COX-2 selective NSAIDs and paracetamol

Question 1

What are coxibs?

Answer 1

COX-2 selective NSAIDs

Question 2

What is paracetamol

Answer 2

CNS selective COX inhibitor

Question 3

What are the GI adverse effects of NSAIDs?

Answer 3

Prostaglandins:

• reduce gastric acid secretions
• increase mucosal blood flow
• increase secretion of mucus
• increase secretion of bicarbonate

Hence, NSAIDs lead to:

• Dyspepsia
• Nausea
• Vomiting
• Ulcer formation and potential haemorrhage risk in chronic users (NSAID is also an antiplatelet!)

Question 4

What are the Renal Adverse effects of NSAIDs?

Answer 4

Alters renal blood flow dynamics - important for setting up filtration gradients

Inhibition of Prostaglandin (thick ascending limb of Loop of Henle):

• sodium retention
• water retention
• peripheral oedema
• hypertension

Inhibition of Prostacyclin (DCT):

• suppresses renin angiotensin and aldosterone system
• hyperkalemia
• acute renal failure

Question 5

Does the inhibition of prostacyclin counter the effects of the inhibition of prostaglandin?

Answer 5

No.
NSAID prevention of the absorption of 1-2% of Na+ at the DCT (by prostacyclin inhibition) cannot make up for the reabsorption of 25% of Na+ in the TAL of the LOH
Hence hypernatremia and hypertension are not corrected.

Question 6

What are other adverse effects of NSAIDs (other than GI and renal)

Answer 6

1. Psuedo-allergic reaction
   - skin rashes
   - swelling
   - itching
   - nasal congestion
   - anaphylactic shock
2. Asthma - bronchospasms in susceptible individuals
3. Bleeding - failure of haemostasis, bruising

Question 7

How do NSAIDs cause allergic reactions and aspirin sensitive asthma?

Answer 7

Because of the inhibition of COX, there is pooling of arachidonic acid, causing increased Leukotriene production (by 5-lipoxygenase enzymes) hence leading to bronchospasm in asthmatics (LTD4) and allergic reaction-like symptoms
NOT ALL PATIENTS only some but is serious for them

Question 8

Why are adverse effects stronger for aspirin than for other NSAIDs?

Answer 8

it is an irreversible COX inhibitor.

Question 9

What is the difference between COX 1 and COX 2?

Answer 9

COX 1:

• physiologic stimulus
• constitutive
• housekeeping

COX 2:

• inflammatory stimulus
• inducible
• inflammation

Question 10

Why are COX 2 inhibitors better than COX 1 inhibitors?

Answer 10

This is because they have less side effects as it does not inhibit the constitutive COX 1.

Question 11

Rank the COX inhibitors from bad to good for GIT

Answer 11

COX 1
Ketoprofen
Piroxicam
Indometacin
Aspirin
Naproxen
Diclofenac
Mefenamic acid
Meloxicam
Celecoxib
Parecovib
Etoricoxib
COX 2 - still do inhibit some COX 1 and hence are not completely safe but are safer

Question 12

What are the difference in clinical effects for COX 1 vs COX 2 inhibitors?

Answer 12

Anti inflammatory (COX 2 > COX 1)
Analgesic (COX 2 > COX 1)
Antiplatelet (COX 1 > COX 2) with the exception of aspirin as it is an irreversible cox inhibitor
Prothrombotic (COX 2 > COX 1)

Question 13

Does COX 2 have housekeeping abilities?

Answer 13

Yes in some tissues!

• CNS
• Kidneys
• Female reproductive tract
• Synovium

Question 14

What are some unwanted side effects of COX 2 inhibition?

Answer 14

1. Renal Toxicity (kidneys have both COX 1 and COX 2 constitutive expression
2. Reduced ovulation - delayed follicular rupture hence reducing pregnancy chances
3. Premature closure of ductus arteriosus (fetal lung bypass) in late pregnancy - fetus will drown in utero as it tries to use lungs to breathe

Question 15

Who is contraindicated in COX 2 inhibitors? (INCLUDES NSAIDs)

Answer 15

Pregnant woman in the 3rd trimester

Question 16

What other adverse effects do COX 2 inhibitors have?

Answer 16

1. Impairment of wound healing
   Hence it may exacerbate ulcers thus ulcers should be treated first before using Coxibs.
   Must be used in caution for patients with existing ulcers and other ulcer risk factors.
   Slows down healing after surgery due to post surgical analgesia (NSAIDs) –> inhibition of thrombosis (by COX 1) and whole cascade for healing (COX 2)
2. Increased risk of thrombosis
   Relative increase in thromboxane due to pooling of arachidonic acid, causes platelet aggregation to be favoured, increasing risk of thrombosis.

Question 17

What is an example of a CNS selective COX inhibitor?

Answer 17

Paracetamol (Acetaminophen)

Ibuprofen may exhibit some CNS selectivity

Question 18

What are the advantages of Paracetamol

Answer 18

• Good analgesic
• Potent antipyretic
• Spares the GI tract (does not inhibit COX in periphery)
• Few and uncommon side effects
• Few drug-drug interactions
• Safe for paediatric use

Question 19

What are disadvantages of Paracetamol?

Answer 19

• Weak anti-inflammatory (does not inhibit COX in periphery) unless it is directly given to tissue eg. dental
• Toxic doses (close to therapeutic dose due to narrow therapeutic window) can cause nausea, vomiting and liver damage
• Allergic skin reactions

Question 20

How is hepatotoxicity exacerbated by overdose and chronic alcohol use/abuse?

Answer 20

Major pathway of paracetamol breakdown results in non toxic metabolites.

1. Minor pathways of paracetamol results in toxic metabolites - this reaction is catalysed by P450 2E1 (CYP2E1) which is induced by alcohol
2. Converting toxic metabolites to nontoxic metabolites is catalysed by gluthathione. However, it is depleted by alcohol and by paracetamol overdose.

Question 21

What is the treatment for paracetamol toxicity?

Answer 21

N-acetyl-cystein (NAC)

Question 22

Are coxibs good antipyuretics?

Answer 22

No. They weakly cross to CNS