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Neuroscience and mental health year 2 > NSAIDS > Flashcards

NSAIDS Flashcards

1
Q

Summarise the use of NSAIDs in the U.K

A

Widely prescribed (16 million prescriptions annually in England)
6% patients reported possible adverse drug reaction- mostly in elderly patients
(> 15% elderly at any one time)
Available over the counter
Increased risk of GI and CVS
deaths

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2
Q

Ultimately, why are NSAIDs so widely used

A

Due to their analgesic, antipyretic and anti-inflammatory effects.

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3
Q

Summarise the analgesic effects of NSAIDs

A

Relief of mild-to-moderate pain (analgesic)
Toothache, headache, backache
Postoperative pain (opiate sparing)
Dysmenorrhea (menstrual pain)

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4
Q

Describe the anti-pyretic effects of NSAIDs

A

Reduction of fever (antipyretic)

Influenza

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5
Q

Describe the anti-inflammatory effect of NSAIDs

A

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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6
Q

Summarise how NSAIDs work

A

Inhibition of prostaglandin and thromboxane
synthesis
Lipid mediators derived from arachidonic acid
Cyclo-oxygenase enzymes
Widely distributed (virtually every cell)
Not stored pre-formed (so no need to deplete existing prostaglandins and thromboxane)
Receptor-mediated
Mechanism of Action: inhibit cyclo-oxygenase enzymes, preventing formation of prostaglandin H2 - hence limiting downstream prostanoid products

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7
Q

Describe the danger posed by NSAIDs

A

Although usually safe when used correctly, they can have extremely serious side-effects, particularly with long-term use or when used at high therapeutic doses.
§ Deaths from NSAIDs are on par with road traffic accidents (half due to GI upsets, and half due to CVS issues).
o ~2000 deaths/annum in 2011.

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8
Q

What are the main prostanoids

A

Prostaglandins (D2, E2 and F2a)
Prostacyclin (PGI2)
Thromboxane A2

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9
Q

What is the role of COX (1 and 2)

A

Arachidonic acid (from phospholipid membrane) – Prostaglandin H2 - this is the rate limiting step
Which is then converted by specific synthases to:
· Thromboxane A2
· Prostacyclin (PGI2)
· Prostaglandin D2, E2, F2a

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10
Q

Describe the naming of the prostanoid receptors

A

Naming based on agonist potency
Prostanoid receptors aren’t very specific - they are named based on which prostanoid they have the highest affinity for (e.g. DP1 has the highest affinity for PGD2)

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11
Q

State the prostanoid receptors

A 
DP1, DP2 
EP1, EP2, EP3, EP4 
FP 
IP1, IP2 
TP
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12
Q

Summarise the function of prostanoids

A

Prostanoids have both G protein-dependent and -independent effects (both desirable and undesirable)
Knock out mice show that prostanoid effects are extremely complex
Physiological and pro-inflammatory

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13
Q

What is PGE2 often referred to as

A

The ‘ringmaster’ prostanoid

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14
Q

Describe the formation of arachidonic acid in the phospholipid membrane

A

Physical, chemical, inflammatory and mitogenic stimuli stimulate the production of arachidonic acid from membrane phospholipids (catalysed by PLA2).

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15
Q

Describe the receptors that PGE2 can activate

A

PGE2 can activate 4 Receptors

(EP1-4)

cAMP-dependent and independent downstream mechanisms

EP1- Increased Ca2+ mobilisation
EP2,4- Increased cAMP
EP3-both

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16
Q

State the unwanted effects of PGE2

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

Plasticity and cell injury

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17
Q

What did a study on rats show about the effects of PGE2 (using a PGE2 analogue) on pain threshold

A

The PGE2 analogue reduced the pain threshold (i.e less stimuli was needed to ilicit a pain response).
Stimulation of PG receptors in the periphery sensitizes the nociceptors which cause pain both acutely and chronically.
EP4 receptor antagonist blocks the effect of the PGE2 analogue

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18
Q

Describe one mechanism of action for the noiciceptive effects of PGE2

A 
PGE2 activates GPCR EP receptor (Gas)
cAMP mediated (AC converts ATP -- cAMP)
Activates P2X3 nocioceptors
PGE2 only – PKA only 
PGE2  + inflammation Epac pathway activated and additionally, more PGE2 produced
Greater activation of P2X3 receptors

EPAC and PKA pathways both mediated by cAMP

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19
Q

Describe some other mechanisms explaining how PGE2 causes pain perception

A

§ Activation of EP1 and EP4 receptors (in spine & periphery). - increase pain transmission
§ Endocannabinoid involvement. ((neuromodulators in thalamus, spine and periphery)

· This is not mutually exclusive – i.e. cross-talk between prostanoids and endocannabinoids

NSAIDS increase beta-endorphin in spine- an opiod neuropeptide

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20
Q

What is important to remember about aspirin

A

In addition, aspirin only is used as an anti-aggregatory drug to inhibition platelet aggregation in patients who are at risk of stroke or myocardial infarct

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21
Q

Describe the mechanism for the pyrogenic effects of PGE2 (upon stimulation by an inflammagen such as LPS)

A

PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
This is why NSAIDs reduce your body temp if you have the flu
NOTE: there is a bit of a lag between PGE2 rising and temperature rising

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22
Q

Essentially, why do NSAIDs have so many side effects

A

The diversity of actions of prostanoids explains why inhibiting their synthesis with NSAIDs can have many unwanted effects.

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23
Q

Summarise the role of PGE2 in inflammation

A

PGE2 role in Inflammation extremely complex

Not generalisable

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24
Q

Which prostanoid receptor is responsible for signalling in acute inflammation

A

EP3 (on mast cells)

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25
Q

Which prostanoid receptor is responsibe for the effects of PGE2 on the immune system

A

EP4

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26
Q

Which diseases are treated with NSAIDs due to its effects on the immune system

A 
Multiple Sclerosis and Rheumatoid Arthris  (Th17 mediated)
Contact Dermatitis (Th1 cells involved)
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27
Q

What is the problem with PGE2 inhibiting apoptosis

A

Inhibition of apoptosis increases the likelihood of necrosis
NOTE: there are 3 prostanoids, 7 prostanoid receptors and 2 downstream signalling pathways involved

28
Q

Describe the beneficial, physiological actions of prostanoids

A

Bronchodilation (although there is evidence that PGE2 can desensitise β2adrenoceptors)
Gastroprotection
Renal salt and water homeostasis
Vasoregulation (dilation and constriction depending on receptor activated)

29
Q

Why should NSAIDs not be given to asthma patients

A

~10% asthma patients experience worsening symptoms with NSAIDS
Cyclooxygenase inhibition favours production of leukotrienes - bronchoconstrictors
Mouse Knockouts for mPGE2 synthase get aspirin-induced “asthma” , suggesting PGE2 is normally protective- lose bronchodilation effects of prostanoids.
NSAIDS should not be taken by asthmatic patients

30
Q

Describe the gastric-cytoprotective effects of prostanoids (mediated by COX1)

A

PGE2 downregulates stomach acid production )parietal cells
PGE2 stimulates mucus production
PGE2 stimulates bicarbonate production

Dose-dependent reduction- more PGE2- greater reduction in production of gastric acid

31
Q

Describe how NSAIDs increase the risk of gastric and duodenal ulceration

A

About half the deaths
from NSAIDs result from
gastrointestinal causes

o NSAIDs therefore increase the risk of ulceration à resulting in 1000 deaths/annum.
§ The ulceration is thought to be due to blocking of COX1…
§ Fewer deaths when using Celecoxib (COX2-selective inhibitor) rather than normal NSAIDs.

32
Q

Summarise the two main isoforms of COX

A

COX-1 and COX-2 with different (but overlapping) cellular distributions
Aspirin is COX-1 selective and particularly bad at causes ulcers
Maybe COX-2 selective NSAIDS won’t cause ulcers
Coxib family: selectively reversibly inhibit COX-2 (example: celecoxib)
Very similar in structure- COX-2 just has a binding pocket in its active site that differs.

33
Q

What are the main effects of PGE2 on the kidney

A

Increases renal blood flow

34
Q

Describe how NSAIDs cause renal toxicity

A

o Renal toxicity via:
§ Constriction of afferent renal arteriole.
§ Reduction in renal artery flow.
§ Reduced glomerular filtration rate.

35
Q

Describe the distribution of COX-1 and COX-2 in the nephron

A

Both expressed in the glomerulus
COX-2- ascending limb and macula densa
COX-1- DCT and collecting duct

36
Q

As protanoids are complex vasoregulators, describe the unwanted cardiovascular effects of NSAIDs

A 
NSAIDS can have serious unwanted cardiovascular effects 
Vasoconstriction
Salt and water retention 
Reduced effect of antihypertensives 
50% deaths from NSAIDs are cardiovascular 
Hypertension 
Myocardial infarction 
Stroke
37
Q

Describe the relationship between the cardiovascular effects and COX-2 inhibitors.

A

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

38
Q

Outline a mechanism for the cardiovascular toxicity of coxibs (COX-2 selective inhibitors)

A

Related to its thrombotic and anti-platelet effect
they selectively inhibit PGI2 production whilst sparing the production of TxA2
PGI2 and PGE2 suppressed
Causes loss of control on mediators, which act phystiologically to instigate thrombosis
Increased BP and causes atherogenesis.

Non-selective NSAIDs and COX-2 selective NSAIDs both increase cardiac work
Also, all NSAIDs produce oxygen free radicals, which can contribute to cardiovascular disease

39
Q

Outline a schemata for the cardiovascular effects of coxibs focussing on the vascular endothelial cell

A

Reduces PGI2
Leading to:
Unrestrained platelet activation onto ruptured coronary plaques- leading to an enhanced probability of coronary atherothrombosis
Also leads to a reduction in NO- which can also lead to unrestrained platelet activation but also cause heart failure.

40
Q

Outline a schemata for the cardiovascular effects of coxibs focussing on the cardiomyocytes

A

Reduced PGI2 and PGE2:
Decreased protection against arrhythmias and oxidative injury
Leading to increased risk of HF

41
Q

Outline a schemata for the cardiovascular effects of coxibs, focussing on the renal system

A

Cortical COX-2:
Reduction in PGI2:
Reduced renal blood flow and reduced GFR
Increased blood pressure- HF and increased long-term CVD risk

Medullary COX-2:
Decreased PGE2, leading to increased salt and water retention
This increases BP

42
Q

Describe the spectrum of side effects of NSAIDs

A

All NSAIDS increase risk of GI bleeds and CVS events

But:
COX-1 inhibition (Piroxicam) à increased GI risk.
§ COX-2 inhibition (coxibs) à increased CVS risk

Ibuprofen lies in the middle

43
Q

Summarise the risk vs benefit of NSAID use

A

Analgesic use
Usually occasional
Relatively low risk of side effects

Anti-inflammatory use
Often sustained
Higher doses- often in elderly whos metabolism is impaired anyway-worsening risk
Relatively high risk of side effects

44
Q

Describe the relative GI and CVS risks of COX-1 selective and COX-2 selective NSAIDs when compared to non-selective NSAIDs.

A 
COX-1 selective: 
· Same CVS risk as non-selective NSAIDs 
· Increased GI risk 
COX-2 selective: 
· Decreased GI risk 
· Increased CVS risk
45
Q

Apart from giving a coxib, what else can be done to minimise the G.I side effects of NSAIDs

A

Topical application (to reduce dose)
Minimise NSAID use in patients with history of GI ulceration
Treat H pylori if present
If NSAID essential, administer with omeprazole or other proton pump inhibitor (to decrease gastric acid production).
Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g.
Alcohol consumption
Anticoagulant or glucocorticoid steroid use

46
Q

Describe some of the ongoing developments of NSAIDs to make them safer

A

Dual COX and LOX inhibitors
For asthmatic patients
No safe option on the market (liver injury)
Nitric oxide or Hydrogen sulphide releasing NSAIDS
NO and H2S protective to GI and CVS
A number of options undergoing testing
Late stage clinical trials

47
Q

What are the normal RENAL functions of prostanoids

A

Afferent arteriolar vasodilation (increased GFR)
Increased salt and water excretion

Therefore NSAIDS lead to:
Salt and water retention
HTN
Haemodynamic acute kidney injury

48
Q

What are the normal cardiovascular functions of prostanoids

A

Vaascular (COX-2, PGI2)
vasodilation
inhibit platelet aggregation

Platelet (COX-1, TXA2)
vasoconstriction

Therefore, NSAIDs lead to stroke and MI

49
Q

Summarise aspirin

A

Unique among the NSAIDS
Selective for COX-1
Binds IRREVERSIBLY to COX enzymes (binds covalently and acetylates the active site).
Has anti-inflammatory, analgesic and anti-pyretic actions
Reduces platelet aggregation

50
Q

Describe the role of prostanoids on platelet aggregation

A

TXA2 (made by COX-1) released by platelets which encourages platelet aggregation
Prostacyclin (PGI2) (made by both COX-1 and 2)released by endothelial cells which inhibits platelet aggregation

51
Q

Describe how aspirin reduces platelet aggregation

A

§ Reduces platelet aggregation.
o Platelets:
§ Reduces TXA2 production via COX1, no re-production as the platelet has no nucleus.
o Endothelial cells:
§ Reduces PGI2 synthesis by COX1/2. Reproduction possible due to nucleus.
o Thus, less TXA2 and still PGI2 so reduced platelet aggregation.

52
Q

Why is it important to use low doses of aspirin

A

A low dose will allow the endothelial cells to resynthesise COX-1, which can then continue to produce prostacyclin
A high dose would mean that the COX-1 in the endothelial cells would be inhibited as it is being produced, thus decreasing prostacyclin production as well as thromboxane production
Inhibition of prostacyclin synthesis is proportional to inhibition of COX-2
We don’t want to inhibit prostacyclin production too much so we’d like to keep COX-2 inhibition low

53
Q

Summarise the anti-platelet actions of aspirin

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 resynthesis of COX-2

54
Q

Describe the unwanted effects of aspirin

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
55
Q

Describe Reye’s syndrome associated with aspirin

A

Patients under 20
Viral infection and aspirin
Damage to mitochondria leading to ammonia production resulting in damage to astrocytes – oedema in brain

56
Q

Summarise paracetemol

A

Is a widely used effective analgesic for mild-to-moderate pain which is available over the counter
Has anti-pyretic action
Has minimal anti-inflammatory effect
Therefore it is not a NSAID

57
Q

Summarise the proposed mechanisms that may explain how paracetamol works

A

Not understood, probably central and peripheral
? COX- 3
? Via Cannabinoid receptors
? Interaction with endogenous opioids
?interaction with 5HT and adenosine receptors

58
Q

Describe how paracetamol overdose may lead to irreversible liver failure

A

CYP2E1 converts N-acetyl-p-aminophenol to N-acetyl-p-benzochinon-imine (NAPQI)- THIS IS A TOXIC METABOLITE
Normally this toxic metabolite is mopped up by glutathione and converted into a reduced inactive form via glutathione-s-transferase
In overdose, the glutathione stores are depleted and the free toxic metabolite binds indiscriminately to any –SH groups
The –SH groups tend to be on key hepatic enzymes and this interference leads to cell death

59
Q

Describe an antidote for paracetamol poisoning

A

Add compound with –SH groups
Usually intravenous Acetylcysteine
Occasionally oral methionine
Could be added to the formulation but increased cost
Acetyl cysteine used in cases of attempted suicide and accidental poisoning
If not administered early enough, liver failure may be unpreventable – transplant only option

60
Q

Describe the legislation on OTC sales of paracetamol

A

Deliberate overdose more common than accidental poisoning
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 substantially, as have registrations for liver transplants

These have reduced the number of deaths caused by paracetamol overdose in the UK
Deaths have fallen by 43% since 2009.

61
Q

What is the key difference between COX-1 and COX-2

A

COX-1 is constitutive (i.e. it is present all the time). It is found in many cell types and its main roles are in the regulation of homeostatic functions (make sure you can name some examples).
In contrast, COX-2 is mainly inducible and by cell types than COX1 and in particular by pro-inflammatory cells such as leukocytes. It has both pathological and physiological functions.

62
Q

Describe the two steps in COX mediated AA metabolism

A

Both COX isoforms catalyse two different reactions. The first step is an oxygenation, which converts arachidonate to PGG2. The second step is a peroxidation, catalysed by a different part of the enzyme, which converts PGG2 to the product PGH2.

63
Q

Why is aspirin different to all NSAIDs

A

Aspirin is different to all other NSAIDs because it binds irreversibly to cyclo-oxygenase enzymes. The consequences of this are that its actions are much longer-lasting than those of other NSAIDs and can only be reversed by de novo synthesis of new enzyme.
Aspirin binds 200-fold more avidly to COX-1 than to COX-2.

64
Q

How may aspirin cause nephritis

A

Reduced creatinine clearance and possible nephritis

65
Q

What are the NICE guidelines for coxibs

A

Those with a history of ulcers/GI bleeding
Patients over 65
Patients taking other drugs which increase risk of GI sideeffects
Patients needing maximal doses of NSAIDS long-term

66
Q

Describe the roles of the different prostanoids

A

PGE2, PGF2, PGD2- pain, fever and inflammation
prostacyclin - vasodilation, anti-platelet, anti-atherogenic
TXA2- vasoconstrictor, pro-platelet, pro-atherogenic

Neuroscience and mental health year 2 (24 decks)

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