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Yr 2 LCRS - Pharm > 18 - NSAIDS > Flashcards

18 - NSAIDS Flashcards

1
Q

What is a NSAID?

A

Non-Steroidal Anti-Inflammatory Drugs

A drug class that reduce pain, decrease fever, prevent blood clots and, in higher doses, decrease inflammation.

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2
Q

Outline facts regarding the use of NSAIDs in the UK

A
  • Widely prescribed (16 million prescriptions annually in England)
  • Very widely used, especially by the elderly
    • (> 15% at any one time)
  • Available over the counter
  • Increased risk of GI and CVS deaths
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3
Q

What are NSAIDs used to treat?

A

Relief of mild-to-moderate pain (analgesic)

  • Toothache, headache, backache
  • Postoperative pain (opiate sparing)
  • Dysmenorrhea (menstrual pain)

Reduction of fever (antipyretic)

  • Influenza

Reduction of inflammation (anti-inflammatory)

  • Rheumatoid arthritis
  • Osteoarthritis
  • Other forms of musculo-skeletal inflammation
  • Soft tissue injuries (strains and sprains)
  • Gout
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4
Q

In an overall sense, explain how NSAIDs work?

A

NSAIDS inhibit prostanoid synthesis

Prostanoids have a variety of actions including acting as inflammatory mediators

Receptor-mediated action

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5
Q

What do NSAIDs inhibit?

A

The Cyclo-Oxygenase Enzymes (COX 1 and 2)

(and as a result, prevent prostanoid production)

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6
Q

What prostanoid receptors exist?

A

10 known receptors

5 known prostanoids (agonists)

Receptors named based on agonist potency, however they are not totally specific

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

Naming based on agonist potency

Prostanoids have both G protein-dependent and -independent effects

Knock out mice show that prostanoid effects are extremely complex

Physiological and pro-inflammatory (pathological) actions

Prostaglandins can activate more than one type of receptor to a certain degree

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7
Q

What are prostanoids?

A

Prostanoids

Lipid mediators

Derived from arachidonic acid

  • Prostaglandins
  • Thromboxane
  • Prostacyclin
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8
Q

How are prostanoids formed?

A

COX = rate limiting step for the production of all prostanoids.

Production all begins with arachidonic acid (with a very open structure).

Arachidonic acid has a very open structure

The products of COX action look a bit more like tadpoles

All the products have a closed structure, with a 5-membered ring and 2 lipid tails

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9
Q

What prostanoids are formed from arachidonic acid?

A

The prostaglandins produced are:

  • PGI2 (prostacyclin)
  • PGE2
  • PGD2
  • PGF2
  • Thromboxane A2
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10
Q

What effects do prostanoids have on their receptors?

A

Prostanoids have both G protein-dependent & -independent effects (not all actions G-protein mediated)

Knock out mice show that prostanoid effects are extremely complex

Side effects are both physiological and pro-inflammatory

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11
Q

What can be the consequences of inhibition of prostanoid production?

A

INHIBITION OF PROSTANOID PRODUCTION CAN HAVE MULTIPLE, COMPLEX CONSEQUENCES

Take PGE2 as an example

  • PGE2 can activate 4 different receptors (EP1, EP2, EP3 and EP4)
  • Some receptors can work through 2 different mechanisms (EP2)
  • There are G-protein (cAMP-dependent and independent downstream) mechanisms.
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12
Q

What are some unwanted effects of PGE2?

A
  • Increased pain perception
  • Increased body temperature
  • Acute inflammatory response
  • Immune responses
  • Tumorigenesis
  • Inhibition of apoptosis
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13
Q

How can PGE2 analogues lower pain thresholds?

A

PGE2 ANALOGUES LOWER THE PAIN THRESHOLD

  • Nociceptors cause pain, both ACUTELY and CHRONICALLY (when stimulated, you feel PAIN)
  • Stimulation of PG receptors in the periphery sensitises nociceptors
  • Therefore, lowers pain threshold
  • A less painful stimulus will produce pain nonetheless
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14
Q

How do prostanoids lower the pain threshold?

A

Mechanisms are unclear:

  • 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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15
Q

How is PGE2 pyrogenic?

A

PGE2 IS PYROGENIC – PGE2 resets the hypothalamic thermostat

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

Temperature increase: PGE2 stimulates hypothalamic neurones, and influences homeostatic thermostat

Flu patients treated with NSAIDs saw a decrease in body temperature

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16
Q

What is the role of PGE2 in inflammation?

A

PGE2 ROLE IN INFLAMMATION IS EXTREMELY COMPLEX

The role of PGE2-EP3 signalling in acute inflammation

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 release
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17
Q

List some desirable physiological effects of PGE2 and other prostanoids

A

Bronchodilation

  • many COX products cause bronchodilation
  • prostanoids are COX products

Renal salt and water homeostasis

Gastro-protection

Vaso-regulation (dilation and constriction depending on receptor activated)

18
Q

Despite many COX products causing bronchodilation, name an exception to this

A

PGD2 is a bronchoconstrictor

19
Q

What can the consequence of NSAIDs be for asthma patients?

A

NSAIDS block COX enzymes

  • Around 10% of asthma patients experience worsening symptoms with NSAIDS
  • Cyclooxygenase inhibition favours production of leukotrienes (bronchoconstrictors)
  • Mouse knockouts for mPGE2 synthase get aspirin-induced “asthma” (suggests PGE2 is protective)
  • NSAIDS should not be taken by asthmatic patients
20
Q

How can PGE2 regulate salt and water homeostasis?

A

PGE2 regulates salt and water homeostasis

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

21
Q

What is the role of PGE2 in gastric cytoprotection?

A

Parietal cells normally produce HCl, secreting it into the stomach

The cells lining the stomach therefore must be protected from the highly acidic environment

They 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

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

22
Q

Outline the two COX isoforms

A

It was believed that COX-1 was physiological and the inducible COX-2 was pathological

  • This is WRONG

Pharmacologists worked hard to make selective COX-2 inhibitors, only to get relatively poor results

COX-1 and COX-2 have different (but frequently overlapping) cellular distributions

23
Q

What COX isoforms do NSAIDs inhibit?

A

Most NSAIDs

  • reversibly inhibit both isoforms
  • example: ibuprofen

Coxib family:

  • selectively reversibly inhibit COX-2
  • example: celecoxib

It was hypothesized that these drugs would be gastroprotective

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

The Coxib family are brilliant at inhibiting and preventing gastric damage, but there are other effects

24
Q

How do prostanoids act as vasoregulators?

A

NSAIDS can have serious unwanted cardiovascular effects:

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

It is becoming acknowledged that use of NSAIDs poses a risk of:

  • Hypertension
  • Myocardial infarction
  • Stroke
25
Q

What are the cardiovascular effects of COX-2 inhibitors?

A

There is increasing evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear.

All the prostanoids have some actions on vasoconstriction or vasodilation – so they all affect the vasculature or platelet aggregation.

If we look specifically at COX-2 (found in the vascular endothelial and smooth muscle cells, the heart and the kidney), there are complex effects. When these are blocked, many unwanted CVS actions may result.

26
Q

What type of events do NSAIDs increase the risk of?

A

All NSAIDS increase risk of GI bleeds and CVS events

There is a range of NSAIDs along the bottom.

  • Coxibs are on the left hand side (the most selective for COX-2).
  • Piroxicam is on the right hand side (most selective for COX-1 and still reversible).
  • In the middle is IBUPROFEN.

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.

27
Q

What are the risks and benefits of NSAID use?

A

Analgesic use:

  • usually occasional
  • relatively low risk of side effects

Anti-inflammatory use:

  • often sustained
  • higher doses
  • relatively high risk of side effect
28
Q

What strategies, other than COX-2 selective NSAIDS, are there 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
29
Q

What is aspirin?

A

Unique among the NSAIDS

  • 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
30
Q

What do the effects of aspirin depend on?

A

The effects of aspirin are DOSE-DEPENDENT

31
Q

What is the action of high-dose aspirin?

A

Inhibit thromboxane production

Will also reduce prostacyclin production

There is BARELY ANY ACTION ON PLATELET AGGREGATION. This is because endothelial cell COX enzymes will be in a permanent state of inhibition.

32
Q

What substances, made in the body, can affect platelet aggregation?

A

Platelets produce thromboxane

  • enhances platelet action (pro-aggregatory)
  • thromboxane A2 made by COX-1 in the platelet

Endothelial cells produce prostacyclin (PGI2)

  • decreases platelet action (anti-aggregatory)
  • in the endothelial cell is both COX-1 and COX-2
  • so PGI2 is reduced, but probably not totally
33
Q

What is the action of low-dose aspirin?

A

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.

34
Q

What are 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

35
Q

What are the major side-effects of aspirin seen 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

36
Q

Is paracetomol a NSAID?

A

Paracetomol:

  • 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
37
Q

What is the mechanism of action of paracetomol?

A

Mechanism is not well understood

  • Probably central AND peripheral mechanism
  • COX-3?
  • Cannabinoid receptors?
  • Endogenous opioids interaction?
  • 5HT and adenosine receptor interaction?
38
Q

What can paracetomol overdose cause?

A

It may cause irreversible liver failure

Paracetamol:

  • normally metabolised by the cytochrome P450 complex
  • 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.

39
Q

What is the antidote for paracetomol 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
40
Q

What is the legislation surrounding over-the-counter sale of analgesics?

A

1998 pack size of paracetamol restricted to 16 x 500 mg tablets per pack

2009 guidelines stating

  • No more than 2 packs per transaction
  • Illegal to sell more than 100 paracetamol in one transaction
  • Since 2009, deaths from paracetamol overdose have fallen by 43% (~70 people a year) and about 60% fewer registrations for liver transplants (~40 people a year)

Yr 2 LCRS - Pharm (44 decks)

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