not enough said about nsaids
TRANSCRIPT
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Not enough SAID about NSAIDs
Presented by Julia Harris CRNA, MSN, FAANA
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Physiology of Acute Localized Inflammation
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Physiology of Acute Localized Inflammation
• Inflammatory Mediators Include• Histamines • Prostaglandins• Cytokines
• Bradykinin• IL1• TNF 𝛂
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Cell Injury
Once damaged, the bilipid layer of cells are converted into arachidonic acid.
Arachidonic Acid is the precursor to inflammatory agents
Bonnesen, K., & Schmidt, M. (2021); Zagon, I. S., & McLaughlin, P. J. (Eds.). (2017).
Steroids
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Pain pathway?Central Nervous system
COX-1 & COX-2 is believed to be involved in the nociception that is exerted by peripheral somatosensory components, and COX-2 expression can be up-regulated upon inflammation
Bonnesen, K., & Schmidt, M. (2021).; https://www.kenhub.com/en/library/anatomy/ascending-and-descending-tracts-of-the-spinal-cord
SpinothalamicTrackProstaglandins
2nd Order Neuron
3rd Order Neuron
1st Order Neuron
Substance P
Periaqueductal Gray
Nucleus Raphe Magnus
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Cox-1 & Cox-2
• Inflammation• Pain• Fever
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Cyclooxygenase-1(COX-1)• Is a key enzyme in synthesis of prostaglandins from arachidonic acid.• Continuously expressed in most
tissues
• Maintains the mucus lining of stomach• Prostaglandins E2 & I2
• Maintains normal renal function• Thromboxane A2
• Prothrombotic
Vane JR, Bakhle YS, Botting RM (1998): Bonnesen, K., & Schmidt, M. (2021).
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Cyclooxygenase-2(Cox-2)
• Is a Key Enzyme in synthesis of prostaglandins from arachidonic acid.
• Upregulated in response to inflammatory processes
• Pro-inflammatory cytokines
• Growth factors
• Synovial Fluid
• Prostacyclin-PGX• Antithrombotic
Bonnesen, K., & Schmidt, M. (2021).; Jang, Y., Kim, M., & Hwang, S. W. (2020).; Mitchell, J. A., & Kirkby, N. S. (2019).; Quinn, J. H., Kent, J. H., Moise, A., & Lukiw, W. J. (2000).; Vane JR, Bakhle YS, Botting RM (1998).
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Kidneys
• Prostaglandin I2 & E2 are thought to modulate intrarenal artery contractility through
• prostaglandin E2-EP4, • Prostacyclin-IP
• Thromboxane A2-TP
Eskildsen, M. P., Hansen, P. B., Stubbe, J.
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Clotting (hemorrhage vs. thrombotic events)
• Blocking prostacyclin's (antithrombotic) and promoting thromboxane A2 (prothrombotic) increases atherogenesis in early stages of atherosclerosis, and mildly elevates systolic BP.
Bonnesen, K., & Schmidt, M. (2021); Aw, T. J., Haas, S. J., Liew, D., & Krum, H. (2005).
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NAIDS
• Analgesics
• Anti-inflammatory
• Antipyretic
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Intended Effects & SE Relative selectivity of some commonly used NSAIDs. Data shown as the logarithm of their ratio of IC80 (drug concentration to achieve 80% inhibition of cyclooxygenase). *Aspirin graphed for IC50
Value due to it showing significantly more COX-1 selectivity at lower doses and graph using higher concentrations does not accurately reflect the usage or selectivity of aspirin. Source: Lippincott Illustrated Reviews, Pharmacology. Whalen, Karen
COX-1 Enzyme• Stomach Integrity• Renal function• Prothrombotic
COX-2 Enzyme• Pro-inflammatory• Synovial Fluid• Antithrombotic
Both COX-1 & COX-2 inhibitors• Analgesics• Anti-inflammatory• Antipyretic
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Literature: GI Complications
• Long term use (3 years)
• All NSAID regimens increased upper GI complications
• (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001).
Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala, N., Emberson (2013)
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Literature: Bleeding ImplicationsLong Term Use (3 years)
There is undoubted increased cardiac events with chronic NSAIDs use.
Short Term?
Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala, N., Emberson (2013)
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Literature: Renal Implications
• “NSAID use is not always wrong because clinical practice not infrequently requires choosing the least-bad option in situations where every option is problematic”
• Debates in Nephrology (2020)
Barreto, E. F., & Feely, M. A. (2020).
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• Randomized, double-blind, placebo-controlled trial of IV Ibuprofen
• 455 Septic patients
• 10mg/kg Ibuprofen every 6 hours for 8 doses
• Serum creatinine and urinary output were measured serially over 5 days• No significant differences in renal
function were detected
• No increased incidence of GI bleeding, or other adverse evets
The Effects of Ibuprofen on the Physiology and Survival of Patients with Sepsis (1997)
The Effects of Ibuprofen on the Physiology and Survival of Patients with Sepsis (1997)
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• A Multi-Center, Randomized, Double-Blind, Parallel, Placebo-Controlled Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of Intravenous Ibuprofen for the Treatment of Fever in Critically Ill and Non-Critically Ill Adults (2010)
• N=120
• Subjects were excluded for creatinine >3.0
• 1 dose every 6 hours X4 up to 400mg)
• There were no statistically significant differences between the groups when compared to placebo• Bleeding• Renal Function
• No clinically significant nephrotoxic effects through study day 28
Morris, P. E., Promes, J. T., Guntupalli, K. K (2010)
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• An Integrated Safety Analysis of Intravenous Ibuprofen (Caldolor) in Adults (2015)
• Review of 10 trials
• >1,750 adult patients
• The incidence of adverse events was lower in patients receiving IV Ibuprofen vs. placebo
• No hematological or renal detriment
Southworth, S. R., Woodward, E. J., Peng, A
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Pre-op Drug and Dosing options for Anesthesia
• Celebrex 400mg PO Pre-op X1• Celebrex 200mg PO q 12 hrs. post-op
• Mobic 15-30 mg
• Etodolac 200mg
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Questions?
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ReferencesAw, T. J., Haas, S. J., Liew, D., & Krum, H. (2005). Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Archives of internal medicine, 165(5), 490–496. https://doi.org/10.1001/archinte.165.5.IOI50013
Barreto, E. F., & Feely, M. A. (2020). Can NSAIDs be used safely for analgesia in patients with CKD?: PRO. Kidney360, 1(11), 1184–1188. https://doi.org/10.34067/kid.0004582020
Bernard, G. R., Wheeler, A. P., Russell, J. A., Schein, R., Summer, W. R., Steinberg, K. P., Fulkerson, W. J., Wright, P. E.,Christman, B. W., Dupont, W. D., Higgins, S. B., & Swindell, B. B. (1997). The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. The New England journal of medicine, 336(13), 912–918. https://doi.org/10.1056/NEJM199703273361303
Bonnesen, K., & Schmidt, M. (2021). Re-categorization of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) according to clinical relevance: Abandoning the ´traditional NSAID´ terminology. The Canadian journal of cardiology, S0828-282X(21)00349-4. Advance online publication. https://doi.org/10.1016/j.cjca.2021.06.014
Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala, N., Emberson, J., Merhi, A., Abramson, S., Arber, N., Baron, J. A., Bombardier, C., Cannon, C., Farkouh, M. E., FitzGerald, G. A., Goss, P., Halls, H., Hawk, E., Hawkey, C., Hennekens, C., Hochberg, M., Holland, L. E., Kearney, P. M., Laine, L., … Baigent, C. (2013). Vascular and upper gastrointestinal effects ofnon-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet (London, England), 382(9894), 769–779. https://doi.org/10.1016/S0140-6736(13)60900-9
Eskildsen, M. P., Hansen, P. B., Stubbe, J., Toft, A., Walter, S., Marcussen, N., Rasmussen, L. M., Vanhoutte, P. M., & Jensen, B. L. (2014). Prostaglandin I2 and prostaglandin E2 modulate human intrarenal artery contractility through prostaglandin E2-EP4, prostacyclin-IP, and thromboxane A2-TP receptors. Hypertension (Dallas, Tex. : 1979), 64(3), 551–556. https://doi.org/10.1161/HYPERTENSIONAHA.113.03051
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Gan T. J. (2010). Diclofenac: an update on its mechanism of action and safety profile. Current medical research and opinion, 26(7), 1715–1731. https://doi.org/10.1185/03007995.2010.486301
Jang, Y., Kim, M., & Hwang, S. W. (2020). Molecular mechanisms underlying the actions of arachidonic acid-derived prostaglandins on peripheral nociception. Journal of neuroinflammation, 17(1), 30. https://doi.org/10.1186/s12974-020-1703-1
Mitchell, J. A., & Kirkby, N. S. (2019). Eicosanoids, prostacyclin and cyclooxygenase in the cardiovascular system. British journal of pharmacology, 176(8), 1038–1050. https://doi.org/10.1111/bph.14167
Morris, P. E., Promes, J. T., Guntupalli, K. K., Wright, P. E., & Arons, M. M. (2010). A multi-center, randomized, double-blind, parallel, placebo-controlled trial to evaluate the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for the treatment of fever in critically ill and non-critically ill adults. Critical care (London, England), 14(3), R125. https://doi.org/10.1186/cc9089
Quinn, J. H., Kent, J. H., Moise, A., & Lukiw, W. J. (2000). Cyclooxygenase-2 in synovial tissue and fluid of dysfunctional temporomandibular joints with internal derangement. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons, 58(11), 1229–1233. https://doi.org/10.1053/joms.2000.16619
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Southworth, S. R., Woodward, E. J., Peng, A., & Rock, A. D. (2015). An integrated safety analysis of intravenous ibuprofen (Caldolor(®)) in adults. Journal of pain research, 8, 753–765. https://doi.org/10.2147/JPR.S93547
Vane, J. R., Bakhle, Y. S., & Botting, R. M. (1998). Cyclooxygenases 1 and 2. Annual review of pharmacology and toxicology, 38, 97–120. https://doi.org/10.1146/annurev.pharmtox.38.1.97
Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincott illustrated reviews: Pharmacology (6th ed.). Philadelphia, PA: Wolters Kluwer.
Zagon, I. S., & McLaughlin, P. J. (Eds.). (2017). Multiple Sclerosis: Perspectives in Treatment and Pathogenesis. Codon Publications. The Role of Arachidonic Acid–Mediated Neuroinflammation. Figure 1, [Schematic representation of the arachidonic...].Available from: https://www.ncbi.nlm.nih.gov/books/NBK470143/figure/chapter7.f1/doi: 10.15586/codon.multiplesclerosis.2017.ch7
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