6.3 Paracetamol, NSAIDs and Coxibs Flashcards
(41 cards)
[Paracetamol]
What are the indications for paracetamol?
- Analgesic – mild to moderate pain
- Anti-pyretic
- Does not have any anti-inflammatory action and so is not traditionally classified as an NSAID.
- Can be used together with NSAIDs synergistically
[Paracetamol]
What are the mechanism of actions for paracetamol?
In spite of its ubiquitous usage, its mechanism of action is still not certain
Probably central acting ? COX- 3 ? Via Cannabinoid receptors ? Interaction with endogenous opioids ?interaction with 5HT and adenosine receptors
[Paracetamol]
What is the onset via oral route?
onset <1 hour, good bioavailability of 80%
[Paracetamol]
What is the onset via iv route?
onset 5 to 10 mins for analgesia, 30 mins for antipyretic
[Paracetamol]
What is the duration via iv route?
4-6 hours
[Paracetamol]
Metabolism of Paracetamol? - Metabolised by the liver to _________ and __________ conjugates.
- A small amount is metabolised by CYP2E1 to a highly reactive intermediate compound ________________, which is conjugated rapidly with glutathione and inactivated.
- At toxic doses, the glutathione conjugation is overwhelmed and NAPQI then causes _____________. This accounts for the toxicity in paracetamol overdose.
sulphate; glucuronide;
N-acetyl-p-benzoquinone imine (NAPQI);
hepatic cell necrosis
[Paracetamol]
What is the side effects?
Generally well tolerated
In overdose, paracetamol can cause acute liver failure
- Intentional overdoses occur in suicidal attempts
- Unintentional overdoses can also occur. Many over the counter (OTC) medications contain paracetamol and doctors and patients may not be aware that they are exceeding the recommended maximum daily doses.
- Caution in patients with ______________, heavy alcohol drinkers or those who sustained acute liver derangements
- Consider all the different paracetamol-containing products and routes that the patient may be taking. E.g. Paracetamol PO and supp. Anarex + Paracetamol + panadeine + Ultracet. OTC medication.
pre-existing liver impairment;
What are the common use of NSAIDs?
- Analgesia – though there is a ceiling effect
- Anti-inflammatory effect –inflammatory conditions like Rheumatoid Arthritis, dysmenorrhoea
- Anti-pyretic effect
Which NSAID is used for Reduction of Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis?
PR diclofenac
Which NSAID is used for Reduction of Closure of Patent Ductus Arteriosus?
IV indomethacin or ibuprofen
Physical Properties of NSAIDs
- Most are strong organic acids with pKAs in the ________ range. Therefore extensively ionised at physiologic pH.
- Well absorbed orally
- Negligible first-pass hepatic metabolism
- Tightly bound to ___________
- Small volumes of distribution
- Most are cleared by the liver via ____________
3-5;
albumin;
glucuronidation
[NSAIDs: Classification]
What are considered salicylates?
Aspirin
[NSAIDs: Classification]
What are considered Propionic Acids (Profens)?
Ibuprofen, Ketoprofen, Naproxen
[NSAIDs: Classification]
What are considered Aryl/Hetroarylacetic Acids?
Indomethacin, Ketorolac. Diclofenac
[NSAIDs: Classification]
What are considered Anthranilates (Fenamates)?
Mefenamic Acid
[NSAIDs: Classification]
What are considered Oxicams (“Enol Acids”)?
Piroxicam
What is the mechanism of action of NSAIDs?
- NSAIDS inhibit the production of prostanoids
- Prostanoids are inflammatory mediators
- They are derived from arachidonic acid (phospholipids)
- Prostaglandins and thromboxanes
Prostanoid receptors
- DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP
- Naming based on agonist potency
- All ___________, but also have effects independent of G proteins
- Knock out mice show that prostanoid effects are extremely complex
- Role in both normal physiology, as well as in pro-inflammatory states
G protein coupled
Two main isoforms of COX
Cox 1
- ___________ (made all the time)
- _________ (found in nearly all cell types)
- Physiological
Cox-2
- Mainly __________ (made in response to specific stimuli)
- Very widespread
- ______________ roles
Constitutive;
Ubiquitous;
inducible;
Physiological and pro-inflammatory
Which 4 receptors do PGE2 activate?
EP1, EP2, EP3, EP4,
Which 5 pathways do EP2 activate?
Proliferation, metastasis
1) JNK –> Pfn 1 –> Factin
2) Ras –> Erk
2) PI3K/ AKt –> GSK3b –> b catenin
Inflammation, neurotoxicity
4) cAMP –> EPAC/ Rap
Neurosurvival, neuroplasticity
5) cAMP –> PKA/ CREB
How does Prostaglandin E2 lowers the pain threshold?
Stimulation of PG receptors on nerve endings sensitizes nociceptors to chemical and thermal stimuli which cause pain
How is PGE2 pyrogenic?
PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
Gastrointestinal effects of NSAIDS
- Patients may experience dyspepsia, develop peptic ulcer disease or GI bleeding
- COX 1 is needed to produce the prostaglandins needed for ______________ via several pathways.
- One of the mechanisms is that prostaglandins (e.g. PGE2) are needed for _____________ and ______________ by the epithelial cells. This forms an alkaline, unstirred water layer on the gastric mucosa which prevents damage from the gastric acid.
- As such, non-selective NSAIDs which inhibit COX-1 (in addition to COX-2), can potentially lead to GI side effects.
gastric mucosal protection;
glycoprotein (mucin) stimulation; bicarbonate secretion
