Lecture 15– Non-steroidal anti- inflammatory drugs

Question 1

prostanoid synthesis

Answer 1

• The therapeutic benefit of prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) is a result of inhibiting down stream products of arachidonic acid
• Most of the adverse effects of NSAIDs stem form the inhibition of this pathway too
• Arachidonic acid derived primarily from dietary linoleic acid – vegetable oils converted hepatically to arachidonic acid and incorporated into phospholipids
• Found throughout the body – particularly in muscle, brain, liver and kidney
• Prostanoids are prostaglandins, prostacyclin and thromboxane’s
• Prostanoids are produced locally on demand – different enzymes, different prostanoids, short half lives so fine local control

Question 2

Prostanoids are

Answer 2

prostaglandins, prostacyclin and thromboxane’s

Question 3

PGE2

Answer 3

Prostaglandin E2

maintains GI system (good stomach health)

• regulates acid secretion in parietal cells

Question 4

PGE3,PGF21, PGD2 responsible for

Answer 4

Pain pyrexia inflammation

Question 5

PGI2

Answer 5

prostacyclin released by healthy endothelium to prevent platelet aggregation- increases cAMP, decreases calcium

• Cytoprotective CVS
• Also contributes to maintenance of blood flow and mucosal repair (good for GI)

Question 6

TXA2

Answer 6

thromboxane A2 - most potent endogenous platelet aggregatory factors (secreted in granules from platelets leading to activation of other platelets via TXA2 receptors

• Generally bad for the CVS (e.g. platelet aggregation)

Question 7

fine balance between ……. and …… in terms of CVS health

Answer 7

PGI2 (anti-platelet aggregation) and TXA2 (pro-platelt aggregation)

Question 8

Prostanoids signal through many GPCRs

Answer 8

Results in different reactions in different tissues

Question 9

prostanoid summary

Answer 9

• Types: PGE2, PGF2α, PGD2, PGI2 (prostacyclin) and TXA2 (thromboxane)
  
  • TXA2 and PGI2 have apposing vascular effects
  • Fine balance between them crucial – haemodynamic and thrombogenic control
• Act locally at GPCRs specific action depends on receptor subtype and location

Question 10

action of locqal………. can enhance prostanoid action

Answer 10

autacoids- histamine and bradykinin

Question 11

Imbalance/disruption to prostanoids plays significant role in

Answer 11

hypertension, MI and stroke risk

Question 12

Diet rich in fish oils (Ω fatty acids) – “The Mediterranean diet” proposed to

Answer 12

lead to conversion ofTXA3 to PGI3 – better prostanoids – lower incidence of CVD?

Question 13

Cyclooxygenases

Answer 13

Controls conversion of arachidonic acid to various prostanoids

Two functional isoforms

Question 14

2 isoforms of COX

Answer 14

COX-1 and COX-2

Question 15

COX-1x

Answer 15

• COX-1- constitutively active across most tissues

Question 16

COX-2

Answer 16

inducible (mostly)- in chronic inflammation. Constitutively in brain, kidney and bone

Question 17

NSAIDS

Answer 17

• Widely prescribed as analgesic and anti-inflammatories
• Chemically dissimilar to each other resulting in varying antipyretic, analgesic and anti-inflammatory properties

Question 18

NSAIDS single common mode of action

Answer 18

• inhibition of COX ↓prostaglandin, prostacyclin and thromboxane synthesis (which is good and bad)
• Compete with arachidonic acid for hydrophobic site of COX enzymes – COX enzyme inhibitors

Question 19

COX-1 and COX-2 present in different amounts in

Answer 19

different tissues

Question 20

NSAIDS- analgesia

Answer 20

• Local peripheral action at side of pain- greater efficacy if tissue inflamed
• Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2 (causes pain)
• Most effective after several days dosing

Question 21

NSAIDs- antipyretic

Add

Answer 21

• PGE2 is a critical component in the preoptic area of the hypothalamus - thermoregulatory centre
• Can be stimulated by pyrogens e.g. cytokines
• Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature

Question 22

NSAID- anti-inflammatory

Answer 22

• During inflammation ↑COX activity → prostaglandin mediated increase in vasodilatation and oedema
• NSAIDs reduce production of prostaglandins released at site of injury
• Vasodilation in post capillary venules contributes to increased permeability and local swelling- NSAIDs inhibit this
  
  • Symptomatic relief with COX inhibition – little effect on underlying chronic condition (wont cure just helps with inflammation)

Question 23

other anti-inflammatory actions of NSAIDS

Answer 23

• Other MOAs - Reduction in other anti-inflammatory mediators independent of COX may be associated with some effects ↓reactive oxygen species by oxygen scavenging properties?
  
  • link to possible reduction in some cancers?

Question 24

NSAIDS can be differentiated by their

Answer 24

• selectivity e.g. for COX-1 or COX-2
  
  • E.g. low dose aspirin favours COX-1

Question 25

what has lead to the development of selective COX-2 inhibitors

Answer 25

* High prevalence of ADRs attributable to COX-1 led to selective COX-2 inhibitors (coxibs) * COX-2 selective compounds inhibit COX-2 with much greater selectivity than COX-1 at therapeutic doses (if higher than this would also work on COX-1) e.g. celecoxib and etoricoxib * Non-COX-2 selective compromise all other NSAIDS

Question 26

**Gastrointestinal complications- most common ADR**

Answer 26

* Most common ADR * Dyspepsia * Nausea * Peptic ulceration * Bleeding * Perforation * Exacerbation of IBD

Question 27

**Gastrointestinal complications- contraindications**

Answer 27

* Elderly * Prolonged use * Smoking * Alcohol * History of peptic ulceration * H. pylori

Question 28

GI complications - DDI

Answer 28

* DDI * Aspirin * Glucocorticoid steroids * Anticoagulation (PPI should be considered)

Question 29

* MOA of GI problems

Answer 29

* Decrease mucus and bicarbonate secretion * Increase acid secretion * Decreased mucosal blood flow--\>enhanced cytotoxicity and hypoxia

Question 30

**Renal considerations**- ADRs *

Answer 30

* NSAIDs produce **reversible decrease in GFR** and decreased renal blood flow due to **reduced amounts of PGE2/PGI2 which causes vasodilation** * Therapeutic dose in healthy person- less issue * Concern with chronic use and people with CKD * Prostaglandins inhibit sodium absorption in the collecting duct- natriuresis- NSAIDS inhibit this action therefore increase in * Sodium * Water * BP (5mmHg)

Question 31

renal considerations- contraindications

Answer 31

* CKD * Heart failure * Both due to decrease in GFR

Question 32

Renal considerations- DDIs

Answer 32

* ACEi * ARBs * Diuretics

Question 33

renal consideration summary

Answer 33

Question 34

**Selective COX-2 inhibitors**

Answer 34

**e.g. Celecoxib and etoricoxib** The intention of COX-2 inhibitors was to avoid inhibition of homeostatic actions mediated by COX-1 – reducing GI ADRs * Less inhibitory action on COX-1 but selectivity for COX-2 varies among drugs * Less GI ADRs, renal ADRs *similar* to non-selective * Do not share antiplatelet action * But inhibit PGI2 - potentially leading to unopposed aggregatory effects – CVS risk problem * *Some* evidence of less analgesic effect

Question 35

when are selective COX-2 inhibitors used

Answer 35

Can be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment – reduced GI side effects

Question 36

* ALL NSAIDs increase risk of

Answer 36

* MI including in low risk people (↓PGI2 in coronary vasculature?) * Reduced cycloprotective of the CVS by removing PGI2 etc

Question 37

**NSAIDs and protein binding**

Answer 37

* NSAIDs displace other protein bound drugs- increasing free drug conc of other drugs * Particularly high protein bound drugs e.g. * sulfonylureas- hypoglycaemia * methotrexate – accumulation and hepatotoxicity * warfarin- increased risk of bleeding * MOA= competitive displacement * Likely dose adjustment needed and increase monitoring

Question 38

**Indication of NSAIDS**

Answer 38

* Inflammatory conditions – joint and soft tissue * Osteoarthritis – topical NSAID and paracetamol should be tried first * Postoperative pain * Topical use on cornea * Menorrhagia (moderate reduction in blood loss) * Low dose aspirin for platelet aggregation inhibition * Opioid sparing when used in combination * Cancer reduction – by up to 30 - 50% - nuclear transcription factors, reduced cell proliferation, inflammation......???

Question 39

**Contraindications of NSAID use**

Answer 39

* Cardiovascular disease – risk * Renal function - age * GI disease - previous use of NSAIDs * DDIs – ACEi and ARBs, steroids, diuretics, methotrexate, warfarin (not exhaustive list) * Level of pain, pyrexia, level of inflammation * Third trimester of pregnancy – not sustained use – delayed labour and early closure of ductus arteriosus

Question 40

**When prescribing NSAIDs consider…**

Answer 40

LOWEST EFFECTIVE DOSE FOR THE SHORTEST TIME NECESSARY TAKING INTO ACCOUNT PATIENT SPECIFIC RISK FACTORS

Question 41

paracetamol is neither a

Answer 41

NSAID or opiate

Question 42

summary of paracetamol

Answer 42

* Analgesic and antipyretic action * For mild to moderate analgesia and very useful in fever * Generally well tolerated with fewer ADRs * No effect on platelets and limited effect on GI

Question 43

**MOA of paracetamol**

Answer 43

* Still not understood * Activity may be mediated by COX-2 selective inhibition in CNS (spinal cord)- decreasing pain signals to higher centres * Very little anti-inflammatory action

Question 44

why does paracetamol have very little anti-inflammatory action

Answer 44

* Related to peroxidases * Peroxide is important for the activity of paracetamol In peripheral inflammation there is high levels of peroxidases which break down peroxide- therefore cant help with inflammation in peripheral tissue

Question 45

**Pharmacokinetics of paracetamol**

Answer 45

* Well absorbed from GI * T1/2 around 2.5 hours * Inactivated by conjugation in the liver

Question 46

NAPQI

Answer 46

* Reactive metabolite of paracetamol (phase 1 reaction)- some analgesic effect * At normal therapeutic doses- conjugation with glutathione renders NAPQI harmless (Phase 2 reaction) * HOWEVER hepatic glutathione is limited so if too much paracetamol is taken there is not enough glutathione to power the phase 2 reaction - toxic

Question 47

paracetamol overdose caused by

Answer 47

limited amount of glutathione * Therefore another reaction takes place * NAPQI highly nucleophilic- oxidising key metabolic enzymes ultimately causing cell death- necrosis and apoptosis (particularly to the liver) * 150mg/kg sufficient to cause irreversible damage

Question 48

**Paracetamol overdose**

Answer 48

**Paracetamol overdose** * Can be asymptomatic for many hours * Nausea, vomiting and abdominal pain – first 24 hours * Maximal liver damage occurs at 3-4 days * Due to accumulation of NAPQI (not enough glutathione to power phase 2 reaction) * Therefore NAPQI starts causing necrosis of cells esp in the liver

Question 49

**Paracetamol overdose treatment**

Answer 49

* Activated charcoal- only of use if paracetamol overdose recently taken * Lethionine (oral drug) * **Glutathione thiol replacement – IV N- acetylcysteine**

Question 50

**N-acetylcysteine in treatment of paracetamol overdose**

Answer 50

* Replaces glutathione * Used when [paracetamol] conc in plasma is to the right of the curve line)