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Year 2 LCRS - Pharmacology > NSAIDS > Flashcards

NSAIDS Flashcards

1
Q

What are he properties of NSAIDS?

What are they used for?

A

ANALGESIC PROPERTIES:

  • Relief of mild-to-moderate pain
  • Toothache, headache, backache
  • Postoperative pain (opiate sparing so people can take less opiates)
  • Dysmenorrhea (menstrual pain)

ANTIPYRETIC:
- reduction of fever e.g. influenza

ANTI-INFLAMMATORY: - - Reduction of inflammation

  • Rheumatoid arthritis
  • Osteoarthritis
  • Other forms of musculoskeletal inflammation
  • Soft tissue injuries (strains and sprains)
  • Gout
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2
Q

What are prostanoids?

A

lipid mediators, derived from arachidonic acid e.g prostaglandins, thromboxane, prostocyclin

act as inflammatory mediators

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3
Q

How do NSAIDS work?

A

inhibit production of prostanoids by COX enzymes

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4
Q

How many prostanoid receptors are there?

A

10 (named based on potency)
DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1, IP2, TP

*not specific

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5
Q

What are the prostaglandins produced by arachadonic acid?

A
  • PGI2 (prostacyclin)
  • PGE2
  • PGD2
  • PGF2
  • thromboxane A2
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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 effects do PGE2 analogues have on the pain threshold?

A

Nociceptors cause pain, both ACUTELY and CHRONICALLY

Stimulation of PG receptors in the periphery sensitises nociceptors -> LOWER PAIN THRESHOLD

  • EP1 receptors and EP4 receptors (EP4 in periphery and spine)
  • Endocannabinoids (neuromodulators in thalamus, spine and periphery)
  • Increasing beta-endorphin in spine
  • Not mutually exclusive
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8
Q

What is the effects of PGE2 on the hypothalamus?

A

PGE2 stimulates hypothalamic neurones initiating a rise in body temperature

Animals were treated with lipopolysaccharide (found on gram –ve bacteria, highly pro-inflammatory). Once injected, the levels of PGE2 raised dramatically, followed by dramatic increase in temperature

  • Flu patients treated with NSAIDs saw a decrease in body temperature
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9
Q

How is PGE2 involved in inflammation?

A

EP3 works through multiple mechanisms - calcium regulated and through G protein coupled receptors.

  • There is cross-talk between cells
  • 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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10
Q

What are the desirable actions of PGE2 (and other prostanois)?

A
  • Bronchodilation
  • Renal salt and water homeostasis
  • Gastro-protection
  • Vaso-regulation (dilation and constriction depending on receptor activated)
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11
Q

How do NSAIDS affect asthma?

A

Around 10% of asthma patients experience worsening symptoms with NSAIDS

Cyclooxygenase inhibition favours production of leukotrienes (bronchoconstrictors)

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12
Q

What is the role of PGE2 in salt regulation?

A

Both COX isoforms (COX 1 and 2) are involved at multiple points in the nephron. PGE2 has a role in renal blood flow (INCREASES FLOW)

  • So NSAIDs can cause renal toxicity
  • Constriction of afferent renal arteriole
  • Reduction in renal artery flow
  • Reduced glomerular filtration rate
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13
Q

What is the role of PGE2 in gastric cytoprotection?

A

Parietal cells normally produce HCl, secreting it into the stomach. Cells lining stomach produce a mucous layer and also protect themselves by bicarbonate secretion

  • PGE2 normally down-regulates HCl secretion (reduces the irritant in the first place)
  • PGE2 also stimulates mucus and bicarbonate secretion (increases production of protective layer)
  • THESE ARE BOTH COX 1 DEPENDENT ACTIONS
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14
Q

What are the effects of NSAIDS on the digestive system?

A

NSAIDs increase risk of gastric and duodenal ulceration (around 1000 deaths annually in England)

  • NSAIDs are taken orally, so there is a high load in the stomach
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15
Q

What does the coxib family of drugs do?

A

selectively inhibit both COX isoforms

  • Although these drugs did reduce the incidence of ulceration dramatically, there were complications
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16
Q

What are the unwanted effects of NSAIDS?

A
  • Vasoconstriction
  • Salt and water retention
  • Reduce the effects of antihypertensive drugs

Risk of:

  • Hypertension
  • Myocardial infarction
  • Stroke
  • All NSAIDS increase risk of GI bleeds and CVS events - The more selective the drugs are for COX-1, the more likely you are to get a GI bleed. The more selective the drugs for COX-2, the more likely you are to have a cardiovascular event.
17
Q

What strategies other than COX-2 selective NSAIDS are used for limiting GI side effects?

A
  • Topical application
  • Minimise NSAID use in patients with history of GI ulceration
  • Treat H pylori if present (trigger factor for ulcers)
    -If NSAID is essential, administer with omeprazole or other proton pump inhibitor
  • Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g.
    > Alcohol consumption
    > Anticoagulant or glucocorticoid steroid use
18
Q

How does aspirin work?

A

Selective for COX-1 - Binds IRREVERSIBLY to COX enzymes

It works by acetylation of the active site of both enzymes, but PARTICULARLY COX-1

  • Has anti-inflammatory, analgesic and anti-pyretic actions, reduces platelet aggregation
19
Q

What does it mean to say the effects of aspirin are dose dependent?

A

Platelets produce thromboxane, which enhances platelet action via COX-1 (pro-aggregatory)

Endothelial cells produce prostacyclin (PGI2), which decreases platelet action (anti-aggregatory)

  • In the endothelial cell is both COX-1 and COX-2 – so PGI2 is reduced, but probably not totally

LOW DOSE ASPIRIN: The nucleus in the endothelial cell simply replenishes COX enzymes. However, platelets do not have a nucleus. Therefore they cannot recover to produce more thromboxane after aspirin. This leads to NO RE-SYNTHESIS of COX-1 in platelets -> OVERALL REDUCED AGGREGATION OF PLATELETS.

HIGH DOSE ASPIRIN: There is BARELY ANY ACTION ON PLATELET AGGREGATION – this is because endothelial cell COX enzymes will be in a permanent state of inhibition

  • Giving aspirin at a high dose will inhibit thromboxane production - but it will also reduce prostacyclin production
20
Q

What is the anti-platelet actions of aspirin due to?

A
  • Very high degree of COX-1 inhibition which effectively suppresses TxA2 production by platelets
  • Covalent binding which permanently inhibits platelet COX-1
  • Relatively low capacity to inhibit COX-2
  • Use low dose to allow endothelial re-synthesis of COX-2
21
Q

What are the major side effects of aspirin at therapeutic doses?

A
  • Gastric irritation and ulceration
  • Bronchospasm in sensitive asthmatics
  • Prolonged bleeding times
  • Nephrotoxicity
  • Side effects likely with aspirin because it inhibits COX covalently, not because it is selective for COX-1
22
Q

Is paracetamol an NSAID?

A
  • Is a good analgesic for mild-to-moderate pain
  • Has anti-pyretic action
  • Does NOT have any anti-inflammatory effect
  • Therefore it is not a NSAID
23
Q

What are the consequences of a paracetamol overdose?

A

Overdose can cause irreversible liver failure

  • Paracetamol is normally metabolised by the cytochrome P450 complex -> A toxic metabolite is produced (NAPQI), which is highly reactive.

At a therapeutic dose, NAPQI is produced is very small amounts and will be mopped up by glutathione. If glutathione is depleted (saturated with NAPQI) the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death

24
Q

What is the antidote for paracetamol poisoning?

A
  • Add compound with –SH groups (usually intravenous acetylcysteine, occasionally oral methionine)
  • Acetyl cysteine used in cases of attempted suicide and accidental poisoning
  • If not administered early enough, liver failure may be unpreventable

Year 2 LCRS - Pharmacology (32 decks)

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