NSAIDsx

NSAIDs Prostaglandins (PGs) • Produced in all nucleated cells except lymphocytes • Functions o Renal vasodilation o Gastric mucosal protection o Platelet activation and aggregation o Male erection, ovulation, labour o Tissue growth and wound healing • Pathologic function o Vasodilation and ↑vascular permeability in inflammation  extravasation of protein-rich fluid and leukocytes o Sensitization of pain receptors to bradykinin  pain o Raise set temperature point in hypothalamus due to circulating pyrogens from inflammatory cells or destroyed bacteria PG Formation 1. AA cleaved from membrane phospholipids by phospholipase A2 2. AA converted to PGs by COX-1 and COX-2 • Previously believed that COX-1 was responsible for making normal PGs and COX2 was inducible during pathologies but COX-2 is also involved in some physiological processes • Important PGs o PGD2 o PGE2 o PGI2: prostacyclin o PGF2 • All have 20 carbons, a 5 carbon ring and 2 double bonds between carbons • COX also produces TXAs • Both COX-1 and COX-2 also metabolise other polyunsaturated ω-3-fatty acids; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) • In this way, series-3 PGs are formed  less inflammation • EPA and DHA compete with AA for COX pathways  antiinflammatory effect • For significant effect, 3g of EPA/day needed over several months Mechanism of NSAIDs • 1st generation of NSAIDs inhibit activity of both COX-1 and COX-2 • All NSAIDs act as competitive inhibitors, except aspirin which non-competitively disables the enzyme • According to the model, wanted effected achieved by blocking COX-2 selectivity and unwanted effect are from COX-1 inhibition. This is not always true. Paracetamol • NSAID but pathway not fully understood • Selective COX-2 inhibitor • Direct suppression of spinal nerve sensitivity • Modulation of endocannabinoid system in CNS involved with pain • Little anti-inflammatory effect Drugs on the Market • Paracetamol (Pmol): dymadon, febridol, Panadol, panamax, paralgin: schedule 2 • Pmol + 8-10mg codeine: codalgin, codapane, febridol plus, panadeine, panamax co: schedule 3 • • Pmol + 30mg codeine: “-forte” schedule 4 Pmol + codeine + doxylamine (sedative antihistamine): mersyndol: schedule 3 • Pmol 665mg slow release: Panadol osteo: schedule 2 • Pmol is found in many cold and flu combinations with phenylephrine and pseudoephedrine (decongestants), antihistamines chlorpheniramine and antitussive dextromethorphan Paracetamol Drugs • Common adult dose is 500-1000mg • Recommended daily max is 4000mg • Prolonged use increases risk of CV and renal complications • Acute overdose  liver failure o Liver toxicity is due to metabolite NAPQI o At usual dose, NAPQI is detoxified by glutathione o Antidote acetylcysteine or NAC is precursor to glutathione, given IV o NAPQI reacts with SH groups on glutathione. Once glutathione is depleted NAPQI will react with cellular macromolecules and cause cytotoxicity First Generation NSAIDs • Aspirin o Usually 300mg or 500mg dose o Aspirin alone: unscheduled or schedule 2 o + 10mg codeine – schedule 3 o + dihydrocodeine – schedule 2 • Ibuprofen o Advil, nurofen, brufen o Usually schedule 2, topical gels unscheduled • Ketoprofen o Orudis, oruvail o Schedule 4, topical gels unscheduled • Naproxen o Naprofem, naprogesic, nurolast 275mg schedule 2 o Anaprox, crysanal, inza, naprosyn, proxen,   • 500mg schedule 4 Piroxicam o Schedule 4, topical gel unscheduled • Diclofenac o Voltaren, clonac, fenac: schedule 4 o Imflac, viclofen, voltaren rapid 25: schedule 3 o Voltaren rapid 12.5: schedule 2 o Gels e.g. dencorub, voltaren emugel) unscheduled • Mefenamic acid: ponstan - schedule 2 • Tiaprofenic acid: surgam - schedule 4 • Ketorolac: toradol, ketoral - schedule 4 NSAID Wanted Effects • Anti-inflammatory: ↓PGE2, ↓PGI2,  ↓vasodilation  ↓oedema (inflammatory cell accumulation is not removed) • Analgesic: ↓PGs synthesis  ↓nociceptor sensitisation  ↓effect of bradykinin and 5-hydroxytryptamine • Anti-pyretic: circulating pyrogens (IL-1)  ↑PGs in CNS  ↑set point  fever NSAIDs Unwanted Effects • Stomach: Heartburn, pain, nausea, vomiting, acute gastritis with bleeding, peptic ulcers in chronic use o Especially evident with indomethacin, ketoprofen, piroxicam o ↑Acid secretion, ↓mucous production, ↓HCO 3-, aspirin can directly irritate mucosa o • Renal o ↓GFR, fluid/Na retention, ↑BP by 3-4mmHg • Skin/respiratory o Rashes, bronchospasm, due to shift in AA metabolism to lipoxygenase pathway and leukotrienes • Rarely, liver damage and bone marrow depression in chronic high dose • Possible inhibition of ovulation and fertility problems • Linked to erectile dysfunction COX-2 Selective Inhibitors (Coxibs) • Lower incidence of GIT symptoms • High risk of thrombosis  MI, stroke • High risk of kidney related effects • Platelet activity is affected by 2 PGs o PGI 2: COX-1 and COX-2 in vascular endothelium  PGI2  inhibit aggregation of platelets o TXA2: COX-1 in platelets  TXA2  stimulate aggregation • Non-selective COX-inhibitors block both types of COX but more so in platelets because they’re unable to produce more COX (they don’t carry protein synthesis process) o This effect is especially seen with aspirin as its irreversible o Permanently disables platelets until new platelets are formed • Main COX-2 selectives are celecoxib, etoricoxib, parecoxib • CV risk related to degree of COX-2 inhibition • Therefore, coxibs not recommended for patients with CAD, history of MI/stroke/TIAs, etc Indications for NSAIDs • Antipyretic: ibuprofen, paracetamol, aspirin o But contraindicated in children due to link with Reye’s syndrome • Analgesia: NSAIDs not very effective at managing visceral pain or neuropathic pain (neuropathy, neuralgia) • Anti-inflammatory • Anti-thrombotic in secondary prevention of stroke and MI