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Year 2 - LCRS - Pharmacology > NSAIDS (23.02.2020) > Flashcards

NSAIDS (23.02.2020) Flashcards

1
Q

What effects do NSAIDs have? (3 terms)

A
  • analgesic
  • anti-pyretic
  • anti-inflammatory
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2
Q

Why are NSAIDs so commonly used and perscribed?

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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3
Q

Broadly said, how do NSAIDs work?

A
  • Inhibition of prostaglandin and thromboxane synthesis
  • Lipid mediators derived from arachidonic acid
  • Cyclo-oxygenase enzymes
  • Widely distributed
  • Not stored pre-formed
  • Receptor-mediated
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4
Q

What is the difference between NSAIDs and paracetamol?

A
  • Paracetamol has a minimal anti-inflammatory effect (whereas NSAIDs have all 3: pain, fever, inflammation)
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5
Q

How are prostaglandins synthesised?

A
  1. arachidonic acid ➡️ Prostaglandin H2 (via COX 1 and COX 2)
  2. PG2 ➡️ Prostacyclin (PGI2) or PGE2 or PGD2 or PGF 2alpha or TXA2 (via specific syntheses)
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6
Q

Prostanoid receptors

A
  • 10 known receptors
  • 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
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7
Q

What receptors can PGE2 activate?

A
  • EP1, EP2, EP3, EP4
  • PGE2 can activate 4 ReceptorscAMP-dependent and independent downstream mechanisms
  • 1 and 3 cause Ca2+ mobilisation; 2,3,4 cause cAMP effects
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8
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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9
Q

What are the possible MoAs of the analgesic effects of NSAIDs? (here with PGE inhibition)

A

a) 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 -> less pain b/c of decreased sensitivity

  • cAMP mediated
  • Activates P2X3 nocioceptors
  • PGE2 only – PKA only
  • PGE2 + inflammation Epac pathway activated and additionally, more PGE2 produced
  • Greater activation of P2X3 receptors (more recruitment, greater perception of pain)
  • > see slide 11

c) EP1receptors and/or EP4 receptors (in periphery and spine)
d) Endocannabinoids (neuromodulators in thalamus, spine and periphery)
e) NSAIDS increase beta-endorphin in spine

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10
Q

Epac pathway

A
  • PGE2 binds to EP
  • this activates adenyl cyclase (ATP -> cAMP)
  • this starts 2 pathways:
    a) PKA
    b) Epac1,Epac2 -> Rap1, Ras -> PKC -> F-actin -> P2X3 receptor
  • > P2XR is a nociceptor, the prostaglandin causes more recruitment of the nociceptors and greater perception of pain.
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11
Q

Pyrogenic properties of PGE2

A
  • PGE2 is pyrogenic
  • PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
  • this mechanism is well understood
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12
Q

What is the role of PGE2 in inflammation?

A
  • extremely complex!!

- promotes inflammation

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13
Q

What are the beneficial actions of PGE2 and other prostaniods?

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)
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14
Q

Why should asthma patients not take NSAIDs?

A
  • Many cyclo-oxygenase products cause bronchodilation
  • ~10% asthma patients experience worsening symptoms with NSAIDS
  • Cyclooxygenase inhibition favours production of leukotrienes - bronchoconstrictors (Leukotrienes are powerful bronchoconstrictors)
  • Mouse Knockouts for mPGE2 synthase get aspirin-induced “asthma” , suggesting PGE2 is normally protective
  • NSAIDS should not be taken by asthmatic patients
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15
Q

What is the role of PGE2 in gastroprotection?

A
  • down regulates HCl secretion
  • stimulates mucous and bicarbonate secretion

(Parietal cells)

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16
Q

What kind of deaths do NSAIDs cause?

A
  • 50% from GI causes (ulceration, bleeds)

- 50% of NSAID deaths are cardiovascular

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17
Q

The 2 main iso forms 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 (Fewer ulcers with celecoxib than with conventional NSAIDs!!)
  • Coxib family: selectively reversibly inhibit COX-2 (example: celecoxib)
18
Q

Why have COX-2 inhibitors proved less successful than hoped?

A
  • Evidence that selective COX-2 inhibitors pose higher risk of cardiovascular disease than conventional NSAIDS even though mechanism is unclear
19
Q

What is the role of PGE2 in the nephrons? What are the effects of NSAIDs?

A
  • PGE2 increases renal blood flow
  • NSAIDs can cause renal toxicity
    - Constriction of afferent renal arteriole
    - Reduction in renal artery flow
    - Reduced glomerular filtration rate

-PGE2 also regulates salt and water homeostasis (glomerulus, ascending LoH, macula dense, dct, collecting duct)

20
Q

Prostanoids and vasoregulation: What are the effects of NSAIDs on the CV-system?

A

Prostanoids are complex vasoregulators

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
21
Q

Possible mechanism of cardiovascular toxicity of Coxibs

A
  • coxibs CV-risk
  • > related to its thrombotic nature
  • > COX2 inhibition causes PG suppression (PGI2 and PGE2)
  • > creates prothrombic environment
  • > loss of control on mediators which act physiologically to instigate thrombosis
  • > increased BP and causes atherogenesis
22
Q

What are the cardiovascular effects of COX2 inhibitors?

A
  • ⬆️ probability of coronary atherothrombosis
  • ⬆️ risk of HF
  • ⬆️ long-term CV risk

-> see slide 29 to understand the mechanism behind this.

23
Q

What are the riss of NSAIDs in chronic (mainly for inflammatory conditions) and in acute (analgesia) use?

A

Analgesic use
Usually occasional
Relatively low risk of side effects

Anti-inflammatory use
Often sustained
Higher doses
Relatively high risk of side effects

24
Q

GI and CV risk among different NSAIDs

A
  • the NSAIDs are on a spectrum of CV and GI risk
  • COX2 selectivity is higher risk of CV problems
  • COX1 selectivity is higher risk of GI problems

-> see slide 30

25
Q

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

A
  • Topical application
  • 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
  • Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g.
    • Alcohol consumption
    • Anticoagulant or glucocorticoid steroid use
26
Q

What are ideas in terms of developing NSAIDs that may be 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
27
Q

What are the main side effects of NSAIDS?

A

COX-1 inhibition:

  • GI bleeds
  • peptic ulcers

COX inhibition:

  • sodium and water retention
  • hypertension
  • hemodynamic acute kidney injury

COX2 > COX1 inhibition:

  • stroke
  • MI

(see slide 34)

28
Q

Aspirin

A
  • Unique among the NSAIDS
  • Selective for COX-1
  • Binds IRREVERSIBLY to COX enzymes
  • Has anti-inflammatory, analgesic and anti-pyretic actions
  • Reduces platelet aggregation
29
Q

What are the effects of prostanoids on platelet aggregation?

A
  • Platelets -> TXA2 (via COX1) promote platelet aggregation (irreversible because platelets don’t have a nucleus)
  • the endothelium -> PGI2 (via COX 1 and COX 2) inhibit platelet aggregation. (reversible because they are bucketed and can replenish COX1 and COX2)
30
Q

What are the effects of aspirin on platelet aggregation?

A
  • Platelets -> TXA2 (via COX1) promote platelet aggregation (irreversible because platelets don’t have a nucleus)
  • the endothelium -> PGI2 (via COX 1 and COX 2) inhibit platelet aggregation. (reversible because they are bucketed and can replenish COX1 and COX2)

Anti-platelet actions due to:

  • Aspirin will inhibit COX-1 (this will affect the platelets proportionally more than the endothelium) and therefore platelet aggregation is inhibited.
  • 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
31
Q

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
32
Q

What is the problem with giving aspirin to young patients?

A
  • Aspirin and Reye’s syndrome
  • Patients under 20
  • Viral infection and aspirin
  • Damage to mitochondria leading to ammonia production resulting in damage to astrocytes – oedema in brain
33
Q

Reye’s syndrome

A
  • very rare disorder that can cause serious liver and brain damage (liver starts failing, buildup of toxins and brain oedema)
  • mainly affects children and young adults under 20 years of age
  • mostly affects them when recovering from a viral infection e.g. chicken pox or flu
  • can be associated with taking aspirin during the viral infection
  • If it’s not treated promptly, it may lead to permanent brain injury or death.
34
Q

Paracetamol

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

MoA:

  • Not understood, probably central and peripheral
  • ? COX- 3
  • ? Via Cannabinoid receptors
  • ? Interaction with endogenous opioids
  • ?interaction with 5HT and adenosine receptors
35
Q

How does paracetamol overdose cause liver failure?

A
  • in the metabolism of paracetamol there is a highly active compound, NAPQI, that is formed and should react with glutathione to be inactivated
  • In paracetamol overdose the glutathione stores are depleted
  • NAPQI readily binds to thiol (SH) groups
  • thiol groups of key hepatic enzymes and causes cell death
36
Q

How do you treat paracetamol overdose?

A
  • Add compound with –SH groups (usually i.v. Acetylcysteine) -> NAPQI will readily bind to this and less to hepatic enzymes
  • 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
  • there is legislation to prevent purchasing too high doses of paracetamol
37
Q

Legislation regarding otc 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
38
Q

MCQ 1: Aspirin is unique among NSAIDs because..

a) It has no effect on COX-1
b) It has no effect on COX-2
c) It binds covalently to COX enzymes
d) It binds covalently to TP receptors
e) It causes gastric ulceration

A

b?

39
Q

MCQ2: Inhibition of which enzyme will reduce platelet aggregation with fewest side effects?

a) COX-1
b) COX-2
c) Prostacyclin synthase
d) Prostaglandin E synthase
e) Thromboxane A2 synthase

A

e?

40
Q

ARQ1:

Assertion: Inhibition of PGI2 synthesis by low dose aspirin decreases the risk of stroke
Because : Decreased PGI2 reduces platelet aggregation

a) Assertion true, reason true and explains assertion
b) Assertion true, reason true but does not explain assertion
c) Assertion true, reason false
d) Assertion false, reason true
e) Assertion false, reason false

A

e?

41
Q

MCQ 3:
Why has the number of deaths from paracetamol overdose fallen steadily in England and Wales?

a) More livers are available to provide transplants for patients after paracetamol overdose
b) Paracetamol can only be purchased in a formulation which contains the antidote
c) Paracetamol has been replaced by better analgesics
d) Paracetamol is now only available on prescription
e) The quantity of paracetamol which can be purchased over the counter is restricted by law

A

e)

Year 2 - LCRS - Pharmacology (34 decks)

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