• Used for low intensity pain, to reduce fever, and as an anti-inflammatory (325 to 650 mg)
• Used to reduce inflammation in RA (1 to 4 g/day)
• Long-term use at low doses ⇒ ↓ incidence of colon cancer and possibly other cancers

Question 14

Aspirin

Pharmacokinetics

Answer 14

• Readily absorbed from stomach or small intestine
  
  • Weak acid ⇒ uncharged and better absorbed in the stomach
  • Surface area of small intestine much greater ⇒ large amount also absorbed there
• Widely distributed in all tissues ⇒ CSF, peritoneal cavity, synovial fluid
• Bound to plasma proteins ⇒ can displace other drugs ⇒ ↑ toxicity
• ASA acetylates albumin
• Deacylated in liver and plasma by esterases → salicylic acid (also an NSAID)
• Low dose (325 to 650 mg) ⇒ T_½ = 3 hours min
• High dose (1 g) ⇒ T_½ = 15 hours
  
  • D/t saturation of metabolic paths (zero order kinetics)
• Urinary excretion is pH dependent
  
  • Sodium bicarbonate ↑ urine pH ⇒ ↑ excretion of salicylic acid (weak acid is charged at alkaline pH)

Question 15

Aspirin

Unique Adverse Effects

Answer 15

• Strong ass. b/t ASA taken for viral illnesses and development of Reye’s syndrome
  
  • See confusion, brain swelling, and liver damage
• Salicylism
• Acid-base imbalance
• Gout
  
  • Therapeutic levels ⇒ ↓ uric acid elimination
  • Toxic levels ⇒ ↑ uric acid elimination

Question 16

Aspirin

Hypersensitivity

Answer 16

• Aspirin-exacerbated respiratory disease (AERD)
  
  • Low incidence in general population
  • ↑ to ~ 20% in asthma & higher in pts w/ asthma + nasal polyps
  • Likely d/t shift of arachidonic acid metabolism to leukotriene pathway
• Aspirin induced urticaria/angioedema
  
  • May be due to histamine release
• True anaphylaxis is rare

Question 17

Aspirin

High Therapeutic Doses

Answer 17

• Uncouples ox. phos. mainly in skeletal muscle ⇒
• ↑ O₂ consumption ⇒
• ↑ metabolic production of CO₂ ⇒
• ⊕ Respiration by ↑ CO₂ & a direct effect on respiratory center ⇒
• Hyperventilation ⇒ respiratory alkalosis ⇒
• Renal compensation via HCO₃^- excretion ⇒
• Fever, dehydration, hypokalemia ⇒
• Compensated respiratory alkalosis

Question 18

Aspirin Poisoning

Moderate Doses

Answer 18

Moderate toxicity causes salicylism

Symptoms:

Sweating

Vomiting

Epigastric pain

Tinnitus

Blurred vision

Question 19

Aspirin Poisoning

Toxic Doses

Answer 19

• High concentrations depress the respiratory center ⇒
• Retention of CO₂ ⇒
• Plasma HCO₃^- is already low, so retention of CO₂ leads to an uncompensated respiratory acidosis ⇒
• Superimposed on a metabolic acidosis d/t build up of pyruvic,
• lactic and acetoacetic acids and aspirin itself ⇒
• Fever, dehydration, hypokalemia

Question 20

Aspirin Poisoning

Management

Answer 20

• Therapeutic levels usu. < 300 ug/ml
• Mild or moderate salicylism (500-750ug/ml)
  
  • Requires only oral or IV rehydration
  • Particular attention to K⁺ supplements
• Marked signs/symptoms of salicylism or levels > 750 ug/ml
  
  • Requires specific elimination therapy
    
    1. Oral activated charcoal
    2. Alkalinization of urine
    3. Hemodialysis is required for any of the following:
       
       • Levels > 1,000 mg/ml (7.25 mmol/l)
       • Persistent/progressive acidosis
       • Deteriorating level of consciousness

Question 21

Ibuprofen

Answer 21

• ~ Equal to ASA for relief of arthritic pain
• Lower frequency of GI irritation
• Used for rheumatoid arthritis and osteoarthritis
  
  • 2,400 mg/day is anti-inflammatory
  • Lower doses have analgesic properties
• May also be used for PDA
• Concomitant use with ASA may limit anti-inflammatory and anti-platelet effect
• Cross allergy with aspirin
• Naproxen also in this category of drugs

Question 22

Indomethacin

Answer 22

• Very potent COX inhibitor
• Significant GI toxicity
• Indications:
  
  • For moderate to severe arthritis pain
    
    • Reserved for use in gouty arthritis, ankylosing spondylitis, and osteoarthritis of the hip
  • May also be used for PDA
• Sulindac is a prodrug related to indomethacin
  
  • Side effects less severe

Question 23

Ketorolac

Answer 23

• Only NSAID available for IM admin
• Also given intranasal and PO
• For moderate to severe pain (e.g. postoperative pain)
• Analgesic potency equal to a moderate dose of morphine
• Not used as an anti-inflammatory
• Short-term use only (1-5 days)
• High level of GI upset, renal effects, risk of bleeding
  
  • Do not use before surgery

Question 24

Celecoxib

Answer 24

Relatively COX-2 selective

Anti-inflammatory & analgesic w/o GI damage

Indications:

• OA and RA in adult patients
• Management of acute pain in adults
• Treatment of primary dysmenorrhea
• Management of familial adenomatous polyposis (FAP)
  
  • ↓ # of adenomatous colorectal polyps

Question 25

Rofecoxib & Valdecoxib

Answer 25

**COX-2 Seletive** Removed from the market d/t significant ↑ incidence of MI and sudden death

Question 26

NSAID Recommendations

Answer 26

**Naproxen** appears to have _lowest risk for CV adverse effects._

Question 27

Acetaminophen MOA & Actions

Answer 27

"**Paracetamol**" _Not an NSAID_ **⇒ Analgesic & antipyretic but NOT anti-inflammatory** Exact MOA unknown May **⊗** another isozyme of cyclooxygenase (COX-3)

Question 28

Acetaminophen Toxicity Pathogenesis

Answer 28

* Metabolized by **cytochrome P-450 mixed function oxidase** * Resulting **benzoquinone** **imine** reacts w/ **glutathione** to form * **non-toxic metabolite** * Large doses deplete glutathione * Metabolite reacts with **sulfhydryl groups in hepatic proteins** ⇒ necrosis

Question 29

Acetaminophen Toxicity Treatment

Answer 29

Treatment consists of _providing free SH groups_ to detox benzoquinone imine intermediate ## Footnote **Give N-acetyl cysteine (Mucomyst)**

Question 30

Acetaminophen Recommendations

Answer 30

FDA Recommendation for Acetaminophen: **650 mg every 4-6 hours** (max 3,250 mg/24 hours) **1,000 mg every 6 hours** (max 3,000 mg/24 hours)

Question 31

Medication-overuse Headache

Answer 31

* **Caused by use of excessive quantities of abortive or analgesic medications** * \> 15 days per month * **Daily or near daily headache** * Varies in severity, type, and location * Predictable, frequent early morning (2AM to 5AM) headaches * **Low pain threshold upon physical or cognitive exertion** * _Headaches accompanied by:_ * **Weakness** * **Nausea and other GI symptoms** * **Restlessness, anxiety, irritability** * **Mood and cognitive defects** * Development of tolerance to analgesics