NSAIDs Flashcards
What is a drug?
A chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.
Drugs are generally derived from…?
Plants or animals, created synthetically, or produced by genetic engineering.
What are medicines?
Contain drug/s plus other agents e.g. preservatives, bulking agents, solvents
What happens in Phase 1 trials?
First time in humans - a small number of healthy volunteers (50-200) take part to examine the pharmacologic actions and safe dosage range of a drug, how it is absorbed, distributed, metabolised and excreted.
What happens in Phase 2 trials?
Studies in volunteers (100-400) with the disease to assess if the drug has any effect and at what doses.
What happens in Phase 3 trials?
Determine efficacy; Randomised controlled trials of the drug among 1000-3000 highly-selected individuals with the disease. Compare the drug to placebo or to an alternative treatment.
What are the limitations of phase 3 trials?
Restricted population studied
Numbers are limited
Women and older people with multiple diseases often excluded
Children excluded
Duration of study limited
No information on benefits, risks, outcomes associated with long-term us
Outcome studied may be a surrogate not the clinical outcome of interest
Studies are not powered to determine adverse effects so knowledge about safety is very limited
People taking the drug are unlikely to all be like the phase 3 study population
What are phase 4 studies?
Studies of safety/pharmacovigilance
NSAIDs are effective as…?
Analgesics and for reducing inflammation
What was the first NSAID?
Aspirin
What was already being used in Roman times to treat inflammation?
Plants containing salicylic acid and its derivatives, e.g. willow bark
When was salicylic acid first synthesised?
When was it first registered?
1859
1899
How many aspirin tablets are consumed each year?
10 to the 11, e.g. 32,000 tons
When was the mechanism of action of aspirin first known?
1970s
Which NSAIDs prescription rate has increased significantly recently?
Naproxen
What is the Cyclo-oxygenase enzyme (Cox) involved in?
Prostaglandin synthesis from arachidonic acid and oxygen
What are the actions of prostaglandins?
Pyretic Pro-inflammatory Hyperalgesic Inhibit gastric acid secretion Generated by platelets Contract the uterus Increase renal blood flow
What are the actions of aspirin?
Antipyretic, anti-inflammatory, analgesic, GI side effects, anti-platelet effect, delays labour and may lead to kidney problems
What did John Vane demonstrate in 1971?
That aspirin, salicylate and indomethacin blocked the production of PGs in vitro.
When was ibuprofen launched (prescription only)?
When did it become available over the counter?
1969
1983
Which COX enzyme has physiological functions?
Which has an inflammatory role?
COX-1 (constitutive)
COX-2 (inducible)
What are the three broad categories of COX inhibition mechanisms?
Category 1 - rapid competitive reversible binding of COX-1 and COX- 2 (e.g. ibuprofen)
Category 2: rapid, lower-affinity reversible binding followed by time-dependent, higher-affinity, slowly reversible binding of COX-1 and COX-2 (e.g. diclofenac)
Category 3: rapid reversible binding followed by covalent modification of COX-1 and/or COX-2 (non-competitive, irreversible) (e.g. aspirin).
Why is low-dose aspirin cardio-protective?
It falls into category 3, where there is irreversible covalent modification. Platelet COX-1 is irreversibly inhibited for the lifetime of the platelet hence aggregation inhibited.
Give some examples of COX-2 selective NSAIDs.
Rofecoxib and celecoxib
Inhibition of COX-1 and -2 by a non-selective NSAID
NSAID blocks entrance channel to COX-1
Binding/transformation of Arachidonic Acid prevented
Inhibition of COX-2 by a COX-2 selective NSAID
Fits into COX-2 side pocket
Too bulky to fit into COX-1 entry channel so Arachidonic Acid can reach COX-1 site for transformation
What is the major unwanted adverse effect of COX-1 inhibition?
Loss of gastric protection, causing ulcers and bleeding
Why was Rofecoxib withdrawn voluntarily from the market in 2005?
Pharmacovigilance studies and other randomised controlled trials revealed cardiovascular risk problems.
Which NSAID should not be prescribed for people with ischaemic heart disease?
Diclofenac (non-selective but potent COX-2 inhibitor)
Which NSAIDs are associated with an increased risk of CVS disease?
Rofecoxib, diclofenac, high-dose ibuprofen and celecoxib
Which NSAID appears to have a neutral risk for CVS disease at high and low doses?
Naproxen (suppresses platelet thromboxane production)
Why do all NSAIDs appear to be associated with increased heart failure risk in vulnerable individuals?
Impact on homeostasis/intravascular fluid volumes
