To inject Xanax, you would need to extract the pure drug: crush up the amount of pills you want to inject. Mix with alcohol. Let the mixture settle. Siphon off the alcohol. Mix sediment with water and it is ready to inject. Please be careful.
Infusion is the process of extracting chemical compounds or flavors from plant material in a solvent such as water, oil or alcohol, by allowing the material to remain suspended in the solvent over time (a process often called steeping). An infusion is also the name for the resultant liquid. The process of infusion is distinct from decoction, which involves boiling the plant material, or percolation, in which the water passes through the material (as in a coffeemaker).
The first recorded use of essential oils was in the 10th or 11th century by the Persian polymath Avicenna, possibly in The Canon of Medicine.][
Tea is far older than this, dating back to the 10th century BC as the earliest recorded reference.
An infusion is a very simple chemical process used with botanicals that are volatile and dissolve readily, or release their active ingredients easily, in water, oil or alcohol. The botanicals are typically dried herbs, flowers or berries. The liquid is typically boiled (or brought to another appropriate temperature) and then poured over the herb, which is then allowed to steep in the liquid for a period of time. The liquid may then be strained or the herbs otherwise removed from the liquid. Unless the infusion is to be consumed immediately, it may then be bottled and refrigerated for future use.
The amount of time the herbs are left in the liquid depends on the purpose for which the infusion is being prepared. Usually steeping for not more than 15 to 30 minutes, or until the mix cools, will create a beverage with optimal flavor. Steeping for a longer time typically results in a somewhat bitter-tasting infusion. Four (4) hours, however, is a more appropriate length of time for achieving herbal potency if health benefits are the priority. Quantities of the herb and liquid used will vary according to the herb or how strong the infusion is required to be. A common proportion used is 28 g (one ounce) of herb to 0.5 L (one pint) of liquid.
There have been several accessories and techniques for removing the steeped or left over products that were used to infuse liquids such as water, oil, or alcohol. The use of a metal steeper, which looks like a metal clamp. Tea infusers work as strainers and assist in removal of used herbs,leaves, etc., from over steeping or leaving residues. French presses are commonly used to infuse water with various teas and coffee. There are product lines such as Zing anything that are easy on the go beverage and oil infusers. Lastly, and most commonly used, the tea bag. Tea bags today are made with filter paper and filled with various tea flavors.
A common example of an infusion is tea, and many tisanes are prepared in the same way. Lemon, chamomile, senna, apple, ginger, rooibos, and a great many other plants are used individually or in combination. Herbal infusions in water and oil are both commonly used as herbal remedies. Coffee can also be made through infusion (as in a French press), but is more often made through percolation.
Plants with desirable flavors may be steeped in an edible oil or vinegar for an extended period; the infused oil or vinegar is often sold still containing the plant, and is then used as flavoring. Chiles, lemon, garlic, and many other plants may be used. There can be ambiguity in the labeling of these oils: for example, what is described as sesame oil may be oil extracted from sesame seeds, or another vegetable oil infused with sesame.
Trimix is an injectable three-drug prescribed medication used to treat erectile dysfunction. The active ingredients in the mixture are usually alprostadil, papaverine, and phentolamine. The injection must be compounded by a pharmacy and administered via intracavernosal injection. Trimix is typically compounded by a pharmacy in a sterile environment and then frozen. The compound is stable for up to 6 months while stored frozen and for 1 month if stored refrigerated beginning at the time of manufacture.
(trade name Xanax
, available among other generic names) is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the A
GABA gamma-amino-butyric acid receptor. Alprazolam is commonly used and FDA approved for the medical treatment of panic disorder, and anxiety disorders, such as generalized anxiety disorder (GAD) or social anxiety disorder (SAD). Alprazolam is available for oral administration in compressed tablet (CT) and extended-release capsule (XR) formulations. Alprazolam possesses anxiolytic, sedative, hypnotic, skeletal muscle relaxant, anticonvulsant, and amnestic properties.
Alprazolam has a fast onset of action and symptomatic relief. Ninety percent of peak effects are achieved within the first hour (although onset may begin at 8–25 minutes of ingestion) of using either in preparation for panic disorder, and full peak effects are achieved in 1.5 and 1.6 hours respectively. Peak benefits achieved for generalized anxiety disorder (GAD) may take up to a week. Tolerance to the anxiolytic/antipanic effects is controversial with some authoritative sources reporting the development of tolerance, and others reporting no development of tolerance; tolerance will however, develop to the sedative-hypnotic effects within a couple of days. Withdrawal symptoms or rebound symptoms may occur after ceasing treatment abruptly following a few weeks or longer of steady dosing, and may necessitate a gradual dose reduction.
Alprazolam is the most prescribed and the most misused benzodiazepine on the U.S. retail market. The potential for misuse among those taking it for medical reasons is controversial with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs and others stating that there is a substantial risk of abuse and dependence in both patients and non-medical users of alprazolam and that the pharmacological properties of alprazolam, high affinity binding, high potency, having a short elimination half-life as well as a rapid onset of action increase the misuse potential of alprazolam. Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior. Alprazolam is classified as a schedule IV controlled substance by the U.S. Drug Enforcement Administration (DEA).
Alprazolam is mostly used to treat anxiety disorders, panic disorders, and nausea due to chemotherapy. The FDA label advises that the physician should periodically reassess the usefulness of the drug.
Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks. It however is not a first line treatment, since the development of selective serotonin reuptake inhibitors, and alprazolam is no longer recommended for the treatment of panic disorder (in Australia) due to concerns regarding tolerance, dependence and abuse. Evidence supporting the effectiveness of alprazolam in treating panic disorder has been limited to 4 to 10 weeks. However, people with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit.
In the US alprazolam is FDA-approved for the treatment of panic disorder with or without agoraphobia. Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence, as of 2002.
In the US alprazolam is FDA-approved for the management of anxiety disorders (a condition corresponding most closely to the APA Diagnostic and Statistical Manual
DSM-IV-TR diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety associated with depression is responsive to alprazolam. Demonstrations of the effectiveness by systematic clinical study are limited to 4 months duration for anxiety disorder. However, the research into antidepressant properties of alprazolam is of poor quality and only assessed the short-term effects of alprazolam against depression. In one study, some long term, high-dosage users of alprazolam developed reversible depression. In the UK, alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.
Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.
Benzodiazepines cross the placenta, enter into the fetus and are also excreted with breast milk. The use of benzodiazepines during pregnancy or lactation has potential risks. The use of alprazolam in pregnancy is believed to be associated with congenital abnormalities. Diazepam and chlordiazepoxide have a better safety profile in pregnancy than alprazolam.
Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam. Use in the last trimester may cause fetal drug dependence and withdrawal symptoms in the post-natal period as well as neonatal flaccidity and respiratory problems. However, in long-term users of benzodiazepines abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines.
Benzodiazepines, including alprazolam, are known to be excreted in human milk. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.
Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals. Particular care should be taken in pregnant or elderly patients, patients with substance abuse history, particularly alcohol dependence and patients with comorbid psychiatric disorders. Use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with the following conditions: myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression, marked neuromuscular respiratory weakness including unstable myasthenia gravis, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other drugs in the benzodiazepine class, borderline personality disorder (may induce suicidality and dyscontrol).
Like all central nervous system depressants, including alcohol, alprazolam in larger-than-normal doses can cause significant deterioration in alertness, combined with increased feelings of drowsiness, especially in those unaccustomed to the drug's effects. People driving or conducting activities that require vigilance should exercise caution in using alprazolam or any other depressant until they know how it affects them.
Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness.
Allergic reactions are unlikely to occur. The only common side effect is sleepiness when treatment is initiated.
Possible side effects include:
Although unusual, the following paradoxical reactions have been shown to occur:
Alprazolam is primarily metabolised via CYP3A4. Combining CYP3A4 inhibitors such as cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in excessive accumulation of alprazolam. This may result in exacerbation of its adverse effect profile.
Imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day. Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.
Alcohol is one of the most important and common interactions. Alcohol and benzodiazepines such as alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken the worse the interaction. Combination of alprazolam with the herb kava can result in the development of a semi-comatose state. Hypericum conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.
Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and any other drugs that have been taken.
Alprazolam overdoses cause excess central nervous system (CNS) depression and may include one or more of the following symptoms:
In a study of deaths in Palm Beach County where the drug alprazolam was detected, approximately 50% of cases were attributed to poly-drug use (the combined toxicity of two or more drugs). The majority of these cases included either cocaine or methadone. Alprazolam alone caused only 1% of the deaths. These results indicate alprazolam has a very low incidence of causing death when taken alone.
Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA
gamma-amino-butyric acid receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA A receptors and, thus, GABAergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects.
Withdrawal and rebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.
Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the patient may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the patient's actually being drug-dependent.
Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment. There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a patient stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.
In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users, and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.
Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness.
Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety
Delirium and seizures have been anecdotally reported in the medical literature from abrupt alprazolam discontinuation.
In a 1983 study of patients who had taken long-acting benzodiazepines, e.g., clorazepate, for extended periods, the medications were stopped abruptly. Only 5% of patients who had been taking the drug for less than 8 months demonstrated withdrawal symptoms, but 43% of those who had been taking them for more than 8 months did. With alprazolam – a short-acting benzodiazepine – taken for 8 weeks, 35% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.
The benzodiazepines diazepam (Valium) and oxazepam (Serepax) have been found to produce fewer withdrawal reactions than alprazolam (Xanax), temazepam (Restoril/Normison), or lorazepam (Temesta/Ativan). Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms experienced during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/-tolerant drugs, use of other short-acting, high-potency benzodiazepines, and method of discontinuation.
Alprazolam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma alprazolam concentrations are usually in a range of 10–100 μg/L in persons receiving the drug therapeutically, 100–300 μg/L in those arrested for impaired driving and 300–2000 μg/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs will cross-react with alprazolam, but confirmation and quantitation is usually performed using chromatographic techniques.
Alprazolam is classed as a high-potency benzodiazepine and is a triazolobenzodiazepine, namely a benzodiazepine with a triazole ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine receptor site on the A
GABA receptor and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. The GABAA
receptor is made up of 5 subunits out of a possible 19, and GABAA
receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Benzodiazepines and in particular alprazolam causes a marked suppression of the hypothalamicpituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic and amnesic.
Administration of alprazolam has been demonstrated to elicit an increase in striatal dopamine concentrations.
Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.
In vitro, alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.
Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (Cyp3A4), to two major metabolites in plasma: 4-hydroxyalprazolam and α- hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Half-lives are similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam coincentration were always less than 4%. The reported relative potencies in benzodiazepines receptor binding experiments and in animals models of induced seizure inhibition are 0.2 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.
Alprazolam and its metabolites are excreted primarily in the urine.
Alprazolam is a chemical analog of triazolam that differs by the absence of a chlorine atom in the o
-position of the 6-phenyl ring. The same scheme that was used to make triazolam can be used to make alprazolam, with the exception that it begins with 2-amino-5-chlorobenzophenone. However, a non-standard way of making alprazolam has been suggested, which comes from 2,6-dichloro-4-phenylquinoline, the reaction of which with hydrazine gives 6-chloro-2-hydrazino-4-phenylquinoline. Boiling this with triethyl orthoacetate in xylene leads to the heterocyclization into a triazole derivative. The resulting product undergoes oxidative cleavage using sodium periodate and ruthenium dioxide in an acetone–water system to give 2-[4-(3′-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxymethylation of the last using formaldehyde and subsequent substitution of the resulting hydroxyl group by phosphorus tribromide,gives 2-[4-(3′-methyl-5′-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone. Substitution of the bromine atom with an amino group using ammonia and the spontaneous, intramolecular heterocyclization following that reaction gives alprazolam.
Alprazolam was first released by Upjohn (now a part of Pfizer). It is covered under , which was filed on 29 October 1969, granted on 19 October 1976, and expired in September 1993. Alprazolam was released in 1981. The first approved indication was panic disorder. Alprazolam was originally perceived to have been a poor investment, as Upjohn management did not believe there to be a market for panic disorder-oriented anxiolytics. However, alprazolam soon proved itself in clinical phase, FDA-mandated trials. It became a blockbuster drug with two years of its original marketing in the US market. Today, it is clinically known for not only anxiolytic properties, but also a forgiving and statistically significant anti-depressant profile, given its triazolebenzodiazepine skeletal structure, it does maintain some affinity for serotonergic receptors. Today it is the most commonly prescribed benzodiazepine in the United States, and has been available as generic instant-release and extended-release tablets for years.
Alprazolam may be also be indicated for the treatment of Generalized Anxiety Disorder, as well as for the treatment of anxiety conditions with co-morbid depression. Alprazolam is also often prescribed with instances of hypersomnia and co-morbid sleep deficits.
There is a substantial risk of abuse and dependence in both patients and non-medical users of alprazolam; the pharmacological properties of alprazolam such as high affinity binding, high potency, being short-acting and having a rapid onset of action increase the abuse potential of alprazolam. The physical dependence and withdrawal syndrome of alprazolam also adds to the addictive nature of alprazolam. In the small subgroup of individuals who escalate their doses there is usually a history of alcohol or other substance use disorders. Despite this, most prescribed alprazolam users do not misuse their medication, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation. However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise. The New York Times
also reported in 2011 that "The Centers for Disease Control and Prevention last year reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008."
Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States. A large-scale nationwide U.S. government study conducted by SAMHSA found that, in the U.S., benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency and urgent care facilities. Men and women use benzodiazepines recreationally as commonly. The report found that alprazolam is the most common benzodiazepine for recreational use followed by clonazepam, lorazepam, and diazepam. The number of emergency room visits due to benzodiazepines increased by 36% between 2004 and 2006.
Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or in ED use between 2004 and 2006.
At a particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence and people with borderline personality disorder.
Alprazolam, along with other benzodiazepines, is often used with other recreational drugs. These uses include aids to relieve the panic or distress of dysphoric ("bad trip") reactions to psychedelic drugs, such as LSD, and the drug-induced agitation and insomnia in the "comedown" stages of stimulant use, such as amphetamine, allowing sleep. Alprazolam may also be used in conjunction with other depressant drugs, such as alcohol, marijuana, heroin or other opiates, in an attempt to enhance the psychological effect of these drugs.
The poly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose which may result in fatal respiratory depression.
A 1990 study claimed that diazepam has a higher misuse potential relative to other benzodiazepines, and that some data suggests that alprazolam and lorazepam resemble diazepam in this respect.
Anecdotally injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization) and decay of muscle tissue (rhabdomyolysis). Alprazolam is practically not soluble in water, when crushed in water it will not fully dissolve (40 µg/ml of O2
H at pH 7). There have also been anecdotal reports of alprazolam being snorted. Due to the low weight of a dose, alprazolam in one case was found to be distributed on blotter paper in a manner similar to LSD.
Alprazolam is available in English-speaking countries under the following brand names:
In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration. Under the UK drug misuse classification system benzodiazepines are class C drugs (Schedule 4). In the UK, alprazolam is not available on the NHS and can only be obtained on a private prescription. Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV. In Ireland, alprazolam is a Schedule 4 medicine. In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968). In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription.
dsrd (o, p, m, p, a, d, s), sysi/epon, spvo
proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
Lethal injection is the practice of injecting a person with a fatal dose of drugs (typically a barbiturate, paralytic, and potassium solution) for the express purpose of causing the immediate death of the subject. The main application for this procedure is capital punishment, but the term may also be applied in a broad sense to euthanasia and suicide. It kills the person by first putting the person to sleep, and then stopping the breathing and heart, respectively.
Lethal injection gained popularity in the late twentieth century as a form of execution intended to supplant other methods, notably electrocution, hanging, firing squad, gas chamber, and beheading, that were considered to be more painful. It is now the most common form of execution in the United States of America.
The concept of lethal injection as a means of putting someone to death was first proposed on January 17, 1888, by Julius Mount Bleyer, a New York doctor who praised it as being cheaper than hanging. Bleyer's idea, however, was never used. The British Royal Commission on Capital Punishment (1949–53) also considered lethal injection, but eventually ruled out it after pressure from the British Medical Association (BMA).
On May 11, 1977, Oklahoma's state medical examiner, Jay Chapman, proposed a new, less painful method of execution, known as Chapman's Protocol: "An intravenous saline drip shall be started in the prisoner's arm, into which shall be introduced a lethal injection consisting of an ultra-short-acting barbiturate in combination with a chemical paralytic." After the procedure was approved by anesthesiologist Stanley Deutsch, the Reverend Bill Wiseman introduced the method into the Oklahoma legislature, where it passed and was quickly adopted (Title 22, Section 1014(A)). Since then, until 2004, thirty-seven of the thirty-eight states using capital punishment introduced lethal injection statutes. On August 29, 1977, Texas adopted the new method of execution, switching to lethal injection from electrocution. On December 7, 1982, Texas became the first state to use lethal injection to carry out capital punishment, for the execution of Charles Brooks, Jr..
The People's Republic of China began using this method in 1997, Guatemala in 1998, the Philippines in 1999, Thailand in 2003, and the Republic of China (Taiwan) in 2005. Vietnam reportedly now uses this method. The Philippines has since abolished the death penalty.
Nazi Germany's T-4 Euthanasia Program used lethal injection as one of several methods to destroy what the Nazi government dubbed "life unworthy of life".
Lethal injection has also been used in cases of euthanasia to facilitate voluntary death in patients with terminal or chronically painful conditions. Both applications have used similar drug combinations.
The export of drugs to be used for lethal injection was banned by the European Union (EU) in 2011, together with other items under the EU Torture Regulation.
The People's Republic of China used to execute prisoners exclusively by means of shooting, but has been changing over to lethal injection in recent years. The specific lethal injection procedures, including the drug or drugs used, are a state secret and not widely known. In at least some cases, prisoners facing death by lethal injection have been sedated at a prison, then placed inside an execution van that is disguised to look like a regular police van.
The condemned person is strapped onto a gurney; two intravenous cannulae ("IVs") are inserted, one in each arm. Only one is necessary to carry out the execution; the other is reserved as a backup in the event the primary line fails. A line leading from the IV line in an adjacent room is attached to the prisoner's IV, and secured so the line does not snap during the injections.
The arm of the condemned person is swabbed with alcohol before the cannula is inserted. The needles and equipment used are also sterilized. There have been questions about why these precautions against infection are performed despite the purpose of the injection being death. There are several explanations: cannulae are sterilized during manufacture, so using sterile ones is routine medical procedure. Secondly, there is a chance that the prisoner could receive a stay of execution after the cannulae have been inserted, as happened in the case of James Autry in October 1983 (he was eventually executed on March 14, 1984). Finally, it would be a hazard to prison personnel to use unsterilized equipment.
Following connection of the lines, saline drips are started in both arms. This, too, is standard medical procedure: it must be ascertained that the IV lines are patent, ensuring the chemicals do not mix in the IV lines and occlude the needle, preventing the drugs from reaching the subject. A heart monitor is attached so prison officials can determine when death has occurred.
The intravenous injection is usually a series of drugs given in a set sequence, designed to first induce unconsciousness followed by death through paralysis of respiratory muscles and/or by cardiac arrest through depolarization of cardiac muscle cells. The execution of the condemned in most states involves three separate injections (in sequential order):
The drugs are not mixed externally as that can cause them to precipitate. Also, a sequential injection is key to achieve the desired effects in the appropriate order: administration of the pentobarbital essentially renders the inmate unconscious; the infusion of the pancuronium bromide induces complete paralysis, including that of the lungs and diaphragm rendering the inmate unable to breathe. The injection of a highly concentrated solution of potassium chloride could cause severe pain at the site of the IV line as well as along the punctured vein, but it will interrupt the electrical activity of the heart muscle and cause it to stop beating, bringing about the death of the inmate.
The intravenous tubing leads to a room next to the execution chamber, usually separated from the offender by a curtain or wall. Typically a prison employee trained in venipuncture inserts the needle, while a second prison employee orders, prepares and loads the drugs into the lethal injection syringes. Two other staff members take each of the three syringes and secure them into the IVs. After the curtain is opened to allow the witnesses to see inside the chamber, the condemned offender is then permitted to make a final statement. Following this, the warden will signal that the execution may commence, and the executioner(s) (either prison staff or private citizens depending on the jurisdiction) will then manually inject the three drugs in sequence. During the execution, the condemned's cardiac rhythm is monitored. Death is pronounced after cardiac activity stops. Death usually occurs within seven minutes, although the whole procedure can take up to two hours, as was the case with the execution of Christopher Newton on May 24, 2007. According to state law, if a physician's participation in the execution is prohibited for reasons of medical ethics, then the death ruling can be made by the state Medical Examiner's Office. After confirmation that death has occurred, a coroner signs the condemned’s death certificate.
In three states (Delaware, Illinois and Missouri) there is a lethal injection machine designed by Massachusetts-based Fred A. Leuchter that comprises two components: the delivery module and the control module.(Illinois has since abolished the death penalty.) Two staff members each have a station in which they key the machine on and depress two stations buttons to be ready in case of mechanical failure. Each person presses one station button on the console which travels to a computer which starts all three injections electronically. The computer then deletes who actually started the syringes so that participants are not aware if their syringe contained saline or one of the drugs necessary for execution (to assuage guilt in a manner similar to the blank cartridge in execution by firing squad). The delivery module has eight syringes. The end syringes containing saline, syringes 2, 4, 6 containing the lethal drugs for the main line and syringes 1, 3, 5 containing the injections for the back-up line. The system was used in New Jersey before the abolition of the death penalty in 2007. Illinois previously used the computer, and Missouri and Delaware use the manual injection switch on the delivery panel.
In 2011, after pressure by activist organizations, the manufacturers of sodium thiopental and pentobarbital halted supply of the drugs to U.S. prisons performing lethal injections and required all resellers to do the same.
Typically, three drugs are used in lethal injection. Sodium thiopental is used to induce unconsciousness, pancuronium bromide (Pavulon) to cause muscle paralysis and respiratory arrest, and potassium chloride to stop the heart.
Sodium thiopental (US trade name: Sodium Pentothal) is an ultra-short acting barbiturate, often used for anesthesia induction and for medically induced coma. The typical anesthesia induction dose is 0.35 grams. Loss of consciousness is induced within 30–45 seconds at the typical dose, while a 5 gram dose (14 times the normal dose) is likely to induce unconsciousness in 10 seconds.
A full medical dose of Thiopental reaches the brain in about 30 seconds. This induces an unconscious state. Within 5 to 20 minutes only 15% of the drug remains in the brain, with the rest redistributed to the rest of the body.
The half-life of this drug is about 11.5 hours, and the concentration in the brain remains at around 5–10% of the total dose during that time. When a 'mega-dose' is administered, as in state-sanctioned lethal injection, the concentration in the brain during the tail phase of the distribution remains higher than the peak concentration found in the induction dose for anesthesia. This is the reason why an ultra-short acting barbiturate, such as thiopental, can be used for long-term induction of medical coma.
Historically, thiopental has been one of the most commonly used and studied drugs for the induction of coma. Protocols vary for how it is given, but the typical doses are anywhere from 500 mg up to 1.5 grams. It is likely that this data was used to develop the initial protocols for state-sanctioned lethal injection, according to which one gram of thiopental was used to induce the coma. Now, most states use 5 grams to be absolutely certain the dosage is effective.
Barbiturates are the same class of drug used in medically assisted suicide. In euthanasia protocols, the typical dose of thiopental is 1.5 grams, the Dutch Euthanasia protocol indicates 1-1.5 grams or 2 grams in case of high barbiturate tolerance. The dose used for capital punishment is therefore about 3 times more than the dose used in euthanasia.
Pancuronium bromide (Trade name: Pavulon): The related drug curare, like pancuronium, is a non-depolarizing muscle relaxant (a paralytic agent) that blocks the action of acetylcholine at the motor end-plate of the neuromuscular junction. Binding of acetylcholine to receptors on the end-plate causes depolarization and contraction of the muscle fiber; non-depolarizing neuromuscular blocking agents like pancuronium stop this binding from taking place.
The typical dose for pancuronium bromide in capital punishment by lethal injection is 0.2 mg/kg and the duration of paralysis is around 4 to 8 hours. Paralysis of respiratory muscles will lead to death in a considerably shorter time.
Other drugs in use are tubocurarine chloride and succinylcholine chloride.
Pancuronium bromide is a derivative of the alkaloid malouetine from the plant Malouetia bequaertiana.
Potassium is an electrolyte, 98% of which is intracellular. The 2% remaining outside the cell has great implications for cells that generate action potentials. Doctors prescribe potassium for patients when there is insufficient potassium, called hypokalemia, in the blood. The potassium can be given orally, which is the safest route; or it can be given intravenously, in which case there are strict rules and hospital protocols on the rate at which it is given.
The usual intravenous dose is 10–20 mEq per hour and it is given slowly since it takes time for the electrolyte to equilibrate into the cells. When used in state-sanctioned lethal injection, bolus potassium injection affects the electrical conduction of heart muscle. Elevated potassium, or hyperkalemia, causes the resting electrical potential of the heart muscle cells to be lower than normal (less negative). Without this negative resting potential, cardiac cells cannot repolarize (prepare for their next contraction).
Depolarizing the muscle cell inhibits its ability to fire by reducing the available number of sodium channels (they are placed in an inactivated state). ECG changes include faster repolarization (peaked T-waves), PR interval prolongation, widening of the QRS, and eventual sine-wave formation and asystole. Cases of patients dying from hyperkalemia (usually secondary to renal failure) are well known in the medical community, where patients have been known to die very rapidly, having previously seemed to be normal.
Potassium chloride is also used in certain abortions to terminate pregnancies. (See, e.g., Justice Anthony Kennedy's description in the U.S. Supreme Court's opinion in Gonzales v. Carhart. )
It is also used in cardioplegia (cardo-Heart; plegia-paralysis) solutions used to arrest the heart during cardiac surgeries performed on a heart-lung machine.
The Ohio protocol, developed after the incomplete execution of Romell Broom, ensures the rapid and painless onset of anesthesia by only using sodium thiopental and eliminating the use of Pavulon and potassium as the second and third drugs, respectively. It also provides for a secondary fail-safe measure using intramuscular injection of midazolam and hydromorphone in the event intravenous administration of the sodium thiopental proves problematic.
The brief for the U.S. courts written by accessories, the State of Ohio implies that they were unable to find any physicians willing to participate in development of protocols for executions by lethal injection, as this would be a violation of the Hippocratic Oath, and such physicians would be thrown out of the medical community and shunned for engaging in such deeds, even if they could not lawfully be stripped of their license.
On December 8, 2009, Kenneth Biros became the first person executed using Ohio's new single-drug execution protocol. He was pronounced dead at 11:47 a.m. EST, 10 minutes after receiving the injection. On September 10, 2010, Washington became the second state to use the single-drug Ohio protocol with the execution of Cal Coburn Brown. Currently, seven states (Arizona, Georgia, Idaho, Ohio, South Dakota, Texas and Washington) have used the single-drug execution protocol. Four additional states (Arkansas, Kentucky, Louisiana and Missouri) have announced that they are switching to a single-drug protocol but, as of May 2013, have not executed anyone since switching protocols.
After sodium thiopental began being used in executions, Hospira, the only American company that made the drug, stopped manufacturing it due to its use in executions. The subsequent nationwide shortage of sodium thiopental led states to seek for other drugs. Pentobarbital, a drug often used for animal euthanasia, was used as part of a three drug cocktail for the first time on December 16, 2010, when John David Duty was executed in Oklahoma. It was then used as the drug in a single drug execution for the first time on March 10, 2011, when Johnnie Baston was executed in Ohio.
Euthanasia can be accomplished either through oral, intravenous, or intramuscular administration of drugs. In individuals who are incapable of swallowing lethal doses of medication, an intravenous route is preferred. The following is a Dutch protocol for parenteral (intravenous) administration to obtain euthanasia, with the old protocol listed first and the new protocol listed second:
A euthanasia machine may allow an individual to perform the process alone.
In 2006, the Supreme Court ruled in Hill v. McDonough that death-row inmates in the United States could challenge the constitutionality of states' lethal injection procedures through a federal civil rights lawsuit. Since then, numerous death-row inmates have brought such challenges in the lower courts, claiming that lethal injection as currently practiced violates the ban on "cruel and unusual punishment" found in the Eighth Amendment to the United States Constitution. Lower courts evaluating these challenges have reached opposing conclusions. For example, courts have found that lethal injection as practiced in California, Florida, and Tennessee is unconstitutional. On the other hand, courts have found that lethal injection as practiced in Missouri, Arizona, and Oklahoma is constitutionally acceptable.
On September 25, 2007, the United States Supreme Court agreed to hear a lethal injection challenge arising from Kentucky, Baze v. Rees. In Baze, the Supreme Court addressed whether Kentucky's particular lethal injection procedure comports with the Eighth Amendment and will determine the proper legal standard by which lethal injection challenges in general should be judged, all in an effort to bring some uniformity to how these claims are handled by the lower courts. Although uncertainty over whether executions in the United States would be put on hold during the period in which the United States Supreme Court considers the constitutionality of lethal injection initially arose after the court agreed to hear Baze, no executions took place during the period between when the court agreed to hear the case and when its ruling was announced, with the exception of one lethal injection in Texas hours after the court made its announcement.
On April 16, 2008, the Supreme Court rejected Baze v. Rees thereby upholding Kentucky's method of lethal injection in a majority 7–2 decision. Ruth Bader Ginsburg and David Souter dissented. Several states immediately indicated plans to proceed with executions.
The American Medical Association believes that a physician's opinion on capital punishment is a personal decision. Since the AMA is founded on preserving life, they argue that a doctor "should not be a participant" in executions in any professional capacity with the exception of "certifying death, provided that the condemned has been declared dead by another person" and "relieving the acute suffering of a condemned person while awaiting execution". Amnesty International argues that the AMA's position effectively "prohibits doctors from participating in executions." The AMA, however, does not have the authority to prohibit doctors from participation in lethal injection, nor does it have the authority to revoke medical licenses, since this is the responsibility of the individual states.
Typically, most states do not require that physicians administer the drugs for lethal injection, but many states do require that physicians be present to pronounce or certify death][.
Some states specifically detail that participation in a lethal injection is not to be considered practicing medicine. For example, Delaware law reads "the administration of the required lethal substance or substances required by this section shall not be construed to be the practice of medicine and any pharmacist or pharmaceutical supplier is authorized to dispense drugs to the Commissioner or the Commissioner's designee, without prescription, for carrying out the provisions of this section, notwithstanding any other provision of law" (excerpt from Title 11, Chapter 42, § 4209). State law allows for the dispense of the drugs/chemicals for lethal injection to the state's Department of Corrections (DOC) without a prescription.
Opponents of lethal injection believe that it is not actually painless as practiced in the United States. Opponents argue that the thiopental is an ultra-short acting barbiturate that may wear off (anesthesia awareness) and lead to consciousness and an uncomfortable death wherein the inmate is unable to express their discomfort because they have been rendered paralyzed by the paralytic agent.
Opponents point to the fact that sodium thiopental is typically used as an induction agent and not used in the maintenance phase of surgery because of its short acting nature. Following the administration of thiopental, pancuronium bromide is given. Opponents argue that pancuronium bromide not only dilutes the thiopental, but (since the inmate is paralyzed) also prevents the inmate from expressing pain. Additional concerns have been raised over whether inmates are administered an appropriate level of thiopental owing to the rapid redistribution of the drug out of the brain to other parts of the body.
Additionally, opponents argue that the method of administration is also flawed. They state that since the personnel administering the lethal injection lack expertise in anesthesia, the risk of failing to induce unconsciousness is greatly increased. In reference to this problem, Jay Chapman, the creator of lethal injection, said, "It never occurred to me when we set this up that we’d have complete idiots administering the drugs." Also, they argue that the dose of sodium thiopental must be customized to each individual patient, not restricted to a set protocol. Finally, the remote administration results in an increased risk that insufficient amounts of the lethal injection drugs enter the bloodstream.
In total, opponents argue that the effect of dilution or improper administration of thiopental is that the inmate dies an agonizing death through suffocation due to the paralytic effects of pancuronium bromide and the intense burning sensation caused by potassium chloride.
Opponents of lethal injection, as currently practiced, argue that the procedure employed is designed to create the appearance of serenity and a painless death, rather than actually providing it. More specifically, opponents object to the use of Pancuronium bromide, arguing that its use in lethal injection serves no useful purpose since the inmate is physically restrained. Therefore the default function of pancuronium bromide would be to suppress the autonomic nervous system, specifically to stop breathing.
In 2005, University of Miami researchers, in cooperation with an attorney representing death row inmates, published a research letter in the medical journal The Lancet. The article presented protocol information from Texas and Virginia which showed that executioners had no anesthesia training, drugs were administered remotely with no monitoring for anesthesia, data were not recorded and no peer-review was done. Their analysis of toxicology reports from Arizona, Georgia, North Carolina, and South Carolina showed that post-mortem concentrations of thiopental in the blood were lower than that required for surgery in 43 of 49 executed inmates (88%); 21 (43%) inmates had concentrations consistent with awareness. This led the authors to conclude that there was a substantial probability that some of the inmates were aware and suffered extreme pain and distress during execution. The authors attributed the risk of consciousness among inmates to the lack of training and monitoring in the process, but carefully make no recommendations on how to alter the protocol or how to improve the process. Indeed, the authors conclude, "because participation of doctors in protocol design or execution is ethically prohibited, adequate anesthesia cannot be certain. Therefore, to prevent unnecessary cruelty and suffering, cessation and public review of lethal injections is warranted."
Paid expert consultants on both sides of the lethal injection debate have found opportunity to criticize the 2005 Lancet article. Subsequent to the initial publication in the Lancet, three letters to the editor and a response from the authors extended the analysis. The issue of contention is whether Thiopental, like many lipid-soluble drugs, may be redistributed from blood into tissues after death, effectively lowering thiopental concentrations over time, or whether thiopental may distribute from tissues into the blood, effectively increasing post-mortem blood concentrations over time. Given the near-absence of scientific, peer-reviewed data on the topic of thiopental post-mortem pharmacokinetics, the controversy continues in the lethal injection community and in consequence, many legal challenges to lethal injection have not used the Lancet article.
In 2007, the same group that authored The Lancet study extended its study of the lethal injection process through a critical examination of the pharmacology of the barbiturate thiopental. This study – published in the online journal PloS Medicine – confirmed and extended the conclusions made in The Lancet article and go further to disprove the assertion that the lethal injection process is painless.
To date these two studies by the University of Miami team serve as the only critical peer-reviewed examination of the pharmacology of the lethal injection process. These findings also appear true to be further supported by increased reporting of problematic lethal injections in the United States.
The execution can be painlessly accomplished, without risk of consciousness, by the injection of a single large dose of a barbiturate. By this logic, the use of any other chemicals is entirely superfluous and only serves to unnecessarily increase the risk of pain during the execution. Another possibility would be the infusion of a powerful and fast-acting narcotic, such as fentanyl, which would ensure comfort while suppressing the victim's respiratory drive.
When sodium pentobarbital, a barbiturate used in animal euthanasia, is administered in an overdose, it causes rapid unconsciousness. Respiratory arrest follows next, through paralysis of the diaphragm and collapse of the lungs. The drug would then suppress cardiac activity, thus causing death.
On occasion, there have also been difficulties inserting the intravenous needles, sometimes taking over half an hour to find a suitable vein. Typically, the difficulty is found in convicts with a history of intravenous drug use.][ Opponents argue that the insertion of intravenous lines that take excessive amounts of time are tantamount to being cruel and unusual punishment. In addition, opponents point to instances where the intravenous line has failed, or where there have been adverse reactions to drugs, or unnecessary delays during the process of execution.
On December 13, 2006, Angel Nieves Diaz was not executed successfully in Florida using a standard lethal injection dose. Diaz was 55 years old, and had been sentenced to death for murder. Diaz did not succumb to the lethal dose even after 35 minutes, necessitating a second dose of drugs to complete the execution. At first, a prison spokesman denied Diaz had suffered pain, and claimed the second dose was needed because Diaz had some sort of liver disease. After performing an autopsy, the Medical Examiner, Dr. William Hamilton, stated that Diaz’s liver appeared normal, but that the needle had been pierced through Diaz’s vein into his flesh. The deadly chemicals had subsequently been injected into soft tissue, rather than into the vein. Two days after the execution, then-Governor Jeb Bush suspended all executions in the state and appointed a commission “to consider the humanity and constitutionality of lethal injections.” The ban was lifted by Governor Charlie Crist when he signed the death warrant for Mark Dean Schwab on July 18, 2007. On November 1, 2007, the Florida Supreme Court unanimously upheld the state's lethal injection procedures.
A study published in 2007 in the peer-reviewed journal PLoS Medicine suggested that "the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable".
The execution of Romell Broom was abandoned in Ohio on September 15, 2009, after prison officials failed to find a vein after 2 hours of trying on his arms, legs, hands and ankle. This has stirred up intense debate in the United States about lethal injection.
Due to its use for executions in the US, the UK introduced a ban on the export of sodium thiopental in December 2010, after it was established that no European supplies to the US were being used for any other purpose. The restrictions were based on "the European Union Torture Regulation (including licensing of drugs used in execution by lethal injection)". From 21 December 2011 the European Union extended trade restrictions to prevent the export of certain medicinal products for capital punishment, stating that "The Union disapproves of capital punishment in all circumstances and works towards its universal abolition".
The combination of a barbiturate induction agent and a nondepolarizing paralytic agent is used in thousands of anesthetics every day. Supporters of the death penalty argue that unless anesthesiologists have been wrong for the last 40 years, the use of pentothal and pancuronium is safe and effective. In fact, potassium is given in heart bypass surgery to induce cardioplegia. Therefore, the combination of these three drugs is still in use today. Supporters of the death penalty speculate that the designers of the lethal injection protocols intentionally used the same drugs as used in every day surgery to avoid controversy. The only modification is that a massive coma-inducing dose of barbiturates is given. In addition, similar protocols have been used in countries that support euthanasia or physician-assisted suicide.
Thiopental is a rapid and effective drug for inducing unconsciousness, since it causes loss of consciousness upon one circulation through the brain due to its high lipophilicity. Only a few other drugs, such as methohexital, etomidate, or propofol have the capability to induce anesthesia so rapidly. (Narcotics such as Fentanyl are inadequate as induction agents for anesthesia.) Supporters argue that since the thiopental is given at a much higher dose than for medically induced coma protocols, it is effectively impossible for the condemned to wake up.
Anesthesia awareness occurs when general anesthesia is inadequately maintained, for a number of reasons. Typically, anesthesia is induced with an intravenous drug, but maintained with an inhaled anesthetic given by the anesthesiologist (note that there are several other methods of safely and effectively maintaining anesthesia). Barbiturates are used only for induction of anesthesia and these drugs rapidly and reliably induce anesthesia, but wear off quickly. A neuromuscular blocking drug may then be given to cause paralysis which facilitates intubation, although this is not always required. The anesthesiologist has the responsibility to ensure that the maintenance technique (typically inhalational) is started soon after induction to prevent the patient from waking up.
General anesthesia is not maintained with barbiturate drugs. An induction dose of thiopental wears off after a few minutes because the thiopental redistributes from the brain to the rest of the body very quickly. However, it has a long half-life, which means that it takes a long time for the drug to be eliminated from the body. If a very large initial dose is given, little or no redistribution takes place (since the body is saturated with the drug), which means that recovery of consciousness requires the drug to be eliminated from the body, which is not only slow (taking many hours or days), but unpredictable in duration, making barbiturates very unsatisfactory for maintenance of anesthesia.
Thiopental has a half-life of approximately 11.5 hours (however, the action of a single dose is terminated within a few minutes by redistribution of the drug from the brain to peripheral tissues) and the long acting barbiturate phenobarbital has a half-life of approximately 4–5 days. It contrasts towards the inhaled anesthetics have extremely short half-lives and allow the patient to wake up rapidly and predictably after surgery.
The average time to death once a lethal injection protocol has been started is about 7 – 11 minutes. Since it only takes about 30 seconds for the thiopental to induce anesthesia, 30–45 seconds for the pancuronium to cause paralysis, and about 30 seconds for the potassium to stop the heart, death can theoretically be attained in as little as 90 seconds. Given that it takes time to administer the drug, time for the line to flush itself, time for the change of the drug being administered, and time to ensure that death has occurred, the whole procedure takes about 7–11 minutes. Procedural aspects in pronouncing death also contribute to delay and, therefore, the condemned is usually pronounced dead within 10 – 20 minutes of starting the drugs. Supporters of the death penalty say that a huge dose of thiopental, which is between 14 – 20 times the anesthetic induction dose and which has the potential to induce a medical coma lasting 60 hours, could never wear off in only 10 to 20 minutes.
Death penalty supporters state that the claim that pancuronium dilutes the sodium thiopental dose is erroneous. Supporters argue that pancuronium and thiopental are commonly used together in surgery every day and if there were a dilution effect, it would be a known drug interaction.
Drug interactions are a complex topic. Some drug interactions can be simplistically classified as either synergistic or inhibitory interactions. In addition, drug interactions can occur directly at the site of action, through common pathways or indirectly through metabolism of the drug in the liver or through elimination in the kidney. Pancuronium and thiopental have different sites of action, one in the brain and one at the neuromuscular junction. Since the half-life of thiopental is 11.5 hours, the metabolism of the drugs is not an issue when dealing with the short time frame in lethal injections. The only other plausible interpretation would be a direct one, or one in which the two compounds interact with each other. Supporters of the death penalty argue that this theory does not hold true. They state that even if the 100 mg of pancuronium directly prevented 500 mg of thiopental from working, there would be sufficient thiopental to induce coma for 50 hours. In addition, if this interaction did occur, then the pancuronium would be incapable of causing paralysis.][
Supporters of the death penalty state that the claim that the pancuronium prevents the thiopental from working, yet is still capable of causing paralysis, is not based on any scientific evidence and is a drug interaction that has never before been documented for any other drugs.][Supporters of the death penalty question if this is an invented false claim.][
Amnesty International, Human Rights Watch, Death Penalty Information Center, Reprieve, and other anti-death penalty groups have not proposed a lethal injection protocol which they believe is less painful. Supporters of the death penalty argue that the lack of an alternative proposed protocol is testament to the fact that the painfulness of the lethal injection protocol is not the issue. Instead supporters argue that the issue is the continued existence of the death penalty, since if the only issue was the painfulness of the procedure, then Amnesty International, HRW, or the DPIC should have already proposed a less painful method.
Regardless of an alternative protocol, some death penalty opponents have claimed that execution can be less painful by the administration of a single lethal dose of barbiturate.][ Supporters of the death penalty, however, state that the single drug theory is a flawed concept.][Terminally ill patients in Oregon who have requested physician-assisted suicide have received lethal doses of barbiturates. The protocol has been highly effective in producing a painless death, but the time to cause death can be prolonged. Some patients have taken days to die, and a few patients have actually survived the process and have regained consciousness up to three days after taking the lethal dose. In a Californian legal proceeding addressing the issue of the lethal injection cocktail being "cruel and unusual," state authorities said that the time to death following a single injection of a barbiturate could be as much as 45 minutes.
Scientifically, this is readily explained. Barbiturate overdoses typically cause death by depression of the respiratory center, but the effect is variable. Some patients may have complete cessation of respiratory drive, whereas others may only have depression of respiratory function. In addition, cardiac activity can last for a long time after cessation of respiration. Since death is pronounced after asystole and given that the expectation is for a rapid death in lethal injection, multiple drugs are required; specifically potassium chloride to stop the heart. In fact, in the case of Clarence Ray Allen a second dose of potassium chloride was required to attain asystole. The position of most death penalty supporters is that death should be attained in a reasonable amount of time.
Supporters of the death penalty agree that the use of pancuronium bromide is not absolutely necessary in the lethal injection protocol. Some supporters believe that the drug may decrease muscular fasciculations when the potassium is given, but this has yet to be proven.][
An injection (often referred to as a "shot" in US English, or a "jab" in UK English) is an infusion method of putting fluid into the body, usually with a syringe and a hollow needle which is pierced through the skin to a sufficient depth for the material to be administered into the body. An injection follows a parenteral route of administration; that is, administration via a route other than through the digestive tract.
There are several methods of injection or infusion, including intradermal, subcutaneous, intramuscular, intravenous, intraosseous, and intraperitoneal. Long-acting forms of subcutaneous/intramuscular injections are available for various drugs, and are called depot injections.
Injections are among the most common health care procedures, with at least 16 billion administered in developing and transitional countries each year. 95% of injections are administered in curative care, 3% are for immunization, and the rest for other purposes, such as blood transfusions.
In an intramuscular injection, the medication is delivered directly into a muscle. Many vaccines are administered intramuscularly, as are codeine, metoclopramide, and many other medications. Many drugs injected intramuscularly are absorbed into the muscle fairly quickly, while others are more gradual. Injections to the buttocks are known to reach the bloodstream quickly due to the large amount of muscular tissue and corresponding blood supply.
Generally, intramuscular injections are administered by a trained medical professional; however, prescribed self-administered intramuscular injections are becoming more common for patients who require these injections routinely.
A depot injection is an injection, usually subcutaneous or intramuscular, of a pharmacological agent which releases its active compound in a consistent way over a long period of time. Depot injections are usually either solid or oil-based. Depot injections may be available as certain forms of a drug, such as decanoate salts or esters. Examples of depot injections include Depo Provera and haloperidol decanoate. Prostate cancer patients receiving hormone therapy usually get depot injections as a treatment or therapy. Zoladex is an example of a medication delivered by depot for prostate cancer treatment or therapy.
The advantages of using a long-acting depot injection include increased medication compliance due to reduction in the frequency of dosing, as well as more consistent serum concentrations. A significant disadvantage is that the drug is not immediately reversible, since it is slowly released. In psychiatric nursing, a short acting depot, zuclopenthixol acetate (Clopixol Acuphase), which lasts in the system from 24 – 72 hours, is now more regularly used for rapid tranquillisation.
Various animals, and some plants, have been injecting for various reasons long before humans began doing so in a process commonly called stinging. Some examples include:
The pain of an injection may be lessened by prior application of ice or topical anesthetic, or simultaneous pinching of the skin. Recent studies suggest that forced coughing during an injection stimulates a transient rise in blood pressure which inhibits the perception of pain. Sometimes, as with an amniocentesis, a local anesthetic is given. The most common technique to reduce the pain of an injection is simply to distract the patient.
Babies can be distracted by giving them a small amount of sweet liquid, such as sugar solution, during the injection, which reduces crying.
40% of injections worldwide are administered with unsterilized, reused syringes and needles, and in some countries this proportion is 70%, exposing millions of people to infections.
Another risk is poor collection and disposal of dirty injection equipment, which exposes healthcare workers and the community to the risk of needle stick injuries. In some countries, unsafe disposal can lead to re-sale of used equipment on the black market. Many countries have legislation or policies that mandate that healthcare professionals use a safety syringe (safety engineered needle) or alternative methods of administering medicines whenever possible.
Open burning of syringes, which is considered unsafe by the World Health Organization, is reported by half of the non-industrialized countries.
According to one study, unsafe injections cause an estimated 1.3 million early deaths each year.
To improve injection safety, the WHO recommends:
1. Changing the behavior of health care workers and patients.
2. Ensuring the availability of equipment and supplies.
3. Managing waste safely and appropriately.
A needle tract infection is an infection that occurs when pathogenic micro-organisms are seeded into the tissues of the body during an injection.
, first marketed as Valium
by Hoffmann-La Roche, is a benzodiazepine drug.
It is commonly used to treat anxiety, panic attacks, insomnia, seizures (including status epilepticus
), muscle spasms (such as in tetanus cases), restless legs syndrome, alcohol withdrawal, benzodiazepine withdrawal, opiate withdrawal syndrome and Ménière's disease. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.
It possesses anxiolytic, anticonvulsant, hypnotic, sedative, skeletal muscle relaxant, and amnestic properties. The pharmacological action of diazepam enhances the effect of the neurotransmitter GABA by binding to the benzodiazepine site on the receptorA
GABA (via the constituent chlorine atom) leading to central nervous system depression.
Adverse effects of diazepam include anterograde amnesia (especially at higher doses) and sedation, as well as paradoxical effects such as excitement, rage or worsening of seizures in epileptics. Benzodiazepines also can cause or worsen depression. Long-term effects of benzodiazepines such as diazepam include tolerance, benzodiazepine dependence and benzodiazepine withdrawal syndrome upon dose reduction. After cessation of benzodiazepines, cognitive deficits may persist for at least six months and it was suggested that longer than six months may be needed for recovery from some deficits. Diazepam also has physical dependence potential and can cause serious problems of physical dependence with long term use. Compared to other benzodiazepines, though, physical withdrawal from diazepam following long term use is usually far more mild due to its long elimination half-life. Nevertheless, urgent action by national governments to improve prescribing practices has been recommended. Diazepam is the drug of choice for treating benzodiazepine dependence, with its low potency, long duration of action and the availability of low-dose tablets making it ideal for gradual dose reduction and the circumvention of withdrawal symptoms.
Advantages of diazepam are a rapid onset of action]
[ and high efficacy rates, which is important for managing acute seizures, anxiety attacks and panic attacks; benzodiazepines also have a relatively low toxicity in overdose. Diazepam is a core medicine in the World Health Organization's Essential Drugs List
, which list minimum medical needs for a basic health care system. Diazepam, first synthesized by Leo Sternbach, is used to treat a wide range of conditions, and has been one of the most frequently prescribed medications in the world since its launch in 1963.
Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia before certain medical procedures (e.g., endoscopy).
Intravenous diazepam or lorazepam are first line treatments for status epilepticus; However, lorazepam has advantages over diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to 12 months of treatment, effectively rendering it useless for that purpose. Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood pressure control measures have failed. Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain. However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm. Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. Baclofen or tizanidine is sometimes used as an alternative to diazepam.
The anticonvulsant effects of diazepam can help in the treatment of seizures due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, soman (or other organophosphate poisons; See #CANA), lindane, chloroquine, physostigmine, or pyrethroids Diazepam is sometimes used intermittently for the prophylaxis of febrile seizures caused by high fever in children and neonates under five years of age. Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup individuals with treatment resistant epilepsy benefit from long-term benzodiazepines and for such individuals clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects.
Diazepam has a broad spectrum of indications (most of which are off-label), including:
Dosages should be determined on an individual basis, depending upon the condition being treated, severity of symptoms, patient body weight, and any comorbid conditions the patient may have.
Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation and rectal forms.
The United States military employs a specialized diazepam preparation known as CANA (Convulsive Antidote, Nerve Agent), which contains a mixture of diazepam, atropine and pralidoxime. One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using autoinjectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care.
Use of diazepam should be avoided, when possible, in individuals with the following conditions:
Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia and hangover effects, as well as falls. Long-term use of benzodiazepines such as diazepam is associated with tolerance, benzodiazepine dependence and benzodiazepine withdrawal syndrome. Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before using benzodiazepines is not impaired. Tolerance to the cognitive-impairing effects of benzodiazepines does not tend to develop with long-term use, and the elderly are more sensitive to them. Additionally after cessation of benzodiazepines cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression. Infusions or repeated intravenous injections of diazepam when managing seizures for example may lead to drug toxicity, including respiratory depression, sedation and hypotension. Tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Adverse effects such as sedation, benzodiazepine dependence and abuse potential limit the use of benzodiazepines.
Diazepam has a range of side effects common to most benzodiazepines, including:
Less commonly, paradoxical side effects can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of drug or alcohol abuse and or aggression. Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts. Very rarely dystonia can occur.
Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.
During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.
Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation), leading to respiratory arrest and death.
Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.
Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms.
Withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life.
Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regimen. Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. Approximately one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience a withdrawal syndrome upon cessation.
Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience little or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%.
Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines. Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction. There is a significant risk of pharmacological dependence on diazepam and patients experiencing symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer. In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.
Improper or excessive use of diazepam can lead to psychological dependence/drug addiction. At a particularly high risk for diazepam misuse, abuse or psychological dependence are:
Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if physical dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in these people is not recommended.
People suspected of being physiologically dependent on benzodiazepine drugs should be very gradually tapered off the drug. Although rare, withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.
An individual who has consumed too much diazepam typically displays one or more of the following symptoms in a period of approximately four hours immediately following a suspected overdose:
Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Although not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.
The oral 50
LD (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites, esmethyldiazepam, oxazepam, and temazepam; according to samples taken in the hospital and as follow-up.
Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.
An Australian study has found people who take sleeping pills or antianxiety medications are more dangerous on the roads than drunk drivers.
If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, phenothiazines, narcotics and antidepressants.
Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.
Agents that have an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.
Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. Diazepam has anticonvulsant properties. Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity, but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs from some other anticonvulsive drugs with which it was compared. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.
Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high affinity choline uptake in mouse brain cells in vitro
, after pretreatment of the mice with diazepam in vivo
. This may play a role in explaining diazepam's anticonvulsant properties.
Diazepam binds with high affinity to glial cells in animal cell cultures. Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex. Diazepam also decreases prolactin release in rats.
Diazepam binds to a specific subunit on the A
GABA receptor at a site distinct from the binding site of the endogenous GABA molecule, known as an allosteric site. The GABAA
receptor is an inhibitory channel which, when activated, decreases neuronal activity. Benzodiazepines do not supplement for the neurotransmitter GABA, rather benzodiazepines such as diazepam bind to a different location on the GABAA
receptor, resulting in enhanced GABA effects. Benzodiazepines cause an increased opening of the chloride ion channel when GABA binds to its site on the GABAA
receptor, leading to more chloride ions entering the neuron, which in turn leads to enhanced central nervous system depressant effects. Diazepam binds non-selectively to alpha1, alpha2, alpha3 and alpha5 subunit containing GABAA
Because of the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors, it causes inhibitory effects. This arises from the hyperpolarization of the postsynaptic membrane, owing to the control exerted over negative chloride ions by GABAA
Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.
The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.
The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.
Diazepam can be administered orally, intravenously (IV) (needs to be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.
When administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to one hour for both routes of administration. The bioavailability after oral administration is 100%, and 90% after rectal administration. Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; after rectal administration, peak plasma levels occur after 10 to 45 minutes. Diazepam is highly protein bound, with 96 to 99% of the absorbed drug being protein bound. The distribution half-life of diazepam is two to 13 minutes.
When diazepam is administered IM, absorption is slow, erratic and incomplete.
Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood–brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far in excess of the actual dose for any given day.
Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified.
Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam.
Most of the drug is metabolised; very little diazepam is excreted unchanged.
The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration.
Diazepam may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma diazepam concentrations are usually in a range of 0.1-1.0 mg/L in persons receiving the drug therapeutically, 1–5 mg/L in those arrested for impaired driving and 2–20 mg/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation is usually performed using chromatographic techniques.
Diazepam occurs as solid white or yellow crystals with a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions. Diazepam should be stored at room temperature (15–30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.
Diazepam can absorb into plastic, so is not stored in plastic bottles or syringes, etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and does not dissolve.
From a chemical point of view, diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is the most simple of all of the examined derivatives of 1,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, is methylated by dimethylsulfate, which leads to the formation of diazepam.
The second way differs from the first in that the methylation of nitrogen is accomplished before the cyclocondensation reaction. To do this, the initial 2-amino-5-chlorobenzophenone is first tosylated by p-toluenesulfonylchloride and the obtained tosylate transformed into the N-sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-N-tosyl-N-methyl-5-chlorobenzophenone is hydrolyzed in an acidic medium, giving 2-methylamino-5-chlorobenzophenone, which undergoes cyclocondensation by reaction with ethyl ester of glycine hydrochloride, forming the desired diazepam.
Diazepam was the second benzodiazepine invented by Dr. Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives). Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.
Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 2.3 billion tablets. Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia. While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, for example, forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome. In recent years, the public perception of benzodiazepines has become increasingly negative.
Diazepam is a drug of potential abuse and can cause serious problems of addiction and as a result is scheduled. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam. A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways. Between 50 and 64% of rats will self administer diazepam. Benzodiazepines including diazepam in animal studies have been shown to increase reward-seeking behaviours by increasing impulsivity, which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines. In addition, diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study. Diazepam has been found as an adulterant in heroin.
Diazepam drug misuse can occur either through recreational misuse where the drug is taken to achieve a high or when the drug is continued long term against medical advice.
Sometimes, it is used by stimulant users to "come down" and sleep and to help control the urge to binge.
A large-scale, nationwide study conducted by SAMHSA found benzodiazepines in the USA are the most frequently abused pharmaceutical, with 35% of drug-related visits to the emergency department involving benzodiazepines. They are more commonly abused than opiate pharmaceuticals, which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as females. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is, however, alprazolam. Clonazepam is the second-most-abused benzodiazepine. Lorazepam is the third-most-abused benzodiazepine, and diazepam the fourth-most-abused benzodiazepine in the USA.
Benzodiazepines, including diazepam, nitrazepam, and flunitrazepam, account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.
Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden, and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range, suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found in 87% of cases. Diazepam was the most commonly detected benzodiazepine.
Diazepam is regulated in most countries as a prescription drug:
The State of California offers diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program.
Diazepam is used as a short-term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. It can also be used as an appetite stimulant. For emergency treatment of seizures, the typical dose is 0.5cmg/kg intravenously, or 1–2c;mg/kg of the injectable solution administered in the rectum.
gen / txn
noco (m/d/e/h/v/s)/cong/tumr, sysi/epon, injr
proc, drug (N1A/2AB/C/3/4/7A/B/C/D)
dsrd (o, p, m, p, a, d, s), sysi/epon, spvo
proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)
Injection lipolysis is a controversial cosmetic procedure in which drug mixtures are injected into patients with the goal of breaking down fat. This practice, using drugs generally based on phosphatidylcholine and deoxycholate (PCDC), evolved from the initial intravenous use of those drug formulations to treat blood disorders.
In 1966, investigators noted that the intravenous infusion of PC-containing solutions could remove fat emboli. Later, a drug formulation called Lipostabil containing 5% PC and 4.75% deoxycholate (DC) was approved in Germany and used in the treatment of fat embolism, dyslipidemia, and alcohol-induced liver cirrhosis. The first report of Lipostabil injection for fat removal demonstrated that infra-orbital ("under the eyelid") fat could be removed by Lipostabil injection. While no placebo-controlled studies have demonstrated the safety or efficacy of this therapy, numerous retrospective studies of Lipostabil injections have reported the efficacy of this practice. The mixture is injected directly into the subcutaneous fat through multiple microinjections administered over multiple treatment sessions. The desired end result is the removal of localized fat deposits.
On April 7, 2010, the US Food and Drug Administration issued Warning Letters to six U.S. based medical spas and a company in Brazil for making false or misleading statements on their Web sites about drugs they claim will eliminate fat in a procedure called “lipodissolve,” or for otherwise misbranding lipodissolve products. “We are concerned that these companies are misleading consumers,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “It is important for anyone who is considering this voluntary procedure to understand that the products used to perform lipodissolve procedures are not approved by the FDA for fat removal.”
For the complete FDA statement, see here .
To see the warning letter, see .
The FDA has received reports of adverse effects in persons who have had the procedure using these drugs, including permanent scarring, skin deformation, and deep painful knots under the skin in areas where the lipodissolve products have been injected. The warning letters were issued to the following U.S. companies: Monarch Medspa, King of Prussia, Pa; Spa 35, Boise, Idaho; Medical Cosmetic Enhancements, Chevy Chase, Md.; Innovative Directions in Health, Edina, Minn PURE Med Spa, Boca Raton, Fl.; and All About You Med Spa, Madison, Ind. The Brazilian company receiving a warning letter markets lipodissolve products on two Web sites: zipmed.net and mesoone.com.
The FDA is requesting a written response from the U.S. companies within 15 business days of receipt of the warning letters stating how they will correct these violations and prevent similar violations in the future. Each U.S. company has been informed in its warning letter that failure to promptly correct the violations may result in legal action. Each of the companies involved has been cited for a variety of regulatory violations, including making unsupported claims that the products have an outstanding safety record and are superior to other fat loss procedures, including liposuction. Additionally some of the letters indicate that the companies have made claim that lipodissolve products can be used to treat certain medical conditions, such as male breast enlargement, benign fatty growths known as lipomas, excess fat deposits and surgical deformities. The FDA is not aware of clinical evidence to support any of these claims.
Three medical associations have issued health warnings cautioning against the use of injection lypolysis, including the American Society of Plastic Surgeons (ASPS), the American Society for Aesthetic Plastic Surgery (ASAPS), and the American Society of Dermatologic Surgery (ASDS).
The Medicines and Healthcare Products Regulatory Agency, the governmental body regulating the manufacture and commercialization of drugs in the United Kingdom, issued a similar warning to physicians considering the use of these substances for cosmetic purposes, stating these drugs "are being unlawfully advertised in the UK as a cosmetic product for the reduction of fat." The MHRA also pointed out that considerable safety concerns remain because these agents have not been tested in controlled clinical trials. While British physicians can still inject Lipodissolve for fat removal, the drug cannot be promoted as a drug for that purpose. As of July, 2005, The Medical Protection Society, the organization that provides British doctors with legal advice and coverage against litigation costs and damages, ceased offering malpractice insurance for use of Lipodissolve because of safety concerns.