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MD2002 > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are the main actions of NSAIDs?

A
  • anti-inflammatory
  • anti-pyretic
  • analgesic
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2
Q

What is the primary action of NSAIDs?

A

Inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase (COX) enzymes.

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3
Q

What are NSAIDs mainly used for?

A

Rheumatoid arthritis and other chronic conditions associated with arthritis.

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4
Q

How are prostaglandins forms?

A

Generated in tissues from a precursor (arachidonic acid) by COX enzymes. Thromboxanes, prostaglandins and leukotrienes are all products of arachidonic acid metabolism.

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5
Q

What is the relationship between inflammation and prostaglandins?

A

Inflammation is always accompanied by prostaglandin release, predominantly PGE2 but also PGI2. PGD2 is from mast cells. All of these act as potent vasodilators and also synergise with other inflammatory mediators.

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6
Q

What do prostaglandins do in inflammation?

A

Potentiate histamine and bradykinin actions on post-capillary venule permeability and pain sensory nerves. This changes the permeability of capillaries in inflamed regions causing a leak in movement of fluid out of the capillary and into the interstitial space causing swelling.

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7
Q

What is the anti-inflammatory action of prostaglandins?

A

Prostaglandins are very important mediators of inflammation particularly vasodilation and resultant oedema. Less effect on cellular migration or accumulation.

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8
Q

What is the anti-pyretic action of prostaglandins?

A

Body temperature is regulated in the hypothalamus and fever occurs when the set point is raised. Bacterial endotoxins can release IL-1 from macrophages which causes generation of prostaglandins in hypothalamus by COX and so prostaglandins increase the set point.

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9
Q

What is the anti-pyretic action of NSAIDs?

A

NSAIDs act by preventing formation of prostaglandins and therefore preventing an increase in temperature.

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10
Q

What is the anti-inflammatory action of NSAIDs?

A

NSAIDs only affect particular aspects of inflammation in which prostaglandins play a significant role.
NSAIDs can reduce many of the signs of local inflammation but have less effect on vascular permeability, the endothelial cell and capillaries will stay potent and won’t be leaky so this stops the accumulation of fluid in the interstitial space which reduces inflammation.

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11
Q

What is the analgesic action of prostaglandins?

A

Inflamed areas painful due to histamine and bradykinin release. Active nociceptive afferent nerve terminal registers a sharp stimulus.
Prostaglandin synthesis nociceptive nerves to these compounds.

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12
Q

What is the analgesic action of NSAIDs?

A

By preventing prostaglandin production using NSAIDs, this prevents the sensitisation to pain-producing compounds. Prostaglandins increase the effectiveness of histamine and bradykinin.

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13
Q

Name NSAID drugs

A

Aspirin
Selective COX-2 inhibitors (COXIBS)
Propionic acids and fenamates
(Paracetamol) - not technically an NSAID

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14
Q

Explain the mechanism of action of aspirin

A

a lot of acetylsalicylic acid is converted into salicylic acid so the mechanism of action is predominantly due to the reversible inhibition by salicylic acid rather than any direct inhibition by acetylsalicylic acid.

  • acetylsalicylic acid can directly acetylate COX enzymes
  • also metabolised to activate compounds (salicylic acid) by plasma and tissue esterases
  • salicylates found in plasma within 30 mins
  • peak plasma conc within 1-2 hours
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15
Q

Explain the mechanism of action of propionic acids and fenamates

A

they are taken and directly act upon COX inhibitor.
e.g. ibuprofen.
no pro-drugs, well absorbed and last for 4-6hrs

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16
Q

Explain the mechanism of action of selective COX-2 inhibitors

A

These are more ideal as inhibiting COX-1 can result in severe GIT side effects. Drugs which only inhibit COX-2 do exist but they are very expensive to make and so non-selective drugs are more commonly made.

  • Used for osteo and rheumatoid arthritis.
  • Restricted for when traditional NSAIDs produce too severe GIT effects.
  • CV risk needs to be assessed.
17
Q

Explain the mechanism of action of paracetamol

A
  • Good analgesic and antipyretic effect but poor anti-inflammatory action.
  • It is however well tolerated in the GIT.
  • Weak COX inhibitor may be selective inhibitor of CNS-specific COX (COX-3).
  • Given orally and is well absorbed.
  • Peak plasma conc in 30-60mins
  • Half life in plasma 2-4hrs for therapeutic doses
18
Q

What is COX-1?

A

Constitutive (present and expressed all around the body at a baseline level). Important in maintaining GIT integrity (prostaglandins maintain the physiology of cells and secretions but may also modify and influence the effects of ANS on the GI system.

19
Q

What is COX-2?

A

Inducible (isn’t normally expressed, induced by processes such as inflammation). Implicated in cancer development.

20
Q

What are the 2 mechanisms of action of NSAIDs?

A
  1. An irreversible, time-dependent inhibition of the enzyme

2. A reversible, rapid, competitive inhibition of the enzyme

21
Q

Explain the irreversible time-dependent inhibition of the enzyme NSAID mechanism

A
  • Predominantly the way in which aspirin works. Aspirin acetylates the COX enzyme irreversibly, removing it from the functioning pool of enzymes, it can only be replenished by generating more of the enzyme.
  • When you take an aspirin orally, only a percentage will make it to COX enzymes to irreversibly inhibit them. The vast majority of aspirins converted other enzymes to salicylic acid which lack the acetyl group allowing them to inhibit the enzyme but they can still interact with the enzyme which trips it into the rapid inhibition of the enzyme.
22
Q

Explain the rapid, reversible, competitive inhibition of the enzyme NSAID mechanism

A
  • Most NSAIDs work in this way, aspirin can also work in this way as it has a dual mechanism of action.
  • Ibuprofen works this way by binding reversibly to the enzyme. It then competes with natural substance, arachidonic acid.
  • This mechanism of action prevents the production of things that COX enzymes mediate. These drugs will be reversibly inhibited by COX enzymes which act predominantly through this action.
23
Q

What are the major side effects of paracetamol?

A
  • Not as many side effects as NSAIDs due to selectivity for COX enzymes.
  • Major issue is hepatoxicity due to overdose. Normally inactivated in the liver by glucoronate and sulphate conjugation.
  • When these enzymes are saturated, toxic metabolites are formed and this can result in hepatic necrosis.
24
Q

What are the major side effects of selective COX-2 inhibitors?

A
  • Known CV risk
25
Q

What are the major side effects of salicylates?

A
  • Stomach: bleeding and ulcers
  • Systemic: dizziness, nausea, hypersensitivity
  • Metabolic changes: acid/base balance affected
  • Haemostasis: blood clots, blood coagulation
  • CNS: stimulation initially, eventually coma and respiratory depression
  • Renal: insufficiency in susceptible patients and with chronic use and overdose
26
Q

What are the clinical uses of NSAIDs?

A
  • ANTI-INFLAMMATORY ACTIONS - both chronic and acute inflammatory conditions. Dosage for chronic inflammatory disorders is high. Low incidence of side effects is important. COXIBS used for arthritis
  • ANALGESIA - headaches, nausea, cancers, backache post-operative pain
  • SHORT-TERM ANALGESIA - aspirin, paracetamol, ibuprofen
  • LONGER LASTING DRUGS FOR CHRONIC PAIN - naproxen, diclofenac
  • ANTI-PYRETIC - to decrease temperature, paracetamol preferred as it lacks the GIT side effects

MD2002 (6 decks)

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