Introduction to Benzodiazepines
Benzodiazepines have been used since the 1960s to treat anxiety, muscle spasms, insomnia, and seizures for their anxiolytic, hypnotic and anticonvulsive properties. They're useful in treating hallucinogen-induced panic (i.e. bad trips). They largely replaced barbiturates because they're are shown to have much wider safety margins than barbiturates, thus safer. Traditionally they were considered to have a less potential for addiction and dependence, though this is less true in recent years. Benzodiazepine is a family of chemicals structured around benzene and diazepine rings in the core. Though acting via similar mechanisms, each benzodiazepine has differing pharmacological profiles. See the individual sections on specific benzodiazepines for more detailed information.
Some common benzodiazepines in North America are:
Bromazepam(Lexotan) approved in Canada, not in the U.S.
Recreational use of benzodiazepines is quite widespread. In 2007 1.8 million Americans aged 12 or older used tranquilizers nonmedically (National Survey on Drug Use and Health 2007), and 6.5% of those using drugs recreationally for the first time started with tranquilizers.
In the UK it is estimated that approximately 200,000 people use benzodiazepines recreationally (Ashton, 2000).
In Australia, 1.6% of the population had used tranquilizers recreationally in the last year, rising to almost 3% in the 20-29 years age group (2007 National Drug Strategy Household Survey).
In a survey of 15-16 years olds in 35 European countries the average lifetime use of tranquilizers without prescription was 4%. Use of tranquilizers or sedatives without prescription is most common in Poland (17 %), followed by Lithuania (14 %), France (13 %) and the Czech Republic (11 %). (ESPAD, 2003)
Classification and Mechanism of ActionBenzodiazepines are sedative-hypnotic drugs that fall within the broad category of CNS depressants. The most common therapeutic use for them is in the treatment of anxiety disorders. Drugs that are used to relieve anxiety are termed anxiolytics. Benzodiazepines produce sedative, anxiolytic, muscle relaxant, anticonvulsant, and cognitive-impairing effects. Benzodiazepines produce these effects because they act to inhibit the firing of neurons by enhancing the inhibitory effects of the amino acid neurotransmitter GABA (gamma-aminobutyric acid).
GABA is the primary inhibitory neurotransmitter. One of the ways that GABA reduces the chances that a neuron will fire is by binding to and opening chloride ion channels on the neuronal membrane. Benzodiazepines also bind to this ion channel but do not open it. They bind to a different site on the ion channel and when they bind, GABA is more likely to stay on the ion channel and exert a greater effect. There are three types of GABA receptors, only two of which are ion channels and only one of those also bind benzodiazepines. Benzodiazepines bind to the GABA receptor called the GABA-A receptor.
Alcohol and barbiturates are other drugs that interact with and bind to GABA receptors. Benzodiazepines show many of the same effects as alcohol and barbiturates. Benzodiazepines may also show cross tolerance with alcohol and barbiturates. Combining benzodiazepines with alcohol and/or barbiturates is very dangerous due to the potential for respiratory depression and coma leading to death.
Routes of Administration:Benzodiazepines are mostly manufactured in pills, however, they're also available as suppositories, IV injection(triazolam, flunitrazepam, and diazepam emulsion). Midazolam HCl is inherently water soluble, however, the others are made injectable through the use of co-solvents and/or emulsification.
When they're taken orally, they are absorbed through the gastrointestinal tract. When taken orally, they go through the liver before exerting action on the rest of the body. Benzodiazepines are extensively metabolized by the enzymes in the liver known as the Cytochrome P450 enzymes. These enzymes are involved in the first-pass metabolism of many drugs. When benzodiazepines (and other drugs) are taken orally approximately 50% undergoes first pass metabolism. This metabolism deactivates the drug and lessens the effect.
Rectal Administration (Benzodiazepines rectally?) is another method of taking benzodiazepines. When benzodiazepines are taken rectally, only about 33% of the benzodiazepines undergo first pass metabolism. Therefore, rectal administration has an increased effect over oral administration for the same amount of benzodiazepine.
Other known methods of administration completely bypass the gastrointestinal tract and avoid first pass metabolism completely. Some of the other methods of administration of benzodiazepines include the following:
* Injection (Injecting Diazepam (or other benzo) Pills) Note: Injecting pills dangerous and should not be attempted. Pills contain fillers and binders which when injected can cause fatal embolisms. See this thread for more information on the dangers of injecting pills: Injecting Basics: Dangers of IVing pills
* Smoking (The Smoking Benzodiazepines Thread)
* Insufflation or Snorting (Everything SWIY Needs to Know About Snorting Benzodiazepines)
Effects of BenzodiazepinesTherapeutic uses of benzodiazepines include treatment of anxiety, insomnia (by causing drowsiness), seizures (by increasing the seizure threshold), muscle spasms, and alcohol withdrawal.
(Side)effects caused by benzodiazepines may include drowsiness, dizziness, upset stomach, blurred vision, headache, confusion, depression, euphoria, impaired coordination, changes in heart rate, trembling, weakness, amnesia, grogginess, dreaming or nightmares, chest pain, vision changes, jaundice, and paradoxical reactions.
Benzodiazepines are relatively rapid acting and therefore can be used short-term, intermittently, and as needed. This rapid-acting property is useful in the treatment of anxiety which can vary in intensity and for the treatment of acute panic attacks.
Rapid cessation of use can not only result in a return of any treated symptoms but, a compensatory increase reaction resulting in greater than normal symptoms. Rapid cessation can also cause symptoms to appear in subjects who previously had no such symptoms. Some effects resulting from cessation of benzodiazepine use may include insomnia, convulsions and seizures, hyper activity, anxiety, and even delirium tremens in severe cases.
Benzodiazepines are commonly divided into three different groups depending on the length of the half-life (the time required for half of the drug to be metabolized to an inactive form). The short-acting benzodiazepines have half-lives of less than 12 hours. The intermediate-acting benzodiazepines have half-lives of 12 to 24 hours. While the longest lasting benzodiazepines have half-lives over 24 hours. See the individual sections on the specific benzodiazepines for more information.
Due the extremely long half-lives of some benzodiazepines (from several days to over a week), drug interactions must be more carefully considered. Therefore, the long-acting benzodiazepines have a greater associated risk. Taking flurazepam for instance and then drinking heavily even a couple of days later could cause potentially fatal interactions.
A drug named flumazenil is used to counter the effect of benzodiazepines. It is used when excessive sedation is produced during a medical procedure. It is not effective on barbiturates, alcohol or general anesthesia.
Combinations with BenzodiazepinesCombining benzodiazepines with other sedating drugs such as alcohol, marijuana, barbiturates, and opiates can cause life-threatening respiratory depression.
For more information on the dangers of combining other drugs with benzodiazepines, see the following threads:
Benzodiazepines and Alcohol and Stimulants
Warning: Benzos and Booze
Benzodiazepines are useful for treating panic and anxiety induced by psychedelics. Benzodiazepines are also useful for mitigating effects of stimulants (e.g. cocaine and amphetamines) and are often used to assist in coming off stimulants.
Like many drugs, the benzodiazepines are metabolized by the cytochrome P450 family of enzymes. Inhibiting the activity of these enzymes may lead to a greater amount of active benzodiazepine in the blood. Likewise, inducing these enzymes is likely to result in a lower than expected effect.
For more information on enzyme inhibition, see: Grapefruit Juice and Benzodiazepines
Different Uses for BenzodiazepinesBenzodiazepines are typically prescribed for the treatment of anxiety, insomnia, seizures, muscle spasms, and alcohol withdrawal. Due to their usefulness as fast-acting anxiolytics and tranquilizers, benzodiazepines have found a place among recreational drug users for hallucinogen-induced panic and anxiety (bad trips) and to assist in coming down from stimulants.
Benzodiazepines are used recreationally to induce relaxation. Benzodiazepines affect the body in a similar way as alcohol, therefore benzodiazepines are used to achieve a similar high. As sedative hypnotics, benzodiazepines have the potential for abuse and dependence.
The Chemistry of BenzodiazepinesBenzodiazepines vary in lipid solubility which affects whether or not they are quickly absorbed and effective shortly after administration.
Benzodiazepine pKa Bromazepam 11.0 Clonazepam 10.5 (1-position) 1.5 (4-position) Diazepam 3.3 Flunitrazepam 1.8 Flurazepam 8.2 Lorazepam 11.5 Medazepam 6.2 Nitrazepam 10.8 Oxazepam 1.8 Prazepam 3.0
The dangers of BenzodiazepinesRapid cessation of use can cause life-threatening conditions including convulsions, seizures, and delirium tremens. Benzodiazepines are addictive and can cause physical dependence.
When used by themselves benzodiazepines are relatively safe. Overdose of benzodiazepines alone rarely results in death, though concurrent use with other depressants (such as alcohol, barbiturates, and opiates) can be fatal.
Producing BenzodiazepinesChemical Synthesis of Benzodiazepines (Benzo synthesis and chemistry)
Extraction of Diazepam and Lorazepam from Potatoes and Wheat (Diazepam from Potatoes and Wheat)
Forms of BenzodiazepinesThis list is just a collection and is not inclusive of all benzodiazepines. There are many different benzodiazepines that have been synthesized, including many that deviate quite a bit from the benzodiazepine backbone structure.
Benzodiazepines are typically organized by half-life (the time required for half of the drug to be metabolized to an inactive form). Short-acting benzodiazepines have a half-life of less than 12 hours. Intermediate-acting benzodiazepines have a half-life between 12 and 24 hours. Long-acting benzodiazepines have half-lives greater than 24 hours.
Short half-lives mean that the drug is cleared from the body more quickly, effects don’t last as long. Longer half-lives mean that the drug lasts much longer in the body. For the long-acting benzodiazepines, the dose may be lower and the frequency of doses is lower. Long-acting benzodiazepines allow patients to not be required to take as many pills in a given amount of time.
Short-acting Benzodiazepines ( < 12 hr half-life):Triazolam (Halcion) – 1.5 to 5.5 hrs
Midazolam – 1.8 to 6.4 hrs
Brotizolam – 4.4 hrs
Oxazepam – 4 to 14 hrs
Loprazolam (Triazulenone) – 6 to 12 hrs
Lormetazepam – 10 to 12 hrs
Alprazolam (Xanax) – 11.2 hrs (r=6.3 to 15.8
16 in non-elderly adults, r=9 to 26.9, n 16 in elderly)
Intermediate-acting Benzodiazepines (12-24 hr half-life):Lorazepam (Ativan) – 12hrs mean (r=9 to 16 hrs, n= unknown) Tmax = 2hrs
Temazepam – 8 to 20 hrs
Estazolam – 10 to 24 hrs
Bromazepam – 12 to 20 hrs
Chlordiazepoxide (Librium) – 5 to 30 hrs
Clobazam – 18 hrs
Nimetazepam (Erimin) – 20 hrs
Flunitrazepam (Rohypnol) – 18 to 26 hrs
Long-acting Benzodiazepines ( > 24 hr half-life):Nitrazepam – 16 to 38 hrs
Clonazepam (Klonopin) – 18 to 50 hrs
Quazepam (Doral) – 39 hrs
Diazepam (Valium) – 20 to 100 hrs
Phenazepam – 60 hrs
Medazepam (Nobrium) – 36 to 150 hrs
Prazepam – 36 to 200 hrs
Delorazepam - 40 to 140 hrs
Flurazepam – 40 to 250 hrs
Clorazepate –48 hrs
Nordazepam (Nordiazepam, Desmethyldiazepam) – 50 to 120 hrs
Legal status of Benzodiazepines
United NationsMost benzodiazepines are Schedule IV under The Convention of Psychotropic Substances 1971, but flunitrazepam (Rohypnol) is Schedule III due to its use in drug-facilitated sexual assault and drug-facilitated robbery.
USABenzodiazepines are schedule IV in the United States, except for flunitrazepam (Rohypnol) which is schedule I in certain states: Idaho, Florida, Minnesota, New Hampshire, North Dakota, New Mexico, Oklahoma, and Pennsylvania. In addition, flunitrazepam is treated more severely under federal law, being a felony for first offense. The legal prejudice against flunitrazepam is likely due to its notoriety as a date-rape drug.
United KingdomMost benzodiazepines are Class C, Schedule 4 under the Misuse of Drugs Act in the United Kingdom, and require a prescription from a doctor to be obtained. Exceptions include temazepam, flunitrazepam and midazolam which are all schedule 3 and phenazepam which is not currently a controlled substance in the UK.
Penalties for possession are up to 2 years in jail/unlimited fine or both. Penalties for illegal distribution are up to 14 years in jail/unlimited fine or both.
CanadaAll benzodiazepines are Schedule IV under the Canadian Controlled Drugs and Substances Act.
AustraliaIn Australia, both Federal and State governments have laws which regulate drugs. The Customs Act (federal) covers international trafficking and the importation and exportation of drugs. Although there are differences between States, every State also has specific laws and penalties in relation to drugs. If there are differences then state law supersedes federal law.
In all states benzodiazepines without a prescription from a doctor, or keeping, selling or giving benzodiazepines to someone else is illegal, and may result in a prison sentence, a fine or both.
History of BenzodiazepinesThe first benzodiazepine, chlordiazepoxide, was discovered during research on chemical dyes. Chlordiazepoxide was synthesized in 1954 by Leo Sternbach working at Hoffman-La Roche Pharmaceuticals. The chemical was forgotten for several years, but after some follow-up research was marketed in 1960 under the brand name Librium. Diazepam, brand name Valium, was released in 1963.
In the following years, more benzodiazepines were discovered and marketed. The success of benzodiazepines could be attributed to the fact that they were considered safer and less habit-forming than barbiturates. Though the therapeutic index of benzodiazepines is higher than barbiturates, the addiction potential is now considered to be relatively equivalent.
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