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Advances in Pharmacology
Antidotes in anaesthesiaMeyer-Overton revisited
Hugh C. Hemmings Jr, MD, PhD, FRCAJoseph F Artusio Jr Chair and Professor of AnesthesiologySenior Associate Dean for ResearchProfessor of PharmacologyWeill Cornell MedicineAnesthesiologist-in-ChiefNewYork Presbyterian-Weill Cornell Medical Center
17 May [email protected]
www.weillcornellanesthesiology.org
Declarationofinterests§ Research funding from the National Institutes of Health § Editor-in-Chief of the British Journal of Anaesthesia
Definition
antidote: an agent that counteracts a poison
• Are anaesthetics poisons?
Miller-KeaneEncyclopediaandDictionaryofMedicine,Nursing,andAlliedHealth,SeventhEdition.©2003bySaunders,animprintofElsevier,Inc.Allrightsreserved.
The father of toxiciology
• “All things are poison and nothing is without poison, only the dose permits something not to be poisonous”
• First to recognize the analgesic effect of ether and advocate the use of chemicals in medicine
• Never went anywhere without his sword, prodigious drinker, died in a tavern brawl in Salzburg at age 48
Paracelsus (bornPhillippus Aureolus TheophrastusBombastus vonHohenheim,11Novemberor17December1493inEinsiedeln,Switzerland – 24September1541inSalzburg,Austria)Renaissancephysician,botanist,alchemist,astrologer,andoccultist
Types of antidotes
• chemical antidote interacts with a poison and changes its chemical nature to form a harmless substance (pralidoxime-organophosphate)
• physiological antidote counteracts the effects of the poison by producing opposing effects (neostigmine-glycopyrrolate)
• complex formation leading to sequestration (NMB-sugammadex)
• mechanical antidote prevents absorption of the poison (activated charcoal, ipecac)
Classical anaesthesia antidotesDrug/poison Antidote
Acetaminophen/paracetamol Acetylcysteine
Anticholinergic Physostigmine
Anticholinesterase Atropine/Pralidoxime
Benzodiazepine Flumazenil
Ca2+ channel blocker Calcium chloride
Digoxin Anti-digoxinFab
Heparin Protamine sulfate
Malignanthyperthermia Dantrolene
Neuromuscularblocker Anticholinesterase
Opioids Naloxone
Warfarin VitaminK
Novel anaesthesia antidotesDrug/poison Antidote
Localanaesthetics Lipidemulsion
Neuromuscularblockers Encapsulation:sugammadex,calabadion
Neuromuscularblockers Degradation:cysteine
DOAC(dabigatran;DTI) Idarucizumab
DOACs (FXa inhibitors) Adexanet alpha
Generalanaesthesia Methylphenidate/ketamine
Local anaesthetic toxicity
• Local anaesthetics act by blocking voltage-gated Na+ channels essential for neuronal function
• Multiple off-target effects as well• Selectivity based on precise delivery• Relatively common spectrum of dose-related
side effects due to systemic absorption
Diagnosis of local anaesthetic toxicity
• Central nervous system signs (~50%; may be subtle or absent) – Excitation (agitation, confusion, muscle twitching, seizure) – Depression (drowsiness, obtundation, coma or apnea) – Sensory (metallic taste, circumoral numbness, diplopia, tinnitus,
dizziness, hallucination)
• Cardiovascular signs (often the only manifestation of severe toxicity) – Can appear late (>15 min after injection) – Initially may be hyperdynamic (hypertension, tachycardia, ventricular
arrhythmias), then – Progressive hypotension– Conduction block, bradycardia or asystole– Ventricular arrhythmia (ventricular tachycardia, Torsades de Pointes,
ventricular fibrillation)
Immediate treatment
• Stop injecting/Call for help• ABC: intubate, 100% O2, IV access• Control seizures: benzodiazepines, not propofol• CPR/alert cardiopulmonary bypass team• Avoid vasopressin, calcium channel blockers, beta
blockers, lidocaine• Epinephrine <1 mcg/kg doses
• Consider lipid emulsion rescue therapy– 1.5 ml/kg bolus of 20% Intralipid over 1 min with infusion of 0.25-
0.5 ml/kg/min– https://www.asra.com/– http://www.lipidrescue.org/
Evidence to support intravenous lipid rescue therapy
• Low quality evidence: anecdotal case reports and laboratory studies only
• Side effects: rarely pancreatitis, ARDS, fat complex overload syndrome
• Unclear mechanism of action– Sequestration of hydrophobic lipophilic local
anaesthetic molecules questionable• pharmacokinetic effect to accelerate redistribution from
brain and heart– Other mechanisms:
• inotropic effect by activation of VGCC• relief of fatty acid inhibition of VGSC• adrenergic receptor activation• activation of fatty acid receptor GPCR40
Evidence for intravenous lipid rescue therapy
• Published on-line this month in Anesthesiology
• Acetylcholinesterase inhibitors reverse only shallow levels of block (To4R>0.4)– Nonselective: indirectly increases ACh at all cholinergic synapses– Requires a third drug to prevent undesired antimuscarinic effects– Ceiling effect, slow (at least 10 min)
• Encapsulating agent sugammadex reverses even deep levels of block – Bind free extracellular drug to reduce effect-site concentration (NMJ)
• Side effects due to nonspecific binding of other molecules or anaphylaxis– Sugammadex: steroidal hormone (oral contraceptives)
New approaches to reversing neuromuscular blockade: encapsulation
Sugammadex
• A gamma-cyclodextrin that binds and sequesters steroidal NMBs
• Cyclic oligosaccharide with hydrophobic interior
• Unique mechanism that does not involve cholinergic system; but profound bradycardia can still occur
• Reduced residual muscular weakness compared to neostigmine
• Availability and cost are still concernsPinterest.com
Sugammadex
• More rapid and effective in deep block with fewer side effects
Jonesetal., Anesthesiology2008;109:816-24.
Calabadion
• Acyclic flexible oligomer that can accommodate larger molecules
• Reverses both steroidal and benzylisoquinolinium NMBs
• In preclinical development
Grosse-Sundrup etal.,2012
• Benzylisoquinolinums react with thiols and are reversible by cysteine through an intermolecular reaction– React with endogenous Cys– Accelerated by exogenous Cys– N-acetylcysteine is FDA approved
• In preclinical development
New approaches to reversing neuromuscular blockade: cysteine
Heerdt etal.,2015
• Direct oral anticoagulants: small molecule inhibitors of thrombin (DTI) or FXa
• Nonspecific agents include activated charcoal, haemodialysis, prothrombin complex concentrate (PCC)
• Approved without an antidote
Tummala etal.,2016
Specific antidotes against direct oral anticoagulants
Idarucizumab
• Humanized monoclonal antibody Fab domain• Specific high affinity for the DTI dabigatran• Renal excretion; short half life, given by infusion• Immediate, complete sustained reversal of dabigatran
Andexanet alpha• Mutated FXa fragment lacking protease
(procoagulant) activity • Reverses rivaroxaban, apixaban, edoxaban,
fondaparinux• Binds FXa inhibitors with higher affinity acting as a
decoy protein and drug sink• Short half life; requires infusion• Positive interim results• In clinical development;
not yet approved
In the pipeline
• Aripazine: synthetic small molecule that reverses FXainhibitors
• Anivamersen/ pegnivacogin: an RNA aptamer pair (known as REG-1) including (anivamersen) developed to reverse the FIXa inhibitor pegnivacogin
– an alternative to heparin:protamine
Active emergence from general anaesthesia• Pharmacological approaches reverse/accelerate emergence
from general anaesthesia• Methylphenidate accelerates emergence from isoflurane
anaesthesia and induces return of righting reflex (Solt et al., 2011)
– Reduced time to emergence by 68%– Mediated by D1 receptor activation (Taylor et al., 2013)– Also effective for propofol and sevoflurane anaesthesia
• Subanaesthetic dose of ketamine accelerates emergence from isoflurane anaesthesia in rats (Hambrecht-Wiedbuschet al., 2017
– Increased burst suppression ratio by 125%– Reduced emergence time by 44%– “Paradoxical emergence”
Thank you!
• Questions?