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YR2 LCRS Pharmacology > 18. NSAIDS > Flashcards

18. NSAIDS Flashcards

1
Q

why are NSAIDS widely used?

A
  • ANALGESIC PROPERTIES: relief of mild-to-moderate pain, postoperative pain, menstrual pain
  • ANTIPYRETIC: reduction of fever
  • ANTI-INFLAMMATORY: rheumatoid arthritis, osteoarthritis, soft tissue injuries, gout
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2
Q

how do NSAIDS work?

A
  • inhibit prostanoid synthesis (prostanoids = lipid mediators derived from arachidonic acid, e.g. prostaglandins, thromboxane, prostacyclin)
  • prostanoids act as inflammatory mediators
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3
Q

what do NSAIDS do to COX?

A
  • inhibit the cyclo-oxygenase enzymes (COX 1&2)

- COX are the rate limiting step for the production of all prostanoids from arachidonic acid

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4
Q

what are the prostaglandins produced by arachidonic acid?

A
  • PGI2 (prostacyclin)
  • PGE2
  • PGD2
  • PGF2
  • Thromboxane A2
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5
Q

what are the 10 known prostanoid receptors?

A
  • DP1
  • DP2
  • EP1
  • EP2
  • EP3
  • EP4
  • FP
  • IP1
  • IP2
  • TP

(naming based on agonist potency)

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6
Q

what are the unwanted actions of PGE2?

A
  • increased pain perception
  • increased body temperature
  • acute inflammatory response
  • immune responses
  • tumorigenesis
  • inhibition of apoptosis
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7
Q

what do PGE2 analogues do?

A

lower the pain threshold:

  • nociceptors cause pain acutely and chronically (when stimulated you feel pain)
  • stimulation of PG receptors in the periphery sensitises nociceptors (lower pain threshold)
  • a less painful stimulus still produces pain
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8
Q

what does injection of a COX 2 inhibitor do to pain?

A

prevents/reduces the duration of prolonged pain

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9
Q

what does PGE2 do to hypothalamic neurones?

A

stimulates hypothalamic neurones, initiating a rise in body temperature

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10
Q

how is PGE2 involved in inflammation?

A

involves PGE2-EP3 signalling:

  • keratinocytes are stimulated by external stimuli to produce PGE2
  • EP3 receptors on mast cells are in turn stimulated
  • this produces calcium release –> degranulation –> histamine
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11
Q

what desirable physiological actions do PGE2 (and other prostanoids) have?

A
  • bronchodilation
  • renal salt and water homeostasis
  • gastro-protection
  • vaso-regulation
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12
Q

what is PGD2 the exception for?

A

it causes bronchoconstriction instead of bronchodilation

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13
Q

why should NSAIDS not be taken by asthmatics?

A

10% of asthma patients experience worsening symptoms because of the bronchoconstriction caused by the lack of prostanoids due to cyclooxygenase inhibition

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14
Q

how does PGE2 regulate salt and water homeostasis?

A
  • both COX 1&2 are involved at multiple points in the nephron
  • PGE2 has a role in increasing renal blood flow
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15
Q

what can NSAIDS cause in the kidneys?

A

RENAL TOXICITY:

  • constriction of afferent renal arteriole
  • reduction in renal artery flow
  • reduced glomerular filtration rate
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16
Q

what is the role of PGE2 in gastric cytoprotection? what do NSAIDS therefore do to the stomach?

A
  • parietal cells normally produce HCl, secreting it into the stomach
  • the cell lining the stomach therefore must be protected from the highly acidic environment
  • they produce a mucous layer and protect themselves by bicarbonate secretion
  • PGE2 down-regulates HCl secretion and stimulates mucus and bicarbonate secretion (COX 1 dependent actions)
  • NSAIDS increase the risk of gastric and duodenal ulceration
17
Q

what does the Coxib family do?

A

selectively reversibly inhibit COX2 (e.g. celecoxib) to reduce the incidence of ulcerations (as most NSAIDs reversibly inhibit both isoforms such as ibuprofen) however there were complications

18
Q

what does the use of NSAIDS pose a risk for?

A
  • MI
  • hypertension
  • stroke
19
Q

where is COX2 found?

A

in the vascular endothelial and smooth muscle cells, the heart and the kidney

20
Q

how do NSAIDS differ in their risk of GI bleeds and CVS events?

A

the more selective the drug is for COX1 the more likely you are to get a GI bleed

the more selective the drug is for COX2 the more likely you are to have a cardiovascular event

21
Q

describe other strategies other than COX-2 selective NSAIDS for limiting GI side effects

A
  • topical application
  • minimise NSAID use in patients with GI ulceration history
  • treat H pylori if present
  • administer with omeprazole/another proton pump inhibitor
  • minimise NSAID use in patients with other risk factors and reduce risk factors where possible (e.g. alcohol use, anticoagulant/steroid use)
22
Q

what is aspirin and what does it do?

A
  • selective for COX1
  • binds IRREVERSIBLY to COX enzymes
  • works by acetylation of the active site of both enzymes, particularly COX1
  • has anti-inflammatory, analgesic and anti-pyretic actions
  • reduces platelet aggregation
23
Q

why are the effects of aspirin dose-dependent?

A
  • platelets produce thromboxane which enhances platelet action
  • endothelial cells produce prostacyclin which decreases platelet action
  • thromboxane is made by COX1 in the platelet
  • the endothelial cell has both COX1 and COX2 so prostacyclin is reduced (but not completely)
  • giving aspirin at high dose will inhibit thromboxane production but it will also reduce prostacyclin production
24
Q

if aspirin acts to both increase and decrease platelet action how is it effective?

A

the nucleus in the endothelial cell replenishes COX enzymes but platelets have no nucleus so more thromboxane cannot be produced after aspirin

there is therefore an overall reduced aggregation of platelets

25
Q

what are the major side effects of aspirin?

A
  • gastric irritation and ulceration
  • bronchospasm in sensitive asthmatics
  • prolonged bleeding times
  • nephrotoxicity
26
Q

what is paracetamol and what does it do?

A
  • good analgesic for mild-to-moderate pain
  • has anti-pyretic action
  • does not have any anti-inflammatory effect
  • NOT AN NSAID
27
Q

what can overdose of paracetamol cause and why?

A
  • irreversible liver failure
  • paracetamol is normally metabolised by the cytochrome p450 complex and a toxic metabolite NAPQI is produced which is highly reactive
  • at a therapeutic dose NAPQI is produced in small amounts and removed by glutathione
  • if glutathione is saturated with NAPQI the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death
28
Q

what is the antidote for paracetamol poisoning?

A

add compound with -SH group (usually IV acetylcysteine)

29
Q

describe the legislations on over the counter sale of analgesics

A
  • pack size of paracetamol restricted to 16 x 500mg tablets per pack
  • no more than 2 packs per transaction

YR2 LCRS Pharmacology (32 decks)

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