Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol Flashcards
What cleaves fatty acids from the membrane phospholipids
PLA2
What does PLA2 generate
Arachidonic acid (AA)
What is AA
A polyunsaturated (many double bonds) omega-6 fatty acid. It is the most widely used fatty acid precursor of all bioactive lipids
What makes AA a versatile lipid precursor
The number and position of double bonds. The double bonds ‘kink’ the molecule
What do lipoxygenase do
Convert AA into eicosanoids
What eicosanoids further modified to
Leukotrienes
What do leukotrienes have roles in
Chemotaxis, bronchoconstriction and vascular permeability
What are leukotrienes role in bronchoconstriction
They are involved in the inflammatory response
What is PGHS
Prostaglandin-H synthase
What do PGHS enzymes do
Convert AA into endoperoxides (PGG2 and PGH2) which can then be modified into cell-specific prostanoids
What is the PGHS enzyme comprised of
1 unit with 2 catalytic domains: COX domain and and peroxidase domain
What does the COX domain of the PGHS enzyme do
AA and O2 enter the COX domain togetehr and are converted into PGG2
What does the peroxidase domain of the PGHS enzyme do
PGG2 is converted to PGH2
What are the 3 isoforms of PGHS
PGHS-1, PGHS-2 and PGHS-3
What are the physiological (good) effects of PGHS-1
GI tract, platelet, vascular and CNS function
What are the pathophysiological (bad) effects of PGHS-1
Chronic pain, hypertension
What the the physiological (good) effects of PGHS-2
Renal, platelet, vascular, reproductive and CNS function
What are the pathophysiological (bad) effects of PGHS-2
Inflammation, chronic pain, fever, vascular permeability, angiogenesis, tumour growth and neurodegeneration
What can prostaglandins be converted into
PGE2, PGF2, TXA2 and PGI2
What converts prostaglandins
Cell specific prostaglandin synthases/ isomerases
What are the functions of PGE2
Pathophysiology in GI mucosa and renal function, uterine contraction, vasodilation, histamine, bradykinin, eosinophil and basophil chemotaxis
What are the functions of PGF2
Bronchoconstrictor, uterine contractor
What are the functions of PGD2
Bronchoconstrictor, anti-platelet aggregation
What are the functions of TXA2
Platelet aggregation, vasconstrictor
What are the functions of PGI2
Physiology in anti-platelet aggregation, vasodilation, endothelial and CNS function
What are prostaglandin receptors on target cell membranes called
Prostanoid receptors which are all GPCRs (G-protein coupled receptors)
What implications does the fact that the receptors are GPCRs mean
The receptors have paradoxical (opposite to what you expect) effects as the effect that takes place depends on which G protein subtype is activated
What is the class of action of all NSAIDs
They inhibit COX domain activity in PGHS preventing the generation of endoperoxides PGG2 and PGH2 by preventing the catalytic cycle and stopping the ability to produce PGH2 and downstream prostaglandins
What are the therapeutic uses of NSAID inhibition of PGHS-2 (e.g. PGE2) derived prostaglandins
Reduces the extent and duration of local inflammation caused by vasodilation and increased vascular permeability
When prescribing NSAIDs what do you, as a doctor, need to balance
The inflammation response occurring and the response going beyond normal and therefore the need to moderate with NSAIDs
What are NSAIDs not as strong as
Steroids in anti-inflammatory drugs
What are analgesic effects
Decrease in pain and swelling
What are anti-pyretic effects
Decrease in temperature
What two main effects do NSAIDs have
Analgesic and anti-pyretic
How do NSAID have analgesic and anti-pyretic effects
They inhibit PGH2 production
What does PGH2 do
PGH2 supercharges the pain response: PGHS-1 derived from PGE2 normally sensitises Aδ and C nociceptive neurons to serotonin, bradykinin and substance P
What effect does NSAIDs inhibiting hypothalamic PGHS-2 have
PGHS-2 normally generated PGE2 in response to circulating pyrogens, so by clocking PGE2 you stop pyrexia
What is pyrexia
Fever
What are pyrogens and give an example
Something that increases temperature such as PGE2
What is the chemical name for aspirin
Acetyl salicylic acid
What is aspirin the only NSAID to do
Irreversibly inhibit PGHS-1 and PGHS-2
What is the method of action of aspirin
Acetylation of serine residue in the COX domain active site
What is the origin of aspirin
Willow tree bark (containing salicin) was known to reduce pain, fever and inflammation since the time of Hippocrates. Chemists at Bayer derived salcin to the more gastrically tolerable ASA
What is the benefit of using aspirin in most MI pateints
It helps prevent another myocardial infarction because it can reduce the risks of occlusive vascular events by inhibiting platelet aggregation
How is ibuprofen produced
As a racemate which means that a racemic mixture is produced
What is a racemic mixture
A mixture that has stereoisomers
Describe the racemic mixture of ibuprofen
The S-enantiomer (left) is the active NSAID, the righ enantiomer has no effect in the body
What is the method of action of ibuprofen
It competes with AA for the COX domain active site of PGHS-1 and PGHS-2. It is a reversible, competitive inhibitor.
What is the origin of ibuprofen
It is derived from propanoic acid and synthesised by chemists working in boots in the 1960s
What is a new use for ibuprofen that is different from its primary intended use
Some research data indicates that it may be beneficial in preventing/ retarding Parkinson’s disease
What is Rofecoxib
A selective inhibitor of PGHS-2
What was Rofecoxib used for
Prescribed for oesteoarthritis symptoms for which is was very effective
Why do we not selectively target PGE2 receptors
PGHS-2 has significant but subtle cardiovascular effect, data showed those who took high-dosage Rofecoxib had an increased risk of heart attack and stroke
According to the BNF was are the two most important adverse drug reactions associated with NSAID use
Potential for gastric ulceration and compromised renal function
How do NSAIDs cause gastric ulceration
NSAIDs can damage the gastroduodenal mucosa via several mechanisms:
Via which mechanisms do NSAIDs damage the gastroduodenal mucosa
topical irritant effect of these drugs on the epithelium, impairment of the barrier properties of the mucosa, suppression of gastric prostaglandin synthesis, reduction of gastric mucosal blood flow and interference with the repair of superficial injury
How do NSAIDs compromise renal function
Inhibition of PGE2 synthesis can lead to increased sodium reabsorption, causing peripheral oedema
What is another electrolyte disturbance that can occur as a result of prostaglandin synthesis in the kidney
Hypercalcemia, the risk may be particularly high in patients receiving potassium supplementation, potassium-sparing diuretics or ACE inhibitors
What risk factors predispose patients to NSAID-sodium retention and oedema
Diabetes mellitus, renal disease, circulatory compromise and age
What are the effects of NSAIDs on electrolyte and water homeostasis seem to depend upon
Dose (dose-dependent)
When are NSAIDs contra-indicated
If pregnant, sensitised to salicytes/ NSAID allergic, already on an NSAID, do not use ASA if younger than 16 years old
Why should patients under the age of 16 not be given aspirin
There is an association with the development of Reye’s Syndrome
What does Reye’s syndrome have potentially fatal effects in
The brain and the liver
What are the signs and symptoms of Reye’s stage I
Rash on palms and feet, heavy vomitting, lethargy, confusion, nightmares, pyrexial and headaches
What are the signs and symptoms of Reye’s stage II
encephalitis-induced stupor, hyperventilation, fatty liver (steatosis), hyperactive reflexes
What are the signs and symptoms of Reye’s stage III
More of stage I and stage II symptoms, potential for coma, potential for cerebral oedema, occasionally respiratory arrest
What are the signs and symptoms of Reye’s stage IV
Deepening coma, mydriasis (dilation of the pupil) with minimal response to light, hepatic dysfunction
What are the signs and symptoms of Reye’s stage V
Rapid onset of following stage IV: deep coma, seizures, systemic organ failure, flaccidity, hyperammonemia, death
Why is paracetamol your first choice for low levels of pain
It is better tolerated from a gastro point of view than ibuprofen
Why may paracetamol be chosen over NSAIDs
It can have better analgesic (pain) and anti-pyretic (reducing temperature) effects
What does paracetamol have very little of
Anti-inflammatory activity
What is the method of action of paracetamol
Under debate: may affect peroxidase domain activity in PGHS-2 or PGHS-3 in the CNS or its metabolites may be having affects in the CNS
How are the guildines for pain management organised
As a WHO pain ‘ladder’, it was constructed with managing cancer pain in mind
What is the organisation of the WHO pain ladder and associated reccomended drugs
Mild pain (paracetamol and/or NSAIDs) -> moderate pain (paracetamol and weak opioid e.g. codeine phosphate) -> severe pain (strong opioid e.g. morphine or heroin). If neuropathic in severe pain may consider tri-cyclic anti-depressants and/or Na+ channel blockers
Describe opioids
They are very good at relieving pain, however they are associated with addiction
Give one example of when can heroin be prescibed
To help deal with the pain associated with childbirth
What do PGHS enxymes generate
endoperoxidase precursors for all the prostanoids
What do NSAIDs inhibit and how
They inhibit PGHS enzymes, typically by blocking cyclo-oxygenase domain activity
What best described the mechanism of action of aspirin
It causes irreversible inhibition of the cyclo-oxygenase domain of PGHS by acetylation of the key serine residue
