Prostaglandins Study Documents

Prostaglan dins    They are biochemical derivatives of arachidonic acid, found in its esterified form in cell membrane phospholipids They are produced in all nucleated cells in the body, except for lymphocytes. There are numerous and varying physiologic roles: o Maintenance of blood flow through the kidneys and stomach (vasodilation) o Gastric mucosal protection (increased mucus production) o Platelet activation and aggregation o Ovulation and labour (increased uterus contractility) o Tissue growth and wound healing They also have several pathologic roles: o Vasodilation and ↑ vascular permeability in inflammation, leading to leakage of protein-rich fluid and leukocytes into surrounding tissue o Sensitisation of pain receptors to primary pain mediators serotonin (5-HT) and bradykinin 🡪 pain o Possibly sensitisation of spinal sensory neurons involved in the transmission of pain o Raising temperature in the hypothalamus in response to circulating pyrogens released from inflammatory cells or destroyed bacteria Formation of prostaglandins 1. Arachidonic acid is cleaved from membrane phospholipids via the phospholipase A2 enzyme 2. It is then converted into prostaglandins via the cyclo-oxygenase (COX) enzyme (COX-1 and COX-2) 1. COX-1 or ‘constitutive COX’ stimulates formation of prostaglandins involved in physiological processes 1. COX-2 or ‘inducible COX’ is generally responsible for generation of hyperalgesic and pro-inflammatory PGs. However, it is now known that COX-2 is involved in some important physiologic processes 3. PGH2 is the first prostaglandin produced, and it serves as a precursor straight from the arachidonic acid pathway 4. Important prostaglandins generated through COX pathway: PGD2, PGE2, PGI2 (also called prostacyclin), PGF2, and thromboxanes like TXA2, each of them require additional enzymes for their synthesis (like PGE synthase). Factors affecting the COX pathway    Both COX-1 and COX-2 also metabolise two other 20-carbon fatty acids – dihomogamma-linoleic acid (DGLA; ω-6) and eicosapentaenoic acid (EPA; ω-3). This forms series-1 and series-3 prostaglandins, which are confirmed as less inflammatory than series-2. DGLA and EPA compete with arachidonic acid for the COX pathway The use of NSAIDs – Generally first generation NSAIDs inhibit activity of both types of COX. They are competitive inhibitors, with the exception of aspirin which functions by non-competitive inhibition that permanently disables the enzyme. In general, desirable effects are achieved through blocking of COX-2 activity and the unwanted effects are a result of COX-1 inhibition (but not always correct as COX-2 prostaglandins have some important physiologic functions) Paracetamol is clinically different from other NSAIDs in that is has no significant antiinflammatory activity. The exact mechanism of action is unknown but a possible mechanism is that it causes reversible inhibition of COX-1 variant in the brain (sometimes called COX-3) so it has only a central effect. It is now suggested that it works as a selective COX-2 inhibitor o With acute overdoses, paracetamol can cause fatal liver damage, with the risk being increased by alcohol consumption. The toxic effects of paracetamol are due to its metabolite – NAPQI (N-acetyl-p-benzo-quinone imine). At usual doses, generated NAPQI is quickly detoxified with the help of glutathione. In significant paracetamol overdose, glutathione depletion leads to accumulation of NAPQI, which can reacts with cellular macromolecules Non-steroidal anti-inflammatory drugs (NSAIDs) Desired effects of NSAIDs  Anti-inflammatory – NSAIDs reduce the components of the inflammatory response that arise due to the actions of COX-2, which are vasodilatation, oedema and pain. By decreasing in PGE and prostacyclin (PGI ), there is a decrease in vasodilatation and, indirectly, oedema; but accumulation of inflammatory cells is not reduced Analgesic – Decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. Relief of headache could be due to decreased prostaglandin-mediated vasodilation. Antipyretic – Prostaglandins in the CNS assist in the elevation of the hypothalamic set point for temperature control in response to circulating pyrogens, thus causing fever; NSAIDs prevent this 2   2 Adverse effects of NSAIDs      GIT/Stomach: heartburn, stomach pain, nausea and vomiting, acute gastritis with bleeding and possible peptic ulcer with chronic use. Prostaglandins inhibit gastric acid secretion and increase production of alkaline mucus; additionally aspirin and some other NSAIDs are sufficiently acidic and also cause direct irritation of the gastric mucosa. The GIT adverse effects can be reduced through suppressing acid production by concomitant use of proton pump inhibitors Renal: in susceptible patients or with existing renal impairment, NSAIDs cause reduced glomerular filtration, fluid and sodium retention and even hypertension Skin/respiratory: rashes and bronchospasm (more common in asthmatics) Less commonly, liver damage and bone marrow depression in long-term treatment with high doses. Possible inhibition of ovulation and fertility problems Selective COX-2 inhibitors      Second-generation NSAIDs inhibit only the activity of COX-2 (also known as coxibs), where the degree of COX-2 selectivity varies. They show less incidence of GIT unwanted effects than non-selective COX inhibitors, hence they are important for patients who take NSAIDs regularly for long periods. However, there is some evidence suggesting that selective COX-2 inhibitors can slightly increase the risk of thrombosis, and hence, increase the risk of myocardial infarction and stroke. Additionally, selective COX-2 inhibitors are more likely to produce kidney-related adverse side effects. The activity of platelets is influenced by two types of prostaglandins: o Prostacyclin (PGI2) – inhibitor of aggregation, generated by vascular endothelium via COX-1 and COX-2 activity o Thromboxane A2 (TXA2) – stimulant of aggregation generated by platelets mainly via COX-1 activity With the administration of non-selective COX inhibitor, both types of PGs are reduced, but as platelets have no protein synthesis capacity, the body responds by producing more PGI2 but not more TXA2 (when it is compensating). This effect is especially seen with aspirin, as it is the only irreversible COX inhibition. However, with a selective COX-2 inhibitor, only the endothelial pathways are being blocked. Since it only reduces the prostacyclin formation but not thromboxane formation, there is increased coagulability = thrombosis risks Indications for NSAIDs     Relief of fever – antipyretic effect (ibuprofen, paracetamol and aspirin) Relief of pain – analgesic effect (headache, toothache, backache, muscular/tendon ache, joint ache, pain after injury of surgery, dysmenhorrea) o NSAIDs are generally not very effective in the management of visceral pain (e.g. myocardial infarction, GIT cancer, panreatitis, gallstones, etc) and neuropathic pain (various forms of neuropathy and neuralgia) Reduction of intensity of inflammation – anti-inflammatory effect in rheumatoid arthritis, ankylosing spondylitis, SLE, etc. Reduction of risk of arterial thrombosis in secondary prevention of strokes and heart attacks o Aspirin strongly inhibits platelet aggregation and the risk for MI and ischaemic stroke o For patients diagnosed with cardiovascular disease, aspiring reduces the chance of a heart attack and ischaemic stroke o Other NSAIDs have much less effect on thrombosis o Aspirin shows only a slim benefit in the prevention of deep vein thrombosis