6.3 Paracetamol, NSAIDs and Coxibs Flashcards
[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
What is the risk factors for NSAID Gastropathy?
- Age > 65years
- Previous ulcer, GI bleed or perforation
- Concomitant drugs that increase GI adverse events e.g. Anti-platelets, anti-coagulants, SSRI, Aspirin, Steroids
- High dose NSAIDS for a prolonged period of time
What are the renal effects of NSAIDs?
- Development of acute renal failure 2nd to renal vasoconstriction
- Modest worsening of hypertension
- Electrolyte and fluid abnormalities like HyperK, HypoNa and oedema in patients with decreased intravascular volume
- May have an increased risk of renal cell cancer
What is the pathogenesis of NSAID renal injury?
In healthy patients, renal prostaglandins have almost no effect on renal perfusion. However, in patients who has chronic renal vasoconstrictions or in low volume states, the vasodilation produced by renal prostaglandins become important in maintaining renal blood flow and GFR. As such, NSAIDs can cause AKI via inhibition of renal prostaglandins.
The increase in blood pressure from NSAIDs is likely due to reduction of renal sodium excretion from inhibition of COX-2.
What are the risk factors for NSAID nephropathy?
- Pre-existing renal disease
- Hypercalcemia as this causes renal vasoconstriction
- States of effective volume depletion like heart failure and cirrhosis
- States of true volume depletion i.e. bleeding, dehydration
- Medications like ACE inhibitors, ARBs, diuretics, aminoglycosides.
What is the hematological effects of NSAIDS?
- Non-selective NSAIDS exert an anti-platelet effect through inhibition of ______, leading to decreased thromboxane A2.
- Thromboxane A2 is needed for _________, _____________.
- Patients with thrombocytopenia, platelet defects (e.g. severe uraemia or von Willebrand disease) or on anti-platelet/anticoagulant medication are at an increased risk.
- The COX-2 specific inhibitors do not affect this pathway.
COX-1;
local vasoconstriction at the site of injury, platelet activation and aggregation.
Cardiovascular effects of NSAIDs
Increased risk of thrombotic cardiovascular events like stroke and myocardial infarction
- Exact mechanism is still unknown. One of the theories is that __________ is needed for the production of PGI-2 in the vascular endothelium. PGI-2 is important for ____________ and is also an _________.
- Another postulation is that NSAIDs cause an increase in arterial pressure, which may predispose to CVS events.
- CCF is also increased in patients on chronic NSAIDs. The likely mechanism is due to the __________________________
COX 2
vasodilation;
anti-thrombotic substance
decrease in renal glomerular filtration and the resultant decrease in excretion of sodium and water.
Aspirin Exacerbated Respiratory Disease (AERD)
A ___________ inhibiting NSAID may precipitate acute exacerbations of airway inflammation in patients with AERD
AERD refers to a combination of
- Asthma
- __________________
- Reactions to aspirin and other COX 1 inhibiting NSAIDs in which symptoms of nasal congestion and bronchoconstriction occur after ingestion
Categorized as a ______________
COX 1;
Chronic rhinosinusitis with nasal polyposis;
Type 1 Pseudoallergic reaction
Is a pregnant woman allowed to have NSAIDs?
- Small possibility of an increased risk of spontaneous abortions in the first few weeks following conception if NSAIDs are taken
- Avoid NSAIDs in the 3rd trimester because of the risk of premature closure of the ductus arteriosus in the fetus.
Should a lactating mother consume NSAIDs?
For lactating mothers, NSAIDs are generally safe but high dose aspirin should be avoided as a significant portion can cross over into the infant.
Should infants and children take NSAIDS?
- Aspirin should be avoided in children as it can precipitate Reye syndrome, which can be life threatening.
- Reye syndrome seems to be triggered by using aspirin to treat a viral illness or infection
- As such, do not use Aspirin in the paediatric population as there are safer alternatives like paracetamol and ibuprofen
Physical properties of Cox-2 inhibitors
- Chemically distinct from NSAIDs
- Highly ____________
- Neutral non-acidic molecules
- Limited solubility in aqueous media
- In particular, ___________ is a sulphonamide which should be avoided in patients with allergy to this chemical group.
- _____________ is currently the only available parenteral form of a coxib. It is a prodrug and is converted to Valdecoxib.
- _____________ has been withdrawn from the market in 2004 as trials showed it had an increased risk of strokes and myocardia infarctions compared to placebo.
lipophilic;
Celecoxib;
Parecoxib;
Rofecoxib (Vioxx)
What are the advantages Coxibs have over NSAIDS?
- Decreased GI side effects
- No increased risk of bleeding as compared to NSAIDs as it does not affect thromboxane A2
- Decreased risk of precipitating bronchospasm in patients with Asthma
What are the disadvantages of coxibs?
- Possibly higher risk of cardiovascular events in relation to NSAIDs
- Has the same risk of renal impairment as non-specific NSAIDs
- More expensive than NSAIDs
What are the strategies for limiting side effects of NSAIDs?
- Lowest effective dose for shortest duration possible
- Topical application
- Administration with omeprazole or other proton pump inhibitor
Aspirin
- Irreversibly acetylate COX enzymes as opposed to the other NSAIDs
- More _____________
Split into low dose and high dose regimes
- Low dose aspirin is <300mg/day. In Singapore, we use the _________ dose for anti-platelet effect.
The anti-inflammatory/analgesic dose of >325mg/day is rarely used because of the high incidence of adverse effects
Interestingly, aspirin is a weak inhibitor of renal prostaglandin synthesis and is unlikely to exert a clinical effect on the kidneys when used at low doses.
COX-1 selective;
100mg;
Aspirin and cardiovascular protection
- Aspirin irreversibly inhibits ______________- in platelets
- As platelets do not have a nucleus and thus is not able to produce new COX and thus generate new Thromboxane A2, the effect of aspirin lasts for the lifespan of the platelets (10 days).
- If aspirin is ceased, the anti-platelet effect is usually insignificant after __________ as the body produces new platelets. As such, if clinically indicated, most guidelines would recommend cessation of aspirin for that duration before an invasive procedure.
Thromboxane A2;
r 5-7 days
What are major side effects of aspirin?
Gastric irritation and ulceration
Bronchospasm in sensitive asthmatics
Prolonged bleeding times
Nephrotoxicity
