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Pharmacology > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

Signs of inflammation and why they happen

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

Pathways of Arachidonic acid release and metabolism

A
  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
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3
Q

What regulates high temperature during inflammation?

A

Hypothalamus

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4
Q

Cyclooxygenases

A

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

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5
Q

How does COX-3 induce fever?

A
  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.
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6
Q

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

A
  • 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.
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7
Q

NSAIDs actions (4)

A

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

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8
Q

NSAIDs indications (6)

A 
Analgesic 
Anti-inflammatory
Anti-pyretic
Anti-platelet
Closing ductus arteriosus in preterm infants 
Relief of pain
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9
Q

NSAIDs local use (3)

A
  • 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)
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10
Q

Adverse effects - quite similar for all of them

A
  • 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
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11
Q

Drug with the lowest and the highest ulcers risk

A

Lowest - ibuprofen

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

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12
Q

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

A

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

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13
Q

Mechanism-based Fitz Gerald hypothesis

A

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

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14
Q

ASPIRIN

-mechanism of action

A
  • 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
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15
Q

ASPIRIN

  • Pharmacokinetics
  • Clinical uses
A
  • 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

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16
Q

ASPIRIN

-Adverse effects (3)

A
  • 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
17
Q

ASPIRIN

-overdose phases

A
  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
18
Q

PARACETAMOL (acetaminophen)

  • mechanism of action (3)
  • pharmacokinetics (4)
A
  • 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
19
Q

PARACETAMOL (acetaminophen)

-indications (3)

A
  • 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
20
Q

PARACETAMOL (acetaminophen)

-Adverse effects (3)

A
  • reversible increase in hepatic enzymes, renal failure and hemolytic anemia is rare
  • dizziness, excitment, disorientation in higher doses
  • 15g may be fatal - severe hepatotoxicity
21
Q

Non-selective reversible COX inhibitors (5)

-names

A 
Diclofenac
Indomethacin
Ibuprofen
Ketorolac
Naproxen
22
Q

Non-selective reversible COX inhibitors

-functions

A

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)

23
Q

COX-2 selective inhibitors (Coxibs)

  • functions (3)
  • names (2)
A
  • 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
24
Q

Meloxicam (4)

A
  • COX-2 inhibitor
  • “preferentially” selective, Celecoxib is more
  • fewer GI symptoms and complications
  • does not affect platelet aggregation
25
Q

Celecoxib (5)

A
  • COX-2 inhibitor
  • more selective
  • fewer GI symptoms and complications
  • does not affect platelet aggregation
  • can interact with warfarin
26
Q

PARACETAMOL (acetaminophen)

-alcohol interaction (3)

A
  • 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)

Pharmacology (29 decks)

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