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3-Quinuclidinyl benzilate

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3-Quinuclidinyl benzilate (QNB, BZ, EA-2277), IUPAC name 1-azabicyclo[2.2.2]oct-3-yl 2-hydroxy-2,2-diphenylacetate, is an odorless military incapacitating agent.[1] Its NATO code is BZ.

BZ is a glycolate anticholinergic compound related to atropine, scopolamine, hyoscyamine, and other deliriants. Dispersal would be as an aerosolized solid (primarily for inhalation) or as agent dissolved in one or more solvents for ingestion or percutaneous absorption.

Acting as a competitive inhibitor of acetylcholine at postsynaptic and postjunctional muscarinic receptor sites in smooth muscle, exocrine glands, autonomic ganglia, and the brain, BZ decreases the effective concentration of acetylcholine seen by receptors at these sites. Thus, BZ causes PNS effects that in general are the opposite of those seen in nerve agent poisoning. CNS effects include stupor, confusion, and confabulation with concrete and panoramic illusions and hallucinations, and with regression to automatic "phantom" behaviors such as plucking and disrobing.

Physostigmine, which increases the concentration of acetylcholine in synapses and in neuromuscular and neuroglandular junctions, is a specific antidote.

Production of BZ is controlled under schedule 2 of the Chemical Weapons Convention.

BackgroundEdit

Following World War II, the United States military investigated a wide range of possible nonlethal, psychoactive incapacitating agents including psychedelic drugs such as LSD and THC, dissociative drugs such as ketamine and phencyclidine, potent opioids such as fentanyl, as well as several glycolate anticholinergics.[2][3]

HistoryEdit

One of the anticholinergic compounds, 3-quinuclidinyl benzilate, was assigned the NATO code BZ and was weaponized at the beginning of the 1960s for possible battlefield use. BZ was invented by Hoffman-LaRoche in 1951.[4] The company was investigating anti-spasmodic agents, similar to tropine, for treating gastrointestinal issues when the chemical was discovered.[4] In 1959 the United States Army began to show interest in using the chemical as a chemical warfare agent.[4] The agent was originally designated TK but when it was standardized by the U.S. Army in 1961 it was designated BZ.[4] The agent commonly became known as "Buzz" because of this abbreviation and the effects it had on the mental state of its casualties.[4]

Military useEdit

The United States had weaponized BZ for delivery in the M44 generator cluster and the M43 cluster bomb until stocks were destroyed in 1989.

Alleged useEdit

In February 1998, the British Ministry of Defence accused Iraq of having stockpiled large amounts of a glycolate anticholinergic incapacitating agent known as Agent 15.[5] Agent 15 is an alleged Iraqi incapacitating agent that is likely to be chemically either identical to BZ or closely related to it. Agent 15 was reportedly stockpiled in large quantities prior to and during the Persian Gulf War. However after the war the CIA concluded that Iraq had not stockpiled or weaponised Agent 15.[6][7]

In January 2013, an unidentified U.S. administration official, referring to an undisclosed U.S. State Department cable, claimed that "Syrian contacts made a compelling case that Agent 15, a hallucinogenic chemical similar to BZ,[8] was used in Homs".[9] However in response to these reports U.S. National Security Council spokesman stated "The reporting we have seen from media sources regarding alleged chemical weapons incidents in Syria has not been consistent with what we believe to be true about the Syrian chemical weapons program".[7][10]

TestingEdit

As stated in psychiatrist James Ketchum’s book Chemical Warfare: Secrets Almost Forgotten, work that evolved when a general envisioned a scheme to incapacitate an entire trawler with aerosolized BZ was dubbed Project DORK.[11] This project was likely related to Project SHAD (Shipboard Hazard and Defense),[citation needed] a series of Cold War-era tests by the United States Department of Defense of biological weapons and chemical weapons related to Project 112. Exposures of subjects who include uninformed and unwilling humans during the testing to the test substances, particularly the exposure to United States military personnel then in service, has added controversy to recent revelations of the project while information about nine of the completed sub-projects of Project 112 has not yet been released.[12]

Sources other than militaryEdit

BZ and related anticholinergic compounds can be synthesized in clandestine laboratories, but its recreational use is almost nonexistent, because of its unpleasant effects. 3-quinuclidinyl benzilate, called QNB in the scientific community, is used in pharmacology as a muscarinic receptor antagonist.

Physiochemical characteristicsEdit

BZ is odorless. It is stable in most solvents, with a half-life of three to four weeks in moist air; even heat-producing munitions can disperse it. It is extremely persistent in soil and water and on most surfaces. It is slightly soluble in water; soluble in dilute acids, trichloroethylene, dimethylformamide, most organic solvents, insoluble with aqueous alkali.[13]

Detection and protectionEdit

BZ is odorless and nonirritating with delayed symptoms several hours after contact.[1] In the field the only immediate indications of its use may be the white smoke emanating from delivered weapons. Though detection methods have been developed for BZ, these have not been standardized for field use and are limited to laboratory analysis or specialized monitoring in industrial facilities (past).

Protection from BZ means blocking it from entry into the body. At dosages adequate for a lung effect there is little risk of absorption through the skin or contact hazards from aerosols that have settled out onto surfaces. The amount of BZ that may settle out on surfaces from an aerosol is too small to represent a hazard from secondary aerosols. Therefore, the most appropriate protective response is to don a protective mask with a good quality aerosol filter. Even improvised respiratory protection (e.g., several folded pieces of cloth over the nose and mouth) may render BZ employment ineffectual.

There is the possibility that BZ could be employed for a skin effect by adding to a skin penetrating solvent, or used for a secondary aerosol through contaminating terrain with bulk micro-pulverized BZ. However, both of these employment schemes are unlikely owing to the high cost and uncontrolled dose (potentially lethal). In any situation where BZ is present in liquid or bulk powder form, adequate skin protection with impermeable protective clothing and gloves is warranted.

ToxicokineticsEdit

BZ is dispersed as an aerosol. It may be micropulverized for dissemination by a disperser (90% dissemination efficiency), or mixed with a pyrotechnic burning mixture for dissemination in burning munitions (70% dissemination efficiency). Alternatively, it may be dissolved in a solvent such as DMSO to enhance percutaneous absorption, though experiments before this proved unsatisfactory for military purposes.

Bioavailability via ingestion and by inhalation of particles 1 micrometer in size approximates 80%, and 40 to 50%, respectively, of a parenterally delivered dose of BZ. Percutaneous absorption of BZ dissolved in propylene glycol yields, after a latent period of up to 24 hours, serum levels approximately 5 to 10% of those achieved with intravenous or intramuscular administration.

Following absorption, BZ is systemically distributed to most organs and biological tissues of the body. Its ability to reach synapses and neuromuscular and neuroglandular junctions throughout the body is responsible for its PNS effects, whereas its ability to cross the blood–brain barrier confers upon it the ability to cause CNS effects. Atropine and hyoscyamine both cross the placenta and can be found in small quantities in breast milk; whether this is also true for BZ is unclear.

Metabolism of BZ would be expected to occur primarily in the liver, with elimination of unchanged agent and metabolites chiefly in the urine.

ToxicityEdit

The characteristic that makes BZ an incapacitating rather than a toxic chemical warfare agent is its high safety margin (ICt50/LCt50) of around 40-fold (range 32 to 384 fold). It has an ID50 of 0.00616 mg per person (i.v.) with a probit slope of 9.2. The respiratory ICt50 (median incapacitating dosage) for BZ is 110 mg·min/m³ (mild activity - 15 l/min rate of breathing), whereas the LCt50 is often estimated to be around 3,800 - 41,300 mg·min/m³.[14]

Toxicodynamics (mechanism of action)Edit

The agent BZ and other anticholinergic glycolates act as competitive inhibitors of the neurotransmitter acetylcholine neurons (1) at postjunctional muscarinic receptors in cardiac and smooth muscle and in exocrine (ducted) glands and (2) at postsynaptic receptors in neurons. As the concentration of BZ at these sites increases, the proportion of receptors available for binding to acetylcholine decreases and the end organ "sees" less acetylcholine. (One way of visualizing this process is to imagine BZ coating the surface of the end organ and preventing acetylcholine from reaching its receptors.) Because BZ has little to no agonist activity with respect to acetylcholine, high concentrations of BZ essentially substitute a "dud" for acetylcholine at these sites and lead to clinical effects reflective of understimulation of end organs.

Clinical effectsEdit

Peripheral effects:

The PNS effects of BZ are, in general, readily understood as those of understimulation of end organs and are qualitatively similar to those of atropine. Decreased stimulation of eccrine and apocrine sweat glands in the skin results in dry skin and a reduction in the ability to dissipate heat by evaporative cooling. The skin becomes warm partly from decreased sweating and partly from compensatory cutaneous vasodilatation, (also causing red skin discolouration) as the body attempts to shunt a higher proportion of core-temperature blood as close as possible to the surface of the skin. With decreased heat loss, the core temperature itself rises.

Understimulation of other exocrine glands leads to xerostomia (dry mouth), thirst, and decreased secretions from lacrimal, nasal, bronchial, and gastrointestinal glands.

Decreased cholinergic stimulation of pupillary sphincter muscles allows alpha-adrenergically innervated pupillary dilating muscles to act essentially unopposed, resulting in mydriasis. Similar effects on cholinergic ciliary muscles produce paralysis of accommodation. Other smooth muscle effects from BZ intoxication include decreased bladder tone and decreased urinary force with possibly severe bladder distention.

BZ typically raises the heart rate initially, but hours later, depending on the dose of BZ, the heart rate falls to normal or may become slow. Either the peripheral vagal blockade has ceased or the stimulation of the vagal nucleus has occurred.

Neither atropine nor BZ can act directly at the postjunctional nicotinic receptors found in skeletal muscle, but BZ-exposed patients nonetheless exhibit muscle weakness. This weakness, along with incoordination, heightened stretch reflexes, and ataxia, is probably due to the effects of BZ at CNS sites.

The PNS effects of BZ are essentially side effects that are useful in diagnosis, but incidental to the CNS effects for which the incapacitating agents were developed. These CNS effects include a dose-dependent decrease in the level of consciousness, beginning with drowsiness and progressing through sedation to stupor and coma. The patient is often disoriented to time and place. Disturbances in judgment and insight appear. The patient may abandon socially imposed restraints and resort to vulgar and inappropriate behavior. Perceptual clues may no longer be readily interpretable, and the patient is easily distracted and may have memory loss, most notably short-term memory. In the face of these deficits, the patient still tries to make sense of his environment and will not hesitate to make up answers on the spot to questions that confuse him. Speech becomes slurred and often senseless, and loss of inflection produces a flat, monotonous voice. References become concrete and semiautomatic with colloquialisms, clichés, profanity, and perseveration. Handwriting also deteriorates. Semiautomatic behavior may also include disrobing (perhaps partly because of increased body temperature), mumbling, and phantom behaviors such as constant picking, plucking, or grasping motions ("woolgathering" or carphology).

BZ was referenced in the Vietnam War film Jacob's Ladder, but the effects depicted in the film are not accurate. No evidence exists that BZ sends people exposed to it into a homicidal frenzy, as the film suggests.

Central effectsEdit

Central nervous system mediated perceptual disturbances in BZ poisoning include both illusions (misidentification of real objects) and hallucinations (the perception of objects or attributes that have no objective reality). Hallucinations resulting from anticholinergics such as BZ tend to be realistic, distinct, easily identifiable (often commonly encountered objects or persons), panoramic, and difficult to distinguish from reality. They also have the tendency to decrease in size during the course of the intoxication. This is in contrast to the typically vague, ineffable, and transcendent-appearing hallucinations induced by psychedelics such as LSD.

Another prominent CNS finding in BZ poisoning is behavioral lability, with patients swinging back and forth between quiet confusion and self-absorption in hallucinations, to frank combativeness. Moreover, as other symptoms begin to resolve, intermittent paranoia may be seen. Automatic behaviors common during resolution include the crawling or climbing motions called "progresso obstinato" in old descriptions of dementia.

BZ produces effects not just in individuals, but also in groups. Sharing of illusions and hallucinations (folie à deux, folie en famille, and "mass hysteria") is exemplified by two BZ-intoxicated individuals who would take turns smoking an imaginary cigarette clearly visible to both of them but to no one else.[15] [Clarification] When one observed subject mumbled, "Gotta cigarette?" His delirious companion held out an invisible pack, he followed with, "S'okay, don't wanna take your last one." In another test it was reported two victims of BZ played tennis with imaginary rackets.[16]

Time course of effectsEdit

Clinical effects from ingestion or inhalation of BZ appear after an asymptomatic or latent period that may be as little as 30 minutes, or as long as 20 hours; the usual range is 0.5 to 4 hours, with a mean of 2 hours. However, effects may not appear up to 36 hours after skin exposure to BZ.

Once effects appear, their duration is typically 72 to 96 hours and are dose-dependent. Following an ICt50 of BZ, severe effects may last 36 hours, but mild effects may persist for additional days.

The clinical course from BZ poisoning can be divided into the following four stages:

  1. Onset or induction (zero to four hours after exposure), characterized by parasympathetic blockade and mild CNS effects.
  2. Second phase (4 to 20 hours after exposure), characterized by stupor with ataxia and hyperthermia.
  3. Third phase (20 to 96 hours after exposure), in which full-blown delirium is seen but often fluctuates from moment to moment.
  4. Fourth phase, or resolution, characterized by paranoia, deep sleep, reawakening, crawling or climbing automatisms, and eventual reorientation.

Signs and symptomsEdit

  • Restlessness
  • Dizziness or giddiness
  • Failure to obey orders
  • Confusion
  • Erratic behavior
  • Stumbling or staggering
  • Drymouth (cottonmouth)
  • Tachycardia at rest
  • Elevated temperature
  • Flushing of face
  • Blurred vision
  • Pupillary dilation
  • Slurred or nonsensical speech
  • Hallucinations
  • Disrobing
  • Mumbling
  • Stupor and coma
  • Inappropriate smiling or laughter
  • Irrational fear
  • Distractibility
  • Difficulty expressing self
  • Elevated blood pressure
  • Stomach cramps and vomiting
  • Euphoric, relaxed, unconcerned attitude
  • Hypotension and/or dizziness on sudden standing
  • Tremor
  • Clinging or pleading
  • Seemingly reasonless crying
  • Decrease in disturbance with reassurance

Atropine intoxication from MARK I autoinjector use in a patient not exposed to nerve agents may create similar PNS effects to those seen in BZ intoxication. However, marked confusion from atropine is not normally seen until a total of six or seven autoinjectors have been given (in a hot, dehydrated, or battle-stressed individual, less atropine would probably suffice). Circumstantial evidence may be helpful in this situation. Heat stroke may also generate hot, dry, and confused or stuporous casualties and needs to be considered in the differential diagnosis. Patients with anxiety reactions are usually oriented to time, place, and person but may be trembling, crying, or otherwise panicked. The classic picture of unconcern or "la belle indifférence" may characterize a patient with a conversion reaction, but these patients are also likely to be oriented and lack the anticholinergic PNS signs of BZ poisoning.

Medical managementEdit

The admonition to protect oneself first may be difficult when dealing with any intoxication involving a latent period, since initially asymptomatic exposure to health care providers may already have occurred during the same time frame in which patients were exposed. Protection of medical staff from already absorbed and systemically distributed BZ in a patient is not needed.

General supportive management of the patient includes decontamination of skin and clothing (ineffective for already absorbed agent but useful in preventing further absorption of any agent still in contact with the patient), confiscation of weapons and related items from the patient, and observation. Physical restraint may be required in moderately to severely affected patients. The greatest risks to the patient's life are (1) injuries from his or her own erratic behavior (or from the behavior of similarly intoxicated patients) and (2) hyperthermia, especially in patients who are in hot or humid environments or are dehydrated from overexertion or insufficient water intake. A severely exposed patient might be comatose with serious cardiac arrhythmias and electrolyte disturbances. Management of heat stress assumes a high priority in these patients. Because of the prolonged time course in BZ poisoning, consideration should always be given to evacuation to a higher echelon of care.

As a competitive inhibitor of acetylcholine, BZ effectively decreases the amount of acetylcholine "seen" by postsynaptic and postjunctional receptors throughout the body. Specific antidotal therapy in BZ poisoning is therefore geared toward raising the concentration of acetylcholine in these synapses and junctions. Any compound that causes a rise in acetylcholine concentration can potentially overcome BZ-induced inhibition and restore normal functioning; even the nerve agent VX has been shown to be effective when given under carefully controlled conditions. The specific antidote of choice in BZ poisoning is the carbamate anticholinesterase physostigmine (eserine; Antilirium), which temporarily raises acetylcholine concentrations by binding reversibly to anticholinesterase on the postsynaptic or postjunctional membrane. Physostigmine is similar in many ways to pyridostigmine and is equally effective when used as a pre-exposure antidotal enhancer ("pretreatment") in individuals at high risk for subsequently encountering soman. However, physostigmine is not used for this purpose because the doses required cause vomiting through CNS mechanisms. In the case of BZ poisoning, a nonpolar compound such as physostigmine is used specifically because penetration into the brain is required in those individuals who already have CNS effects from BZ.

In BZ-intoxicated patients, physostigmine is minimally effective during the first four hours after exposure but is very effective after four hours. Oral dosing generally requires one and a half times the amount of antidote as does IM or IV administration. However, effects from a single intramuscular injection of physostigmine last only about 60 minutes, necessitating frequent re-dosing. It must be emphasized that physostigmine does not shorten the clinical course of BZ poisoning and that relapses will occur if treatment is discontinued prematurely. The temptation to substitute a slow intravenous infusion for intramuscular injections should be tempered by the awareness that IV infusion may lead to nerve-agent-like bradycardia, and too rapid infusion might cause arrhythmias, excessive secretions (to the point of compromising air exchange), and convulsions. Moreover, the sodium bisulfite in commercially available preparations of physostigmine may cause life-threatening allergic responses.

History and toxicity of physostigmineEdit

The antagonism between physostigmine (the elixir of calabar bean) and atropine (tincture of belladonna) was first reported in 1864 by a physician who successfully treated prisoners who had become delirious after drinking tincture of belladonna. Physicians did not notice this report until the 1950s when atropine coma (in which 50 mg or so of atropine were given to certain psychiatric patients) was successfully treated with physostigmine after the "therapeutic benefit" had been attained. Again, this went unnoticed until a controlled study, reported in 1967, indicated that anticholinergic intoxication could be successfully, albeit transiently, reversed by physostigmine.

The administration of physostigmine by the IV route in a delirious but conscious and otherwise healthy patient is not without peril. It is sometimes difficult to keep a delirious patient quiet long enough to administer the drug (at 1 mg/min is the marketed solution of 1 mg/ml). Even if administered correctly (very slowly), the heart rate may decline from 110 to 45 beat/min over a period of 1 to 2 minutes. The difference in the onset of the effects after IM and IV administration of physostigmine is a matter of only several minutes. Since its use is rarely lifesaving, this slight difference in time of response is inconsequential.

Physostigmine is a safe and effective antidote if used properly. In a conscious and delirious patient it will produce very effective but transient reversal of both the peripheral and central effects of cholinergic blocking compounds. Its use by the IV route is not without hazards. It absolutely should NOT be used in a patient with cardiorespiratory compromise, hypoxia, or acid-base imbalance with a history of seizure disorders or arrhythmias.

TriageEdit

An immediate casualty (possible but unlikely) would be one with cardiorespiratory compromise or severe hyperthermia.

The delayed casualty would present with pronounced or worsening anticholinergic signs.

A minimal casualty from a strictly medical standpoint might have mild PNS or CNS anticholinergic effects.

An expectant casualty (also possible but unlikely) would have severe cardiorespiratory compromise in a situation in which treatment or evacuation resources are too limited to allow the necessary attention to be directed to him or her.

ChemistryEdit

Preparation of 3-quinuclidone (c.f. quinuclidine) has been documented.[17]

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The last step of the procedure appears to be a Dieckmann cyclization (intramolecular Claisen condensation) followed by decarboxylation.

Additionally, benzilic acid is made in a few steps starting from benzaldehyde and cyanide catalyst.

3-Quinuclidone is a drug precursor for medicinal (neuroprotective) as well as military applications, c.f. PNU-282,987.

ReferencesEdit

  1. 1.0 1.1 QNB: Incapacitating Agent. Emergency Response Safety and Health Database. National Institute for Occupational Safety and Health. Accessed April 20, 2009.
  2. Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants. (1984)
  3. Ketchum - Chemical Warfare: Secrets Almost Forgotten (2006)
  4. 4.0 4.1 4.2 4.3 4.4 Kirby, Reid. "Paradise Lost: The Psycho Agents", The CBW Conventions Bulletin, May 2006, Issue no. 71, pp. 2-3, accessed December 11, 2008.
  5. Iraqi `zombie gas' arsenal revealed
  6. Template:Cite report
  7. 7.0 7.1 Jeffrey Lewis. Why everyone's wrong about Assad's zombie gas. Foreign Policy. URL accessed on 28 January 2013.
  8. Intelligence Update: Chemical Warfare Agent Issues
  9. includeonly>Rogin, Josh. "Secret State Department cable: Chemical weapons used in Syria", 15 January 2013. Retrieved on 16 January 2013.
  10. includeonly>"U.S. plays down media report that Syria used chemical weapons", Reuters, 16 January 2013. Retrieved on 28 January 2013.
  11. Army’s Hallucinogenic Weapons Unveiled
  12. MILITARY OPERATIONS ASPECTS OF SHAD AND PROJECT 112 page 4: http://fhp.osd.mil/CBexposures/pdfs/oct9h02.pdf
  13. US Army FM 3-9
  14. * Goodman E (2010). Ketchum J, Kirby R Historical Contributions to the Human Toxicology of Atropine, 120, Eximdyne.
  15. Medical Management of Chemical Casualties
  16. CBRNE - Incapacitating Agents, Agent 15
  17. Template:OrgSynth

External linksEdit

Template:US Army

Template:U.S. chemical weapons Template:Chemical warfare



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