Non-Steroidal Inflammatory Drugs

Question 1

Give some background on non-inflammatory drugs.

Answer 1

Very widely used
About 50 drugs - significant structural heterogeneity
Principle action - targets key enzymes in prostaglandin synthesis

Three primary therapeutic effects

• Analgesia
• Anti-inflammatory
• Antipyretic

Question 2

Tell me about the inflammatory response.

Answer 2

Fundamental response of the body to injurious stimuli
- Includes a wide variety of noxious agents

Normally a protective response to reduce risk of further damage to organism
Alerts body through signalling pain
- Reduces further risk of damage through continued
use/activity

Question 3

Tell me about autacoids.

Answer 3

Diverse range of local molecular mediators and signalling agents employed

Examples:
Bradykinins, Histamine, Cytokines, Leukotrienes, Nitric oxide, Neuropeptides

Eicosanoids - includes prostaglandins

Signalling overlap ensures robust inflammatory response

Key feature is localised release + short half lives allow fine control of the signalling response

Question 4

What are eicosanoids ?

Answer 4

They are 20 carbon long phospholipid derivatives used as signalling molecules

Variation in synthetic routes give rise to different classes

All Eicosanoid classes derived from Arachidonic acid which is cleaved from cell membrane phospholipids

Question 5

What are prostanoids?`

Answer 5

A class of Eicosanoids

Examples:
Prostaglandins (PGs)
Prostacyclins
Thromboxanes

Question 6

Tell me about Cyclo-Oxygenase (COX) enzymes.

Answer 6

Enzymes involved in synthesis of PGs

Cell membrane phospholipids
\/ (Phospholipase A2 removes phosphate group)
Arachidonic acid
\/ (COX-1/COX-2)
PG 'G'
\/ (COX-1/COX-2)
PG 'H'
\/ (Specific PG enzymes)
PGs 'D, E, F, I'

Question 7

Tell me about PG ‘E’

Answer 7

Most important in mediating inflammatory response

Vasodilation
Hyperalgesia
Fever
Immunodilation

Question 8

What is special about COX-1?

Answer 8

It is constitutively expressed (always there)
It is expressed in a wide range of tissues
PG synthesis by COX-1 has major cytoprotective role
- Gastric mucosa
- Myocardium
- Renal parenchyma
- Ensures local perfusion - reduces ischemia
Due to this most ADRs caused by NSAIDS are due to COX-1 inhibition

Question 9

What is special about COX-2?

Answer 9

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

Main therapeutic effects of NSAIDS therefore occur through COX-2 inhibition

Question 10

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

Answer 10

COX-1 is ‘tight’
It has a smaller hydrophobic tunnel where the active site is.
Small, sharp, aspirin-like drugs fit in both mouths

COX-2 is ‘baggy’
Bigger hydrophobic tunnel
Easier for things to get in
Big, Blunt drugs only fit into COX-2 mouth

Question 11

Gibe some general pharmacology of prostaglandins.

Especially PG ‘E’

Answer 11

Prostaglandins bind at GPCRs
Specific action depends on PG receptor type
Often action includes synergising effects of other autacoids - e.g. Bradykinin/Histamine
PG ‘E’ has at least 4 main types: EP 1-4

Question 12

How are prostaglandins involved in inflammatory response.

Answer 12

A range of autacoids and prostanoids released post injury
Especially PGE2 and PGD2
Released from local tissues and blood vessels
Autacoid release also induces expression of COX-2
Synergise with other autacoids - Bradykinin/Histamine

PGs act as potent vasodilators
- But they don’t increase vascular permeability

Question 13

What are some of the effects of PG ‘E’ in terms of inflammatory response.

Answer 13

EP2 receptor Gs
Increase vasodilation

EP1 receptor Gq (on C fibres)
Increase peripheral nociception
Increased neuronal to Bradykinin
Inhibition of K+ channels
Increased Na+ channels sensitivity

In combination these act to increase ‘C’ fibre activity
(PGs may also activate previously silent ‘C’ fibres)

Question 14

How do PGs lead to increased peripheral sensitisation?

Answer 14

EP 1 binding leads to increased ‘C’ fibre activity

EP 1 is a Gq GPCR, activation leads to increased intracellular Ca2+

Increased Neurotransmitter release

Other autacoids involved increase sensitivity

Question 15

How do PGs lead to increase central nociception?

Answer 15

Increased sustained nociceptive signalling peripherally result in increase in cytokine levels in dorsal horn cell body

This causes increase in COX-2 synthesis and increase PGE2 synthesis

PGE2 then acts via local GPCR EP2 receptor (Gs type)
(This increases sensitivity + discharge rate of secondary interneurons)
Increase in cAMP
Increase in PKA
Decrease in Glycine receptor binding affinity
Increase in pain perception

Question 16

How do PGs and other Eicosanoids induce pyrexia?

Answer 16

In infected/inflammatory states bacterial endotoxins stimulate macrophage release IL-1
IL-1 within the hypothalamus (via induction of COX-2?) stimulates PGE2 synthesis
PGE2 via EP3 receptor - Gi type GPCR
Results in both increased heat production and decreased heat loss

Question 17

What are the main therapeutic effects of NSAIDs?

Answer 17

Anti-inflammatory
Antipyretic
Analgesic

Main therapeutic effects achieved via competitive COX-2 inhibition

Question 18

Tell me about some of the pharmacokinetics of NSAIDs.

Answer 18

Typically given orally but many topical preparations for soft tissue injury

Linear pharmacokinetics within therapeutic dose range

T1/2 has two groups:
- T1/2 10 hrs

Many heavily bound to plasma protein 90-99%

Question 19

What are the ADRs of NSAIDs?

Answer 19

Inhibition of COX-1 leads to many side-effects
Most ADRs seen in GI

GI
- Stomach pain
- Nausea
- Heart burn
- Gastric bleeding
- Ulceration
(Can offset GI ADRs with PPI or misoprostol)

Renal/Renovascular ADRs
In patients with compromised hepatic/renal/heart function
PGE2 and PGI2 maintain renal blood flow
- Reduced GFR
- Further risk of renal compromise
- Na+/K+/Cl- and H2O retention follow with increased likelihood of hypertension

Vascular
- Risk increase bleeding time, increase bruising

Hypersensitivity

• Skin rashes usually mild
• Rare but very serious - Stevens Johnson syndrome
• Bronchial asthma be careful

Reyes syndrome (paediatric)
- Rare but serious brain/liver injury - usually in viral
infections treated with aspirin risk of damage

Question 20

How can NSAIDs be used in conjunction with opiates?

Answer 20

In combination with low dose opiates
- Extends therapeutic range for treating pain

Acts by different mechanisms to extend range

Reduces ADRs seen with opiates alone

Question 21

What is the significance of using NSAIDs in combination?

Answer 21

Often occurs due to self medicating with NSAIDs

NSAIDs given together increases risk of ADRs
Given together they can affect each others PK/PDs due to competition for plasma protein binding sites
(Many NSAIDS heavily bound)

NSAIDs + low dose Aspirin - compete for COX-1 binding sites - may interfere with cardio protective action of aspirin

Question 22

What is the significance of using NSAIDs and other drugs?

Answer 22

NSAID protein binding can affect PK/PDs

Highly protein bound drugs affected by NSAID:
Sulphonylurea (Hypoglycaemia)
Warfarin (Increased bleeding)
Methotrexate (Wide ranging serious ADRs)

Question 23

What is special about aspirin?

Answer 23

The first NSAID
Relatively higher long term risk of ADRs
The only NSAID to irreversibly inhibit COX enzymes by acetylation

T1/2 less then 30 minutes
Hydrolysed in plasma to salicylate
Salicylate PKs dose dependent
At lower doses, first order, T1/2=4 hours
Higher doses - zero order kinetics
Salicylate is a standard NSAID

Question 24

Tell me about Paracetamol.

Answer 24

It is a unique ‘non NSAID’ non opiate analgesic
Known as a NOAD
Very effective for mild/moderate analgesia and fever
Unknown mechanism
(Might work in CNS on a COX-3 isoform)

At therapeutic doses has much better ADR profile than other NSAIDs
(Long term use can lead to higher risk of toxicity)

Small therapeutic window
Caution in those with compromised hepatic function or alcoholics
At higher doses it becomes zero order

Toxicity caused by increase in NAPQI
Which is highly reactive nucleophilic and binds with cellular macromolecules / mitochondria
Leads to necrotic hepatic cell death
Can also lead to renal failure

Question 25

How do you treat a paracetamol overdose?

Answer 25

Treatment must be given as soon as possible
Time dependant, hepatic toxic effects peak 72-96 hours post ingestion

If seen within 0-4hrs
- Activated charcoal orally reduce uptake by 50-90%

0-36hrs - Starts N-Acetylcysteine iv

Methionine by mouth if NAC cannot be given promptly