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 2018hchemmi@med.cornell.edu

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?