Lecture 25 Flashcards
What are immune cell mediators?
Cytokines, chemokines colony-stimulating factors, adhesion molecules, eicosanoids, endocrine
How do steroidal anti-inflammatory drugs work?
Act via intracellular receptors to regulate gene expression/transcription
glucocorticoids have immuno-suppresive effects, the glucocorticoid receptor is expressed by most cell types and activated by both cortisol and aldosterone
The activated receptor will move from the cytoplasm to the nucleus and alter gene transcription…
as well as interfering with NF-kB which is a major inflammation associated transcription factor
What are the genomic effects of glucocorticoids?
Down regulation of the proinflammatory genes:
Pro-inflammatory cytokines
COX-2
Phospholipase A2
Endothelians
Inducible nitric oxide synthase
Up regulation of:
IL-4/IL-10 which are anti-inflammatory cytokines
Lipocortins/annexis which are PLA2 inhibitors
What are the different types of glucocorticoid preparations?
Oral such as dexamethasone
Inhalable such as fluticasone
topical such as prednisone and some injected forms
What are the general features of steriodal anti-inflammatory drugs?
Very broad spectrum drugs in terms of cellular targets and array of inflammatory parameters that can be influenced however long term use is contr-indicated and they can have serious side effects
What are NSAIDs?
Non steroidal anti inflammatory drugs
These are not narcotics but rather drugs which inhibit prostaglandin synthesis through blocking the function of COX enzymes
Used as an effective low cost treatment for pain and swelling
What are some common NSAIDs?
Asprin
Ibuprofen
Diclofenac
Naproxen
How do NSAIDs work?
They block the enzymatic function of COX (cyclooxygenase) which is normally used to convert arachidonic acid to prostaglandin H2 which is a precursor of the series 2 prostanoids
This can cause the side effect of blocking some non-inflammatory drugs
What are the pathways of prostanoid biosynthesis?
Glycerophospholipids produce arachidonic acid via phospholipases
Arachidonic acid is then broken down into chemical mediators by COX
if COX I is used then PGE2 (gastroprotective), PGI2 (vasodilatory), TXA2 (coagulation) are produced
if COX II is used then PGE2 (inflammatory), PGI2 (vasodilatory) and TXA2 (vasoconstrictor) are produced
COX I is constitutively while COX II is induced by inflammatory diseases
What are the features of aspirin?
Actually acetylsalicylic acid which is widely used and irreversibly inhibits OCX I
Is a first line drug for migraine sufferers and an effective inhibitor of PG mediated pain
Cans also inhibit TXA2 release by platelets allowing it to be anti-thrombotic
Can have significant side effects such as GI tract ulceration and gastritis
What are the features of paracetamol?
good anti-pyretic and analgesic but ineffective against inflammation
It reduces prostaglandin synthesis, is a weak inhibitor of COX I and II, was thought to be a COX III inhibitor but this is not the case
Metabolised in the liver to a toxic metabolite which has the potential to cause serious liver damage
Have a very low therapeutic index, 10 times the adult dose can be fatal
What are the adverse effects of NSAIDs?
Gastric upsets, ulcers and GI bleeding dues to loss of protective PGE2 from COX I
Renal complications due to reduced blood flow
Increased clotting time from PXA2
Asthmatics may have an allergic type response to NSAIDs mediated by leuktriene-mediated
Hepatic toxicity, skin rashes and others
Early pregnancy loss/fertility complications
Complications are largely associated with COX I inhibition
What are COX II selective COX inhibitors?
Compounds designed to selectively inhibit the COX II isoform which is pain and inflammation associated, but leaves the COX I isoform which is used in maintenance and protection uninhibited
This is done by designing compounds with high affinity for COX II active site but low affinity for COX I active site
What was the results of selective COX II inhibtors?
GI irritation and ulcer rate was reduced with similar efficacy to non selective NSAIDs suggesting these would be useful in long term treatment use of chronic conditions
However many of them suffered unexpected adverse effects such as celecoxib being associated with acute cardiovascular events
Rofecoxib increasing risk of thrombotic events
Hundreds of thrombotic and embolytic cases being attributed to celecoxib/rofecoxib in the USA alone
This could have been due to loss of COX-2 derived prostacyclin which is cardioprotective
Both drugs caused increased blood pressure with some evidence of renal imapriment
