Prostaglandins and NSAIDS Flashcards

1
Q

How many standard aspirin tablets are taken every year worldwide?

A. 100 billion

B. 1 billion

C. 100 million

D. 1 million

A

A. 100 billion

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2
Q

LO Lecture 1 and 2

A

Lecture 1

  • Introduce the cellular and chemical mediators of local immune response to tissue damage/infection highlighting broad role of autacoids.
  • Introduce the steroidal approaches used as anti-inflammatory treatments.
  • Define Prostaglandins and related eicosanoids as important lipid mediators.
  • Explain synthesis and mechanisms of action of the major prostaglandins.
  • Highlight physiological actions of prostaglandins and potential therapeutic uses
  • Lecture 2
  • Describe NSAIDs as broad and selective inhibitors of COX enzymes.
  • Show how NSAIDs are used clinically and indicate potential side effects.
  • Highlight how aspirin’s unique mode of COX inhibition extends it use to cardiovascular treatment.
  • Describe recent experiments that hint at the mode of action for Paracetamol
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3
Q

Tell me about local inflammation through distinct cell types and chemical mediators

What cells are affected by tissue damage/ infection and what chemicals are produced in response?

A
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4
Q

Tell me about chronic inflammation

A
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5
Q

Tell me about inflammatory mediators and how they induce complex molecular and cellular response dependent on changes in gene expression

A
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6
Q

Pharmacological use of physiological steroid hormone pathways has powerful anti-inflammatory effects

Tell me the prime mode of action?

What different chemicals are produced from this process? and provide examples

A
  • Prime mode of action is to bind nuclear receptors to +vely or –vely effect transcription. Additional non-genomic effects
  • Physiologically the corticosteroids act widely increase metabolism
  • Pharmacologically cortisol and synthetic steroids (e.g., dexamethasone) increase anti-inflammatory gene expression (e.g. annexin -1) and reduce expression of pro-inflammatory gene expression (e.g. COX-2)
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7
Q

Despite the potent anti-inflammatory response. There are limits to steroidal approach. Tell me about some of these limits

A
  • Long term effects are undesirable.
  • Suppress the response to infection (act against the immune response),
  • Cause widespread metabolic disturbances (impact on steroid production)
  • Iatrogenic Cushing’s syndrome (wide systemic dysfunction),
  • Growth suppression in children (important function in osteoclasts)
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8
Q

What are Eicosanoids?

A

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, 20 carbon units in length.

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9
Q

Tell me the lipid metabolites derived from arachodonic acid or residual after aracidonic acid removal

Tell me some key differences between some of them

A
  • Polar head is hydrophilic and outside of the membrane
  • Prostaglandins and leukotrienes key difference between them is that leukotrienes have no rings/ not cyclic and there’s an oxygen group in the ring of PGs but not in leukotrienes
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10
Q

Tell me the full sequence of eicosanoid like signalling

A
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11
Q

After eicosanoid like signalling, what is uptake followed by?

A

Uptake is followed metabolism by “prostaglandin specific enzymes” followed by subsequent catabolism (breakdown) by fatty-acid-oxidizing enzymes.

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12
Q

Tell me the concentrations that eicosanoids work in?

A

pM-nM

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13
Q

What is antihistamine?

A

A competitive antagonist to the histamine receptor

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14
Q

When histamine binds to its own receptor, what concentrations does it work in?

A

µm

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15
Q

Major arachidonic acid and downstream intermediatory metabolism to generate resealable mediators

A
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16
Q

Phospholipid membrane

A
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17
Q

Tell me the role of cyclooxygenase and NSAIDs

A
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18
Q

Potent and controllable (rapid catabolism) of prostaglandin promotes clinical use. Tell me some of these clinical uses

A

Gynaecological and obstetric.

  • Misoprost (Stable PGE) pregnancy termination or induction of labour.
  • Carboprost (analogue of PGF2α) to treat postpartum haemorrhage.

Gastrointestinal

  • Misoprost to prevent peptic ulcers in patients taking NSAIDs (perhaps ironically).

Cardiovascular

  • Presurgical maintenance of arterial ducts prior to surgical correction in congenital
  • Heart disease (alprostadil, PGE).
  • Inhibit platelet aggregation if preferred route heparin during dialysis also used in
  • Pulmonary hypertension.

Ophthalmic.

  • Open angle glaucoma (increase in intraocular pressure): latanoprost (PGF2α) eye drops
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19
Q

Blocking the action of prostaglandin may also benefit. Tell me some the associations with the production and synthesis of prostaglandins…

A

Pain

  • Prostaglandins sensitize nociceptors to pain transducers like Bradykinin.
  • May also contribute to vasodilatory effects associated with headache.

Fever

  • Prostaglandins PGE2 reset to a higher set point the temperature sensing systems of the
  • hypothalamus. This central effect of the prostaglandins is pyretic (i.e. leads to fever).

Chronic inflammation

  • Prostaglandin lead directly to swelling (vasodilation)
  • Indirectly promote oedema (further swelling) sensitizing the effect of other mediators
  • cause local pain
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20
Q

Tell me about arachidonic acid and COX-1 and COX-2

A
21
Q

Name some NSAIDs (Non-steroidal anti-inflammatory drugs)

A

In addition to aspirin, nonselective NSAIDs, such as piroxicam, mefenamic acid, diclofenac, naproxen, and selective cyclooxygenase-2 (COX-2) inhibiting NSAIDs, such as celecoxib and rofecoxib

COX-2 inhibitors are a subclass of nonsteroidal antiinflammatory drugs (NSAIDs)

Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs.

22
Q

How do NSAIDS work?

A

The main mechanism of action of NSAIDs is the inhibition of the enzyme cyclooxygenase (COX)

23
Q

WHat is COX-1 and COX-2 main role?

A

Cycloxygenase-1: housekeeping function

Cycloxygenase-2: induced gene (protein) by inflammatory response (cytokines like interleukin 1-b)

24
Q

What do both COX enzymes produce and what does this contribute to?

Therefore, what effect will blocking COX have?

A

Both COX enzymes produce prostanoids which contribute to pain, fever and swelling in chronic inflammation

Blocking COX will have positive anti-inflammatory effects

Also have housekeeping function in production of the gastric (stomach) mucosa and bicarbonate ions thus some potential side effects.

Less well reported but clear protective function of prostanoids in the vascular wall, kidney and lungs.

25
Q

The reduction of bioactive prostaglandins is involved in what?

A

Reduction of bioactive prostaglandins involved in pain, swelling and fever production.

26
Q

Tell me the clinical uses of NSAIDS and the potential side effects

A

Clinical uses

  • Analgesic headache, backache, post-operative pain relatively short-term (Aspirin, ibuprofen), chronic pain (long-acting drugs-piroxicam. Short term isn’t convenient else would have to take multiple times a day which is inconvenient so need to design drugs to take less frequently for a long period of time).
  • Anti-inflammatory chronic conditions rheumatoid arthritis requires doses and longer
  • term use-balance against associated side effects. If chronic use is required avoid drugs with large gastrointestinal side effects and potentially use COX-2 drugs (celecoxib (ib in a drug means that it acts as an inhibiter)).
  • Antipyretic-paracetamol preferred formulation reduced side effects.
  • NSAIDs show wide individual reaction that inform drug use. Quite personalized.

Side effects

  • Gastrointestinal loss of PG dependent gastric protection. COX-2 selective drugs
  • circumvent this but are compromised by own potential adverse cardiovascular effects.
  • Skin reactions particularly with certain classes of NSAIDs (e.g. mefenamic acid).
  • Renal effects impact on the PGI2 and PGE2 mediated changes in kidney blood flow.
  • This issue is restricted to use of high concentrations of NSAIDs Phenactein and
  • very high doses of paracetamol
27
Q

Some important considerations for the use of the NSAIDS is the plasma half-life, drug specificity and potential for side effects. Tell me the about these drugs…

  • Aspirin
  • Indomethacin
  • Ibuprofen
  • Piroxicam
  • Celicoxib
  • Rofecoxib
  • Paracetamol
A
28
Q

Tell me about structure/ function of COX dependent metabolism of arachidonic acid

Tell me the reaction that occurs

A
29
Q

Tell me about the structural differences in COX-1 and COX-2 that give rise to drug selectivity

A
  • Both COX-1 and COX-2 are non-selectively blocked by drug plugging up channel prevent arachidonic acid entering their substrate binding site.
  • Drug inhibition is relatively instantaneous.
  • Involves NSAID binding to key residues shared between COX-1 and COX-2 channel.
  • Both the narrow (COX-1) and the wider (COX-2) channel are blocked
30
Q

Whats the reaction from arachidonic acid –> PGH2

Name the enzymes involved

A
31
Q

Explain why size matters for the COX-2 selective inhibitors

A
  • COX-2 selective drugs more rigid and fill more space and therefore cannot gain access to the COX-1 channel.
  • Bulky COX-2 drugs gain access to the drug binding site shared with COX-1
  • In addition, they bind to a site created by the isoleucine/valine exchange seen in COX-2.
  • Unlike non-selective inhibitors COX-2 selective inhibition increase with time
  • Celecoxib blocks entrance of arachidonic acid
32
Q

What does the crystal structure of NSAIDS define?

A

The drug binding site

33
Q

NSAIDs are dimers (?) and have key molecules within them which help determine their function and what they bind with. Name these molecules and their role

A

Haem group: Important for paracetamol modes of action

Ser530: Important for aspirin modes of action

Ile523: Found in COX-1 whilst Val523 is found in COX-2

Arg120: Determines COX-1 or COX-2 selectivity

34
Q

Tell me the dual activity that both occur wihtin the same protein of COX-1 and COX-2

A

1. Cyclooxygenase

  • Arachodonic acid –> PGG2.

2. Peroxidase.

  • Prostaglandin H2 synthase
  • PGG2 –> PGH2
35
Q

Tell me about how aspirin affects COX

A
  • Aspirin acetylates (covalently modifies) serine 530 in the COX-1 and COX-2 enzyme active site.
  • Supports its use as conventional NSAID.
36
Q

How does aspirin affect platelets and why is this affect different to that seen in other cells?

A
  • In platelets this inhibits the COX-1 dependent production of thromboxane A2. Thus, inhibits aggregation.
  • Platelet aggregation central mechanism in clotting and predisposition to cardiovascular disease.
  • Platelets anucleate cells thus circulate with the proteins they need-cannot make more.
  • Small doses of aspirin (relatively non adverse) inhibit platelet aggregation by thromboxane A2 chronically, it takes 7 days to produce new platelet.
  • Platelets vs other cells in the body is that platelets don’t have a nucleus
37
Q

Paracetamol (acetaminophen) is a pro-drug for an important what?

A

analgesic

38
Q

Tell me some important facts about paracetamol

A
  1. Paracetamol has good analgesic and antipyretic activity.
  2. Only at higher doses than required for 1 is there a clear anti-inflammatory action.
  3. High dose led to a COX inhibition that may produce anti-inflammatory effects.
  4. It does not block AA delivery like standard NSAIDs.
  5. Based on the chemical environment, particularly oxidizing potential, it can modify the porphyrin of the Haem group at the catalytic sit of COX.
  6. COX-2 seems particularly vulnerable
39
Q

Tell me about COX inhibitor but additional modes of action for paracetamol (acetaminophen)…

A

1. TRPV-1 (cation channel) that is activated in pain is a target seems to be activated.

2. Metabolism of Acetaminophen (AcAP) in cells to para-aminophenol (pAP).

3. pAP reacts with AA catalysed by Fatty acid Hydrolase (FAAH) to generate AM404.

  • *4A.** This activates the TRPV1 centrally to contribute analgesia.
  • *4B.** Increases the level of cannabinoid signalling in the central nervous system
40
Q

Which mediators of inflammation are acted on by NSAIDs…

A. degradative enzymes such as protrases, hyaluronidases

B. Eicosanoids (arachidonic acid metabolites) sich a prostaglandins, thromboxanes and leukotrienes

C. Vasoactive amines such as histamine and serotonin

D. Biologically derived oxidants such as hydrogen peroxide and superoxide anion

E. Plasma proteins and peptides such as products of the complement and kinin

A

B. Eicosanoids (arachidonic acid metabolites) sich a prostaglandins, thromboxanes and leukotrienes

41
Q

Can you recall any side effects from the use of steroids?

A
  • immuno suppression
  • long term undesirable effects
  • cushings
  • growth suppression
  • etc.
42
Q

All of the following chemical mediators released at the site of inflammation cause pain except…

  • Histamine
  • PGE2
  • Bradykinin
  • Glucocorticoids
A

D. Glucocorticoids

43
Q

Which enzyme is responsible to convert PGG2 to PGH2?

A. Phospholipase A2

B. COX

C. Fatty-acid-oxidising enzyme

D. PAF

A

B. COX

44
Q

Among the following, choose the NSAID with the highest COX-2 selectivity…

A. Aspirin

B. Ibuprofen

C. Rofecoxib

D. Celecoxib

E. Piroxicam

A

C. Rofecoxib

45
Q

COX enzymes use a protein channel to allow arachidonic acid into the catalytic center, which COX has a narrower channel?

A. COX1

B. COX2

A

A. COX1

46
Q

Aspirin is currently used to reduce the long-term risks of a second stroke in patients who’ve had an ishchemic stroke, which particular cell type does it target for this application?

A

Platelets

47
Q

Does paracetamol block arachidonic acid delivery?

A. Yes

B. No

C. Not sure

A

B. NO

48
Q

Can you indicate the key position at COX that determines the size of the protein channel for recieving arachidonic acid?

A

Ile523

49
Q

Activation of TRPV1 centrally causes:

A. Pain relief

B. Pain

C. No effects on pain

A

A. Pain relief