Ethanol also called ethyl alcohol pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid with the structural formula CH3CH2OH, often abbreviated as C2H5OH or C2H6O. A psychoactive drug and one of the oldest recreational drugs known, ethanol produces a state known as alcohol intoxication when consumed as a beverage. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a solvent, and as a fuel. In common usage, it is often referred to simply as alcohol or spirits.
Ethanol is the systematic name defined by the IUPAC nomenclature of organic chemistry for a molecule with two carbon atoms (prefix “eth-“), having a single bond between them (suffix “-ane”), and an attached -OH group (suffix “-ol”).
The term ‘ethyl’ is the Anglicised version of the German word äthyl, which was coined in 1838 by Liebig. It was modeled after the related term ‘methyl’ both terms originate from Greek, and share the segment ‘yl’, which is equivalent to ‘hyle’ meaning stuff. However, the preceding segment differs – ‘eth’, is equivalent to ‘aither’, meaning ether. Thus the word ‘ethyl’ is a contraction of ‘aither hyle’.Liebig used the term ‘ethyl alcohol’ to distinguish between ethanol and other alcohols.
The term “alcohol” now refers to a wider class of substances in chemistry nomenclature, but in common parlance it remains the name of ethanol. Ultimately a medieval loan from Arabic al-kuḥl, use of alcohol in this sense is modern, introduced in the mid 18th century. Before that time, Middle Latin alcohol referred to “powdered ore of antimony; powdered cosmetic”, by the later 17th century “any sublimated substance; distilled spirit” use for “the spirit of wine” (shortened from a full expression alcohol of wine) recorded 1753. The systematic use in chemistry dates to 1850.
Ethanol is a volatile, colorless liquid that has a slight odor. It burns with a smokeless blue flame that is not always visible in normal light.
The physical properties of ethanol stem primarily from the presence of its hydroxyl group and the shortness of its carbon chain. Ethanol’s hydroxyl group is able to participate in hydrogen bonding, rendering it more viscous and less volatile than less polar organic compounds of similar molecular weight, such as propane.
Ethanol is slightly more refractive than water, having a refractive index of 1.36242 (at λ=589.3 nm and 18.35 °C).
The triple point for ethanol is 150 K at a pressure of 4.3 × 10−4 Pa.
Ethanol is a versatile solvent, miscible with water and with many organic solvents, including acetic acid, acetone, benzene, carbon tetrachloride, chloroform, diethyl ether, ethylene glycol, glycerol, nitromethane, pyridine, and toluene. It is also miscible with light aliphatic hydrocarbons, such as pentane and hexane, and with aliphatic chlorides such as trichloroethane and tetrachloroethylene.
Ethanol’s miscibility with water contrasts with the immiscibility of longer-chain alcohols (five or more carbon atoms), whose water miscibility decreases sharply as the number of carbons increases. The miscibility of ethanol with alkanes is limited to alkanes up to undecane, mixtures with dodecane and higher alkanes show a miscibility gap below a certain temperature (about 13 °C for dodecane). The miscibility gap tends to get wider with higher alkanes and the temperature for complete miscibility increases.
Ethanol-water mixtures have less volume than the sum of their individual components at the given fractions. Mixing equal volumes of ethanol and water results in only 1.92 volumes of mixture. Mixing ethanol and water is exothermic, with up to 777 J/mol being released at 298 K.
Mixtures of ethanol and water form an azeotrope at about 89 mole-% ethanol and 11 mole-% water or a mixture of about 96 volume percent ethanol and 4% water at normal pressure and T = 351 K. This azeotropic composition is strongly temperature- and pressure-dependent and vanishes at temperatures below 303 K.
Hydrogen bonding causes pure ethanol to be hygroscopic to the extent that it readily absorbs water from the air. The polar nature of the hydroxyl group causes ethanol to dissolve many ionic compounds, notably sodium and potassium hydroxides, magnesium chloride, calcium chloride, ammonium chloride, ammonium bromide, and sodium bromide. Sodium and potassium chlorides are slightly soluble in ethanol. Because the ethanol molecule also has a nonpolar end, it will also dissolve nonpolar substances, including most essential oils and numerous flavoring, coloring, and medicinal agents.
The addition of even a few percent of ethanol to water sharply reduces the surface tension of water. This property partially explains the “tears of wine” phenomenon. When wine is swirled in a glass, ethanol evaporates quickly from the thin film of wine on the wall of the glass. As the wine’s ethanol content decreases, its surface tension increases and the thin film “beads up” and runs down the glass in channels rather than as a smooth sheet.
An ethanol-water solution that contains 40% ABV (alcohol by volume) will catch fire if heated to about 26 °C (79 °F) and if an ignition source is applied to it. This is called its flash point. The flash point of pure ethanol is 16.60 °C (61.88 °F), less than average room temperature.
The flash points of ethanol concentrations from 10% ABV to 96% ABV are shown below:
- 10% — 49 °C (120 °F)
- 12.5% — about 52 °C (126 °F)
- 20% — 36 °C (97 °F)
- 30% — 29 °C (84 °F)
- 40% — 26 °C (79 °F)
- 50% — 24 °C (75 °F)
- 60% — 22 °C (72 °F)
- 70% — 21 °C (70 °F)
- 80% — 20 °C (68 °F)
- 90% — 17 °C (63 °F)
- 96% — 17 °C (63 °F)
Alcoholic beverages that have a low concentration of ethanol will burn if sufficiently heated and an ignition source (such as an electric spark or a match) is applied to them. For example, the flash point of ordinary wine containing 12.5% ethanol is about 52 °C (126 °F).
Grades Of Ethanol
Ethanol is available in a range of purities that result from its production or, in the case of denatured alcohol, are introduced intentionally.
Pure ethanol and alcoholic beverages are heavily taxed as a psychoactive drug, but ethanol has many uses that do not involve consumption by humans. To relieve the tax burden on these uses, most jurisdictions waive the tax when an agent has been added to the ethanol to render it unfit to drink. These include bittering agents such as denatonium benzoate and toxins such as methanol, naphtha, and pyridine. Products of this kind are called denatured alcohol.
Absolute or anhydrous alcohol refers to ethanol with a low water content. There are various grades with maximum water contents ranging from 1% to a few parts per million (ppm) levels. Absolute alcohol is not intended for human consumption. If azeotropic distillation is used to remove water, it will contain trace amounts of the material separation agent (e.g. benzene). Absolute ethanol is used as a solvent for laboratory and industrial applications, where water will react with other chemicals, and as fuel alcohol. Spectroscopic ethanol is an absolute ethanol with a low absorbance in ultraviolet and visible light, fit for use as a solvent in ultraviolet-visible spectroscopy.
Pure ethanol is classed as 200 proof in the USA, equivalent to 175 degrees proof in the UK system.
Rectified spirit, an azeotropic composition of 96% ethanol containing 4% water, is used instead of anhydrous ethanol for various purposes. Wine spirits are about 94% ethanol (188 proof). The impurities are different from those in 95% (190 proof) laboratory ethanol.
Ethanol is classified as a primary alcohol, meaning that the carbon its hydroxyl group attaches to has at least two hydrogen atoms attached to it as well. Many ethanol reactions occur at its hydroxyl group.
As A Fuel
The largest single use of ethanol is as a motor fuel and fuel additive. More than any other major country, Brazil relies on ethanol as a motor fuel. Gasoline sold in Brazil contains at least 25% anhydrous ethanol. Hydrous ethanol (about 95% ethanol and 5% water) can be used as fuel in more than 90% of new cars sold in the country. Brazilian ethanol is produced from sugar cane and noted for high carbon sequestration. The US uses Gasohol (max 10% ethanol) and E85 (85% ethanol) ethanol/gasoline mixtures.
Ethanol may also be utilized as a rocket fuel, and is currently in lightweight rocket-powered racing aircraft.
Australian law limits of the use of pure ethanol sourced from sugarcane waste to up to 10% in automobiles. It has been recommended that older cars (and vintage cars designed to use a slower burning fuel) have their valves upgraded or replaced.
According to an industry advocacy group for promoting ethanol called the American Coalition for Ethanol, ethanol as a fuel reduces harmful tailpipe emissions of carbon monoxide, particulate matter, oxides of nitrogen, and other ozone-forming pollutants.Argonne National Laboratory analyzed the greenhouse gas emissions of many different engine and fuel combinations. Comparing ethanol blends with gasoline alone, they showed reductions of 8% with the biodiesel/petrodiesel blend known as B20, 17% with the conventional E85 ethanol blend, and that using cellulosic ethanol lowers emissions 64%.
Ethanol combustion in an internal combustion engine yields many of the products of incomplete combustion produced by gasoline and significantly larger amounts of formaldehyde and related species such as acetaldehyde.This leads to a significantly larger photochemical reactivity that generates much more ground level ozone. These data have been assembled into The Clean Fuels Report comparison of fuel emissions and show that ethanol exhaust generates 2.14 times as much ozone as does gasoline exhaust.When this is added into the custom Localised Pollution Index (LPI) of The Clean Fuels Report the local pollution (pollution that contributes to smog) is 1.7 on a scale where gasoline is 1.0 and higher numbers signify greater pollution. The California Air Resources Board formalized this issue in 2008 by recognizing control standards for formaldehydes as an emissions control group, much like the conventional NOx and Reactive Organic Gases (ROGs).
World production of ethanol in 2006 was 51 gigalitres (1.3×1010 US gal), with 69% of the world supply coming from Brazil and the United States. More than 20% of Brazilian cars are able to use 100% ethanol as fuel, which includes ethanol-only engines and flex-fuel engines. Flex-fuel engines in Brazil are able to work with all ethanol, all gasoline or any mixture of both. In the US flex-fuel vehicles can run on 0% to 85% ethanol (15% gasoline) since higher ethanol blends are not yet allowed or efficient. Brazil supports this population of ethanol-burning automobiles with large national infrastructure that produces ethanol from domestically grown sugar cane. Sugar cane not only has a greater concentration of sucrose than corn (by about 30%), but is also much easier to extract. The bagasse generated by the process is not wasted, but is used in power plants to produce electricity.
The United States fuel ethanol industry is based largely on corn. According to the Renewable Fuels Association, as of October 30, 2007, 131 grain ethanol bio-refineries in the United States have the capacity to produce 7.0 billion US gallons (26,000,000 m3) of ethanol per year. An additional 72 construction projects underway (in the U.S.) can add 6.4 billion US gallons (24,000,000 m3) of new capacity in the next 18 months. Over time, it is believed that a material portion of the ≈150-billion-US-gallon (570,000,000 m3) per year market for gasoline will begin to be replaced with fuel ethanol.
One problem with ethanol is its high miscibility with water, which means that it cannot be efficiently shipped through modern pipelines, like liquid hydrocarbons, over long distances. Mechanics also have seen increased cases of damage to small engines, in particular, the carburetor, attributable to the increased water retention by ethanol in fuel.
In 2011, the Open Fuel Standard Coalition introduced a bill into Congress that would mandate most cars sold in the United States to be warranted to run on ethanol, as well as methanol and gasoline. The bill aims to provide enough financial incentive to find better ways to make ethanol fuel so it could compete economically against gasoline.
Ethanol is the principal psychoactive constituent in alcoholic beverages, with depressant effects on the central nervous system, It has a complex mode of action and affects multiple systems in the brain, most notably increasing the activity of GABA receptors. Through positive allosteric modulation, it enhances the activity of naturally produced GABA. Other psychoactives such as benzodiazepines, barbiturates exert their effects by binding to the same receptor complex, thus have similar CNS depressant effects.
Alcoholic beverages vary considerably in ethanol content and in foodstuffs they are produced from. Most alcoholic beverages can be broadly classified as fermented beverages, beverages made by the action of yeast on sugary foodstuffs, or distilled beverages, beverages whose preparation involves concentrating the ethanol in fermented beverages by distillation. The ethanol content of a beverage is usually measured in terms of the volume fraction of ethanol in the beverage, expressed either as a percentage or in alcoholic proof units.
Fermented beverages can be broadly classified by the foodstuff they are fermented from. Beers are made from cereal grains or other starchy materials, wines and ciders from fruit juices, and meads from honey. Cultures around the world have made fermented beverages from numerous other foodstuffs, and local and national classifications for various fermented beverages abound.
Distilled beverages are made by distilling fermented beverages. Broad categories of distilled beverages include whiskeys, distilled from fermented cereal grains; brandies, distilled from fermented fruit juices; and rum, distilled from fermented molasses or sugarcane juice. Vodka and similar neutral grain spirits can be distilled from any fermented material (grain and potatoes are most common); these spirits are so thoroughly distilled that no tastes from the particular starting material remain. Numerous other spirits and liqueurs are prepared by infusing flavors from fruits, herbs, and spices into distilled spirits. A traditional example is gin, which is created by infusing juniper berries into a neutral grain alcohol.
The ethanol content in alcoholic beverages can be increased by means other than distillation. Applejack is traditionally made by freeze distillation, by which water is frozen out of fermented apple cider, leaving a more ethanol-rich liquid behind. Ice beer (also known by the German term Eisbier or Eisbock) is also freeze-distilled, with beer as the base beverage. Fortified wines are prepared by adding brandy or some other distilled spirit to partially fermented wine. This kills the yeast and conserves a portion of the sugar in grape juice; such beverages are not only more ethanol-rich but are often sweeter than other wines.
Alcoholic beverages are used in cooking for their flavors and because alcohol dissolves hydrophobic flavor compounds.
Just as industrial ethanol is used as feedstock for the production of industrial acetic acid, alcoholic beverages are made into vinegar. Wine and cider vinegar are both named for their respective source alcohols, whereas malt vinegar is derived from beer.
Pure ethanol will irritate the skin and eyes. Nausea, vomiting and intoxication are symptoms of ingestion. Long-term use by ingestion can result in serious liver damage. Atmospheric concentrations above one in a thousand are above the European Union Occupational exposure limits.
Effects On The Central Nervous System
Ethanol is a central nervous system depressant and has significant psychoactive effects in sublethal doses; for specifics, see “Effects of alcohol on the body by dose”. Based on its abilities to change the human consciousness, ethanol is considered a psychoactive drug. Death from ethanol consumption is possible when blood alcohol level reaches 0.4%. A blood level of 0.5% or more is commonly fatal. Levels of even less than 0.1% can cause intoxication, with unconsciousness often occurring at 0.3–0.4%.
The amount of ethanol in the body is typically quantified by blood alcohol content (BAC), which is here taken as weight of ethanol per unit volume of blood. The table at the right summarizes the symptoms of ethanol consumption. Small doses of ethanol, in general, produce euphoria and relaxation; people experiencing these symptoms tend to become talkative and less inhibited, and may exhibit poor judgment. At higher dosages (BAC > 1 g/L), ethanol acts as a central nervous system depressant, producing at progressively higher dosages, impaired sensory and motor function, slowed cognition, stupefaction, unconsciousness, and possible death.
Ethanol acts in the central nervous system by binding to the GABA-A receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., it is a positive allosteric modulator).
Prolonged heavy consumption of alcohol can cause significant permanent damage to the brain and other organs. See Alcohol consumption and health.
According to the US National Highway Traffic Safety Administration, in 2002 about “41% of people fatally injured in traffic crashes were in alcohol related crashes”.The risk of a fatal car accident increases exponentially with the level of alcohol in the driver’s blood.Most drunk driving laws governing the acceptable levels in the blood while driving or operating heavy machinery set typical upper limits of blood alcohol content (BAC) between 0.02% and 0.08%.
Discontinuing consumption of alcohol after several years of heavy drinking can also be fatal. Alcohol withdrawal can cause anxiety, autonomic dysfunction, seizures, and hallucinations. Delirium tremens is a condition that requires people with a long history of heavy drinking to undertake an alcohol detoxification regimen.
The reinforcing effects of alcohol consumption are also mediated by acetaldehyde generated by catalase and other oxidizing enzymes such as cytochrome P-4502E1 in the brain. Although acetaldehyde has been associated with some of the adverse and toxic effects of ethanol, it appears to play a central role in the activation of the mesolimbic dopamine system.
Ethanol is classified as a teratogen. See fetal alcohol syndrome.
Frequent drinking of alcoholic beverages has been shown to be a major contributing factor in cases of elevated blood levels of triglycerides.
Ethanol is not a carcinogen. However, the first metabolic product of ethanol in the liver, acetaldehyde, is toxic, mutagenic, and carcinogenic.
Ethanol is also widely used, clinically and over the counter, as an antitussive agent.
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first such drug, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and made available in 1960 by Hoffmann–La Roche, which has also marketed the benzodiazepine diazepam (Valium) since 1963.
Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, and muscle relaxant properties; also seen in the applied pharmacology of high doses of many shorter-acting benzodiazepines are amnesic-dissociative actions.These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate- or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety.
In general, benzodiazepines are safe and effective in the short term, although cognitive impairments and paradoxical effects such as aggression or behavioral disinhibition occasionally occur. Long-term use is controversial due to concerns about adverse psychological and physical effects, increased questioning of effectiveness and because benzodiazepines are prone to cause tolerance, physical dependence, and, upon cessation of use after long term use, a withdrawal syndrome. Due to adverse effects associated with the long-term use of benzodiazepines, withdrawal from benzodiazepines, in general, leads to improved physical and mental health.The elderly are at an increased risk of suffering from both short- and long-term adverse effects.
There is controversy concerning the safety of benzodiazepines in pregnancy. While they are not major teratogens, uncertainty remains as to whether they cause cleft palate in a small number of babies and whether neurobehavioural effects occur as a result of prenatal exposure;they are known to cause withdrawal symptoms in the newborn. Benzodiazepines can be taken in overdoses and can cause dangerous deep unconsciousness. However, they are much less toxic than their predecessors, the barbiturates, and death rarely results when a benzodiazepine is the only drug taken; however, when combined with other central nervous system depressants such as alcohol and opiates, the potential for toxicity and fatal overdose increases.Benzodiazepines are commonly misused and taken in combination with other drugs of abuse. In addition, all benzodiazepines are listed in Beers List, which is significant in clinical practice. Moreover, in geriatric medicine, if benzodiazepines are necessary, those with short half-lives (e.g. lorazepam & oxazepam) are preferred, as they do not require hepatic oxidation.
Benzodiazepines possess sedative, hypnotic, anxiolytic, anticonvulsant, muscle relaxant, and amnesic actions,which are useful in a variety of indications such as alcohol dependence, seizures, anxiety, panic, agitation and insomnia. Most are administered orally; however, they can also be given intravenously, intramuscularly or rectally.:189 In general, benzodiazepines are well-tolerated and are safe and effective drugs in the short term for a wide range of conditions. Tolerance can develop to their effects and there is also a risk of dependence, and upon discontinuation a withdrawal syndrome may occur. These factors, combined with other possible secondary effects after prolonged use such as psychomotor, cognitive, or memory impairments, limit their long-term applicability.The effects of long-term use or misuse include the tendency to cause or worsen cognitive deficits, depression and anxiety.
Due to their effectiveness, tolerability, and rapid onset of anxiolytic action, benzodiazepines are frequently used for the treatment of anxiety associated with panic disorder. However, there is disagreement among expert bodies regarding the long-term use of benzodiazepines for panic disorder. The views range from those that hold that benzodiazepines are not effective long-term and that they should be reserved for treatment-resistant cases to that they are as effective in the long term as selective serotonin reuptake inhibitors.
The American Psychiatric Association (APA) guidelines note that, in general, benzodiazepines are well tolerated, and their use for the initial treatment for panic disorder is strongly supported by numerous controlled trials. APA states that there is insufficient evidence to recommend any of the established panic disorder treatments over another. The choice of treatment between benzodiazepines, SSRIs, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, and psychotherapy should be based on the patient’s history, preference, and other individual characteristics. Selective serotonin reuptake inhibitors are likely to be the best choice of pharmacotherapy for many patients with panic disorder, but benzodiazepines are also often used, and some studies suggest that these medications are still used with greater frequency than the SSRIs. One advantage of benzodiazepines is that they alleviate the anxiety symptoms much faster than antidepressants, and therefore may be preferred in patients for whom rapid symptom control is critical. However, this advantage is offset by the possibility of developing benzodiazepine dependence. APA does not recommend benzodiazepines for persons with depressive symptoms or a recent history of substance abuse. The APA guidelines state that, in general, pharmacotherapy of panic disorder should be continued for at least a year, and that clinical experience support continuing benzodiazepine treatment to prevent recurrence. Although major concerns about benzodiazepine tolerance and withdrawal have been raised, there is no evidence for significant dose escalation in patients using benzodiazepines long-term. For many such patients stable doses of benzodiazepines retain their efficacy over several years.
Guidelines issued by the UK-based National Institute for Health and Clinical Excellence (NICE), carried out a systematic review using different methodology and came to a different conclusion. They questioned the accuracy of studies that were not placebo-controlled. And, based on the findings of placebo-controlled studies, they do not recommend use of benzodiazepines beyond two to four weeks, as tolerance and physical dependence develop rapidly, with withdrawal symptoms including rebound anxiety occurring after six weeks or more of use.
Nevertheless, benzodiazepines continue to be prescribed for the long-term treatment of anxiety disorders, although specific antidepressants and psychological therapies are recommended as the first-line treatment options with the anticonvulsant drug pregabalin indicated as a second- or third-line treatment and suitable for long-term use.NICE stated that long-term use of benzodiazepines for panic disorder with or without agoraphobia is an unlicensed indication, does not have long-term efficacy, and is, therefore, not recommended by clinical guidelines. Psychological therapies such as cognitive behavioural therapy are recommended as a first-line therapy for panic disorder; benzodiazepine use has been found to interfere with therapeutic gains from these therapies.
Benzodiazepines are usually administered orally; however, very occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.
Generalized Anxiety Disorder
Benzodiazepines have robust efficacy in the short-term management of generalized anxiety disorder (GAD), but were not shown to be effective in producing long-term improvement overall. According to National Institute for Health and Clinical Excellence (NICE), benzodiazepines can be used in the immediate management of GAD, if necessary. However, they should not usually be given for longer than 2–4 weeks. The only medications NICE recommends for the longer term management of GAD are antidepressants.
Likewise, Canadian Psychiatric Association (CPA) recommends benzodiazepines alprazolam, bromazepam, lorazepam, and diazepam only as a second-line choice, if the treatment with two different antidepressants was unsuccessful. Although they are second-line agents, benzodiazepines can be used for a limited time to relieve severe anxiety and agitation. CPA guidelines note that after 4–6 weeks the effect of benzodiazepines may decrease to the level of placebo, and that benzodiazepines are less effective than antidepressants in alleviating ruminative worry, the core symptom of GAD. However, in some cases, a prolonged treatment with benzodiazepines as the add-on to an antidepressant may be justified.
Prolonged convulsive epileptic seizures are a medical emergency that can usually be dealt with effectively by administering fast-acting benzodiazepines, which are potent anticonvulsants. In a hospital environment, intravenous clonazepam, lorazepam, and diazepam are first-line choices, clonazepam due to its stronger and more potent anticonvulsant action, lorazepam due to its faster onset and diazepam for its longer duration of action. In the community, intravenous administration is not practical and so rectal diazepam or (more recently) buccal midazolam are used, with a preference for midazolam as its administration is easier and more socially acceptable.
When benzodiazepines were first introduced, they were enthusiastically adopted for treating all forms of epilepsy. However, drowsiness and tolerance become problems with continued use and none are now considered first-line choices for long-term epilepsy therapy.Clobazam is widely used by specialist epilepsy clinics worldwide and clonazepam is popular in the Netherlands, Belgium and France. It was approved for use in the United States in 2011. In the UK, both clobazam and clonazepam are second-line choices for treating many forms of epilepsy.Clobazam also has a useful role for very short-term seizure prophylaxis and in catamenial epilepsy.
Discontinuation after long term use in epilepsy requires additional caution because of the risks of rebound seizures. Therefore, the dose is slowly tapered over a period of up to six months or longer.
Although benzodiazepines are much safer in overdose than their predecessors, the barbiturates, they can still cause problems in overdose.Taken alone, they rarely cause severe complications in overdose;statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug. However, combining these drugs with alcohol, opiates or tricyclic antidepressants markedly raises the toxicity.The elderly are more sensitive to the side effects of benzodiazepines, and poisoning may even occur from their long-term use.The various benzodiazepines differ in their toxicity; temazepam appears to be most toxic in overdose and when used with other drugs.The symptoms of a benzodiazepine overdose may include; drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.
A reversal agent for benzodiazepines exists, flumazenil (Anexate). Its use as an antidote is not routinely recommended due to the high risk of resedation and seizures.In a double-blind, placebo-controlled trial of 326 patients, 4 patients suffered serious adverse events and 61% became resedated following the use of flumazenil. Numerous contraindications to its use exist. It is contraindicated in patients with a history of long-term use of benzodiazepines, those having ingested a substance that lowers the seizure threshold or may cause an arrhythmia, and in those with abnormal vital signs.One study found that only 10% of the patient population presenting with a benzodiazepine overdose are suitable candidates for treatment with flumazenil.
Individual benzodiazepines may have different interactions with certain drugs. Depending on their metabolism pathway, benzodiazepines can be roughly divided into two groups. The largest group consists of those that are metabolized by cytochrome P450 (CYP450) enzymes and possess significant potential for interactions with other drugs. The other group comprises those that are metabolized through glucuronidation, such as lorazepam, oxazepam, and temazepam, and, in general, have few drug interactions.
Many drugs, including oral contraceptives, some antibiotics, antidepressants, and antifungal agents, inhibit cytochrome enzymes in the liver. They reduce the rate of elimination of the benzodiazepines that are metabolized by CYP450, leading to possibly excessive drug accumulation and increased side-effects. In contrast, drugs that induce cytochrome P450 enzymes, such as St John’s wort, the antibiotic rifampicin, and the anticonvulsants carbamazepine and phenytoin, accelerate elimination of many benzodiazepines and decrease their action. Taking benzodiazepines with alcohol, opioids and other central nervous system depressants potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing, and other adverse effects that have potential to be lethal.Antacids can slow down absorption of some benzodiazepines; however, this effect is marginal and inconsistent.
Benzodiazepines are considered to be major drugs of abuse.Benzodiazepine abuse is mostly limited to individuals who abuse other drugs, i.e., poly-drug abusers. The majority of prescribed users do not abuse their medication. On the international scene, benzodiazepines are categorized as Schedule IV controlled drugs by the INCB, apart from flunitrazepam which is a Schedule III drug under the Convention on Psychotropic Substances.Some variation in drug scheduling exists in individual countries; for example, in the United Kingdom, midazolam and temazepam are Schedule III controlled drugs. British law requires temazepam (but not midazolam) to be stored in safe custody. Safe custody requirements ensures that pharmacists and doctors holding stock of temazepam must store it in securely fixed double-locked steel safety cabinets and maintain a written register, which must be bound and contain separate entries for temazepam and must be written in ink with no use of correction fluid (although a written register is not required for temazepam in the United Kingdom). Disposal of expired stock must be witnessed by a designated inspector (either a local drug-enforcement police officer or official from health authority).Benzodiazepine abuse ranges from occasional binges on large doses, to chronic and compulsive drug abuse of high doses.
Benzodiazepines are used recreationally and by problematic drug misusers. Mortality is higher among poly-drug misusers that also use benzodiazepines. Heavy alcohol use also increases mortality among poly-drug users.Dependence and tolerance, often coupled with dosage escalation, to benzodiazepines can develop rapidly among drug misusers; withdrawal syndrome may appear after as little as three weeks of continuous use. Long-term use has the potential to cause both physical and psychological dependence and severe withdrawal symptoms such as depression, anxiety (often to the point of panic attacks), and agoraphobia.Benzodiazepines and, in particular, temazepam are sometimes used intravenously, which, if done incorrectly or in an unsterile manner, can lead to medical complications including abscesses, cellulitis, thrombophlebitis, arterial puncture, deep vein thrombosis, and gangrene. Sharing syringes and needles for this purpose also brings up the possibility of transmission of hepatitis, HIV, and other diseases. Benzodiazepines are also misused intranasally, which may have additional health consequences. Once benzodiazepine dependence has been established, a clinician usually converts the patient to an equivalent dose of diazepam before beginning a gradual reduction program.
A 1999–2005 Australian police survey of detainees reported preliminary findings that self-reported users of benzodiazepines were less likely than non-user detainees to work full-time and more likely to receive government benefits, use methamphetamine or heroin, and be arrested or imprisoned.Benzodiazepines are sometimes used for criminal purposes; they serve to incapacitate a victim in cases of drug assisted rape or robbery.
Overall, anecdotal evidence suggests that temazepam may be the most psychologically habit-forming (addictive) benzodiazepine. Temazepam abuse reached epidemic proportions in some parts of the world, in particular, in Europe and Australia, and is a major drug of abuse in many Southeast Asian countries. This led authorities of various countries to place temazepam under a more restrictive legal status. Some countries, such as Sweden, banned the drug outright.Temazepam also has certain pharmacokinetic properties of absorption, distribution, elimination, and clearance that make it more apt to abuse compared to many other benzodiazepines.