Central Nervous System (CNS)-Acting Chemicals by Sofía Sola Sancho, Maria Hemme and Ayah wafi Office of the Science Policy Advisor α2-adrenergic receptor agonist examples Toxic chemicals that target the central nervous system (CNS). These chemicals can act as anaesthetics, sedatives, and analgesics. Specific CNS-acting chemicals discussed in the context of the Chemical Weapons Convention have in- BZ (3-quinuclidinyl benzilate) cluded α2-adrenergic receptor agonists, inhaled anaesthetics, fentanils and the Schedule 2A.03* chemical BZ. BZ is a glycolate anticholinergic compound and is a only Dexmedetomidine N “CNS-acting chemical” found in the Annex of Chemicals HN of the Chemical Weapons Convention (Schedule 2A.03*). Mechanism of action: Dexmedetomidine Properties • Presynaptic activation of the α2-adrenoceptor, inhibiting norepinephrine • Odourless crystalline powder with bitter taste. α-Adrenergic Presynaptic cell • Persistent in soil and water and on most surfaces. release, preventing entry of the neurotransmitter into the synaptic junction synapse Fentanils (negative feedback). • Half-life in moist air ~ 3-4 weeks. • Fentanils are a highly potent family of opioid narcotic analgesic drugs. • Postsynaptic activation of the α1-adrenoceptor • The family includes fentanyl, a narcotic linked to an increased risk of overdose amongst opioid addicts. Antidote: Physostigmine • inhibiting sympathetic activity. This results in decreased blood pres- BZ • As of May 2018, there were 20 fentanil derivatives scheduled under the Single Convention on Narcotic Drugs • Temporarily raises acetylcholine concentrations by sure and heart rate. α2 Receptor Properties • Fentanyl and its analogues binding reversibly to anticholinesterase. • Produces analgesic, sedative, and anxiolytic effects. have higher potency than mor-

3 • Fentanyl and its analogues are solids that require aerosolisation for weaponisation phine and heroin. • Occupational exposure band (OEB) 5: control exposure to < 1 μg/m . α1 Receptor purposes. • Poor drug dosage, poly-drug Safety Ratio of BZ Cl use and addiction are all con- H H • Routes of exposure for fentanils include inhalation (aerosolized form), oral exposure N N tributors to the high rates of overdose, respiratory depres- The large difference between the median Postsynaptic or ingestion. Transdermal absorption is possible (for example, the use of transdermal Clonidine lethal concentration (LCt50) and the median N cell 200000 incapacitating concentration (IC ) allows for Cl patches), however as the process is slow, such that brief incidental exposures may not t50 Clonidine the onset of CNS-acting symptoms to appear Mechanism of action: 112 cause significant opioid toxicity. at a dosage much lower than a lethal dose. Fentanyl derivative Amide group Piperidine ring N-Alkyl chain Aniline ring 0 50000 • Reduces release of noradrenaline at both central and peripheral 100000 150000 200000 N S sympathetic nerve terminals. N-Alkyl chain Sufentanil O O Mechanism of action of Dexmetomidine and Clonidine. Piperidine ring 3 • Produces dose-related sedation, analgesia and anxiolysis. N Dose in [mg.min/m ] Carfentanil O O

• A reduction in the effective dose of other anaesthetic agents Amide group F N Ocfentanil Presynaptic and opioids is also observed. O Mechanism of action: cell N O O 3 Aniline ring • LC50 (rat inh): 19.7 mg/m /4 Hours Remifentanyl O O O • Acts as a competitive inhibitor of the neurotrans-

• LD50 (rat i.v.): 29 mg/kg N Fentanyl 3-Fluorofentanyl mitter acetylcholine (ACh) in postsynaptic ACh re- Acetyl F CoA CoA Structure and substitution positions for fentanyl and ceptors. derivatives. N Enzyme Pivaloylfentanyl Acetylcholine Ch Mechanism of action: • As the concentration of BZ at these sites increases, N α'-methyl Butyrylfentanyl the proportion of receptors available for binding to • In the CNS, fentanils bind to opioid N Cyclopentenilfentanyl acetylcholine decreases, resulting in an understim- Choline (Ch) receptors, specifically μ-receptors. BZ N ulation of nerve signal transduction. These receptors are found predom- Cyclopropylfentanyl Acetic acid Inhaled anaesthetic examples • When administered by inhalation (in aerosolised

N inantly in the brain and spinal cord para-chloro Valerylfentanyl Cl form), absorption to the bloodstream is more pro- AChE Acetylcholine • They act to depress CNS function. Mechanism of action: N nounced than with oral administration. receptor Halothane Valerylfentanyl • Bioavailbility from inhalation ex- • Enhances aminobutyric acid (GABA) binding to its chloride ion-channel receptor. Postsynaptic γ- N CNS effects: Acetylfentanyl posure can range from 12-100%. cell • The increase in intra-cellular chloride levels produces an inhibitory effect (anaesthesia). • Stupor, ataxia, confusion, and confabulation. In- O N Furanylfentanyl duces concrete and panoramic illusions and hallu- CoA = Coenzyme A No anaesthetic N Cl- 4F-iBF F cinations. AChE = Acetylcholinesterase Halothane Presynaptic GABA O N cell Tetrahydrofuranylfentanyl (THF-F) Peripheral effects: Isoflurane • Mydriasis, blurred vision, dry mouth and skin, initial- N Mechanism of action of BZ. Methoxyacetylfentanyl O ly rapid heart rate; later, normal or slow heart rate.

N ortho-methyl Cyclopropylfentanyl Binding site µ-opioid receptor (MDR) N Crystal structure of the μ-opioid recep- Acryloylfentanyl Isoflurane tor bound to a morphinan antagonist F Inhaled anaesthetic (Protein Data Bank Structure 4DKL) N Cl- 2'-fluoro ortho-Fluorofentanyl Sevoflurane F GABA A receptor GABA Anaesthetic Effects: Toxicity Antidotes: Naloxone hydrochloride (Narcan) or Naltrexone Postsynaptic • Loss of pain sensation O O O O cell • Opioid receptor antagonists. N N O • Miosis O O N • Bind to the opioid receptors more strongly than a fentanyl derivative, but do not ac- Carfentanil N • Decreased intestinal paristalsis (constipa- tivate the receptor. I N • Quickly reverse signs and symptoms, especially life-threatening respiratory depres- N tion) Sufentanil O S Sevoflurane sion. II I II • Nausea and vomiting N Fentanyl O • Short half-life, symptoms may return in an apparently stabilized patient and antidotes III • Dose-dependent respiratory depression III Mechanism of action of Inhaled anaesthetics. might need to be readministered. N (which can lead to death) • 0.4 mg is the standard starting dose but for some fentanyl derivatives doses up to 2 Alfentanil IV F N O N LD : the lowest dosage of a substance observed to cause a fatality • Diminished mental alertness resulting in Lo mg have been required. O N N N Narcan Naltrexone α- Methylfentanyl O N O N HO within a specific subject population under a specific set of exposure a feeling of drowsiness, euphoria, sleepi- V IV HO HO conditions. LD : the median value of all the observed dosages of a N 50 Fluorofentanyl N N O substance resulting in a fatality within a specific subject population ness, and unconsciousness P- N H VI H under a specific set of exposure conditions. LC : the median value of OH 50 O OH O HO N Acetylfentanyl V VII VIII all the observed concentrations (based on an exposure time) of a sub- N VI VII stance resulting in a fatality within a specific subject population under O a specific set of exposure conditions. Lethal dose and lethal concen- O Morphine tration values are statistics derived from specific populations and ex- VIII posure conditions (typically controlled animal studies), they may not 0 20 40 60 80 100 120 140 be representative of alternate populations and/or exposure conditions. LD50 (mg/kg)