Cox inhibitors Flashcards
How do COX enzymes work
go to the lumen of the endoplasmic reticulum, turn arachidonic acid into prostaglandin G2 using cyclooxygenase activity
then turn that into to prostaglandin H2 via peroxidase activity at a different active site
that is then transported outside of the lumen
turned to specific prostanoids via specific enzymes
COX-1 vs COX-2
COX-1 is constative, and continuously produced in the stomach, kidney, platelets, vascular endothelial cells. it forms the prostaglandins required for normal physiological function.
COX-2 is induced by pro-inflammatory cytokines (TNF alpha, IL-1) and growth factors (PAF). it produces the prostaglandins for the signalling of pain, and inflammation and it causes fever.
Functions of PGI2 and TXA2
prostacyclin causes vasodilation, bronchodilation, and lowers platelet aggregation
Thromboxane causes vasoconstriction, bronchoconstriction, and platelet aggregation
COX-1-mediated prostaglandins
PGE2: !!!! main prostaglandin made by COX-1 vasodilation in the kidneys, bronchodilation (good for asthmatic patients), lowers gastric acid secretion, increases gastric mucus secretion (protects stomach), induces labour, controls temperature in the cns
PGD2: vasodilation, lowers platelet aggregation
PGF2alpha: bronchoconstriction, uterus contraction
Mechanism of action of fever
In normal physiological function, when body temperatures increase above the point set by the hypothalamus, heat losing mechanisms activate
In fever this point is elevated
Tissues are damaged, inflamed, infected
Neutrophils release IL-1
COX-2 enzymes are stimulated
PGE2 synthesis in hypothalamus is increased
Increases heat production and reduces heat loss mechanisms
Increased body temperature – fever
COX analgesia mechanism
Inhibition of synthesis of nociceptive prostaglandins PGE2 and PGF2alpha
Only effective against low to moderative pain (dental pain, pain from inflammation, chronic post operative pain) and not visceral pain (exception: menstrual pain)
COX antipyresis mechanism
Inhibition of synthesis of PGE2 that stimulates the temperature-controlling centre of the hypothalamus
Does not help with raised temperature caused by non-inflammatory stimuli such as exercise
Cannot be given to children below 16 years old because of risk of Reye’s syndrome
COX anti-inflammatory mechanism
Inhibition of prostaglandin synthesis.
Can only provide symptomatic relief from chronic inflammation like rheumatoid arthritis or gout
Closure of ductus arteriosus
If a child has their aorta connected to pulmonary artery, then indomethacin is given to speed up the closure of the ductus arteriosus
Pharmacokinetics of NSAIDs
Generally weak acids, so when administered orally they absorbed well in the stomach and internal mucosa
High bioavailability (95% bond to plasma proteins)
Metabolised in the liver
NSAID common side effects
Pain, erosions, and bleeding in the GIT
Salt and water retention, and oedema in the renal system
Headaches, dizziness, depression
Inhibits labour, prolongs gestation
Bronchial asthma
Inhibition of platelet aggregation
Aspirin vs other NSAIDs: mechanism of action
Other NSAIDS bind competitively to COX, while Aspirin binds irreversibly to a serine residue in the active site of the enzyme
How do selective COX-2 inhibitors work?
While the two COX enzymes have 60% homology in amino acids, COX-2 has a slightly larger active site than COX-1, meaning larger chemicals will fit in COX-2 but not COX-1
This also causes aspirin to have a 10-100 times higher sensitivity to COX-1 than COX-2
Doses of aspirin
Secondary prevention of cardiovascular disease, long-term treatment of ischaemic stroke: 75mg/day
Unstable angina, myocardial infarction, acute ischaemic stroke: 300mg/day
Mild to moderate pain, pyrexia: 300-900 mg every 4-6 hours to a maximum of 4g/day
Sulindac
Reduces polyps independent of its COX activity, especially in those with familial adenomatous polyposis
EGF inhibition (??)
Indomethacin
Potent COX inhibitor, but also inhibits phospholipases, reduces neutrophil migration, and decreases b and t cell proliferation
Only used in those with inflammation and fever that was not responding to other treatments due to its side effects
Ductus arteriosus closure
Probenecid prolongs indomethacin’s half-life by habiting both renal and biliary clearance
Ibuprofen
Has a mild and short-lived antiplatelet effect
Treats: migraine, dental pain, pyrexia, post operative analgesia, mild to moderate pain such as dysmenorrhoea, pain and inflammation in rheumatic disease and other Musculo skeletal disorders
Topical NSAIDs
Pain relief in acute conditions such as sprains and strains
One week treatment
Topical NSAIDs may be as effective as oral ones with fewer GI side-effects
Concurrent use of oral and topical NSAIDS should be avoided
Eg. Ibuprofen, ketoprofen, diclofenac, felbinac
Effects of selective COX-2 inhibitors
Analgesic, antipyretic, anti-inflammatory, lower risk of serious upper GIT side effects
However can be prothrombotic, because you’re stopping the endothelium from producing prostacyclin (COX-2 dependant), but not the endothelium from producing thromboxane (COX-1 dependant)
When to use selective COX-2 inhibitors
In patients with high risk or previous history of:
Gastro-duodenal ulcer
Gastric-duodenal perforation
Gastro-intestinal bleeding
ONLY AFTER ASSESSMENT OF CARDIOVASCULAR RISK
Cautions with selective COX-2 inhibitors
Mild cardiac failure
Left ventricle failure
Hypertension
Patients with oedema for any other reason
Patients at risk of developing heart disease
Contraindications for selective COX-2 inhibitors
Ischaemic heart disease
Moderate or severe heart failure
Cerebrovascular disease
Peripheral arterial disease
Severe hepatic disfunction
Celecoxib
Proprietary name: Celebrex
10x more selective for COX-2 than COX-1
Half-life: 10 hours, with a peak after 2-4 hours
Metabolised by the liver
Elimination: urinary and faecal
Used for: acute pain (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis)
Dose: 100/200 mg bid
Side effects: rashes, flatulence, insomnia, constipation, palpitation, fatigue, paraesthesia, muscle cramps, taste alterations (rare)
Etoricoxib
Proprietary name: Arcoxia
2nd gen
100x more selective for COX-2
Half life: 20 hours
Metabolism: hepatic
Elimination: 90% urinary excretion
Uses: osteoarthritis, rheumatoid arthritis, gouty arthritis, relief of musculoskeletal pain, surgery
Dose: 30/60/90/120 mg once daily
Side effects: similar to above, monitor hepatic function
Parecoxib
Proprietary name: Dynastat
Water-soluble pro-drug of valdecoxib
IM or IV use
Serum half-life: 15-50 minutes, max concentration reached withing 15 mins
Uses: short term (max 3 days) management of postoperative pain at 20-40mg/6-12hr with a max of 80mg/day
Paracetamol
Non-opioid analgesic
Alternative to NSAIDs for analgesic and antipyretic effects, but not anti-inflammatory effects
Aka tylenol, or acetaminophen
Paracetamol metabolism and toxicity
When paracetamol is metabolised by cytochrome P450 enzymes it forms a metabolite called NAPQI (n-acetyl-p-benzoquinonamine) which can cause cell death if not reacted with glutathione, and that following metabolite is renally excreted
Paracetamol overdose is treated by giving acetylcysteine, a precursor of glutathione
Causes hepatotoxicity
If acetylcysteine is give before 8 hours there is almost complete protection, from 8-24 hours lower protection but lower mortality, and after 24 hours it is shown to decrease mortality in established hepatotoxicity
