COX-2 selective NSAIDs and paracetamol Flashcards
What are coxibs?
COX-2 selective NSAIDs
What is paracetamol
CNS selective COX inhibitor
What are the GI adverse effects of NSAIDs?
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!)
What are the Renal Adverse effects of NSAIDs?
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
Does the inhibition of prostacyclin counter the effects of the inhibition of prostaglandin?
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.
What are other adverse effects of NSAIDs (other than GI and renal)
- Psuedo-allergic reaction
- skin rashes
- swelling
- itching
- nasal congestion
- anaphylactic shock - Asthma - bronchospasms in susceptible individuals
- Bleeding - failure of haemostasis, bruising
How do NSAIDs cause allergic reactions and aspirin sensitive asthma?
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
Why are adverse effects stronger for aspirin than for other NSAIDs?
it is an irreversible COX inhibitor.
What is the difference between COX 1 and COX 2?
COX 1:
- physiologic stimulus
- constitutive
- housekeeping
COX 2:
- inflammatory stimulus
- inducible
- inflammation
Why are COX 2 inhibitors better than COX 1 inhibitors?
This is because they have less side effects as it does not inhibit the constitutive COX 1.
Rank the COX inhibitors from bad to good for GIT
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
What are the difference in clinical effects for COX 1 vs COX 2 inhibitors?
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)
Does COX 2 have housekeeping abilities?
Yes in some tissues!
- CNS
- Kidneys
- Female reproductive tract
- Synovium
What are some unwanted side effects of COX 2 inhibition?
- Renal Toxicity (kidneys have both COX 1 and COX 2 constitutive expression
- Reduced ovulation - delayed follicular rupture hence reducing pregnancy chances
- Premature closure of ductus arteriosus (fetal lung bypass) in late pregnancy - fetus will drown in utero as it tries to use lungs to breathe
Who is contraindicated in COX 2 inhibitors? (INCLUDES NSAIDs)
Pregnant woman in the 3rd trimester
What other adverse effects do COX 2 inhibitors have?
- 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) - Increased risk of thrombosis
Relative increase in thromboxane due to pooling of arachidonic acid, causes platelet aggregation to be favoured, increasing risk of thrombosis.
What is an example of a CNS selective COX inhibitor?
Paracetamol (Acetaminophen)
Ibuprofen may exhibit some CNS selectivity
What are the advantages of Paracetamol
- 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
What are disadvantages of Paracetamol?
- 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
How is hepatotoxicity exacerbated by overdose and chronic alcohol use/abuse?
Major pathway of paracetamol breakdown results in non toxic metabolites.
- Minor pathways of paracetamol results in toxic metabolites - this reaction is catalysed by P450 2E1 (CYP2E1) which is induced by alcohol
- Converting toxic metabolites to nontoxic metabolites is catalysed by gluthathione. However, it is depleted by alcohol and by paracetamol overdose.
What is the treatment for paracetamol toxicity?
N-acetyl-cystein (NAC)
Are coxibs good antipyuretics?
No. They weakly cross to CNS
