S8) NSAIDs

Question 1

What is the principal action of non-steroidal anti-inflammatory drugs?

Answer 1

Principle action – key enzymes in prostaglandin synthesis

Question 2

What are the three primary therapeutic effects of NSAIDs?

Answer 2

• Analgesia
• Anti-Inflammatory
• Antipyretic

Question 3

Why do NSAIDs commonly have short half lives?

Answer 3

Short half lives allows fine control of the signalling response

Question 4

How are prostaglandins synthesised?

Answer 4

Prostaglandins are synthesised from arachidonic acid

Question 5

Identify two types of prostaglandins

Answer 5

• Prostacyclins
• Thromboxanes

Question 6

Describe the prostaglandin synthesis pathway

Answer 6

Prostaglandins are synthesised from cell membrane phospholipids and arachidonic acid and thereafter catalysed by COX-1/2 to produce specific PG enzymes

Question 7

PG ‘E’ is the most important in mediating the inflammatory response.

Identify four of its functions

Answer 7

• Vasodilation
• Hyperalgesia
• Fever
• Immunomodulation

Question 8

PG synthesis by COX -1 has major cytoprotective role in three locations.

Identify them

Answer 8

• Gastric mucosa
• Myocardium
• Renal parenchyma

Question 9

What is the half life of PG and what is the significance of this for NSAIDs?

Answer 9

• PG t_1/2 short (10 mins) – need constant synthesis
• Due to its constitutive expression, most ADRs caused by NSAIDs are due to COX-1 inhibition

Question 10

What induces COX-2 expression and where is it expressed?

Answer 10

• COX-2 expression induced by inflammatory mediators such as bradykinin
• COX-2 appears to be constitutively expressed in parts of the brain and kidney

Question 11

How do the main therapeutic effects of NSAIDs occur?

Answer 11

Main therapeutic effects of NSAIDs occur via COX-2 inhibition

Question 12

Illustrate how differences in COX-1 and COX-2 tunnel for selective inhibition by different NSAIDs

Answer 12

Question 13

Explain prostaglandin binding with receptors

Answer 13

• Prostaglandins bind with GPCRs
• Specific actions depend on PG receptor types

For PG E, at least four main types: EP 1-4

Question 14

In four steps, describe how prostaglandins act as inflammatory response mediators

Answer 14

⇒ Range of autacoids and prostanoids released from local tissues/blood vessels post injury

⇒ Autacoid release also induces expression of COX-2

⇒ Synergise with other autacoids (bradykinin/histamine)

⇒ PGs act as potent vasodilators & synergise permeating effects of bradykinin/histamine

Question 15

State the effect of prostaglandin release post injury at the following receptors:

• EP2 receptor Gs
• EP1 receptor Gq

Answer 15

• EP2 receptor Gs – ↑ vasodilation
• EP1 receptor Gq – ↑ peripheral nociception

Question 16

With regards to sensitising peripheral nociception, describe the three effects of GPCR activation by EP1

Answer 16

• Increased neuronal sensitivity to bradykinin
• Inhibition of K⁺ channels
• Increased Na⁺ channels sensitivity

All act to increase afferent ‘C’ fibre activity (carry pain stimuli)

Question 17

In four steps, expain how peripheral sensitisation occurs

Answer 17

⇒ EP 1 binding leads to ↑ ‘C’ fibre activity

⇒ ↑ intracellular [Ca²⁺]

⇒ Neurotransmitter release

⇒ Other autacoids involved to ↑ sensitivity

Question 18

In terms of nociception, illustrate the relationship between allodynia and hyperalgesia

Answer 18

• Allodynia is pain due to a stimulus that does not usually provoke pain
• Hyperalgesia is increased pain from a stimulus that usually provokes pain

Question 19

In four steps, explain how sensitising central nociception occurs

Answer 19

⇒ Increased sustained nociceptive signalling peripherally ↑ cytokine levels in dorsal horn cell body

⇒ ↑ COX-2 synthesis and ↑ PGE_{<strong>2</strong>} synthesis

⇒ PGE₂ acts via local EP2 receptor (Gs type)

⇒ ↑ sensitivity and discharge rate of secondary interneurones

Question 20

In four steps, explain how prostaglandins lead to a state of pyrexia

Answer 20

⇒ Bacterial endotoxins stimulate macrophage release of IL-1

⇒ IL-1 stimulates PGE₂ synthesis within hypothalamus

⇒ PGE₂ acts via EP3 receptor (Gi type)

⇒ ↑ heat production and ↓ heat loss

Question 21

The main therapeutic effects achieved via COX-2 inhibition.

Briefly, explain how this occurs

Answer 21

• Pharmacological action for nearly all NSAIDs via competitive inhibition of COX-1 and COX-2
• Occupation of COX-1 /2 hydrophobic channel by NSAID competes with AA site occupation

Question 22

How are NSAIDs administered?

Answer 22

Typically given orally but many topical preparations for soft tissue injury

Question 23

Which pharmacokinetics pattern do NSAIDs illustrate?

Answer 23

Linear pharmacokinetics within therapeutic dose range

Question 24

There are two groups of NSAIDs according to half lives.

Identify them

Answer 24

• T_1⁄2 < 6hrs
• T_1⁄2 >10 hrs

Question 25

How are NSAIDs transported in the blood?

Answer 25

Many heavily bound to plasma protein (90-99%)

Question 26

Describe the therapeutic use of NSAIDs as an anti-inflammatory

Answer 26

Very wide use in **musculoskeletal disorders** – rheumatoid / osteoarthritis

Question 27

Describe the therapeutic use of NSAIDs as an analgesic

Answer 27

- Used for mild to moderate pain accompanying many disease states - Universal use in Hospitals / OTC

Question 28

Inhibition of COX-1 constitutive PG synthesis leads to many side effects. Indicate which patient group this usually affects

Answer 28

Long term use in **elderly** – particularly associated with iatrogenic morbidity and mortality

Question 29

Renal ADRs occur in compromised individuals with HRH or hypovolaemia. What is HRH?

Answer 29

- Heart failure - Renal disease - Hepatic cirrhosis

Question 30

The major ADRs are seen in stomach /GI tract. Identify some

Answer 30

- Stomach pain - Nausea - Heartburn - Gastric bleeding - Ulceration

Question 31

Explain why a gastric ADR can occur by the selective inhibition of COX-1

Answer 31

Gastric COX-1 PGE2 stimulates **cytoprotective mucus secretion** throughout GI tract, reduce acid secretion and promote mucosal blood flow

Question 32

Explain why a renal ADR can occur due to NSAIDs

Answer 32

- PGE₂ and PGI₂ maintain renal blood flow - If reduced by NSAIDs then GFR decreases – further risk of renal compromise (especially neonates/elderly)

Question 33

Apart from GI and renal symptoms, identify some other NSAID ADRs

Answer 33

- **Vascular** – decreased bleeding time, bruising haemorrhage - **Hypersensitivity** – skin rashes, bronchial asthma - **Rare serious brain/liver injury** – usually in viral infections treated with aspirin risk of damage

Question 34

What are the therapeutic benefits from combining NSAIDs with low dose opiates?

Answer 34

- Extends therapeutic range for treating pain - Reduces ADRs seen with opiates alone

Question 35

Identify three highly protein bound drugs affected by NSAIDs

Answer 35

- Sulphonylurea - Warfarin - Methotrexate

Question 36

What is the effect of NSAIDs given in combination with aspirin?

Answer 36

**NSAIDs + low dose Aspirin** – compete for COX-1 binding sites and may interfere with cardioprotective action of Aspirin

Question 37

What is the result of multiple NSAIDS given in combination?

Answer 37

- Increase risk of ADRs – often occurs due to self medication with NSAIDs - Affect each others PK/PDs due to competition for plasma protein binding sites

Question 38

Describe how aspirin acts uniquely in the body

Answer 38

- Only NSAID to **irreversibly inhibit COX enzymes** by acetylation - **T_1⁄2 \< 30 minutes** rapidly hydrolysed in plasma to salicylate

Question 39

Why is paracetamol a unique non NSAID?

Answer 39

Paracetamol is a unique ‘non NSAID’ as it has virtually no anti-inflammatory action – more of a **NOAD** (non-opiate anagelsic drug)

Question 40

When is paracetamol used?

Answer 40

Paracetamol is very effective for mild/moderate **analgesia** and **fever**

Question 41

What is the therapeutic dose for paracetamol?

Answer 41

**Therapeutic dose:** 8 x 500 mg tablets/day

Question 42

In normal doses, paracetamol displays linear pharmacokinetics. How is it metabolised?

Answer 42

- Mainly **Phase II Conjugation** – Glucoronide 60%, Sulphate 30% - Some **Phase 1 Oxidation** – NAPQI 10%

Question 43

NAPQI is very reactive and toxic. How is it detoxified?

Answer 43

- At normal doses, NAPQI is detoxified by Phase II conjugation with **Glutathione** - Linear detoxification step limited by **availability of Glutathione**

Question 44

What is a toxic dose of paracetamol?

Answer 44

**Single doses \> 10 g** (20 tablets) potentially fatal

Question 45

At high doses, paracetamol pharmacokinetics become zero order. Describe paracetamol metabolism at high doses

Answer 45

- First step Phase II metabolism saturated - ↑ Phase I production of NAPQI - Phase II conjugation of NAPQI with glutathione rate limited – also saturated

Question 46

Paracetamol overdoses are time dependent – delayed hepatoxic effects peak 72 - 96 hrs post ingestion. How can this be treated?

Answer 46

- 0-4hrs – **activated charcoal** orally reduce uptake by 50-90% - 0-36 hrs – start **N-Acetylcysteine** IV - **Methionine** orally (if NAC cannot be given promptly)