NSAIDs

Question 1

Signs of inflammation and why they happen

Answer 1

1. Redness - vasodilation
2. Heat - vasodilation
3. Swelling - influx of proteins and phagocytic cells
4. Pain - local release of enzymes and increased tissue pressure

Question 2

Pathways of Arachidonic acid release and metabolism

Answer 2

1. Stimulus - trauma, hormones, Immunoglobulins, Phagocytosis…
2. Phospholipase A is active
3. Arachidonic acid is produced from phospholipids of the membrane
4. COX and LOX are produced
5. COX –> protanoids (prostaglandins, prostacyclin, thromboxane)
   LOX –> HETEs, Leukotrienes, Lipoxins

Question 3

What regulates high temperature during inflammation?

Answer 3

Hypothalamus

Question 4

Cyclooxygenases

Answer 4

COX-1 - active 24h/day, present in most cells, generates prostanoids for “housekeeping” functions

COX-2 - expression varies depending on a stimulus, major source of prostanoids in inflammation and cancer, primary source of vascular prostacyclin. Responsible for adaptation functions, ex: kidneys.

COX-3 - in brain and heart

Question 5

How does COX-3 induce fever?

Answer 5

1. Interleukin-1 is responsible for fever and it reaches the blood
2. Then it reaches the CNS- thermoregulation center
3. COX-3 is activated
4. Prostaglandins are produced in the CNS
5. They act on the center
6. Increase body temp.

Question 6

How COX-2 selective drugs have effect only on COX-2?

Answer 6

• They do that because COX molecules have different structures
• COX-1 molecules have NO side pocket and COX-2 does
• COX-2 inhibitor have a bulky grouping which fits perfectly to the side pocket.

Question 7

NSAIDs actions (4)

Answer 7

Anti-inflammatory - decrease PGE2 and prostacyclin
Analgesic -decrease prostaglandins
Anti-pyretic - COX-3
Anti-platelet - COX-1 irreversible block

Question 8

NSAIDs indications (6)

Answer 8

Analgesic 
Anti-inflammatory
Anti-pyretic
Anti-platelet
Closing ductus arteriosus in preterm infants 
Relief of pain

Question 9

NSAIDs local use (3)

Answer 9

• No systemic effect - a very high amount is necessary to reach systemic circulation
• Ibuprofen - topical cream absorbed into fascia and muscle and liquid gel
• Diclofenac - topical gel and ophthalmic preparation (post-operative inflammation prevention, relief of pain)

Question 10

Adverse effects - quite similar for all of them

Answer 10

• GI - ulcers, abdominal pain, nausea, vomiting
• Cardiovascular - edema, hypertension, heart failure
• Renal - renal insufficiency, proteinuria, hyperkalemia
• Hepatic - abnormal liver function tests
• These drugs should be avoid in pregnancy
• All have cardiovascular risks but they are most common with COX-2 inhibitors
• RULE: these drugs should always be given in the lowest dose and lowest period possible

Question 11

Drug with the lowest and the highest ulcers risk

Answer 11

Lowest - ibuprofen

Highest - azapropazone, indomethacin (from the ones we need to know)

Question 12

Why are Ibuprofen and Naproxen the better option? What are the main differences between them?

Answer 12

Because they have a better selectivity between COX-1 and COX-2, with the least number of cardiovascular side effects

Naproxen - longer 1/2 life, no interaction with aspirin, less side effects, longer duration of action, inhibition of prostacyclin and thromboxane is equal
Ibuprofen - may interfere with aspirin because it blocks aspirin’s access to COX-1

Question 13

Mechanism-based Fitz Gerald hypothesis

Answer 13

Normally: there is a balance between prostacyclin and thromboxane

When COX-2 inhibitors are used, prostacyclin levels decrease and thromboxane levels increase = risk of thrombus formation is higher!

When COX-1 inhibitors are used, thromboxane levels decrease = anti-thrombotic state

Prostacyclin - COX-2 is responsible for it’s production and its function is vasodilation and stopping platelet aggregation

Question 14

ASPIRIN

-mechanism of action

Answer 14

• IRREVERSIBLY inhibits COX-1 and platelet
• main function: inhibit platelet aggregation (lasts 8-10 days)
• if needed for other functions, higher doses are necessary
• high doses (3-6g/day) –> anti-inflammatory
• only aspirin is not enough to shut down completely platelet aggregation, because platelets have many receptors.
• if patient needs to undergo surgery, aspirin should be discontinued 4-5 days before otherwise patient bleeds out

Question 15

ASPIRIN

• Pharmacokinetics
• Clinical uses

Answer 15

• different kinetics depending on the dosage. 1st order kinetics when dosage is low because everything could be eliminated.
• Zero order kinetics in higher doses because the drug takes long the be eliminated and there is a risk of accumulation

-angina, MI, stroke, Alzheimer’s disease

Question 16

ASPIRIN

-Adverse effects (3)

Answer 16

• Salicylism, Peptic ulceration, Reye’s syndrome (hepatotoxicity), Renal toxicity, hypersensitivity (angioedema)
• do not give it to children with chicken pox or influenza B
• could exacerbate asthma –> COX-1 inhibited –> decrease prostagladin synthesis –> lipoxygenase is not blocked –> leukotrienes are produced –> bronchospasms + congestion

Question 17

ASPIRIN

-overdose phases

Answer 17

1. First phase - respiratory alkalosis
   - increase O2 comsumption –> increase CO2 production –> hyperventilation
   - Salicylism
   - Renal compensation by increase excretion of bicarbonate
2. Second phase - metabolic acidosis
   - medullary depression
   - depletion of bicarbonate, accumulation of salicylic acid

Question 18

PARACETAMOL (acetaminophen)

• mechanism of action (3)
• pharmacokinetics (4)

Answer 18

• inhibits COX-3
• no anti-inflammatory action
• do not excess 4g/day - toxic metabolite (N-acetyl-p-benzoquinone)
• orally
• partially metabolized in the liver, 90% combine with glucuronide and sulphate before excretion
• 5% will leave the body unchanged, 5% will be metabolized by CYP2E1 (to benzoquinoneimine)
• 1/2 life is 2-3h, not affected by renal function

Question 19

PARACETAMOL (acetaminophen)

-indications (3)

Answer 19

• analgesic and anti-pyretic agent
• NO ANTI-INFLAMMATORY ACTIONS
• preferred in patients allergic to NSAIDs, hemophilia, peptic ulcer and those in which bronchospasm is worsened by aspirin

Question 20

PARACETAMOL (acetaminophen)

-Adverse effects (3)

Answer 20

• reversible increase in hepatic enzymes, renal failure and hemolytic anemia is rare
• dizziness, excitment, disorientation in higher doses
• 15g may be fatal - severe hepatotoxicity

Question 21

Non-selective reversible COX inhibitors (5)

-names

Answer 21

Diclofenac
Indomethacin
Ibuprofen
Ketorolac
Naproxen

Question 22

Non-selective reversible COX inhibitors

-functions

Answer 22

Diclofenac - less risk of ulceration, higher CV risks

Ibuprofen - less risk of ulceration, used to close ductus arteriosus in pre-term infants

Indomethacin - used to close ductus arteriosus in pre-term infants, extra anti-inflammatory effects (gout)

Ketorolac - analgesic, NO anti-inflammatory effects, can replace morphine in mild to moderate pain

Naproxen - longer 1/2 life, least CV effects, local use is also possible (topical preparation and ophthalmic solution)

Question 23

COX-2 selective inhibitors (Coxibs)

• functions (3)
• names (2)

Answer 23

• inhibit prostaglandin synthesis by the COX-2 enzyme without inhibiting COX-1 “housekeeping” functions
• no impact on platelet aggregation
• higher incidence of cardiovascular side effects
• Meloxicam
• Celecoxib

Question 24

Meloxicam (4)

Answer 24

• COX-2 inhibitor
• “preferentially” selective, Celecoxib is more
• fewer GI symptoms and complications
• does not affect platelet aggregation

Question 25

Celecoxib (5)

Answer 25

- COX-2 inhibitor - more selective - fewer GI symptoms and complications - does not affect platelet aggregation - can interact with warfarin

Question 26

PARACETAMOL (acetaminophen) | -alcohol interaction (3)

Answer 26

- Alcohol makes CYP2E1 more active --> changes the way of metabolization of the drug --> more NAPQ1 is metabolized --> super toxic for the liver - Glutathione is necessary to neutralize this toxic metabolite - Paracetamol toxicity - use Acetylcysteine (percursor of glutathione)