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17. Clinical Pharmacology and Therapeutics > 13. NSAIDs > Flashcards

13. NSAIDs Flashcards

1
Q

What are the three primary therapeutic effects of NSAIDs?

A

Analgesia, anti-inflammatory, antipyretic.

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2
Q

Name some autacoids.

A

Bradykinins, histamine, cytokines, leukotrienes, nitric oxide, neuropeptides, eicosanoids - includes prostaglandins.

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3
Q

What are eicosanoids?

A

20 C phospholipid derivatives used as signalling molecules.

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4
Q

What are the different classes of eicosanoids?

A

Prostaglandins, prostacyclins, thromboxanes, leukotrienes.

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5
Q

What are eicosanoid classes derived from?

A

Arachidonic acid, cleaved from cell membrane phospholipids.

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6
Q

What synthesises prostaglandins?

A

Cyclo-oxygenase enzymes (COX enzymes).

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7
Q

Outline the mechanism of PG ‘G’ and PG ‘H’ formation.

A

Cell membrane phospholipids -> arachidonic acid (phospholipase A2) -> PG ‘G’ (COX-1/COX-2) -> PG ‘H’ (COX-1/COX-2).

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8
Q

Which prostaglandin is most important in mediating inflammatory response?

A

PG ‘E’.

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9
Q

What are the effects of PG ‘E’?

A

Vasodilaton, hyperalgesia, fever, immunomodulation.

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10
Q

Where is COX-1 expressed?

A

Across a wide range of tissue types.

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11
Q

What is the role of PG synthesised by COX-1?

A

Cytoprotective role in gastric mucosa, myocardium, renal parenchyma, ensures optimised local perfusion (reduces ischaemia).

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12
Q

What is the half life of COX-1 synthesised PG?

A

Short, around 10 mins so it needs to be synthesised constantly.

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13
Q

What is the result of NSAIDs acting to inhibit COX-1?

A

ADRs.

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14
Q

Where is COX-2 expressed?

A

Only in injured tissues, induced by inflammatory mediators, or constitutively in brain and kidney.

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15
Q

What is the result of NSAIDs acting to inhibit COX-2?

A

Therapeutic effects.

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16
Q

What is the difference in structure of COX-1 and COX-2?

A

COX-1 is tight, COX-2 is baggy.

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17
Q

How is selective inhibition by different NSAIDs achieved with COX-1 and COX-2 enzymes?

A

COX-1 can only fit smaller drugs, COX-2 can fit larger drugs.

18
Q

What is the action of prostaglandins?

A

Bind GPCRs (action depends on PG receptor type) then has synergising effects of other autacoids.

19
Q

How do prostaglandins respond to inflammation?

A

Autacoids and prostaglandins released post injury from local tissues and blood vessels. Autacoid release induces expression of COX-2 and synergises with other autacoids. PGs act as potent vasodilators and synergise permeating effects of bradykinin and histamine.

20
Q

What is the result of PG ‘E’ acting on EP2 receptors?

A

Increased vasodilation.

21
Q

What is the result of PG ‘E’ acting on EP1 receptors?

A

Increased peripheral nociception. Increases neuronal sensitivity to bradykinin, inhibits K+ channels (prevents hyperpolarisation), increases Na+ channel sensitivity.

22
Q

How is pain felt via EP1 receptors?

A

Painful stimuli carried by afferent C fibres, PGE2 synthesised by surrounding tissue to trauma/injury, other atuacoids are released. PGE2 binds with C fibre neuronal EP1 via Gq GPCR and activates it to have more C fibre activity.

23
Q

What is meant be peripheral sensitisation of EP1 binding?

A

EP1 binding increases C fibre activity, it also increases intracellular Ca2+ via Gq GPCR so there is more neurotransmitter release which gets more autacoids involved -> increased sensitivity.

24
Q

What happens with increased sustained nociceptive signalling peripherally?

A

Increased cytokine levels in dorsal horn cell body so more COX-2 synthesis and PGE2 synthesis. PGE2 acts via local GPCR EP2 receptors to increase sensitivity and discharge rate of secondary interneurones via glycinergic inhibition.

25
Q

What is meant by central sensitisation by PGE2?

A

PGE2 binds EP2 Gs type and activates it so increased cAMP and PKA, decreased glycine receptor binding affinity and increased pain perception.

26
Q

What is the overall effect of activation of EP3 receptors?

A

Pyrexia.

27
Q

How do EP3 receptors cause pain?

A

Endotoxins stimulate macrophages to release IL-1 which acts in hypothalamus to increase PGE2 synthesis. This acts on EP3 Gi GPCRs causing increased heat production and decreased heat loss.

28
Q

What are the general therapeutic effects of NSAIDs?

A

Competitive inhibition of COX-2 (+ COX-1) to cause analgesia, anti-inflammation, and anti-pyrexia.

29
Q

What determines the physician’s choice of NSAID for a patient?

A

The dominant disesae state and the individual patient response.

30
Q

What is the typical route of administration of NSAIDs?

A

Orally, may be topical for soft tissue injury.

31
Q

What are the half lives of NSAIDs?

A

<6hrs or >10hrs.

32
Q

What is the main therapeutic use of anti-inflammatory NSAIDs?

A

Musculoskeletal disorders, such as rheumatoid/osteoarthritis.

33
Q

What are the main therapeutic uses of analgesic NSAIDs?

A

Mild to moderate pain (less effective than opiates), moderate pain.

34
Q

What are the ADRs of NSAIDs due to?

A

Inhibition of COX-1 enzymes.

35
Q

What are the ADRs of NSAIDs?

A

Iatrogenic morbidity and mortality with long term use in elderly, stomach/GI tract symptoms, renal ADRs if HRH or hypovolaemia.

36
Q

What are the GI ADRs of NSAIDs?

A

Stomach pain, nausea, heartburn, gastric bleeding, ulceration.

37
Q

What causes the GI ADRs of NSAIDs?

A

COX-1 PGE2 stimulates cytoprotective mucus secretion throughout the GI tract so reduces acid secretion and promotes mucosal blood flow.

38
Q

What are the rates of GI ADRs with NSAID use?

A

35% of users, if long term 10-30%.

39
Q

How can GI ADRs form NSAIDs be offset?

A

Use PPIs or misoprostol (synthetic PG).

40
Q

Which patients suffer from renal ADRs with NSAID use?

A

HRH compromised - heart failure, renal disease, hepatic cirrhosis - due to compromised renal blood flow.

41
Q

What causes renal ADRs with NSAID use?

A

PGE2 and PGI2 maintain renal blood flow so if decreased then GFR is reduced. Na+/K+/Cl- and H2O retention leads to increased likelihood of hypertension.

42
Q

NOT FINISHED

A

GOT TO SLIDE 30

17. Clinical Pharmacology and Therapeutics (25 decks)

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