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Clinical Pharmacology, Therapeutics & Principles of Prescribing > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

What are autocoids?

Give some examples of autocoids involved in the inflammatory response

A

Biological factors “self drugs”- which act like local hormones

They have a brief duration and act near the site of synthesis

e.g. Bradykinins, Histamine, Cytokines, NO, Leukotrines

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2
Q

What are eicosanoids?

Give examples of such

A

A family of oxygenated derivatives of 20-carbon polyunsaturated fatty acids used as signalling molecules

e.g. prostaglandins, thromboxanes

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3
Q

What are the key features of inflammatory mediators and signalling agents?

A

Localised release

Short half lives - fine control

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4
Q

Prostaglandins are synthesised from what?

A

Arachidonic acid

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5
Q

Which enzymes are responsible for the synthesis of prostaglandins?

A

Cyclo-oxygenase (COX) enzymes

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6
Q

Cell membrane phospholipids are converted to arachidonic acid by which enzyme?

A

Phospholipase A2

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7
Q

Arachidonic acid is converted (by COX-1/COX2) into which prostaglandin followed by which other prostaglandin before they are converted by specific prostaglandin enzymes?

A

1) PG ‘G’
2) PG ‘H’

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8
Q

Which is the most important prostaglandin in mediating inflammatory response?

A

PG ‘E’

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9
Q

What kind of responses are elicited by PG ‘E’?

A

Vasodilatiomnm

Hyperalgesia

Fever

Immunomodulation

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10
Q

PG synthesis by COX-1 has a major cytoprotective role, in which tissues is this particularly important? Why?

A

Gastric mucosa

Myocardium

Renal parenchyma

Because they are very metabolically active tissues

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11
Q

What is the approximate half life of PGs?

What does this mean in relation to their production?

A

10 minutes

They need constant synthesis

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12
Q

COX-1 is constitutively expressed.

In what way does this contribute to the enzymes role in certain ADRs?

A

Most ADRs that are caused by NSAIDs are due to COX-1 inhibition

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13
Q

COX-2 expression is induced by what?

A

Injurious stimuli - inflammatory mediators such as bradykinin

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14
Q

Cox-2 appears to be constitutively expressed in which parts of the body?

A

Brain

Kidney

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15
Q

The main therapeutic effects of NSAIDs occurs via which enzyme?

A

Cox-2

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16
Q

What is the structural difference between COX-1 and COX-2 enzymes?

A

COX-1 is narrow mouthed, has a “tight” opening

COX-2 is wide mouthed, has a “baggy” opening

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17
Q

Prostaglandins bind to which receptors?

A

GPCRs

(G-protein coupled receptors)

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18
Q

What effects do prostaglandins have on local blood vessels?

A

Vasodilation

Allows access by bradykinin and histamine to the site= increased permeability of the site by these and not PGs directly

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19
Q

Which specific prostaglandin E receptor is responsible for vasodilation or surrounding blood vessels?

Which type of GPCR is this?

A

EP2

Gs

20
Q

Which specific Prostaglandin E receptor is responsible for incresed peripheral nociception?

Which kind of GPCR is this?

Where are these receptors found?

A

EP1

Gq

C fibres

21
Q

Painful stimuli is carried why which fibres of the nervous system?

A

C fibres

22
Q

Binding of prostaglandin E to EP1 receptors on C fibres results in which downstream effects?

What is the overall effect of these?

A

Increased neuronal sensitivity to Bradykinin

Inhibition of K+ channels (closer to threshold for AP firing)

Increased Na+ channel sensitivity

Overall effect: increase C fibre activity

23
Q

Explain what is happening at a cellular level when prostaglandin E binds to to EP1 receptors on C fibres

A

PG E binds EP1 (Gq GPCR)

Increased intracellular calcium

Increased neurotransmitter release

Increased sensitivity via other autocoids

24
Q

What is allodynia?

How does this differ from hyperalgesia?

A

The feeling of pain in a tissue given a stimulus that would not normally be painful in that tissue

Hyperalgesia is an increased pain stimulus in a tissue that WOULD normally perceive pain

25
Q

Which three changes in nociception might a patient experience following injury?

A

Spontaneous pain

Allodynia

Hyperalgesia

26
Q

What does increased sustained nociceptive signalling peripherally result in?

A

Increased cytokine levels in the dorsal horn cell body

Leading to central sensitisation to pain (increased pain perception)

27
Q

What happens at a cellular level to cause increased central sensitisation to pain?

A

PG E binds to EP2 receptors (Gs GPCR)

Increased cAMP

Increased PKA

Decreases glycine receptor binding affinity

Increases the discharge rate

28
Q

In infected/inflammed tissue, bacterial endotoxins stimulte macrophages to release what?

What does this then go on to do?

A

IL-1

IL-1 within hypothalamus stimulates PGE synthesis

29
Q

Prostaglandin E interacts with which receptor to cause pyrexia?

A

EP3 receptor which is a Gi GPCR

It results in increased heat production and reduced heat loss

30
Q

The main therapeutic effects of NSAIDs are achieved via inhibition of which enzyme?

What kind of inhibition is this?

A

COX-2 (and 1)

Competitive

31
Q

NSAIDs display _______ pharmacokinetics within the therapeutic dose range

A

Linear

32
Q

What are some of the main ADRs of NSAIDs?

A

Stomach and GI tract: nausea, heart burn, gastric bleeding, ulceration

Renal ADRs: in HF, renal disease

Vascular risk: Increased risk of bleeding, bruising

33
Q

Give an example of a serve hypersensitivity reaction to NSAIDs

A

Stevens Johnson Syndrome

Rash over skin and all mucous membranes within the body

Immune-complex mediated hypersensitvity reaction

34
Q

Explain the reason for GI ADRs with NSAIDs

A

COX-1 inhibition leads to reduced binding to receptors and therefore reducted prostaglandin production

The prostaglandins would normally stimulate cytoprotectice mucus secretion through the GI tract, reduce acid secretion and promote mucosal blood flow

35
Q

What drugs can be combined with NSAIDs to extend their therapeutic range for treating pain?

A

Low dose opiates

36
Q

Are NSAIDs heavily or weakly protein bound?

A

Heavily bound

90-99%

37
Q

NSAIDs can affect PK and PD of other drugs, give some examples.

A

Sulphonylurea

Warfarin

Methotrexate

38
Q

Aspirin is the only NSAID to _________ inhibit COX enzymes by acetylation

A

Irreversibly

39
Q

When aspirin is taken orally, what is its half life?

A

Less than 30 minutes

40
Q

Aspirin in hydrolysed in the plasma to what?

Which kinetics does this display at varying doses?

A

Salicylate

Lower: first order kinetics

Higher: zero order

41
Q

What is the mechanism of action of paracetamol?

A

Unknown

Possibily weak COX-1/2 inhibitor

42
Q

Which order of kinetics does paracetamol show in a healthy patient at normal doses?

A

First order (linear)

(Half life 2-4 hours)

43
Q

What pharmacokinetics does paracetamol show at high doses?

A

Zero order kinetics

44
Q

What is the toxic metabolite produced in the breakdown of paracetamol?

A

NAPQI

45
Q

Why do doses over 10g (20 tablets) cause a potentially fatal response in the patient?

A

NAPQI is produced, glutathione which usually mops it up is saturated due to the excess

Leading to increased production of NAPQI–> unconjugated

Highly reactive- binds with cellular macromolecules and mitochonrdia

Lead to hepatic cell death

46
Q

How can paracetamol iverdose be treated?

A

Activated charcoal orally within 0-4 hours

Acetylcysteine within 0-36 hours

or

Methionine orally if this cannot be given in this time

47
Q

How do we decide whether to treat a patient following paracetamol overdose?

A

Use a treatment decision graph

Which depends on the time after OD and their current plasma level

Clinical Pharmacology, Therapeutics & Principles of Prescribing (22 decks)

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