"QNB" redirects here. For the spoof amateur radio

Amateur radio

Amateur radio is the use of designated radio frequency spectrum for purposes of private recreation, non-commercial exchange of messages, wireless experimentation, self-training, and emergency communication...

 Q code

Q code

The Q code is a standardized collection of three-letter message encodings, also known as a brevity code, all of which start with the letter "Q", initially developed for commercial radiotelegraph communication, and later adopted by other radio services, especially amateur radio...

, see QNB (amateur radio).

3-quinuclidinyl benzilate (QNB, BZ, EA-2277), IUPAC name 1-azabicyclo[2.2.2]Oct-3-yl α-hydroxy-α-phenylbenzeneacetate, is an odorless military incapacitating agent

Incapacitating agent

The term incapacitating agent is defined by the U.S. Department of Defense asLethal agents are primarily intended to kill, but incapacitating agents can also kill if administered in a potent enough dose, or in certain scenarios....

. Its NATO code is BZ. The Iraq

Iraq

Iraq ; officially the Republic of Iraq is a country in Western Asia spanning most of the northwestern end of the Zagros mountain range, the eastern part of the Syrian Desert and the northern part of the Arabian Desert....

i incapacitating agent Agent 15 is believed either to be the same as or similar to BZ.

BZ is a glycolate anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

 compound related to atropine

Atropine

Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...

, scopolamine

Scopolamine

Scopolamine, also known as levo-duboisine, and hyoscine, is a tropane alkaloid drug with muscarinic antagonist effects. It is among the secondary metabolites of plants from Solanaceae family of plants, such as henbane, jimson weed and Angel's Trumpets , and corkwood...

, hyoscyamine

Hyoscyamine

Hyoscyamine is a tropane alkaloid. It is a secondary metabolite found in certain plants of the Solanaceae family, including henbane , mandrake , jimsonweed , tomato and deadly nightshade...

, and other deliriant

Deliriant

The deliriants are a special class of acetylcholine-inhibitor hallucinogen. The term was introduced by David F. Duncan and Robert S...

s. Dispersal would be as an aerosolized solid (primarily for inhalation) or as agent dissolved in one or more solvents for ingestion or percutaneous

Percutaneous

In surgery, percutaneous pertains to any medical procedure where access to inner organs or other tissue is done via needle-puncture of the skin, rather than by using an "open" approach where inner organs or tissue are exposed .The percutaneous approach is commonly used in vascular procedures...

 absorption.

Acting as a competitive inhibitor of acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 at postsynaptic and postjunctional muscarinic receptor sites in smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

, exocrine gland

Exocrine gland

Exocrine glands are a type of ductal glands that secrete their products into ducts that lead directly into the external environment...

s, autonomic ganglia, and the brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

, BZ decreases the effective concentration of acetylcholine seen by receptors at these sites. Thus, BZ causes PNS

Peripheral nervous system

The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...

 effects that in general are the opposite of those seen in nerve agent

Nerve agent

Nerve agents are a class of phosphorus-containing organic chemicals that disrupt the mechanism by which nerves transfer messages to organs...

 poisoning. CNS

Central nervous system

The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 effects include stupor

Stupor

Stupor is the lack of critical cognitive function and level of consciousness wherein a sufferer is almost entirely unresponsive and only responds to base stimuli such as pain. This is often mistaken for delirium and treated with Haldol and or other anti-psychotic drugs...

, confusion

ConFusion

ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...

, and confabulation

Confabulation

Confabulation is the process in which a memory is remembered falsely. Confabulations are indicative of a complicated and intricate process that can be led astray at any given point during encoding, storage, or recall of a memory. Two distinct types of confabulation are often distinguished...

 with concrete and panoramic illusion

Illusion

An illusion is a distortion of the senses, revealing how the brain normally organizes and interprets sensory stimulation. While illusions distort reality, they are generally shared by most people....

s and hallucination

Hallucination

A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...

s, and with regression to automatic "phantom" behaviors such as plucking and disrobing.

Physostigmine

Physostigmine

Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....

, which increases the concentration of acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 in synapses and in neuromuscular and neuroglandular junctions, is a specific antidote

Antidote

An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

.

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

Chemical Weapons Convention

The Chemical Weapons Convention is an arms control agreement which outlaws the production, stockpiling and use of chemical weapons. Its full name is the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction...

.

Background

Following World War II

World War II

World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...

, the United States

United States

The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 military investigated a wide range of possible nonlethal, psychobehavioral chemical incapacitating agents to include psychedelic

Psychedelic

The term psychedelic is derived from the Greek words ψυχή and δηλοῦν , translating to "soul-manifesting". A psychedelic experience is characterized by the striking perception of aspects of one's mind previously unknown, or by the creative exuberance of the mind liberated from its ostensibly...

 indole

Indole

Indole is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Compounds that contain an...

s such as lysergic acid diethylamide

LSD

Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...

 (LSD-25) and marijuana

Cannabis (drug)

Cannabis, also known as marijuana among many other names, refers to any number of preparations of the Cannabis plant intended for use as a psychoactive drug or for medicinal purposes. The English term marijuana comes from the Mexican Spanish word marihuana...

 derivatives, certain tranquilizers like ketamine

Ketamine

Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...

 or fentanyl, as well as several glycolate anticholinergics. Copious amounts of phencyclidine

Phencyclidine

Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...

 are also documented as having been tested on active military personnel, such as in the Edgewood Arsenal experiments

Edgewood Arsenal experiments

The Edgewood Arsenal experiments are said to be related to or part of CIA mind-control programs after World War II, such as MKULTRA. Journalist Linda Hunt, citing records from the U.S...

.

History

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. The company was investigating anti-spasmodic agents, similar to Tropine

Tropine

Tropine is a derivative of tropane containing a hydroxyl group at third carbon. It is also called 3-tropanol.Benzatropine and etybenzatropine are derivatives of tropine. It is also a building block of atropine, a cholinergic drug prototypical of the muscarinic antagonist class.-External Links:*...

, for treating gastrointestinal issues when the chemical was discovered. In 1959 the United States Army

United States Army

The United States Army is the main branch of the United States Armed Forces responsible for land-based military operations. It is the largest and oldest established branch of the U.S. military, and is one of seven U.S. uniformed services...

 began to show interest in using the chemical as a chemical warfare agent. The agent was originally designated TK but when it was standardized by the U.S. Army in 1961 it was designated BZ. The agent commonly became known as "Buzz" because of this abbreviation and the effects it had on the mental state of its casualties.

Military use

In February 1998, the British

United Kingdom

The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

 Ministry of Defence

Ministry of Defence (United Kingdom)

The Ministry of Defence is the United Kingdom government department responsible for implementation of government defence policy and is the headquarters of the British Armed Forces....

 accused Iraq

Iraq

Iraq ; officially the Republic of Iraq is a country in Western Asia spanning most of the northwestern end of the Zagros mountain range, the eastern part of the Syrian Desert and the northern part of the Arabian Desert....

 of having stockpiled large amounts of a glycolate anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

 incapacitating agent known as Agent 15. 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

Gulf War

The Persian Gulf War , commonly referred to as simply the Gulf War, was a war waged by a U.N.-authorized coalition force from 34 nations led by the United States, against Iraq in response to Iraq's invasion and annexation of Kuwait.The war is also known under other names, such as the First Gulf...

. The combination of anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

 PNS

Peripheral nervous system

The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...

 and CNS

Central nervous system

The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 effects aids in the diagnosis of patients exposed to these agents.

Also in 1998, there were allegations that elements of the Bosnian Army used incapacitating agents, inherited from Yugoslav People's Army

Yugoslav People's Army

The Yugoslav People's Army , also referred to as the Yugoslav National Army , was the military of the Socialist Federal Republic of Yugoslavia.-Origins:The origins of the JNA can...

 arsenal, against two Serb-held suburbs of Sarajevo, Ilidza and Nedarici. Physical evidence of BZ use in Bosnia

Bosnia and Herzegovina

Bosnia and Herzegovina , sometimes called Bosnia-Herzegovina or simply Bosnia, is a country in Southern Europe, on the Balkan Peninsula. Bordered by Croatia to the north, west and south, Serbia to the east, and Montenegro to the southeast, Bosnia and Herzegovina is almost landlocked, except for the...

 is unsupported, however.

Sources other than military

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

Pharmacology

Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

 as a muscarinic receptor antagonist

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

.

Physiochemical characteristics

BZ is odorless. It is stable in most solvents, with a half-life

Half-life

Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 of three to four weeks in moist air; even heat-producing munitions can disperse it. It is extremely persistent

Persistence

Persistence may refer to:* Image persistence, in LCD monitors* Multidrug tolerance, a dormant, persistent state of a bacterial population* Persistence , the characteristic of data that outlives the execution of the program that created it...

 in soil

Soil

Soil is a natural body consisting of layers of mineral constituents of variable thicknesses, which differ from the parent materials in their morphological, physical, chemical, and mineralogical characteristics...

 and water

Water

Water is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...

 and on most surfaces. It is slightly soluble in water; soluble in dilute acids, trichloroethylene

Trichloroethylene

The chemical compound trichloroethylene is a chlorinated hydrocarbon commonly used as an industrial solvent. It is a clear non-flammable liquid with a sweet smell. It should not be confused with the similar 1,1,1-trichloroethane, which is commonly known as chlorothene.The IUPAC name is...

, dimethylformamide

Dimethylformamide

Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...

, most organic solvents, insoluble with aqueous alkali.

Detection and protection

BZ is odorless and nonirritating with delayed symptoms several hours after contact. 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.

Toxicokinetics

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

Solvent

A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution that is soluble in a certain volume of solvent at a specified temperature...

 such as DMSO

Dimethyl sulfoxide

Dimethyl sulfoxide is an organosulfur compound with the formula 2SO. This colorless liquid is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water...

 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

Propylene glycol

Propylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound with formula C3H8O2 or HO-CH2-CHOH-CH3...

 yields, after a latent period of up to 24 hours, serum

Blood plasma

Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

 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

Blood-brain barrier

The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 confers upon it the ability to cause CNS effects. Atropine

Atropine

Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...

 and hyoscyamine

Hyoscyamine

Hyoscyamine is a tropane alkaloid. It is a secondary metabolite found in certain plants of the Solanaceae family, including henbane , mandrake , jimsonweed , tomato and deadly nightshade...

 both cross the placenta

Placenta

The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...

 and can be found in small quantities in breast milk

Breast milk

Breast milk, more specifically human milk, is the milk produced by the breasts of a human female for her infant offspring...

; whether this is also true for BZ is unclear.

Metabolism

Metabolism

Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...

 of BZ would be expected to occur primarily in the liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, with elimination of unchanged agent and metabolites chiefly in the urine

Urine

Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

.

Toxicity

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

LD50

In toxicology, the median lethal dose, LD50 , LC50 or LCt50 of a toxin, radiation, or pathogen is the dose required to kill half the members of a tested population after a specified test duration...

 is often estimated to be around 3,800 - 41,300 mg·min/m³.

Toxicodynamics (mechanism of action)

The agent BZ and other anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

 glycolates act as competitive inhibitors of the neurotransmitter acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

 neurons (1) at postjunctional muscarinic

Muscarine

Muscarine, L--muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested...

 receptors in cardiac and smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

 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

Agonist

An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...

 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 effects

Peripheral effects:

• Mydriasis
  Mydriasis
  Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...
  
  , blurred vision
  Blurred vision
  -Causes:There are many causes of blurred vision:* Use of atropine or other anticholinergics* Presbyopia -- Difficulty focusing on objects that are close. The elderly are common victims....
  
  
• Dry mouth, skin
• Initially rapid heart rate
  Tachycardia
  Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
  
   declining to normal or slow heart rate over time
• Possible flushing of the skin
  Flushing (physiology)
  For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
  
  

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

Atropine

Atropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...

. 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

Xerostomia

Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...

 (dry mouth), thirst

Thirst

Thirst is the craving for fluids, resulting in the basic instinct of animals to drink. It is an essential mechanism involved in fluid balance. It arises from a lack of fluids and/or an increase in the concentration of certain osmolites, such as salt...

, and decreased secretions from lacrimal

Lacrimal gland

The lacrimal glands are paired almond-shaped glands, one for each eye, that secrete the aqueous layer of the tear film. They are situated in the upper, outer portion of each orbit, in the lacrimal fossa of the orbit formed by the frontal bone. Inflammation of the lacrimal glands is called...

, 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

Mydriasis

Mydriasis is a dilation of the pupil due to disease, trauma or the use of drugs. Normally, the pupil dilates in the dark and constricts in the light to respectively improve vividity at night and to protect the retina from sunlight damage during the day...

. Similar effects on cholinergic ciliary muscles produce paralysis of accommodation. Other smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

 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

Ataxia

Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...

, 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

Stupor

Stupor is the lack of critical cognitive function and level of consciousness wherein a sufferer is almost entirely unresponsive and only responds to base stimuli such as pain. This is often mistaken for delirium and treated with Haldol and or other anti-psychotic drugs...

 and coma

Coma

In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...

. 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

Memory loss

Memory loss can be partial or total and it is normal when it comes with aging. Sudden memory loss is usually a result of brain trauma and it may be permanent or temporary. When it is caused by medical conditions such as Alzheimers, the memory loss is gradual and tends to be permanent.Brain trauma...

, most notably short-term memory

Short-term memory

Short-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...

. 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

Manner of articulation

In linguistics, manner of articulation describes how the tongue, lips, jaw, and other speech organs are involved in making a sound. Often the concept is only used for the production of consonants, even though the movement of the articulars will also greatly alter the resonant properties of the...

 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

Carphologia

Carphologia is a lint-picking behavior that is often a symptom of a delirious state.Often seen in delirious or semiconscious patients, carphologia describes the actions of picking or grasping at imaginary objects, as well as the patient's own clothes or bed linens...

).

BZ was referenced in the Vietnam War

Vietnam War

The Vietnam War was a Cold War-era military conflict that occurred in Vietnam, Laos, and Cambodia from 1 November 1955 to the fall of Saigon on 30 April 1975. This war followed the First Indochina War and was fought between North Vietnam, supported by its communist allies, and the government of...

 film Jacob's Ladder

Jacob's Ladder (film)

Jacob's Ladder is a 1990 American psychological thriller/horror film directed by Adrian Lyne, based on a screenplay by Bruce Joel Rubin.-Plot:Jacob Singer is a U.S. soldier deployed in the Mekong Delta during the Vietnam War...

, 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 effects

• Disturbances in level of consciousness
  Consciousness
  Consciousness is a term that refers to the relationship between the mind and the world with which it interacts. It has been defined as: subjectivity, awareness, the ability to experience or to feel, wakefulness, having a sense of selfhood, and the executive control system of the mind...
  
  
• Misperceptions and difficulty in interpretation (delusions, hallucinations)
• Poor judgment and insight (denial of illness)
• Short attention span
  Attention span
  Attention span is the amount of time that a person can concentrate on a task without becoming distracted. Most educators and psychologists agree that the ability to focus one's attention on a task is crucial for the achievement of one's goals....
  
  , distractibility, impaired memory (particularly recent)
• Slurred speech
  Manner of articulation
  In linguistics, manner of articulation describes how the tongue, lips, jaw, and other speech organs are involved in making a sound. Often the concept is only used for the production of consonants, even though the movement of the articulars will also greatly alter the resonant properties of the...
  
  , perseveration
• Disorientation
• Ataxia
  Ataxia
  Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
  
  
• Variability (quiet/restless)

Central nervous system

Central nervous system

The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 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

LSD

Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...

.

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 à deux

-Further reading:*Halgin, R. & Whitbourne, S. Abnormal Psychology: Clinical Perspectives on Psychological Disorders. McGraw-Hill. ISBN 0072817216...

, 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. [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.

Time course of effects

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.

Differential diagnosis

The differential diagnosis for irrational and confused patients is a long one and includes anxiety reactions as well as intoxication with a variety of agents, to include hallucinogenic indoles (such as LSD

LSD

Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...

), cannabinoids (such as the delta-9-tetrahydrocannabinol in marijuana), lead, barbiturates, and bromides. All of these conditions can lead to restlessness, lightheadedness (with associated vertigo and ataxia), confusion, and erratic behavior with or without vomiting. Clues that specifically point to BZ or a related compound are the combination of anticholinergic PNS effects with the CNS effects of slurred and monotonous speech, automatic behavior perseveration

Perseveration

Perseveration is the repetition of a particular response, such as a word, phrase, or gesture, despite the absence or cessation of a stimulus, usually caused by brain injury or other organic disorder. If an issue has been fully explored and discussed to a point of resolution, it is not uncommon for...

, disrobing, and phantom behaviors (such as "woolgathering"), and vivid, realistic, describable hallucinations (decreasing in size over time) in a patient slipping into and out of delirium.

Signs and symptoms

• Restlessness
• Dizziness or giddiness
• Failure to obey orders
• Confusion
• Erratic behavior
• Stumbling or staggering
• Drymouth (cottonmouth)
• Tachycardia
  Tachycardia
  Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
  
   at rest
• Elevated temperature
• Flushing of face
• Blurred vision
• Pupillary dilation
• Slurred or nonsensical speech
• Hallucination
  Hallucination
  A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
  
  s
• Disrobing
• Mumbling
• Stupor and coma
  Coma
  In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
  
  
• Inappropriate smiling or laughter
• Irrational fear
• Distractibility
• Difficulty expressing self
• Elevated blood pressure
• Stomach cramps and vomiting
• Euphoric, relaxed, unconcerned attitude
• Hypotension
  Hypotension
  In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
  
   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 management

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

Physostigmine

Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....

 (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

Pyridostigmine

Pyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier, except possibly in stressful conditions.-Mode of action:...

 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 physostigmine

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.

Triage

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.

Chemistry

Preparation of 3-QUINUCLIDONE (c.f. quinuclidine

Quinuclidine

Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair...

) has been documented.
The last step of the procedure appears to be a Dieckmann cyclization (intramolecular Claisen condensation

Claisen condensation

The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone...

) followed by decarboxylation.

Additionally, benzilic acid

Benzilic acid

Benzilic acid is a white crystalline aromatic acid soluble in many primary alcohols. It can be prepared by heating mixture of benzil, alcohol and potassium hydroxide. The other preparation way is through benzaldehyde, which dimerizates to benzil and it is further transformed by benzilic acid...

 is made in a few steps starting from benzaldehyde

Benzaldehyde

Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...

 and cyanide

Cyanide

A cyanide is a chemical compound that contains the cyano group, -C≡N, which consists of a carbon atom triple-bonded to a nitrogen atom. Cyanides most commonly refer to salts of the anion CN−. Most cyanides are highly toxic....

 catalyst.

3-Quinuclidone is a drug precursor for medicinal (neuroprotective) as well as military

Military

A military is an organization authorized by its greater society to use lethal force, usually including use of weapons, in defending its country by combating actual or perceived threats. The military may have additional functions of use to its greater society, such as advancing a political agenda e.g...

 applications, c.f. PNU-282,987

PNU-282,987

PNU-282,987 is a drug that acts as a potent and selective agonist for the α7 subtype of neural nicotinic acetylcholine receptors. In animal studies, it shows nootropic effects, and derivatives may be useful in the treatment of schizophrenia, although PNU-282,987 is not suitable for use in humans...

.

External links

• Erowid - BZ Vault
• Tear Gases and Chemical Agents - Agent BZ
• eMedicine - Incapacitating Agents: 3-Quinuclidinyl Benzilate
• Possible Abuse of BZ by Insurgents in Iraq
• Center for Disease Control - BZ Incapacitating Agent
• Paradise Lost: The Psycho Agents by Reid Kirby
• Department of Defense - Agent BZ use in Hawaii April through June 1966.
• http://www.iprit.ru/chemical_agents/details/3005 - Quinuclidinyl benzilate.