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S2B2: Pharm > NSAID & Acetaminophen > Flashcards

NSAID & Acetaminophen Flashcards

1
Q

Identify the receptors associated with nociceptive pain?

A

Nociceptive pain = noxious stimuli

all are transduction channels & when they open up they depolarize the nerve terminals - passed on up to pain recognition center of central nervous system

anyway you can prevent the action potentials from being generated in the first place or from making it to recognition center in CNS, you will have analgesia

  • TRPV: temperature sensitive and will respond to increases in skin temp & in your mouth
    • TRPV1 activated by capsation (chemical in peppers that make them hot)
  • ASIC: activated by low pH
  • MA: mechanosensitive
    • hit your finger with a hammer
  • TRPA1: sense pain associated with cold
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2
Q
A
  • inflammatory pain comes from immune cells (mast cells, neutrophils, macrophages) that release a bunch of chemicals
    • histamine
    • bradykinin
    • prostaglandins
      • ​generated by enzymes COX1 & COX2
      • binds to EP/IP receptor
        • activates protein kinase
        • if phosphorylates voltage-gated Na channel, increases it activity, so more action potentials are generated
        • if it phosphorylates a voltage-gated potassium channel, it could shut down that channel, increasing action potential activty in nociceptors
        • pain is perceived
    • ATP
    • H+
    • Interleukins
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3
Q

What if the difference between acute & chronic pain?

A
  • acute
    • less than 3-6 months
    • nociceptive & inflammatory pain
  • chronic
    • more then 3-6 months
    • somatic
      • osteoarthritis
        • nociceptive
      • rheumatoid arthritis
        • inflammatory
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4
Q

Describe the components of inflammatory pain

A
  • inflammatory pain comes from immune cells (mast cells, neutrophils, macrophages) that release a bunch of chemicals
    • histamine
    • bradykinin
    • prostaglandins
      • ​generated by enzymes COX1 & COX2
      • binds to EP/IP receptor
      • activates protein kinase
        • if phosphorylates voltage-gated Na channel, increases it activity, so more action potentials are generated
        • if it phosphorylates a voltage-gated potassium channel, it could shut down that channel, increasing action potential activty in nociceptors
    • pain is perceived
    • ATP
    • H+
    • Interleukins
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5
Q

Describe the synthesis of prostaglandins

A
  • Phospholipids are metabolized by phospholipase A2 to arachadonic acid
    • procesed by cyclooxygenases (focus of NSAIDs)
      • prostaglandins
      • thromboxane
    • processed by lipooxygenase
      • leukotrienes
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6
Q

Describe NSAIDs mechanism of action

A
  • COX1 & COX2 (inhibited by NSAIDs)
    • generate endoperoxidases (precursor for other types of compounds that cause pain)
      • PGI2 synthase will produce prostacyclin
        • Function (relaxes smooth muscle)
          • decreases platelet aggregation
          • decreases vascular tone
          • decreases bronchial tone
          • decreases uterine tone
      • TxA2 synthase will produce thromboxane
        • function
          • increas platelet aggregation
          • increase vascular tone
          • increase bronchial tone
      • PGE2 isomerase or PGF2 synthase will produce prostaglandins (PGE2, PGF2)
        • increase uterine tone
        • decrease vascular tone
        • decrease bronchial tone
        • increase pain
  • aspirins & coxids will inhibit COX enzymes in CNS & PNS
  • acetaminophen will only inhibit COX in CNS
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7
Q

What are the physiologic roles of COX 1 and COX 2?

A
  • COX-1
    • stomach protection - PGE2
    • Platelet aggregation - TxA2
    • Renal blood flow maintenance - PGE2 & PGI2
      • most prominent in renal disease
    • release of eggs from ovaries
  • COX-2
    • renal electrolyte balance - PGE2
      • most prominent in renal disease
    • vasodilation - PGE2 & PGI2
    • Release of eggs from ovaries
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8
Q

Go ahead and draw this

A
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9
Q

These lists are in order of potency

Go ahead and write these down

A
  • Katherine Is A Naturally Impressive Person
  • Claire Does Everything Momo Needs
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10
Q

Clinical uses of NSAIDs?

A
  • NSAID = Non-steroidal anti-inflammatory drugs
  • Analgesia
    • mild to moderate pain
    • used in combination with othr analgesics (e.g. acetaminophen)
    • central and peripheral action
  • Antipyresis (anti-fever)
    • no change in normal temperature
    • acts within the hypothalamus
  • Anti-inflammatory actions
    • treatment for rheumatoid athritis (RA) pain
  • Anti-platelet effects (via COX-1 inhibition)
    • reduced clotting decreases vascular occlusions (decreases MI or Stroke risk)
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11
Q

Pharmacology of NSAIDs?

Metabolism & drug-drug interaction chart?

A
  • diverse chemistry
  • well absorbed in the GI tract
  • >90% protein bound
    • potential drug-drug interactions
  • metabolism: primarily CYP2C9 or glucuronidation
    • potential drug-drug interactions
    • blocker will exacerbate adverse effects
    • inducers can give you treatment failure
  • drug-drug interactions
    • NSAIDs do not block or induce CYP enzymes
    • stong protein bindign may increase plasma concentration of other drugs with strong protein binding
      • methotrexate, digoxin, lithium
    • COX-1 inhibition can increase bleeding risk in patients taking anti-coagulant drugs
    • Renal effects of NSAIDs can interfere with the antihypertensive effects of beta-blockers, ACE inhibitors, ARBs adn diuretics
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12
Q

GI NSAIDs Adverse effects?

A
  • Gastrointestinal (primarily via COX-1 inhibition)
    • block protective effects of PGE in the GI tract
    • Chronic NSAID use is the 2nd most common cause of peptic ulcers
    • reduced risk with more selective COX-2 inhibitors (e.g. celecoxib)
    • patients starting long-term NSAIDs should be tested for Helicobacter pylri to determine ulcer risk
    • manage risk with proton pump inhibitors (e.e omprazole)
      *
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13
Q

Cardiovascular NSAIDs Adverse effects?

A
  • Cardiovascular (all non-aspirin NSAIDS carry CV warning)
    • COX-2 inhibition decreases vasodilation by inhibiting production of PGD2 and PGI2 from endothelium and vascular smooth muscle to increase MI & stroke risk
    • NSAIDs can increase blood pressure & may interfere with anti-hypertensive medication
    • CV events more frequent with more specific COX-2 inhibitors (potent COX-2 inhibitors out of US market)
    • AHA: no NSAIDS fro cardiovascular disease patients
    • AHA: no NSAIDS for CABG patients
      • coronary artery bypass
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14
Q

Describe the NSAID mechanism of cardiovascular risk

A
  • Platelets from COX-1 are generating TxA2
    • TxA2 can increase vasoconstriction & platelet aggregation
  • COX-2 endothelial cells are generating PGI2
    • PGI2 decrease platelet aggregation & vasodilate
  • under normal conditions, these different compounds are in homeostasis, so they keep the blood system in homeostasis

Atherothrombosis (atherosclerotic plaque that build up) - changes blood flow

  • get activated platelets that will generate TxA2
  • stress on endothelial cells generates more PGI2
  • Even with vessel narrowing, the compounds are still in balance
  • Aspirin – primarily inhibits COX-1 to reduce thrombosis, so less TxA2 is procuced
    • but, since the endothelial cells are still stressed, they are still producing a lot of PGI2 helping to vasodilate the vessel
  • In presence of COX-2 inhibitor, PGI2 is decreased, no longer there to counteract vasoconstrictive effects or proplatelet effects of TxA2
    • So now TxA2 is unopposed
      • further vasoconstriction
      • further platelet aggergation
      • can have another thrombotic clot form (MI or stroke)
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15
Q

Bleeding risk Adverse effects of NSAIDs?

A
  • Increased bleeding risk
    • COX-1 activity leads to the generation of TxA2, which increases blood clotting
    • blcking COX-1 can reduce clotting, which is why aspirin is used to reduce MI and stroke risk
    • NSAIDs can interfere with aspirin’s anti-platelet effect to increase MI and stroke risk
    • NSAIDs can severely decrease clotting to increase bleeding risk when given with aspirin or other anti-coagulant drugs (e.g. warfarin)
    • AHA recommends that NSAIDs be avoided in patients taking anti-coagulant drugs
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16
Q

Explain how NSAIDs can interfere with aspirin’s anti-platelet effect to increase MI and stroke risk

A
  • Spot on COX-1 enzyme with aracadonic acid active site that breaks it into the endoperoxides that will turn into Thromboxane & platelet
    • Aspirin binds covalently to a site within COX-1 (permanantly blocks)
  • Aspirin is an irreversible inhibitor of COX-1
    • 1/2 life depends on COX-1 synthesis
    • 8-10 days in platelets (life of the platelet)
    • 6-12 hours in cells that can synthesis new COX-1
    • need to take it every day b/c 100 million platelets generated each day
17
Q

What if someone gets up and takes an ibuprofen before they take their aspirin?

A
  • Ibuprofen got to the COX-1 before Aspirin & is preventing aspirin from accessing its site on COX-1
    • so, aspirin cannot permanently inacitvate COX-1
    • once ibuprofen goes away, increase the risk of MI/stroke
  • This can be controlled by taking aspirin 120 minutes prior to taking the NSAID or usign a more specific COX-2 inhibitor like celecoxib
18
Q

Renal system NSAID adverese effects?

A
  • Renal system
    • production of PGE2 adn PGI2 is upregulated in patients with renal disease to help maintain renal blood flow
    • blockign COX-1 in these patients can prevent vasodilation promoted by PGE2 and PGI2, which can produce renal ischemia and exacerbate renal disease
    • blocking COX-2 can induce sodium retention to increase plasma sodium levels (hypernaturemia)
    • hyperkalemia can also occur, particularly in patients with diabetes mellitus or receiving postassium-sparing diuretics
    • Chance of having a renal injury incrases with age, patients with hypertension & diabetes
19
Q

Which NSAIDs can cause heart failure as an adverse effect?

A
  • Ketorolac
  • Indomethacin
  • Heart failure
    • use of some NSIDs is associated with increased risk of hospitalization for heart failure, even in patients without a previous HF diagnosis
20
Q

How do NSAIDs have an effect on reproduction as an adverse effect?

A
  • Reproduction
    • both COX-1 and COX-2 inhibitors can block ovulation
    • the release of an egg from teh ovary is inhibited
    • In one study, women taking diclofenac ovulated only 6% of the time, while 100% of the control women ovulated
    • not recommended as birth control method
    • chronic use can interfere with woman becoming pregnant

S2B2: Pharm (1 decks)

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