Chemistry:Bupivacaine

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Short description: Local anaesthetic drug
Bupivacaine
Bupivacaine skeletal.svg
Bupivacaine-from-xtal-3D-bs-17.png
Clinical data
Pronunciation/bjuːˈpɪvəkeɪn/
Trade namesMarcaine, Sensorcaine, Posimir, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		Parenteral, topical, implant
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityn/a
Protein binding95%
MetabolismLiver
Onset of actionWithin 15 min[4]
Elimination half-life3.1 hours (adults)[4]
8.1 hours (neonates)[4]
Duration of action2 to 8 hr[5]
ExcretionKidney, 4–10%
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H28N2O
Molar mass288.435 g·mol−1
3D model (JSmol)
Melting point107 to 108 °C (225 to 226 °F)
 ☒N☑Y (what is this?)  (verify)

Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease feeling in a specific area.[4] In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal's epidural space.[4] It is available mixed with a small amount of epinephrine to increase the duration of its action.[4] It typically begins working within 15 minutes and lasts for 2 to 8 hours.[4][5]

Possible side effects include sleepiness, muscle twitching, ringing in the ears, changes in vision, low blood pressure, and an irregular heart rate.[4] Concerns exist that injecting it into a joint can cause problems with the cartilage.[4] Concentrated bupivacaine is not recommended for epidural freezing.[4] Epidural freezing may also increase the length of labor.[4] It is a local anaesthetic of the amide group.[4]

Bupivacaine was discovered in 1957.[6] It is on the World Health Organization's List of Essential Medicines.[7] Bupivacaine is available as a generic medication.[4][8] An implantable formulation of bupivacaine (Xaracoll) was approved for medical use in the United States in August 2020.[9][10][11]

Medical uses

Bupivacaine is indicated for local infiltration, peripheral nerve block, sympathetic nerve block, and epidural and caudal blocks. It is sometimes used in combination with epinephrine to prevent systemic absorption and extend the duration of action. The 0.75% (most concentrated) formulation is used in retrobulbar block.[12] It is the most commonly used local anesthetic in epidural anesthesia during labor, as well as in postoperative pain management.[13] Liposomal formulations of bupivacaine (brand name EXPAREL) have not shown clinical benefit compared to plain bupivacaine when used in traditional perineural injections,[14] although some industry-funded studies have suggested benefits when used in local infiltration.[15][16]

The fixed-dose combination of bupivacaine with Type I collagen (brand name Xaracoll) is indicated for acute postsurgical analgesia (pain relief) for up to 24 hours in adults following open inguinal hernia repair.[10][11]

Bupivacaine (Posimir) is indicated in adults for administration into the subacromial space under direct arthroscopic visualization to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression.[10][17]

Contraindications

Bupivacaine is contraindicated in patients with known hypersensitivity reactions to bupivacaine or amino-amide anesthetics. It is also contraindicated in obstetrical paracervical blocks and intravenous regional anaesthesia (Bier block) because of potential risk of tourniquet failure and systemic absorption of the drug and subsequent cardiac arrest. The 0.75% formulation is contraindicated in epidural anesthesia during labor because of the association with refractory cardiac arrest.[18]

Adverse effects

Compared to other local anaesthetics, bupivacaine is markedly cardiotoxic.[19] However, adverse drug reactions are rare when it is administered correctly. Most reactions are caused by accelerated absorption from the injection site, unintentional intravascular injection, or slow metabolic degradation. However, allergic reactions can rarely occur.[18]

Clinically significant adverse events result from systemic absorption of bupivacaine and primarily involve the central nervous and cardiovascular systems. Effects on the central nervous system typically occur at lower blood plasma concentrations. Initially, cortical inhibitory pathways are selectively inhibited, causing symptoms of neuronal excitation. At higher plasma concentrations, both inhibitory and excitatory pathways are inhibited, causing central nervous system depression and potentially coma. Higher plasma concentrations also lead to cardiovascular effects, though cardiovascular collapse may also occur with low concentrations.[20] Adverse effects on the central nervous system may indicate impending cardiotoxicity and should be carefully monitored.[18]

Toxicity can also occur in the setting of subarachnoid injection during high spinal anesthesia. These effects include: paresthesia, paralysis, apnea, hypoventilation, fecal incontinence, and urinary incontinence. Additionally, bupivacaine can cause chondrolysis after continuous infusion into a joint space.[18]

Bupivacaine has caused several deaths when the epidural anaesthetic has been administered intravenously accidentally.[21]

Treatment of overdose

Animal evidence[22][23] indicates intralipid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anaesthetic overdose, and human case reports of successful use in this way.[24][25] Plans to publicize this treatment more widely have been published.[26]

Pregnancy and lactation

Bupivacaine crosses the placenta and is a pregnancy category C drug. However, it is approved for use at term in obstetrical anesthesia. Bupivacaine is excreted in breast milk. Risks of stopping breast feeding versus stopping bupivacaine should be discussed with the patient.[18]

Postarthroscopic glenohumeral chondrolysis

Bupivacaine is toxic to cartilage and its intra-articular infusions may lead to postarthroscopic glenohumeral chondrolysis.[27]

Pharmacology

Pharmacodynamics

Bupivacaine binds to the intracellular portion of voltage-gated sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. Without depolarization, no initiation or conduction of a pain signal can occur.

Pharmacokinetics

The rate of systemic absorption of bupivacaine and other local anesthetics is dependent upon the dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the preparation.[28]

  • Onset of action (route and dose-dependent): 1–17 min
  • Duration of action (route and dose-dependent): 2–9 hr
  • Half life: neonates, 8.1 hr, adults: 2.7 hr
  • Time to peak plasma concentration (for peripheral, epidural, or caudal block): 30–45 min
  • Protein binding: about 95%
  • Metabolism: hepatic
  • Excretion: renal (6% unchanged)[18]

Chemical structure

Like lidocaine, bupivacaine is an amino-amide anesthetic; the aromatic head and the hydrocarbon chain are linked by an amide bond rather than an ester as in earlier local anesthetics. As a result, the amino-amide anesthetics are more stable and less likely to cause allergic reactions. Unlike lidocaine, the terminal amino portion of bupivacaine (as well as mepivacaine, ropivacaine, and levobupivacaine) is contained within a piperidine ring; these agents are known as pipecholyl xylidines.[13]

Society and culture

Legal status

On 17 September 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Exparel, intended for the treatment of post-operative pain.[29] The applicant for this medicinal product is Pacira Ireland Limited.[29] Exparel liposomal was approved for medical use in the European Union in November 2020.[30]

Economics

Bupivacaine is available as a generic medication.[4][8]

Research

Levobupivacaine is the (S)-(–)-enantiomer of bupivacaine, with a longer duration of action, producing less vasodilation. Durect Corporation is developing a biodegradable, controlled-release drug delivery system for after surgery. As of 2010, it has completed a phase-III clinical trial.[31]

See also

  • Bupivacaine/meloxicam

References

  1. ↑ "Bupivacaine Use During Pregnancy". 13 April 2020. https://www.drugs.com/pregnancy/bupivacaine.html. 
  2. ↑ "Marcaine- bupivacaine hydrochloride injection, solution Marcaine with epinephrine- bupivacaine hydrochloride and epinephrine bitartrate injection, solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=67578b56-7540-487e-1fba-481255620e78. 
  3. ↑ "Sensorcaine MPF- bupivacaine hydrochloride injection, solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e700eb7b-8b14-49c9-96b2-331f18776e45. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 "Bupivacaine Hydrochloride". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/bupivacaine-hydrochloride.html. 
  5. ↑ 5.0 5.1 Cambridge textbook of accident and emergency medicine. Cambridge: Cambridge University Press. 1997. p. 194. ISBN 9780521433792. https://books.google.com/books?id=m0bNaDhkaukC&pg=PA194. 
  6. ↑ Pharmacology and physiology for anesthesia : foundations and clinical application. Philadelphia, PA: Elsevier/Saunders. 2013. p. 291. ISBN 9781437716795. https://books.google.com/books?id=s8CXrbimviMC&pg=PT306. 
  7. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  8. ↑ 8.0 8.1 Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. p. 22. ISBN 9781284057560. 
  9. ↑ "Xaracoll: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209511. 
  10. ↑ 10.0 10.1 10.2 "FDA approval letter". 28 August 2020. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/209511Orig1s000ltr.pdf.  This article incorporates text from this source, which is in the public domain.
  11. ↑ 11.0 11.1 "FDA Approves Xaracoll (bupivacaine HCl) Implant, a Non-opioid, Drug-device Treatment Option for Acute Postsurgical Pain Relief for up to 24 Hours Following Open Inguinal Hernia Repair in Adults" (Press release). Innocoll Pharmaceuticals. 31 August 2020. Retrieved 2 September 2020 – via PR Newswire.
  12. ↑ Lexicomp. "Bupivacaine (Lexi-Drugs)". http://www.online.lexi.com. 
  13. ↑ 13.0 13.1 13.2 Basics of Anesthesia. Churchill Livingstone. November 2, 2006. 
  14. ↑ "Perineural Liposomal Bupivacaine Is Not Superior to Nonliposomal Bupivacaine for Peripheral Nerve Block Analgesia: A Systematic Review and Meta-analysis". Anesthesiology 134 (2): 147–164. February 2021. doi:10.1097/ALN.0000000000003651. PMID 33372953. 
  15. ↑ "Liposomal bupivacaine versus traditional bupivacaine for pain control after total hip arthroplasty: A meta-analysis". Medicine 96 (25): e7190. June 2017. doi:10.1097/MD.0000000000007190. PMID 28640101. 
  16. ↑ "Local Infiltration Analgesia With Liposomal Bupivacaine Improves Pain Scores and Reduces Opioid Use After Total Knee Arthroplasty: Results of a Randomized Controlled Trial". The Journal of Arthroplasty 33 (1): 90–96. January 2018. doi:10.1016/j.arth.2017.07.024. PMID 28802777. 
  17. ↑ "Durect Corporation Announces U.S. FDA Approval of Posimir For Post-Surgical Pain Reduction for up to 72 Hours Following Arthroscopic Subacromial Decompression" (Press release). Durect Corporation. 2 February 2021. Retrieved 13 February 2021 – via PR Newswire.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 "Bupivacaine (Lexi-Drugs)". http://www.online.lexi.com. 
  19. ↑ "[Cardiotoxicity of local anesthetics]". Cahiers d'Anesthésiologie 41 (6): 589–598. 1993. PMID 8287299. 
  20. ↑ Australian Medicines Handbook. Adelaide. 2006. ISBN 978-0-9757919-2-9. 
  21. ↑ "Filipino nurse dies in UK due to wrong use of anaesthetic". ABS-CBN Interactive. 28 January 2014. http://www.abs-cbnnews.com/storypage.aspx?StoryId=104790. 
  22. ↑ "Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats". Anesthesiology 88 (4): 1071–1075. April 1998. doi:10.1097/00000542-199804000-00028. PMID 9579517. 
  23. ↑ "Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity". Regional Anesthesia and Pain Medicine 28 (3): 198–202. 2003. doi:10.1053/rapm.2003.50041. PMID 12772136. 
  24. ↑ "Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest". Anesthesiology 105 (1): 217–218. July 2006. doi:10.1097/00000542-200607000-00033. PMID 16810015. 
  25. ↑ "Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion". Anaesthesia 61 (8): 800–801. August 2006. doi:10.1111/j.1365-2044.2006.04740.x. PMID 16867094. 
  26. ↑ "Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob". Anaesthesia 61 (2): 107–109. February 2006. doi:10.1111/j.1365-2044.2005.04494.x. PMID 16430560. 
  27. ↑ "Articular cartilage and local anaesthetic: A systematic review of the current literature". Journal of Orthopaedics 12 (Suppl 2): S200–S210. December 2015. doi:10.1016/j.jor.2015.10.005. PMID 27047224. 
  28. ↑ "bupivacaine hydrochloride (Bupivacaine Hydrochloride) injection, solution". FDA. http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=1828. 
  29. ↑ 29.0 29.1 "Exparel: Pending EC decision". 17 September 2020. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/exparel.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  30. ↑ "Exparel liposomal EPAR". 15 September 2020. https://www.ema.europa.eu/en/medicines/human/EPAR/exparel-liposomal. 
  31. ↑ "Bupivacaine Effectiveness and Safety in SABER Trial (BESST)". 20 January 2010. https://clinicaltrials.gov/ct2/show/NCT01052012. 

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