Inhalants

Inhalants are solvents or volatile anesthetics that are subject to abuse by inhalation. Most are central nervous system (CNS) depressants, but some are convulsants. As a class they are characterized by high vapor pressure and significant solubility in fat at room temperature. Vapors and gases have been inhaled since ancient times for religious or other purposes, as at the oracle at Delphi. Experimentation with inhalants did not occur to any significant extent until after the discovery of nitrous oxide and the search for volatile anesthetics commenced in earnest. Arguably the most toxic of abused substances, inhalants can produce a wide range of injuries, depending on the chemical constituents of what is inhaled. Many are very complex mixtures formulated for a specific purpose, or are used because they are the least expensive alternative, or both. Thus their purity and safety are in no way comparable with those achieved by pharmaceutical companies manufacturing medications for human consumption.

Inhalants are typically abused by achieving a high airborne concentration of a substance and deliberately inhaling it. With solvents, this typically involves putting the solvent in a closed container, or saturating a piece of cloth and inhaling through it. Compressed gases are sometimes released into balloons and inhaled; directly releasing these substances into the mouth may freeze the larynx, causing laryngospasm and death by asphyxiation. Once the chemical is inhaled, its uptake and duration of action are determined by its solubility in blood and brain, and by the respiratory rate and cardiac output.

The mechanism of action of this class of agents is less well understood than those of other drugs and medications. As CNS depressants, they have been thought to exert their actions by dissolving in membranes and altering their function in a nonspecific way; the potency of these compounds is frequently related to their solubility in membranes. Many consider this relationship to better predict the access of the agent to the site of action, and to be unrelated to the mechanism by which the solvents exert their effects. Solvents impair conduction in isolated nerves, and affect nerves with smaller diameters first. This suggests that parts of the nervous system such as the cortex would be affected before systems consisting of large fibers. There is significant interest in the GABA receptor complex as the site of action of many of these compounds. There is not yet evidence for specific interactions with a receptor, in the sense of a "lock and key" mechanism. However, these agents may "lubricate" or "obstruct" such mechanisms.

Although inhalant abuse has been implicated in a variety of organic diseases, its effects on the nervous system have been of the greatest concern. Such injuries range from paralysis and loss of bowel and bladder control, to permanent impairment of the higher cognitive functions and fine motor control. Those who become involved in inhalant abuse vary across culture and, as in many other types of drug abuse, the vulnerability to becoming dependent on these substances may depend on present economic well-being and perceptions of the possibility of future well-being. Their ability to act as a reward has been demonstrated in laboratory animals, so there is no doubt that they exert powerful actions on the nervous system. Preventive actions are of two types: education about the adverse effects of solvents on bodily function, and the possible formulation of consumer products with less intrinsic toxicity. Some manufacturers have attempted to minimize the abuse of their products by adulterating them with irritants. Intervention strategies for those habitually using inhalants are not different from those employed for other CNS depressant dependence disorders. Frank withdrawal symptoms are rarely seen with organic solvents. They do, however, accumulate under some conditions of use, and can be associated with prolonged delirium and behavioral disturbances.

ALKANES

Alkanes are hydrocarbons of the general formula CnH2n+2;. The potency of this family of straight-chain chemicals increases with the number of carbons. The smaller molecules (methane, ethane, butane, propane) are gases at room temperature; their deliberate inhalation produces cardiac arrhythmias and sudden death. Pentane, hexane, and longer alkanes are liquids that become progressively less volatile. Hexane produces a devastating neurotoxicity. Alkanes are paraffins; cycloparaffins are rings without alternating double bonds; and alkylcycloparaffins have a short substituent on the ring. Alkylcycloparaffins such as methylcyclopentane and methylcyclohexane (hexahydrotoluene) are convulsants.

AMYLNITRITE

Amyl nitrite is a volatile, oily liquid with a sweet, banana-like odor. It is sold by prescription in glass ampules for the treatment of angina pectoris, chest pain caused by the narrowing of vessels in the heart. When the glass ampules are broken, they "pop"; hence they are sometimes called "poppers." Amyl nitrite relaxes the vessels of the heart by relaxing the muscles of the veins as well as all other smooth muscles in the body. When the veins throughout the body dilate, blood pressure falls. Because a minimum blood pressure is required to maintain blood supply to vital organs such as the brain, a reflex protects the brain by increasing heart rate and blood flow. This produces a "rush" as the heart pounds, and there is a throbbing sensation in the head. Users also experience a warm flush as the blood accumulates near the skin because of the dilation of veins. Vision also may "redden" as the retinal vessels dilate. The user may faint if the heart cannot maintain blood flow to the brain. If this occurs, the user falls to the floor, and blood flows to the brain, restoring consciousness. Use in a situation where it is impossible to become horizontal may result in brain damage.

The duration of action of the drug is very brief, and as the effect wears off, the user may experience headache, nausea, vomiting, and a chill. The drop in body temperature occurs because of the loss of heat when the veins dilate and the skin flushes. Use of the drug for prolonged periods, or swallowing the liquid, may produce fatal methemoglobinemia, a "chocolate" blood condition in which the blood is brown and cannot carry oxygen to the brain. The drug produces a thick, crusty brown rash if it is spilled on the skin, and is irritating to the lungs. It is flammable and explosive. Volatile nitrites are converted to nitrosamines in the body, and most nitrosamines are very potent cancer-causing chemicals. There is an association of the use of volatile nitrites with Kaposi's sarcoma, an AIDS-related skin cancer. Volatile nitrites impair the function of the immune system. The physiology of sexual intercourse involves smooth muscle; the nitrites relax those muscles as well and so will affect sexual function.

The prescription requirement for amyl nitrite was eliminated in 1960, and its use became popular; in 1964 prescription requirements were reestablished. "Designer" nitrites, such as butyl and isobutyl nitrites, were then bottled and sold as "room deodorizers" with such names as RUSH, Locker Room, and Aroma of Men, so named because it smelled like a locker room. Since these products were not controlled substances or sold as medicines, they were once legal products.

ANESTHETICS

Anesthetics are used in medicine to permit surgical procedures without pain or consciousness. They are of two types: local and general. A local anesthetic is usually injected near nerves to prevent pain in a limited area, such as a Novocaine injection to anesthetize a tooth. General anesthetics are administered to the whole body and depress the CNS to such an extent that major surgery can be performed without killing the patient from the shock resulting from procedures that otherwise would be unendurable. General anesthetics were developed in the mid-nineteenth century by doctors experimenting, usually on themselves, with the organic solvents available at the time. These experiments were sometimes done by groups of people who inhaled the vapors and described the effects, or passed out. Later, careful experimental work identified volatile chemicals that are used to save lives by permitting surgery that would otherwise be impossible to perform, and that are safe to use and have relatively low toxicity.

Some anesthetics can be given by injection. Short-acting anesthetics are used for brief procedures in medicine and dentistry where inhalation anesthesia is inappropriate or difficult, or for starting anesthesia before longer-acting agents are given to the patient. Drugs used for this purpose include barbiturates such as sodium methohexital and sodium thiopental, and benzodiazepines such as midazolam. Fentanyl and related compounds are used for a longer duration of action. A dissociative anesthetic, ketamine, is used for treating burn patients and small children. These agents affect the brain in a more selective way than other anesthetics, so that there is more muscle tone and better circulation in the head and neck. A related veterinary drug, phencyclidine (PCP), has a longer duration of action; when given to humans, however, it has produced terrifying hallucinations upon recovery. It is subject to abuse.

VOLATILE ANESTHETICS

Volatile anesthetics induce unconsciousness and loss of reflexes for surgical procedures. This CNS depression can be induced by a wide variety of different chemicals; those used in clinical medicine are selected for reasons that include low toxicity, ease of maintaining and adjusting a given depth of anesthesia, and freedom from adverse effects upon recovery. Many compounds were examined in the search for modern anesthetic agents.

The depth of anesthesia depends on how much of the medication is present in the CNS. This in turn depends on how much is in the air, to what extent the anesthetic passes between air and blood, and how much passes from blood to brain (or fat, since the brain is largely fat). An agent that is highly insoluble in blood achieves a plateau, or saturation, concentration very rapidly; an example is nitrous oxide. More soluble agents take a longer time to come to plateau, and take a longer time to be exhaled as well, so recovery from them takes longer. Nitrous oxide and cyclopropane have the same solubility in blood, and take the same amount of time to come to a steady concentration in blood; cyclopropane is more soluble in brain and fat, however, so it takes a much lower concentration to achieve the same effect. (Cycloproane is explosive, and therefore is not used in the operating room.) The way an anesthetic functions in a given individual depends on a number of variables, including the amount of fat in the individual's body, the volume of air inspired per minute, the amount of blood pumped through the lungs per minute, and various preexisting medical conditions.

AROMATIC HYDROCARBON SOLVENTS

Aromatic hydrocarbon solvents have a structure that includes a benzene ring. The simplest form is benzene, a six-membered ring with double bonds and six hydrogen atoms. All other aromatic hydro-carbons have alkyl substituents around the ring; for example, toluene has one methyl group and xylene has two methyl groups.

BENZENE

Benzene is a volatile aromatic hydrocarbon (see above). Its presence in consumer products and in the workplace has been reduced because it causes a form of leukemia. Its chemical formula is C6H6; it is a six-membered ring with alternating double bonds and a hydrogen on each carbon. The ring opens when metabolized, causing the formation of reactive and toxic chemicals. Benzine, a name applied to automotive fuel in Europe, is a solvent mixture.

BLACK JACK

This is a trade name for several inhalant products that contain either volatile nitrites or ethyl chloride.

CHLORINATED HYDROCARBONS

These substances comprise a large class of industrial chemicals. Those which are highly volatile are sometimes subject to abuse. Chlorinated hydro-carbons undergo significant metabolism in the body, and these changes in chemical structure usually result in an increase of the solvent's toxicity. Because many of these metabolic products are reactive chemicals, they can produce injuries to the kidneys, the liver, and the blood-forming organs. Chlorinated hydrocarbon inhalation is also associated with lethal disorders of heart rhythm, ventricular arrhythmias.

CHLOROFLUOROCARBON PROPELLANTS

Halogenated hydrocarbons are relatively nonreactive chemicals with very high vapor pressure that have been used to blow products out of containers through a tiny hole. Their widespread use in the early 1960s was followed by an epidemic of aerosol sniffing that led to cardiac arrhythmias and death among young people. The halogens—chlorine, fluorine, and bromine—are used to make various chemicals for purposes ranging from propellants and refrigerants to fire extinguishers. Their use has been severely limited since the recognition that their release into the atmosphere depletes the upper layers of ozone, exposing the earth to excessive amounts of ultraviolet radiation. Freon is a brand name for a family of commercial products.

CHLOROFORM

Chloroform, CHCl3, was one of the earliest solvents put to use as an anesthetic agent. It has been replaced with agents that are much less toxic. Its use in cough and cold medications is obsolete. Chloroform was widely abused in the nineteenth century.

ETHYL CHLORIDE

This is a local anesthetic, CNS depressant, and refrigerant that has been subject to abuse by inhalation. Ethyl chloride has a very high vapor pressure, and spraying it directly into the mouth may freeze the tissues of the throat and cause fatal laryngospasm (contraction of the muscles of the throat and larynx), and the shutoff of air to the lungs. Ethyl chloride has been sold in canisters and spray cans (e.g., Black Jack). A related chemical, methyl chloride, has similar effects and was used in refrigerators until it was recognized as highly poisonous in closed spaces.

ETHYL ETHER

A volatile anesthetic agent subject to abuse by inhalation, ethyl ether was used as an inhalation anesthetic for many years. It has been supplanted by other agents with fewer recovery side effects, such as headache, nausea, and vomiting. It is explosive. Ethyl ether was drunk during the Whiskey Rebellion of the eighteenth century, when heavy taxes were imposed on whiskey. Consumed by this route, ether "tanned" (hardened dramatically) the soft palate. When swallowed, profound intoxication follows, but recovery is faster than from alcohol. Alcohol is metabolized at a fixed number of grams per hour, except under extreme conditions; ethyl ether is eliminated by exhalation.

FREON

Freon is a brand name applied to a class of aerosol propellants. See Chlorofluorocarbon Propellants, above.

GASOLINE

Gasoline, a fuel that powers internal combustion engines, is a complex petroleum product that is subject to abuse by inhalation. The toxicity produced from gasoline exposure depends on the constituents of the mixture and the route of administration. Oral ingestion of gasoline is usually followed by vomiting; subsequent aspiration of gasoline liquid into the lungs is followed by a frequently fatal chemical pneumonia. Deliberate inhalation of leaded gasoline fumes can lead to brain injury related to absorption of tetraethyl lead, a very toxic chemical.

GLUE

Glues are made by dissolving a sticky or adhesive material in a solvent. When the solvent evaporates, the adhesive material remains attached to the surfaces to which it is applied, sticking them together. Glues are complex mixtures formulated for specific purposes. They are not designed for human consumption. When inhaled, they may produce severe injury or death. Most of the solvents used in glues are flammable, and fires have resulted from their inappropriate use. The solvent mixtures in glues and glue thinners are designed to dissolve the solid glue material and to evaporate evenly at a rate appropriate for the product. Solvents of relatively low industrial purity are used in these products; they are usually complex mixtures whose formulation changes with market price. Their toxicity can be great when concentrated and inhaled. Some manufacturers label their products or add irritants in an attempt to dissuade youths from deliberately inhaling these products.

HEXANE

Hexane is a volatile solvent that contains six carbons in a straight chain and has the chemical formula C6H14. It can cause severe damage to the peripheral nervous system, producing death of the long myelinated nerves (distal axonopathy). This condition results in an inability to walk, loss of muscle mass in all limbs, and sometimes loss of bowel and bladder control. This injury occurs because hexane is metabolized to a gamma-diketone. Another solvent subject to abuse that undergoes the same change in the body is methylbutylketone.

NITROUS OXIDE

Nitrous oxide is a volatile analgesic and anesthetic agent. It was discovered at the beginning of the nineteenth century by Sir Humphry Davy, who was looking for gases and vapors that might have some therapeutic use. Nitrous oxide quickly produces an inebriation that many found pleasurable, and it rapidly became the subject of much experimentation and merrymaking. Nitrous oxide parties became very fashionable, but could not long be limited to the upper classes. Popular demonstrations were conducted, and at one such demonstration Horace Wells noticed that a participant had injured his leg, yet seemed oblivious to the pain. Although Davy had noted that nitrous oxide deadened the pain of his toothaches, it was Wells who underwent the first tooth extraction using nitrous oxide for pain relief. The first widespread use of nitrous oxide for clinically significant pain relief was its use in childbirth by S. Klikovich. Nitrous oxide inhalation is about as effective as 30 mg of morphine for pain relief.

Nitrous oxide is not very soluble in either blood or brain tissue, and consequently it has a short duration of action and requires very high levels to produce effects, on the order of 15 to 30 percent by volume. Because the use of gases at this high a concentration might result in asphyxiation, special equipment is used to guard against this possibility in medical settings. Because it displaces oxygen, nitrous oxide frequently kills those who inhale it for pleasure in closed rooms or automobiles.

Nitrous oxide was long thought to be a relatively innocuous anesthetic, almost as safe as inert gases. Recent work has demonstrated, however, that its inhalation irreversibly inactivates methionine synthetase, and this enzyme inhibition produces a vita-min deficiency that can injure the peripheral nervous system. This was first observed in dentists and others with access to nitrous oxide and who inhaled it habitually. This nervous system injury is associated with numbness and clumsiness of the hands, and with Lhermitte's sign, a lightning-like shooting sensation that occurs when the patient bends the neck.

Nitrous oxide is used in dentistry because it has both analgesic and anxiety-relieving properties. It is used as a carrier gas and inducing agent in major surgery, facilitating induction of anesthesia maintained by other agents. Because it is not very soluble in blood, oxygen must be provided to patients at the end of the surgery, because the nitrous oxide can displace oxygen as it rushes out of the patient's body (diffusion hypoxia).

PERCHLOROETHYLENE

This chlorinated hydrocarbon solvent, used in the dry-cleaning industry, is also known as PERC (see Chlorinated Hydrocarbons, above).

TOLUENE

Toluene (methyl benzene, toluol) is an aromatic hydrocarbon solvent widely used in industrial processes, fuels, and consumer products. It is among the least irritating of the aromatic hydrocarbon solvents. When inhaled, it can produce CNS depression, like alcohol and other solvents. Its pharmacologic effects resemble those of other CNS depressant drugs, displaying actions like those of medications used for the treatment of epilepsy or for the clinical management of anxiety.

Toluene is removed from the body by exhalation and by metabolism. It is metabolized to methylhippuric acid, and is excreted by the kidneys. Overexposure to toluene can produce distal tubular acidosis of the kidney, an injury attributable to excess acidity that is reversible upon termination of exposure. Toluene has been demonstrated to produce loss of high-frequency hearing in laboratory animals following repeated high exposure, such as occurs during solvent abuse. Toluene also has been implicated in severe injuries to the nervous system in a large number of patients who deliberately inhaled toluene-containing solvents. These injuries are characterized by injury and loss of brain tissue. Patients display flattened emotional responses, impaired cognitive abilities, and a wide, shuffling gait associated with injury to the cerebellum. Animal studies have not yet conclusively demonstrated that toluene alone is responsible for this severe brain injury syndrome; nonetheless, solvent abusers who inhale toluene-containing mixtures run a very high risk of irreversible brain injury.

1, 1, 1 TRICHLOROETHANE (TCE)

This is a chlorinated hydrocarbon solvent with very high vapor pressure. It is useful in products that need to dry quickly, such as liquid paper products used to cover errors. The deliberate inhalation of these products has been associated with sudden death from ventricular arrhythmias (see Chlorinated Hydrocarbons, above).

TRICHLOROETHYLENE

A chlorinated hydrocarbon solvent used as a degreaser and dry-cleaning agent, it is subject to abuse by inhalation. When alcohol is consumed after exposure to trichloroethylene, profound blushing of the face occurs, the "degreaser's flush." One of the metabolites of trichloroethylene is chloral hydrate, an anesthetic agent used in "Mickey Finns," drinks used criminally to anesthetize robbery victims.

WHIPPETS

Whippets are small canisters of nitrous oxide used at soda fountains to make whipped cream. They have been incorporated into various products, such as balloon inflators, "carburetor pipes," and other drug paraphernalia (see Nitrous Oxide, above).

(SEE ALSO: Complications; Ethnicity and Drugs; High School Senior Survey; Inhalants: Extent of Use and Complications)

RONALD W. WOOD