NSAIDs

Question 1

Give examples of NSAIDs

Answer 1

Ibuprofen

Naproxen

Diclofenac

Question 2

What are the 3 primary effects of NSAIDs?

Answer 2

Analgesia

Anti-inflam

Antipyretic

Question 3

What is the role of inflammation?

Answer 3

Protective = reduce risk of further damage by MO

Question 4

What are autacoids?

Answer 4

Local molecular mediators/signalling agents with a short half life

Induce expression of COX 2

E.g. Bradykinin, histamines, cytokines, leukotrienes

Question 5

What is the role of cyclo-oxylase (COX) enzymes?

Answer 5

Aid the synthesis of prostaglandins

COX 1/2 produce PGs D, E, F, I

E = most important in mediating inflam response

COX 1 = constitutively expressed (constant) in wide range of tissues

COX 2 = induced by injurious stimuli like inflam mediator bradykinin

Question 6

What is the main therapeutic effect of NSAIDs?

Answer 6

COX 2 competitive inhibition = prostaglandin synthesis inhibition = inflam inhibition

Question 7

Most ADRs caused by NSAIDs are due to what?

Answer 7

COX 1 inhibition

Question 8

How do prostaglandins work?

Answer 8

Bind GPCRs

Binding enhances actin of other autacoids

Question 9

Outline how prostaglandins are involved in the inflam response

Answer 9

Injury = autocoids and prostanoids released

= induced expression of COX 2

= aid synthesis of prostaglandins

= enhanced action of other autacoids (bradykinin and histamine) and potent vasodilator

Question 10

How do prostaglandins enhance pain reception ?

Answer 10

Bind/activate GPCRs =

Increased neuronal sensitivity to bradykinin

Inhibition of K+ channels

Increased Na channels sensitivity

ALL = increased C fibre (carry pain impulses) activity

Question 11

Explain how central nociception is sensitised

Answer 11

PGs active GPCR EP2 receptors =

Removes interneuronal inhibition = greater sensitivity to pain

Question 12

What are the stages of pain?

Answer 12

1) sensitisation of peripheral pain fibres

2) long term pain then causes increased pain perception

Question 13

Outline the role of each prostaglandin receptor

Answer 13

EP 1 = sensitising peripheral pain by increasing C fibre activity

EP 2 = increase vasodilation, sensitising central pain by inhib of inhibitory interneurons

EP 3 = increased heat production and decreased heat loss

Question 14

What are the general therapeutic effects of NSAIDs?

Answer 14

Anti inflam = rheumatoid, osteoarthritis

Analgesics = mild/moderate pain

Antipyretics

Question 15

What ADRs are associated with NSAIDs

Answer 15

COX 1 inhib = many side effects

Elderly long term use = iatrogenic morbidity/mortality

GI = pain, nausea, heartburn, gastric bleeding, ulceration (offset with PPIs)

Renal = decreased GFR

Vascular = increased risk of bleeding

Hypersensitivity = rashes, bronchial asthma

Question 16

Outline the potential drug interactions NSAIDs can have

Answer 16

Combined with low dose opiates = extends therapeutic range for treating pain

NSAIDs in combination = increased risk of ADRs

NSAIDs together = effect each others PK/PD due to competition for plasma proteins

NSAID + low dose aspirin = interfere with cardioprotective action of aspirin

Question 17

What drugs are affected by NSAIDs and why?

Answer 17

Highly protein bound drugs = sulphonylurea, warfarin, methotrexate

Competitive displacement

Question 18

Discuss the use of paracetamol

Answer 18

No anti-inflam action

Effective analgesic and antipyretic

Weak COX 1/2 inhibitor

Primarily acts in CNS

Caution in those with compromised hepatic function (alcoholics)

NAPQI at normal dose is detoxified by conjugation with glutathione

Overdose = oral activated charcoal and start N-acetylcysteine IV

Question 19

What does of paracetamol is potentially fatal?

Answer 19

Single dose >10 g (20 tabs)