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Pharmacology > Lecture 7 - NSAIDs > Flashcards

Lecture 7 - NSAIDs Flashcards

1
Q

What does Phospholipase A2 generate?

A

precursor called arachidonic acid

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2
Q

Role of arachidonic acid

A

acts as secondary messenger and a substrate for groups of enzymes lipoxygenases and cyclooxygenase (COX) to produce lipid-soluble mediators.

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3
Q

what does lipoxygenase enzyme pathway produce?

A

leukotrienes

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4
Q

what does COX pathway lead to?

A

production of Prostaglandins and thromboxanes

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5
Q

what is COX pathway inhibited by?

A

NSAIDs (e.g. aspirin, paracetamol and ibuprofen) during inflammatory response

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6
Q

What do NSAIDs work as?

A
  1. Anti-inflammatory
  2. Analgesic (certain types of pain)
  3. Antipyretic (reducing high temperature)
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7
Q

Structure of COX enzymes

A
  • made up of two identical subunits (dimeric)
  • each subunit has a small carbon-rich knob to anchor into ER
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8
Q

what are the two active sites of COX enzymes?

A
  1. Cyclooxygenase site - buried deep and guides arachidonic acid out of membrane into enzyme.
  2. Peroxidase site - activate heme groups to participate in cyclooxygenase reaction
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9
Q

COX 1 isoform

A
  • expressed in most tissues
  • has homeostatic function
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10
Q

COX2 isoform

A
  • is an inducible enzyme (not expressed in cells)
  • inducible expression in inflammatory cells after cytokine stimulation, GF and tumour promoter.
  • immediate response gene
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11
Q

COX 3 isoform

A
  • variant of COX1
  • expression is limited, found in brain and kidneys
  • paracetamol acts through COX3 (for headaches)
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12
Q

what inhibits the cyclooxygenation reaction of arachidonic acid?

A

COX1 and COX2 inhibiters to prevent production of prostaglandin E2

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13
Q

How is COX2 structure different to COX1?

A

it has a smaller amino acid (valine) to make it a wider channel compared to COX1 which has isoleucine. Means COX2 can selectively filter drugs.

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14
Q

what is the danger of inhibiting prostaglandins?

A

mucous no longer produced by GI tract so no protection from acid (or aspirin) and burns stomach lining. Also maintains blood flow of kidneys.

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15
Q

what is the aspirin action on COX enzymes?

A

acetyl group part connects to serine amino acid to permanently inactivate enzyme.

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16
Q

what is suicide inhibition?

A

identifies a drug that covalently causes a permanent inactivation of the target (e.g. aspirin on COX)
- only solved by forming new enzymes and no drug

17
Q

selectivity of NSAIDs

A
  • most show little selectivity and work same way, except for paracetamol (no anti-inflammatory effect)
18
Q

most desired target for NSAIDs

A

COX2 for its anti-inflammatory effect and COX1 has unwanted side effects (e.g. GI tract). COX2 found in CNS, kidney and tumours

19
Q

Side effects of using NSAIDs

A
  1. causes GI tract issues from acid ( gastric bleeding and ulcers)
  2. effects renal function and could cause kidney failure
  3. causing liver damage as metabolite of phase 1 reaction for paracetamol is toxic.
  4. could cause asthma attacks and skin rashes
20
Q

What NSAID has higher risk of causing gut problems?

A

Naproxen

21
Q

Advantages of COX2 selective drugs

A

NSAIDs like Vioxx and Valdecoxib reduce the unwanted GI tract effects

22
Q

Disadvantages of COX2 selective drugs

A
  • may have cardiovascular effects as mechanism is unknown
  • could increase blood pressure, atherogenesis and thrombotic tendency.
23
Q

Disadvantages of COX1 selective drugs

A
  • controls blood clot formation so patients with bleeding disorders would have an undesired side effect
24
Q

characteristics of aspirin

A
  • has anti-platelet action and reduces inflammation
  • reduces risk of colonic and rectal cancer
  • weak acid, rapid and efficient absorption in ileum
  • suicide inhibitor so action is irreversible
25
Q

characteristics of ibuprofen

A
  • similar action to aspirin accept it is a competitive inhibitor
26
Q

characteristics of paracetamol

A
  • analgesic and lowers body temp (antipyretic)
  • COX3/1 selective
  • well absorbed and metabolised in liver
  • precursor is hepatotoxic in unconjugated form
  • competitive inhibitor
27
Q

clinical use of aspirin

A

used as an antithrombotic for patients at high risk of arterial thrombosis

28
Q

what NSAIDs are used as an anti-inflammatory as clinical use?

A

ibuprofen, naproxen (codeine)

29
Q

what is used as an antipyretic?

A

Paracetamol

Pharmacology (14 decks)

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