NSAIDs Flashcards
Signs of inflammation and why they happen
- Redness - vasodilation
- Heat - vasodilation
- Swelling - influx of proteins and phagocytic cells
- Pain - local release of enzymes and increased tissue pressure
Pathways of Arachidonic acid release and metabolism
- Stimulus - trauma, hormones, Immunoglobulins, Phagocytosis…
- Phospholipase A is active
- Arachidonic acid is produced from phospholipids of the membrane
- COX and LOX are produced
- COX –> protanoids (prostaglandins, prostacyclin, thromboxane)
LOX –> HETEs, Leukotrienes, Lipoxins
What regulates high temperature during inflammation?
Hypothalamus
Cyclooxygenases
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
How does COX-3 induce fever?
- Interleukin-1 is responsible for fever and it reaches the blood
- Then it reaches the CNS- thermoregulation center
- COX-3 is activated
- Prostaglandins are produced in the CNS
- They act on the center
- Increase body temp.
How COX-2 selective drugs have effect only on COX-2?
- 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.
NSAIDs actions (4)
Anti-inflammatory - decrease PGE2 and prostacyclin
Analgesic -decrease prostaglandins
Anti-pyretic - COX-3
Anti-platelet - COX-1 irreversible block
NSAIDs indications (6)
Analgesic Anti-inflammatory Anti-pyretic Anti-platelet Closing ductus arteriosus in preterm infants Relief of pain
NSAIDs local use (3)
- 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)
Adverse effects - quite similar for all of them
- 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
Drug with the lowest and the highest ulcers risk
Lowest - ibuprofen
Highest - azapropazone, indomethacin (from the ones we need to know)
Why are Ibuprofen and Naproxen the better option? What are the main differences between them?
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
Mechanism-based Fitz Gerald hypothesis
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
ASPIRIN
-mechanism of action
- 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
ASPIRIN
- Pharmacokinetics
- Clinical uses
- 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
ASPIRIN
-Adverse effects (3)
- 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
ASPIRIN
-overdose phases
- First phase - respiratory alkalosis
- increase O2 comsumption –> increase CO2 production –> hyperventilation
- Salicylism
- Renal compensation by increase excretion of bicarbonate - Second phase - metabolic acidosis
- medullary depression
- depletion of bicarbonate, accumulation of salicylic acid
PARACETAMOL (acetaminophen)
- mechanism of action (3)
- pharmacokinetics (4)
- 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
PARACETAMOL (acetaminophen)
-indications (3)
- 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
PARACETAMOL (acetaminophen)
-Adverse effects (3)
- reversible increase in hepatic enzymes, renal failure and hemolytic anemia is rare
- dizziness, excitment, disorientation in higher doses
- 15g may be fatal - severe hepatotoxicity
Non-selective reversible COX inhibitors (5)
-names
Diclofenac Indomethacin Ibuprofen Ketorolac Naproxen
Non-selective reversible COX inhibitors
-functions
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)
COX-2 selective inhibitors (Coxibs)
- functions (3)
- names (2)
- 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
Meloxicam (4)
- COX-2 inhibitor
- “preferentially” selective, Celecoxib is more
- fewer GI symptoms and complications
- does not affect platelet aggregation
Celecoxib (5)
- COX-2 inhibitor
- more selective
- fewer GI symptoms and complications
- does not affect platelet aggregation
- can interact with warfarin
PARACETAMOL (acetaminophen)
-alcohol interaction (3)
- 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)
