Diazepam

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History

Diazepam was the second benzodiazepine to be invented by Sternbach of Hoffmann-La Roche, 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 two and a half 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). blueair 501

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets. Diazepamlong with oxazepam, nitrazepam and temazepamepresents 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, e.g., forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome. odor eliminator

Indications air ionizer purifier

Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate 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. Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose.

Diazepam has a broad spectrum of indications (most of which are off-label), including:

Treatment of anxiety, panic attacks, and states of agitation

Adjunctive treatment of other forms of epilepsy

Treatment of neurovegetative symptoms associated with vertigo

Treatment of the symptoms of alcohol, opiate and benzodiazepine withdrawal

Short-term treatment of insomnia

Treatment of tetanus, together with other measures of intensive-treatment

Adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment is coupled with other rehabilitative measures)

Palliative treatment of stiff person syndrome

Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g., before endoscopic or surgical procedures)

Treatment of overdosage with hallucinogens or CNS stimulants

Adjunctive treatment of drug-induced seizures, resulting from exposure to sarin, VX, soman (or other organophosphate poisons; See #CANA), lindane, chloroquine, physostigmine, or pyrethroids

Emergency treatment of eclampsia, along with IV magnesium sulfate

Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy

Used in the treatment for irritable bowel syndrome

Used to treat pain resulting from muscle spasms caused by various dystonias, including blepharospasm

Veterinary uses

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 emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously, or 12 mg/kg of the injectable solution administered in the rectum.

Before judicial executions

The State of California offers diazepam to condemned inmates as a pre-execution sedative as part of their Lethal Injection program.

Dosage

Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have.

Typical dosages for healthy adults range from 2 mg per dose to 10 mg per dose taken 2 to 4 times per day, depending on such factors as body weight and condition being treated. For the elderly or people with liver disorders, initial dose is at the low end of the range, with the dose being increased as required.

Availability

Diazepam is marketed in over 500 brands throughout the world. It is supplied in the following forms:

For oral administration:

Tablets 2 mg, 5 mg, 10 mg. Generic versions available.

Capsules, time-release 15 mg (marketed by Roche as Valrelease)

Liquid solution 1 mg/ml in 500 ml containers and unit-dose (5 mg & 10 mg); 5 mg/ml in 30 ml dropper bottle (marketed by Roxane as Diazepam Intensol)

For parenteral administration:

Solution for IV/IM injection 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.

Note: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly. (See comment above, under Pharmacokinetics, re IM injection).

Seduxen (Diazepam, in Hungary, Russia, Poland, and other Eastern-European countries) is supplied in the following forms:

For oral administration:

Tablets 5 mg

Injection 5 mg/ml for intravenous, intramuscular or subcutaneous usage

For parenteral administration:

Solution for IV/IM injection 5 mg/ml. 2 ml ampoules and syringes; 1 ml, 2 ml, 10 ml vials; 2 ml Tel-E-Ject; also contains 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate and benzoic acid as buffers, and 1.5% benzyl alcohol as a preservative.

Notice: IM injection is largely less effective as the drug is injected into a tetanic muscle with compressed muscular veins. This does not allow the drug to reach the circulation rapidly.

For rectal administration:

Solution

Suppositories 5 mg and 10 mg

Rectal tubes

For inhalation administration: This method uses heating diazepam to form a vapor later producing an aerosol. This allows the drug to be passed through an inhalation route during an inhalation therapy. Provided in doses 220 mg either in a single inhalation or multiple small inhalations

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 (2-PAM). 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 auto-injectors. 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.

Side-effects

Diazepam has a range of side-effects that are common to most benzodiazepines. Most common side-effects include:

Somnolence

Suppression of REM sleep

Impaired motor function

Impaired coordination

Impaired balance

Dizziness and nausea

Depression

Impaired learning

Anterograde amnesia (especially pronounced in higher doses)

Cognitive deficits

Reflex tachycardia

Less common paradoxical side-effects can include nervousness, irritability, insomnia, muscle cramps, changes in libido (increased or decreased libido) and in some cases, rage, and violence. Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts. If these side-effects are present, diazepam treatment should be immediately terminated.

Very rarely dystonia. Benzodiazepines such as diazepam impair learning and memory via their action on benzodiazepine receptors, which causes a dysfunction in the cholinergic neuronal system.

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.

Interactions

If diazepam is to be 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. There is no evidence that 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 increases the central depressive effects of alcohol, other hypnotics/sedatives (e.g., barbiturates), narcotics, and other muscle relaxants. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.

Cimetidine, omeprazole, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine and valproic acid prolong the action of diazepam by inhibiting its elimination.

Alcohol (ethanol) in combination with diazepam may cause a synergistic enhancement of the hypotensive properties of benzodiazepines and alcohol.

Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.

Rifampin, phenytoin, carbamazepine and phenobarbital increase the metabolism of diazepam, thus decreasing drug levels and effects.

Diazepam increases the serum levels of phenobarbital.

Nefazodone can cause increased blood levels of benzodiazepines.

Cisapride may enhance the absorption, and therefore the sedative activity, of diazepam.

Small doses of theophylline may inhibit the action of diazepam.

Diazepam may block the action of levodopa (used in the treatment of Parkinson's Disease).

Diazepam may alter digoxin serum concentrations.

Other drugs that may have interactions with diazepam include: Antipsychotics (e.g. chlorpromazine), MAO inhibitors, ranitidine.

Caffeine may antagonise the effects of diazepam and vice versa.

Smoking tobacco can enhance the elimination of diazepam and decrease its action.

Because it acts on the GABA receptor the herb Valerian may produce an adverse effect.

Foods that acidify the urine can lead to faster absorption and elimination of diazepam, reducing drug levels and activity.

Foods that alkalinize the urine can lead to slower absorption and elimination of diazepam, increasing drug levels and activity.

There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.

Contraindications

Use of diazepam should be avoided, when possible, in individuals with the following conditions:

Ataxia

Severe hypoventilation

Acute narrow-angle glaucoma

Severe hepatic deficiencies (hepatitis and liver cirrhosis decrease elimination by a factor of 2)

Severe renal deficiencies (e.g. patients on dialysis)

Liver disorders

Severe respiratory disorders

Severe sleep apnea

Severe depression, particularly when accompanied by suicidal tendencies

Psychosis

Pregnancy or breast feeding

Caution required in elderly or debilitated patients

Coma or shock

Abrupt discontinuation of therapy

Acute intoxication with alcohol, narcotics, or other psychoactive substances (with the exception of some hallucinogens, where it is occasionally used as a treatment for overdose)

History of alcohol or drug dependence

Myasthenia gravis, or MG, an autoimmune disorder causing marked fatiguability.

Hypersensitivity or allergy to any drug in the benzodiazepine class

Special caution needed

Benzodiazepines require special precaution if used in the alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.

Pediatric patients

Less than 18 years of age Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.

Under 6 months of age Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.

Elderly and very ill patients Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients.

Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.

I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.

Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in floppy infant syndrome.

Pregnancy

Diazepam when taken late in pregnancy, during the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Tolerance and physical dependence

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 that are similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can occur from standard dosages and also after short-term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime. It has been shown in a clinical study that between 50100% of patients on low-dose long-term diazepam therapy are physically dependent on their medication, and experience withdrawal symptoms upon discontinuation from a dose taper. The difference in rates of withdrawal (50100%) varies depending on the patient sample being investigated. For example a random sample of long term benzodiazepine users typically finds that around 50% will experience little or no withdrawal symptoms and the other 50% experiencing notable withdrawal symptoms. Certain select patient groups will 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 6 weeks or longer. In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.

Overdose

Main article: Benzodiazepine overdose

An individual that has consumed too much diazepam will typically display one or more of the following symptoms in the period up around four hours immediately following a suspected overdose.:

Drowsiness

Mental confusion

Hypotension

Impaired motor functions

Impaired reflexes

Impaired coordination

Impaired balance

Dizziness

Coma

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 LD50 (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 important complications, in spite of having high concentrations of diazepam and its metabolitesesmethyldiazepam, oxazepam, and temazepamccording to samples taken in the hospital and as follow-up.

Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.

Physical properties

Diazepam occurs as solid white or yellow crystals and has 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 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution. Diazepam should be stored at room temperature (1530 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, and, therefore, diazepam solution is not stored in plastic bottles or syringes, etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.

Pharmacology

Non-U.S.A. 10mg Valium

Diazepam is a "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, alprazolam, nitrazepam, 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 insofar from some other anticonvulsive drugs it was compared with. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.

Diazepam affects the emotional-motivational component of the pain experience, but not the sensory discriminative component or the central control of pain. 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.

Mechanism of action

See also: Benzodiazepine

Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the binding site of the endogenous GABA molecule. The GABAA receptor is an inhibitory channel which, when activated, decreases neuronal activity.

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 post-synaptic membrane, owing to the control exerted over negative chloride ions by GABAA receptors.

Benzodiazepines including diazepam, however, do not have any effect on the levels of GABA in the brain.

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 to be 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.

Pharmacokinetics

Generic pack of 5mg Diazepam

Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.

When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 15 minutes for IV administration and 1530 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to 1 hour for both routes of administration.

Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, 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 will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.

There is preferential storage of diazepam in some organs including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate and there is clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.

Diazepam undergoes oxidative metabolism by CYP2C19 in the liver as part of the cytochrome P450 enzyme system. It has a biphasic half-life of 12 and 25 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include 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 half-life (t1/2) of 2050 hours, and desmethyldiazepam has a half-life of 30200 hours and is considered to be a long-acting benzodiazepine.

Most of the drug is metabolised; very little diazepam is excreted unchanged.

In humans, the protein binding of diazepam is around 98.5%.

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.

Drug misuse and addiction

See also: Benzodiazepine drug misuse

Diazepam is a drug of potential abuse and addiction. 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 diazepam is used by stimulant users to 'come down' and sleep and to help control the urge to binge.

A large-scale nationwide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug-related visits to the Emergency Department involved benzodiazepines. Benzodiazepines 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 to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.

Patients at a high risk for abuse or addiction

Diazepam can lead to drug abuse and psychological dependence/drug addiction. At a particularly high risk for diazepam misuse, abuse or psychological dependence are:

Patients with a history of alcohol or drug abuse or dependence Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.

Patients with severe personality disorders, such as Borderline Personality Disorder

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 patients is not recommended.

Patients suspected of being physiologically addicted to 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 addiction has occurred in therapeutic or recreational contexts.

Legal status

Diazepam is regulated in most countries as a prescription drug:

International: Diazepam is a Schedule IV controlled drug under the Convention on Psychotropic Substances.

UK: classified as a controlled drug, listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The Misuse of Drugs Act 1971 makes it illegal to possess the drug without a prescription, and for such purposes it is classified as a Class C drug. "List of Controlled Drugs". http://www.homeoffice.gov.uk/documents/cdlist2835.pdf?view=Binary. 

Germany: classified as a prescription drug, or in high dosage as a restricted drug (Betubungsmittelgesetz, Anhang III)

Toxicity

Laboratory tests assessing the toxicity of diazepam, nitrazepam and chlordiazepoxide on mice spermatozoa found that diazepam produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam, however, caused more profound abnormalities than diazepam.

See also

Benzodiazepine

Benzodiazepine dependence

Benzodiazepine withdrawal syndrome

Long-term effects of benzodiazepines

References

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^ Mahajan NN, Thomas A, Soni RN, Gaikwad NL, Jain SM (September 2008). "'Padhar Regime' - A Low-Dose Magnesium Sulphate Treatment for Eclampsia". Gynecol. Obstet. Invest. 67 (1): 2024. doi:10.1159/000158647. PMID 18824861. http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000158647. 

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^ Neurological Encyclopedia. http://www.answers.com/diazepam

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^ http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/190302.htm

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^ Chapman, C. Feather, B. Effects of Diazepam on Human Pain Tolerance and Pain Sensitivity. Psychomatic Medicine, American Psychosomatic Society. 35:330340 (1973)

^ Miller JA, Richter JA (January 1985). "Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes". British Journal of Pharmacology 84 (1): 1925. PMID 3978310. 

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^ Grandison L (1982). "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology 34 (5): 36973. doi:10.1159/000123330. PMID 6979001. 

^ a b c Barondes, Samuel H. (MONTH 1999). Molecules and Mental Illness. New York: Scientific American Library. pp. 190194. ISBN 0-7167-6033-9. 

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^ Zakusov VV; Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA. (October 1977). "Further evidence for GABA-ergic mechanisms in the action of benzodiazepines". Archives internationales de pharmacodynamie et de therapie 229 (2): 31326. PMID 23084. 

^ McLean MJ; Macdonald RL. (February 1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture". J Pharmacol Exp Ther. 244 (2): 78995. PMID 2450203. 

^ Date SK; Hemavathi KG, Gulati OD. (November 1984). "Investigation of the muscle relaxant activity of nitrazepam". Arch Int Pharmacodyn Ther. 272 (1): 12939. PMID 6517646. 

^ Olive G; Dreux C. (January 1977). "Pharmacologic bases of use of benzodiazepines in perinatal medicine". Arch Fr Pediatr. 34(1) (1): 7489. PMID 851373. 

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^ "New Evidence On Addiction To Medicines Diazepam Has Effect On Nerve Cells In The Brain Reward System". Medical News Today. August 2008. http://www.medicalnewstoday.com/articles/119284.php. Retrieved September 25, 2008. 

^ Yoshimura K; Horiuchi M, Inoue Y, Yamamoto K. (January 1984). "[Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats]". Nippon Yakurigaku Zasshi. 83 (1): 3967. PMID 6538866. 

^ Thibot MH; Le Bihan C, Soubri P, Simon P. (1985). "Benzodiazepines reduce the tolerance to reward delay in rats". Psychopharmacology (Berl). 86 (12): 14752. doi:10.1007/BF00431700. PMID 2862657. 

^ Woolverton WL, Nader MA (December 1995). "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology (Berl.) 122 (3): 2306. doi:10.1007/BF02246544. PMID 8748392. 

^ International Narcotics Control Board (1996). "CHAPTER II. OPERATION OF THE INTERNATIONAL DRUG CONTROL SYSTEM". REPORT OF THE INTERNATIONAL NARCOTICS CONTROL BOARD FOR 1996. http://www.incb.org/incb/en/annual_report_1996_chapter2.html#IIB10. Retrieved September 25, 2006. 

^ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry 66 Suppl 9: 3141. PMID 16336040. 

^ Overclocker. "Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines". Erowid Experience Vaults. http://de1.erowid.org/experiences/exp.phpquery=ID=9402.html. Retrieved September 26, 2006. 

^ United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2004). "Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. http://dawninfo.samhsa.gov/files/DAWN2k4ED.htm. Retrieved 9 May 2008. 

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^ Jones AW; Holmgren A, Kugelberg FC. (April 2007). "Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results". Ther Drug Monit. 29 (2): 24860. doi:10.1097/FTD.0b013e31803d3c04. PMID 17417081. 

^ Cosbey SH. (December 1986). "Drugs and the impaired driver in Northern Ireland: an analytical survey". Forensic Sci Int. 32 (4): 24558. doi:10.1016/0379-0738(86)90201-X. PMID 3804143. 

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External links

Roche Pharmaceuticals (AUS) - Valium Product Information

U.S. National Library of Medicine: Drug Information Portal - Diazepam

v  d  e

Benzodiazepines (N05BA, N05CD)

1,4-Benzodiazepines

Bromazepam  Camazepam  Carburazepam  Chlordiazepoxide  Cinolazepam  Clonazepam  Clorazepate  Cyprazepam  Delorazepam  Demoxepam  Diazepam  Doxefazepam  Elfazepam  Ethyl carfluzepate  Ethyl dirazepate  Ethyl loflazepate  Fletazepam  Fludiazepam  Flunitrazepam  Flurazepam  Flutemazepam  Flutoprazepam  Fosazepam  Gidazepam  Halazepam  Iclazepam  Lopirazepam  Lorazepam  Lormetazepam  Meclonazepam  Medazepam  Menitrazepam  Metaclazepam  Motrazepam  Nimetazepam  Nitrazepam  Nitrazepate  Nordazepam  Nortetrazepam  Oxazepam  Phenazepam  Pinazepam  Pivoxazepam  Prazepam  Proflazepam  Quazepam  QH-II-66  Reclazepam  Sulazepam  Temazepam  Tetrazepam  Tolufazepam  Tuclazepam  Uldazepam

1,5-Benzodiazepines

Arfendazam  Clobazam  Lofendazam  Triflubazam

2,3-Benzodiazepines

Girisopam  GYKI-52466  GYKI-52895  Nerisopam  Tofisopam

Triazolobenzodiazepines

Adinazolam  Alprazolam  Estazolam  Flubromazolam  Triazolam

Imidazobenzodiazepines

Bretazenil  Climazolam  Flumazenil  Imidazenil  L-655,708  Loprazolam  Midazolam  PWZ-029  Ro15-4513  Ro48-6791  Ro48-8684  Sarmazenil  SH-053-R-CH3-2

Oxazolobenzodiazepines

Cloxazolam  Flutazolam  Haloxazolam  Mexazolam  Oxazolam

Thienodiazepines

Brotizolam  Ciclotizolam  Clotiazepam  Etizolam

Pyridodiazepines

Lopirazepam  Zapizolam

Pyrazolodiazepines

Ripazepam  Zolazepam  Zomebazam

Pyrrolodiazepines

Premazepam

Benzodiazepine Prodrugs

Avizafone  Rilmazafone

Others

Bentazepam  Devazepide  Ketazolam  Razobazam  Tifluadom

v  d  e

Anticonvulsants (N03)

GABAA receptor agonist

Barbiturates

Barbexaclone  Metharbital  Methylphenobarbital  Pentobarbital  Phenobarbital#  Primidone

Benzodiazepines

Clobazam  Clonazepam  Clorazepate  Diazepam#  Flutoprazepam  Lorazepam  Midazolam  Nimetazepam  Nitrazepam  Temazepam

Other GABA agents

Aromatic allylic alcohols

Stiripentol

Carbonic anhydrase inhibitor

Sulfa drugs

Acetazolamide  Ethoxzolamide  Sultiame  Zonisamide

Channel blockers

Primarily sodium

Hydantoins

Ethotoin  Fosphenytoin  Mephenytoin  Phenytoin#

Carboxamides

Carbamazepine#  Eslicarbazepine acetate  Oxcarbazepine  Rufinamide

Primarily calcium

Succinimides

Ethosuximide#  Mesuximide  Phensuximide

Unknown/ungrouped

Phenyltriazines

Lamotrigine

Oxazolidinediones

Ethadione  Paramethadione  Trimethadione

Ureas

Phenacemide  Pheneturide

Monosaccharides

Topiramate

Indirect GABA agents

Carboxylic acids/

Fatty acid derivatives

GABA transaminase inhibitor: Valproic acid# (Sodium valproate & Valproate semisodium)  Valpromide  Valnoctamide

GABA reuptake inhibitor: Tiagabine

GABA analogs

Gabapentin  Pregabalin  Progabide  Vigabatrin

Unknown/multiple/

unsorted

Carbamates

Emylcamate  Felbamate  Meprobamate  Carisbamate

Pyrrolidines

Brivaracetam  Levetiracetam  Nefiracetam  Seletracetam

Propionates

Beclamide  Lacosamide

Aldehydes

Paraldehyde

Bromides

Potassium bromide  Sodium bromide

#WHO-EM. Withdrawn from market. CLINICAL TRIALS: hase III. Never to phase III

v  d  e

Anxiolytics (N05B)

GABAA PAMs

Benzodiazepine

Adinazolam Alprazolam Bretazenil Bromazepam Camazepam Chlordiazepoxide Clobazam Clonazepam Clorazepate Clotiazepam Cloxazolam Diazepam Ethyl Loflazepate Etizolam Fludiazepam Halazepam Imidazenil Ketazolam Lorazepam Medazepam Nordazepam Oxazepam Pinazepam Prazepam Tofisopam

Carbamates

Emylcamate Mebutamate Meprobamate (Carisoprodol, Tybamate) Phenprobamate Procymate

Nonbenzodiazepines

Abecarnil Adipiplon Alpidem CGS-9896 CGS-20625 Divaplon ELB-139 Etifoxine GBLD-345 Gedocarnil ICI-190,622 L-838,417 NS-2664 NS-2710 Ocinaplon Pagoclone Panadiplon Pipequaline RWJ-51204 SB-205,384 SL-651,498 TP-003 TP-13 TPA-023 Tracazolate Y-23684 ZK-93423

Others

Chlormezanone Etazolate Ethanol (Alcohol) Kavalactones (Kava Kava) Skullcap Valerenic Acid (Valerian)

2 VDCC Blockers

Gabapentin Pregabalin

5-HT1A Agonists

Azapirones: Buspirone Gepirone Tandospirone; Others: Flesinoxan Oxaflozane

H1 Antagonists

Diphenylmethanes: Captodiame Hydroxyzine; Others: Brompheniramine Chlorpheniramine Pheniramine

CRF1 Antagonists

Antalarmin CP-154,526 Pexacerfont Pivagabine

NK2 Antagonists

GR-159,897 Saredutant

MCH1 antagonists

ATC-0175 SNAP-94847

mGluR2/3 Agonists

Eglumegad

mGluR5 NAMs

Fenobam

TSPO agonists

DAA-1097 DAA-1106 Emapunil FGIN-127 FGIN-143

1 agonists

Afobazole Opipramol

Others

Benzoctamine Carbetocin Demoxytocin Mephenoxalone Oxytocin Promoxolane Trimetozine WAY-267,464

Categories: Drugboxes which contain changes to watched fields | Benzodiazepines | Hoffmann-La Roche | Hypnotics | World Health Organization essential medicines | Lactams | Organochlorides

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Lord Chief Justice and Lord Chancellor

Main article: Lord Chief Justice of England and Wales

Since 3 April 2006 the Lord Chief Justice has been the overall head of the judiciary. Previously he was second to the Lord Chancellor, but that office lost its judicial functions under the Constitutional Reform Act 2005. The Lord Chief Justice is also the head of the Criminal Division of the Court of Appeal. He was also President of the Queen's Bench Division of the High Court, but on becoming head of the judiciary that responsibility was transferred to a new office. belkin omniview 4 port

Although the Lord Chancellor is no longer a judge, he still exercises disciplinary authority over the judges, jointly with the Lord Chief Justice. He also has a role in appointing judges. cisco 2950

In law reports, the Lord Chief Justice is referred to as (for example) "Smith LCJ" or "Lord Smith CJ", and the Lord Chancellor as "Smith LC". cisco sfp gbic

Heads of Division

There are four Heads of Divisions the Master of the Rolls, the President of the Queen's Bench Division, the President of the Family Division and the Chancellor of the High Court.

The Master of the Rolls is head of the Civil Division of the Court of Appeal. The other Heads are in charge of the three divisions of the High Court.

The Chancellor of the High Court is President of the Chancery Division of the High Court. Until 2006 this role was nominally held by the Lord Chancellor, but was in practice delegated to the Vice-Chancellor. The Vice-Chancellor was renamed Chancellor of the High Court when the Lord Chancellor's judicial role was abolished.

The Heads of Division are referred to in law reports as "Smith MR", "Smith P", "Smith P", and "Smith C" respectively. Vice-Chancellors from pre-2006 Chancery cases are referred to as "Smith VC".

Justices of the Supreme Court

The judges of the Supreme Court of the United Kingdom are known as Justices of the Supreme Court, and they are also Privy Counsellors.

Before the creation of the Supreme Court, the highest court in England, Wales and Northern Ireland (and the highest court in civil matters in Scotland) was the Judicial Committee of the House of Lords, in which sat the Law Lords (more properly, the Lords of Appeal in Ordinary).

Court of Appeal

Judges of the Court of Appeal are known as Lord Justices, and they too are Privy Counsellors. Before swearing in they may be addressed as The Honourable Lord Justice Smith, and after swearing in as the Right Honourable Lord Justice Smith. Female Lord Justices are only known as Lady Justices informally. Addressed as "My Lord" or "My Lady". In law reports, referred to as "Smith LJ", and, for more than one judge, "Smith and Jones LJJ".

Formerly, Lord Justices of Appeal could only be drawn from barristers of at least 10 years' standing. In practice, much greater experience was necessary and, in 2004, calls for increased diversity among the judiciary were recognised and the qualification period was changed so that, as of 21 July 2008, a potential Lord Justice of Appeal must satisfy the judicial-appointment eligibility condition on a 7-year basis.

See also the list of Lords Justice of Appeal.

High Court

Main article: High Court judge

High Court judges are not normally Privy Counsellors. High Court judges are therefore referred to as the (Right) Honourable Mr/Mrs Justice Smith. Addressed as "My Lord" or "My Lady". In law reports, referred to as "Smith J", and, for more than one judge, "Smith and Jones JJ".

Circuit Judges

Main article: Circuit judge (UK)

Unlike the more senior judges, Circuit Judges are referred to as His/Her Honour Judge {surname} e.g. His/Her Honour Judge Smith. If a circuit judge is appointed who has the same surname as another serving circuit judge, he (she) will be referred to as His (Her) Honour Judge {first name} {surname}. eg His Honour Judge John Smith. Addressed as "Your Honour", unless sitting in the Central Criminal Court (the Old Bailey), in which case addressed as "My Lord(Lady)". In law reports, referred to as "HHJ Smith".

Formerly, Circuit Judges could only be drawn from barristers of at least 10 years' standing. However, in 2004, calls for increased diversity among the judiciary were recognised and the qualification period was changed so that, as of 21 July 2008, a potential Circuit Judge must satisfy the judicial-appointment eligibility condition on a 7-year basis.

Recorders

Main article: Recorder (judge)

A Recorder is a part-time circuit judge, usually a practicing barrister or solicitor. Recorders are addressed in court in the same way as circuit judges (as 'Your Honour'). There is no formal abbreviation for the position and recorders are referred to as 'Mr/Mrs Recorder Smith' (as opposed to circuit judges, who can be referred to as 'HHJ Smith' in judgments, law reports or other legal documents).

Formerly, Recorders could only be drawn from barristers of at least 10 years' standing. However, in 2004, calls for increased diversity among the judiciary were recognized and the qualification period was changed so that, as of 21 July 2008, a potential Circuit Judge must satisfy the judicial-appointment eligibility condition on a 7-year basis.

The senior circuit judge in a metropolitan area will often be given the honorary title of the Recorder of the city e.g. the Recorder of Manchester. Despite still being circuit judges, these recorders are addressed in court as 'Your Lordship/Ladyship' as if they were High Court judges.

Masters and Registrars

A Master is a level of judge in the High Court lower than that of a High Court judge. They are mainly responsible for case management pre-trial, and cases are then heard at trial by a full High Court judge. Masters (who may be male or female) are addressed simply as Master. Each of the divisions has a senior Master who ranks above the other Masters, and each division has a different title. They are:

Queen's Bench Division - Senior Master

Chancery Division - Chief Chancery Master

Costs Office - Senior Costs Judge

Bankruptcy Court - Chief Bankruptcy Registrar

Admiralty Court - Admiralty Registrar

The Senior Master of the Queen's Bench Division also holds the ancient judicial post of King's Remembrancer (Queen's Remembrancer when the monarch is female), and is also the Registrar of Election petitions and Foreign judgments as well as being the designated authority for the Hague Service Convention and Hague Evidence Convention and receiving agency under the EU Service Regulation - Council Regulation (EC) No. 1348/2000 and EU Taking of Evidence Regulation - Council Regulation (EC) No. 1206/2001. The Senior Master is assisted in this role as Central Authority by the Foreign Process Section of the Queen's Bench Action Department at the Royal Courts of Justice.

In spite of their title the Bankruptcy Registrars of the High Court sit in Bankruptcy and in the Companies Court. They hear and dispose of almost all the insolvency and companies cases heard in the High Court, including trials (i.e. cases arising under the Insolvency Act 1986, the Company Directors Disqualification Act 1986, the Companies Acts and related legislation).

Masters and Registrars are not referred to by an abbreviation in the law reports, and appear as "Master Smith" or "Mr/Mrs Registrar Smith".

Formerly, Masters and Registrars could only be drawn from barristers and solicitors of at least 7 years' standing. However, in 2004, calls for increased diversity among the judiciary were recognised and the qualification period was changed so that, as of 21 July 2008, a potential Master or Registrar must satisfy the judicial-appointment eligibility condition on a 5-year basis.

District Judges

"District Judge" is the title given to two different categories of judges. One group of District Judges sit in the County Court, having previously been known as County Court Registrars until the Courts and Legal Services Act 1990. The other group sit in the Magistrates' Courts and were formerly known as Stipendiary Magistrates until the Access to Justice Act 1999. Members of this latter group are more formally known as "District Judge (Magistrates' Courts)" (see the Courts Act 2003). Judges in both groups are addressed as "Sir" or "Madam". In law reports, referred to as "DJ Smith".

Formerly, District Judges could only be drawn from barristers and solicitors of at least 7 years' standing. However, in 2004, calls for increased diversity among the judiciary were recognised and the qualification period was changed so that, as of 21 July 2008, a potential District Judge must satisfy the judicial-appointment eligibility condition on a 5-year basis.

Deputy District Judges

A practising solicitor or barrister who sits part-time as a District Judge (who may be taking his first steps on the route to becoming a full-time District Judge). Retired District Judges may occasionally sit as Deputies. Addressed as "Sir" or "Madam". In law reports, referred to as "DDJ Smith".

Formerly, Deputy District Judges could only be drawn from barristers and solicitors of at least 7 years' standing. However, in 2004, calls for increased diversity among the judiciary were recognised and the qualification period was changed so that, as of 21 July 2008, a potential Deputy District Judge must satisfy the judicial-appointment eligibility condition on a 5-year basis.

Magistrates

Laymen drawn from the community who generally sit in threes in order to give judgment in Magistrates' Courts and Youth Courts. Addressed as "Sir" or "Madam" but often addressed as 'Your Worships' by the police and some lawyers. In law reports, referred to as "John Smith JP" (for Justice of the Peace).

Judicial salaries

There are nine pay points for judges in England and Wales. The following is a simplified list of the salaries with effect from 1 November 2009, showing only the most widely held grades and some of the best known specific appointments. A complete list of all the posts at each pay point can be found on the website of the Ministry of Justice.

Group 1: Lord Chief Justice, 239,845

Group 1.1: Master of the Rolls and Senior Lord of Appeal in Ordinary, 214,165

Group 2: Lords of Appeal in Ordinary and several other appointments, 206,857

Group 3: Lords Justices of Appeal and certain others, 196,707

Group 4: High Court Judges and certain others, 172,753

Group 5: Numerous specialist appointments, including Senior Circuit Judges, 138,548

Group 6.1: Circuit Judges and several other appointments, 128,296

Group 6.2: Numerous specialist appointments, 120,785

Group 7: District Judges, Chairmen of Employment Tribunals, and several other appointments, 111,155

Judges also have a pension scheme, which is considered to be one of the most generous in the British public sector.

See also

Courts of England and Wales

Judicial titles in England and Wales

Judiciary of Hong Kong

References

^ Alex, Allan (October 2006), "Department for Constitutional Affairs", Evidence to the Senior Salaries Review Body, HMSO, pp. 2730, http://www.dca.gov.uk/judicial/judgepay06.pdf, retrieved 2007-12-15 

^ Constitutional Reform Act 2005, s.3

^ "Forms of address for the Judiciary". Judiciary of England and Wales. HMSO. 2007. http://www.judiciary.gov.uk/about_judiciary/forms_of_address/index.htm. Retrieved 2007-12-15. 

^ Supreme Court Act 1981, s.10(3)(b)

^ a b c d e f "Increasing Diversity in the Judiciary". Department for Constitutional Affairs. October 2004. http://www.dca.gov.uk/consult/judiciary/diversitycp25-04.htm. Retrieved 2008-03-05. "CP 25/04" 

^ a b c d e f "Explanatory Notes to Tribunals, Courts And Enforcement Act 2007". Office of Public Service Information. 2007. http://www.england-legislation.hmso.gov.uk/acts/acts2007/en/07en15-d.htm. Retrieved 2008-03-05. "paras.281-316" 

^ a b c d e f Tribunals, Courts and Enforcement Act 2007, s.50/ Sch.10, Pt.1.13

^ Courts Act 1971, s.16(3)(a)

^ Courts Act 1971, s.21(2)

^ Alex, Allan (October 2006), "Department for Constitutional Affairs", Evidence to the Senior Salaries Review Body, HMSO, pp. 5, http://www.dca.gov.uk/judicial/judgepay06.pdf, retrieved 2007-12-15 

External links

Judiciary of England and Wales government website

Department for Constitutional Affairs list of judges

Categories: Judiciary of England and Wales

Canadian Public Debt

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History

Canada federal debt grew steadily between 5% and 10% per year until 1975 when it began to explode; growing for the next 12 years at more than 20% per year. It broke the $100-billion mark in 1981 and the $200-billion mark in 1985. While the growth slowed in 1988, the federal debt continued to climb, breaking $300-billion in 1988, $400-billion 1992, and $500-billion in 1994. It peaked in 1997 at $563-billion.

Over the past decade it had slowly declined to $458-billion in 2008. However the trend has now reversed. The federal debt grew by $5.8-billion in 2008-09, is slated to grow by $55.9-billion in 2009-10 and will continue to grow for years to come. In just the next two years, all the debt repayment of the past eight years will be wiped out. gradual alarm clock

Year antique carriage clocks

Gross Debt in Millions antique clocks mantle

1961-62

$14,825

1970-71

$20,293

1980-81

$91,948

1990-91

$377,656

1996-97

$562,881

2001-02

$511,946

2007-08

$457,637

2008-09 (projected)

$458,737

2009-10 (projected)

$492,437

2010-11 (projected)

$522,337

2011-12 (projected)

$535,237

2012-13 (projected)

$542,537

Foreign ownership

A list of the foreign owners of Canadian Treasury securities

Foreign owners of Canadian Treasury Securities (July 2009)

Nation

billions of dollars

percentage

People's Republic of China

 ?

 ?%

Japan

 ?

 ?%

United Kingdom

 ?

 ?%

Caribbean banking centers

 ?

 ?%

Oil exporters

 ?

 ?%

United States of America

 ?

 ?%

Russia

 ?

 ?%

All other

 ?

 ?%

Grand Total

 ?

Provincial Debt

Municipal Debt

Risks and obstacles

Risks to the Canadian dollar

Long-term risks to financial health of federal government

Debt clocks

In 1993, the Canadian Taxpayers Federation commissioned the construction of a giant debt clock 12 feet long by 8-and-a-half feet high with changeable faceplates for the federal and each provincial government. The clock displayed the per-second increase in debt along with the share for each Canadian family. The clock was toured around the country. The clock went into temporary retirement once the federal government balanced the budget in 1997 and began paying down the federal debt.

In fiscal 2008-09 the debt clock climbed by $183.92 per second, taking federal debt up to $463,700,000,000. After April 1, 2009, the clock, and the federal debt began growing by $1,772.57 per second, which is the equivalent of $106,355 per minute, $6.4-million per hour, or $153-million each day. By March 31, 2010, Canada federal debt is projected to reach $519,600,000,000.

Calculating and projecting the debt

Canada has changed its calculation in 2002-2003 for net debt, before, the net debt was the total liabilities minus total assets, now it is the total liabilities minus financial assets, as the government prefers the concept of "accumulated deficit", which corresponds to the old definition of net debt.

See also

Balance of payments

Budget deficit

Deficit

Economy of Canada

Global debt - the "big picture"

List of countries by current account balance

List of public debt - list of the public debt for many nations, as a percentage of the GDP

National bankruptcy

Proposed bailout of U.S. financial system (2008)

Public debt - a general discussion of the topic

References

^ Canada's Debt History Tax Payers Foundation

^ http://www.debtclock.ca/index.php?option=com_content&view=article&id=44&Itemid=41

External links

Canadian Debt Clock", by The Canadian Taxpayers Federation

Categories: Economy of Canada

Hydroxyzine

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Prescription and use

This section needs additional citations for verification.

Please help improve this article by adding reliable references. Unsourced material may be challenged and removed. (August 2009) massage chair human touch

Hydroxyzine is both an antihistamine and anxiolytic (see below) and its use as a mild tranquilizer is especially common in dentistry and it retains some popularity in obstetrics, where for many years it was especially preferred for its ability to boost the effectiveness of opioids as well as permit later use of scopolamine or benzodiazepines better than other drugs might. recliner massage

Hydroxyzine is prescribed when the onset of an organic disease state manifests through anxiety, as general anxiety disorder, or in other more serious cases as psychoneurosis, and is therefore prescribed as a means of regulating normal function. Hydroxyzine has shown to be as effective as the benzodiazepine drug bromazepam in the treatment of generalised anxiety disorder. Hydroxyzine can also be used for the treatment of allergic conditions, such as chronic urticaria, atopic or contact dermatoses, and histamine-mediated pruritus. These have also been confirmed in both recent and past studies to have no adverse effects on the liver, blood, nervous system or urinary tract.[citation needed] chair cushion massager

Use of hydroxyzine for premedication as a sedative has no effects on belladonna alkaloids, such as atropine, but may, following general anesthesia, potentiate meperidine and barbiturates, and use in pre-anesthetic adjunctive therapy should be modified depending upon the state of the individual.[citation needed]

In other cases, the usage of hydroxyzine is as a form of non-barbiturate tranquilizer used in the pre-operative sedation and treatment of neurological disorders, such as psychoneurosis and other forms of anxiety or tension states.

For dentistry and obstetrics as well as other surgeries and procedures and acute pain situations like accidents, hydroxyzine is useful as a first line anxiolytic and opioid adjunct because it lacks both antagonism and synergy with benzodiazepines and scopolamine, allowing either of these agents to be used simultaneously or later in the procedure if need be.

Hydroxyzine is not thought to be an effective treatment for anxiety if used for a period of over 4 months, and it is therefore a prerequisite of any medical professional prescribing such drugs, to re-assess the usefulness for the individual patient. Rather than its use as an anxiety-reducing agent, hydroxyzine should be reconsidered if the patient has more intense anxiety or other psychoneurosis; then other compounds specifically designed for such conditions should be considered.[citation needed]

Animal research

Aside from its prescription as an antihistamine, hydroxyzine has also shown slight possibilities for use in other species, such as dogs, from results and effects observed in rats with "learned helplessness" induced through the use of random inescapable shocks (max 0.8 mA) administered in 1 minute intervals for a period of 15 seconds for an hour. After the condition was induced, rats were then given a conditioned stimulus of a light, and shocked if unable to move to safety from the area producing the current within 3 seconds. Those unable to move were determined as having a conditioned stimulus of expecting shocks from the initial random condition.

In the initial treatment to this condition, rats were given hydroxyzine as a curative treatment for the shocks received and as a treatment for the prevention of learned helplessness by injection beforehand; results indicating that hydroxyzine decreased the overall amount of escape failures by a similar amount to those observed in diazepam, which achieved similar results, however, with side effects of amnesia. Despite the fact that hydroxyzine clearly increased the ability of the rats to avoid stimuli, it had almost no effect on the rats' ability to respond to the shocks nor remove "stress" after exposure to shocks.

Clinical description

Metabolism and pharmacokinetics

Hydroxyzine can be administered orally or via intramuscular injection. When given orally, hydroxyzine is rapidly absorbed from the gastro-intestinal tract. The effect of hydroxyzine is notable in 30 minutes.

Pharmacokinetically, hydroxyzine is rapidly absorbed and distributed in oral and intramuscular administration, and is metabolised in the liver; the main metabolite (45%) through oxidation of the alcohol moiety to a carboxylic acid, is cetirizine and overall effects are observed within one hour of administration. It has a half-life observed on average of around 710 hours in adults, 67 hours in children, and 1821 hours in the elderly, or those with renal insufficiency, with higher concentrations found in the skin than in the plasma. Cetirizine, although less sedating, is non-dialyzable and possesses similar anti-histaminergic properties. "In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination." "The extent of renal excretion of VISTARIL has not been determined" Administration in geriatrics differs from the administration of hydroxyzine in younger patients; according to the FDA, there have not been significant studies made (2004), which include population groups over 65, which provide a distinction between elderly aged patients and other younger groups. Hydroxyzine should be administered carefully in the elderly with consideration given to possible reduced elimination.[citation needed] Similarly, the use of sedating drugs alongside hydroxyzine can cause over-sedation and confusion if administered in large amountsny form of treatment alongside sedatives should be done under supervision of the patient.[citation needed]

Contraindications

The administration of hydroxyzine in large amounts by ingestion or intramuscular administration during the onset of pregnancy can cause fetal abnormalitieshen administered to pregnant rats, mice and rabbits, hydroxyzine caused abnormalities with doses significantly above that of the human therapeutic range.[citation needed] In terms of humans, a significant dose has not yet been established in studies, and by default, the FDA has introduced contraindication guidelines in regard to hydroxyzine. Similarly the use in those at risk from or showing previous signs of hypersensitivity is also contraindicated.[citation needed]

Other contraindications include the administration of hydroxyzine alongside depressants and other compounds which affect the central nervous system. and if absolutely necessary, it should only be administered concomitantly in small doses. If administered in small doses with other substances, such as mentioned, then patients should refrain from using dangerous machinery, motor vehicles or any other practice requiring absolute concentration, in accordance with safety law.

Studies have also been conducted which show that long-term prescription of hydroxyzine can lead to tardive dyskinesia after years of use, but effects related to dyskinesia have also anecdotally been reported after periods of 7.5 months, such as continual head rolling, lip licking and other forms of athetoid movement. In certain cases, elderly patients' previous interactions with phenothiazine derivatives or pre-existing neuroleptic treatment may have had some contribution towards dyskinesia at the administration of hydroxyzine due to hypersensitivity caused due to the prolonged treatment, and therefore some contraindication is given to the short-term administration of hydroxyzine to those with previous phenothiazine use.

Adverse reactions

For a full list of side effects, consult the full technical specification of hydroxyzine.

Several reactions have been noted in manufacturer guidelines deep sleep, incoordination and dizziness have been reported in children and adults, as well as others such as hypotension, tinnitus and headaches. Gastro-intestinal effects have also been observed, as well as less serious effects such as dryness of the mouth and constipation caused by antimuscarinic properties of hydroxyzine.

Central nervous system problems such as hallucinations or confusion have been observed in rare cases, attributed mostly to overdosage. Such properties have been attributed to hydroxyzine in several cases, particularly in patients treated for neuropsychological disorders, as well as in cases where overdoses have been observed. While there are reports of the "hallucinogenic" or "hypnotic" properties of hydroxyzine, several clinical data trials have not reported such side effects from the sole consumption of hydroxyzine, but rather, have described its overall calming effect described through the stimulation of areas within the formatio reticularis. The description of hallucinogenic or hypnotic properties have been described as being an additional effect from overall central nervous system suppression by other CNS agents, such as lithium or alcohol.

The effect of hydroxyzine has also been tested on the ability of humans in the registration and storage of memory, and was used in comparison with relatively safe drugs, such as hydroxyzine, to illustrate the effects of benzodiazepines, which are thought to have adverse effects on the capacity of memory storage. Hydroxyzine was found to have no adverse effects on memory in relation to lorazepam, which caused several deficiencies in the capacity of memory storage.

In a comparative study with lorazepam on memory effects, patients who had taken hydroxyzine experienced sedative effects similar to drowsiness, but recalled that they felt capable, attentive and able to continue with a memory test under these conditions. Conversely, those under the effects of lorazepam felt unable to continue due to the fact they felt out of control with its effects; 8 out of 10 patients describing tendencies of problems with balance and control of simple motor functions.

Somnolence with or without vivid dreams or nightmares may occur in users with antihistamine sensitivities in combination with other CNS depressants. Hydroxyzine exhibits anxiolytic and sedative properties in many psychiatric patients. Other studies have suggested that hydroxyzine acts as an acute hypnotic, reducing sleep onset latency and increasing sleep duration also showing that some drowsiness did occur. This was observed more in female patients, who also had greater hypnotic response.

Some users may report shortness of breath or wheezing, a result of a mild allergic reaction to the medication itself.

In contrast to drugs in the benzodiazepine class, (i.e. alprazolam, diazepam) which carry a potential for abuse and dependence, hydroxyzine is very unlikely to cause any dependence due to its relative strength compared to other substances.

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly. (See NCQA HEDIS Measure: Use of High Risk Medications in the Elderly, http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf).

References

^ a b RxList, et al. (2004)

^ Llorca PM, Spadone C, Sol O, et al. (November 2002). "Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study". J Clin Psychiatry 63 (11): 10207. PMID 12444816. http://www.psychiatrist.com/privatepdf/2002/v63n11/v63n1112.pdf. 

^ a b United States Food & Drug Administration, (2004), p1

^ a b c Dolan, C. M., (1958)

^ a b c d e f g United States Food & Drug Administration, (2004), p2

^ a b Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989), p229

^ a b c Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989), p228

^ a b Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989), p230

^ a b c United States Food & Drug Administration, (2004), p3

^ a b c Clark, B. G., Araki, M., et al. (1976)

^ a b c UCB South-Africa, et al., (2004)

^ Anderson, P. O., Knoben, J. E., et al. (2002), p794-796

^ Brabander, A. DE, Debert, W., (1990), p1

^ a b Brabander, A. DE, Debert, W., (1990), p3

^ Alford, C.; N. Rombautt, J. Jones, S. Foley, C. Idzikowskit and I. Hindmarch (1992).

Print sources

Hutcheon, D. E.; D.L. Morris, A. Scriabine (December 1956). "Cardiovascular action of hydroxyzine (Atarax)". J Pharmacol Exp Ther. 118 (4): 451460. PMID 13385806. 

Dolan, C. M. (June 1958). "Management of emotional disturbances -- Use of Hydroxyzine (Atarax) in General Practice". Calif Med. 88 (6): 443444. PMID 13536863. PMC 1512309. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1512309&blobtype=pdf. Retrieved 2007-03-09. 

Pfizer Labs, Division of Pfizer Inc, NY, NY 10017 (2004) (pdf). Vistaril (hydroxyzine pamoate) Capsules and Oral Suspension. United States Food and Drug Administration. http://www.fda.gov/cder/ogd/rld/11795s16.pdf. Retrieved 2007-03-09. 

Anderson, Philip O.; James E. Knoben, William G. Troutman (2002). Handbook of Clinical Drug Data. McGraw-Hill Medical. ISBN 0071363629. 

de Brabander, A.; W. Deberdt (1990). "Effect of Hydroxyzine on Attention and Memory". Human Psychopharmacology (John Wiley & Sons) 5 (4): 357362. doi:10.1002/hup.470050408. http://www3.interscience.wiley.com/cgi-bin/abstract/109710652/ABSTRACT?CRETRY=1&SRETRY=0. Retrieved 2007-03-09. 

Clark, B. G.; M. Araki, H. W. Brown (1982). "Hydroxyzine-Associated Tardive Dyskinesia". Ann Neurol. 11 (4): 435. doi:10.1002/ana.410110423. PMID 7103423. 

Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989). "Prevention of earned Helplessness in the Rat by Hydroxyzine". Drug Dev. Res. 17 (3): 227236. doi:10.1002/ddr.430170306. http://www3.interscience.wiley.com/cgi-bin/abstract/109670961/ABSTRACT?SRETRY=0. Retrieved 2007-03-10. 

Alford, C.; N. Rombautt, J. Jones, S. Foley, C. Idzikowskit and I. Hindmarch (1992). "Acute Effects of Hydroxyzine on Nocturnal Sleep and Sleep Tendency the Following Day: a C-EEG Study". Human Psychopharmacology 7 (1): 2535. doi:10.1002/hup.470070104. http://www3.interscience.wiley.com/cgi-bin/abstract/109711163/ABSTRACT. Retrieved 2007-03-10. 

Internet-based

RxList , et al. (2004). "Atarax Indications, Dosage, Storage, Stability". RxList - The internet drug index. http://www.rxlist.com/cgi/generic/hydrox_ids.htm. Retrieved 2007-03-09. 

Medscape (2004). "Vistaril Oral: Monograph - Hydroxyzine Hydrochloride, Hydroxyzine Pamoate". medscape.com. http://www.medscape.com/druginfo/monograph?cid=med&drugid=6144&drugname=Vistaril+Oral&monotype=monograph&print=1. Retrieved 2007-03-09. 

pfizer (2004). "Non-print version of vistaril fact sheet." (PDF). http://www.pfizer.com/pfizer/download/uspi_vistaril.pdf. Retrieved 2007-07-03. 

Drug information pamphlets

UCB South-Africa, et al., (2004). ATERAX 25 mg TABLETS; ATERAX 100 mg TABLETS; ATERAX SYRUP (Manufacturing guidance package insert) Pharmacare Ltd, (a division of Aspen Pharmacare Ltd)

v  d  e

Anxiolytics (N05B)

GABAA PAMs

Benzodiazepine

Adinazolam Alprazolam Bretazenil Bromazepam Camazepam Chlordiazepoxide Clobazam Clonazepam Clorazepate Clotiazepam Cloxazolam Diazepam Ethyl Loflazepate Etizolam Fludiazepam Halazepam Imidazenil Ketazolam Lorazepam Medazepam Nordazepam Oxazepam Pinazepam Prazepam Tofisopam

Carbamates

Emylcamate Mebutamate Meprobamate (Carisoprodol, Tybamate) Phenprobamate Procymate

Nonbenzodiazepines

Abecarnil Adipiplon Alpidem CGS-9896 CGS-20625 Divaplon ELB-139 Etifoxine GBLD-345 Gedocarnil ICI-190,622 L-838,417 NS-2664 NS-2710 Ocinaplon Pagoclone Panadiplon Pipequaline RWJ-51204 SB-205,384 SL-651,498 TP-003 TP-13 TPA-023 Tracazolate Y-23684 ZK-93423

Others

Chlormezanone Etazolate Ethanol (Alcohol) Kavalactones (Kava Kava) Skullcap Valerenic Acid (Valerian)

2 VDCC Blockers

Gabapentin Pregabalin

5-HT1A Agonists

Azapirones: Buspirone Gepirone Tandospirone; Others: Flesinoxan Oxaflozane

H1 Antagonists

Diphenylmethanes: Captodiame Hydroxyzine; Others: Brompheniramine Chlorpheniramine Pheniramine

CRF1 Antagonists

Antalarmin CP-154,526 Pexacerfont Pivagabine

NK2 Antagonists

GR-159,897 Saredutant

MCH1 antagonists

ATC-0175 SNAP-94847

mGluR2/3 Agonists

Eglumegad

mGluR5 NAMs

Fenobam

TSPO agonists

DAA-1097 DAA-1106 Emapunil FGIN-127 FGIN-143

1 agonists

Afobazole Opipramol

Others

Benzoctamine Carbetocin Demoxytocin Mephenoxalone Oxytocin Promoxolane Trimetozine WAY-267,464

v  d  e

Cholinergics

Receptor

Ligands

mAChR

Agonists: 77-LH-28-1 AC-42 AC-260,584 Aceclidine Acetylcholine AF30 AF150(S) AF267B AFDX-384 Alvameline AQRA-741 Arecoline Bethanechol Butyrylcholine Carbachol CDD-0034 CDD-0078 CDD-0097 CDD-0098 CDD-0102 Cevimeline cis-Dioxolane Ethoxysebacylcholine LY-593,039 L-689,660 LY-2,033,298 McNA343 Methacholine Milameline Muscarine NGX-267 Ocvimeline Oxotremorine PD-151,832 Pilocarpine RS86 Sabcomeline SDZ 210-086 Sebacylcholine Suberylcholine Talsaclidine Thiopilocarpine Vedaclidine VU-0029767 VU-0090157 VU-0152099 VU-0152100 VU-0238429 WAY-132,983 Xanomeline YM-796

Antagonists: 3-Quinuclidinyl Benzilate 4-DAMP Anisodamine Anisodine Atropine Atropine Methonitrate Benactyzine Benzatropine (Benztropine) Benzydamine BIBN 99 Biperiden Bornaprine CAR-226,086 CAR-301,060 CAR-302,196 CAR-302,282 CAR-302,368 CAR-302,537 CAR-302,668 CS-27349 Cyclobenzaprine Cyclopentolate Darifenacin DAU-5884 Dimethindene Dexetimide DIBD Dicyclomine (Dicycloverine) Ditran EA-3167 EA-3443 EA-3580 EA-3834 Elemicin Etanautine Etybenzatropine (Ethylbenztropine) Flavoxate Himbacine HL-031,120 Ipratropium J-104,129 Hyoscyamine Mamba Toxin 3 Mamba Toxin 7 Mazaticol Mebeverine Methoctramine Metixene Myristicin N-Ethyl-3-Piperidyl Benzilate N-Methyl-3-Piperidyl Benzilate Orphenadrine Otenzepad Oxybutynin PBID PD-102,807 Phenglutarimide Phenyltoloxamine Pirenzepine Piroheptine Procyclidine Profenamine RU-47,213 SCH-57,790 SCH-72,788 SCH-217,443 Scopolamine (Hyoscine) Solifenacin Telenzepine Tiotropium Tolterodine Trihexyphenidyl Tripitamine Tropatepine Tropicamide WIN-2299 Zamifenacin; Others: 1st Generation Antihistamines (Brompheniramine Chlorpheniramine, Cyclizine, Cyproheptadine, Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Meclizine, Mepyramine/Pyrilamine, Phenindamine, Pheniramine, Tripelennamine, Triprolidine, etc) Tricyclic Antidepressants (Amitriptyline, Doxepin, Trimipramine, etc) Tetracyclic Antidepressants (Amoxapine, Maprotiline, etc) Typical Antipsychotics (Chlorpromazine, Thioridazine, etc) Atypical Antipsychotics (Clozapine, Olanzapine, Quetiapine, etc)

nAChR

Agonists: 5-HIAA A-84,543 A-366,833 A-582,941 A-867,744 ABT-202 ABT-418 ABT-560 ABT-894 Acetylcholine Altinicline Anabasine AR-R17779 Butyrylcholine Carbachol Cotinine Cytisine Decamethonium Desformylflustrabromine Dianicline Dimethylphenylpiperazinium Epibatidine Epiboxidine Ethoxysebacylcholine EVP-4473 EVP-6124 Galantamine GTS-21 Ispronicline Lobeline MEM-63,908 (RG-3487) Nicotine NS-1738 PHA-543,613 PHA-709,829 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A Sebacylcholine SIB-1508Y SIB-1553A SSR-180,711 Suberylcholine TC-1698 TC-1734 TC-1827 TC-2216 TC-5214 TC-5619 TC-6683 Tebanicline Tropisetron UB-165 Varenicline XY-4083

Antagonists: 18-Methoxycoronaridine -Bungarotoxin -Conotoxin Alcuronium Anatruxonium Atracurium Bupropion (Amfebutamone) Chandonium Chlorisondamine Cisatracurium Coclaurine Coronaridine Dacuronium Decamethonium Dextromethorphan Dextropropoxyphene Dextrorphan Diadonium DHE Dimethyltubocurarine (Metocurine) Dipyrandium Dizocilpine (MK-801) Doxacurium Duador Esketamine Fazadinium Gallamine Hexafluronium Hexamethonium (Benzohexonium) Ibogaine Ketamine Kynurenic Acid Levacetylmethadol Malouetine Mecamylamine Memantine Methadone Methorphan (Racemethorphan) Methyllycaconitine Metocurine Mivacurium Morphanol (Racemorphanol) Neramexane Pancuronium Pempidine Pentamine Pentolinium Phencyclidine Pipecuronium Radafaxine Rapacuronium Rocuronium Surugatoxin Suxamethonium (Succinylcholine) Toxiferine Trimethaphan Tropeinium Tubocurarine Vecuronium

Reuptake

Inhibitors

Plasmalemmal

CHT Inhibitors

Hemicholinium-3 (Hemicholine)

Vesicular

VAChT Inhibitors

Vesamicol

Enzyme

Inhibitors

Anabolism

ChAT Inhibitors

1-(-Benzoylethyl)pyridinium 2-(-Naphthoyl)ethyltrimethylammonium 3-Chloro-4-stillbazole 4-(1-Naphthylvinyl)pyridine Acetylseco Hemicholinium-3 Acryloylcholine AF64A B115 BETA CM-54,903 N,N-Dimethylaminoethylacrylate N,N-Dimethylaminoethylchloroacetate

Catabolism

AChE Inhibitors

Reversible: Carbamates: Aldicarb Bendiocarb Bufencarb Carbaryl Carbendazim Carbetamide Carbofuran Chlorbufam Chloropropham Ethienocarb Ethiofencarb Fenobucarb Fenoxycarb Formetanate Furadan Ladostigil Methiocarb Methomyl Miotine Oxamyl Phenmedipham Pinmicarb Pirimicarb Propamocarb Propham Propoxur; Stigmines: Ganstigmine Neostigmine Phenserine Physostigmine Pyridostigmine Rivastigmine; Others: Ambenonium Donepezil Edrophonium Galantamine Huperzine A (Huperzia Serrata) Minaprine Tacrine Zanapezil

Irreversible: Organophosphates: Acephate Azinphos-Methyl Bensulide Cadusafos Chlorethoxyfos Chlorfenvinphos Chlorpyrifos Chlorpyrifos-Methyl Coumaphos Cyclosarin (GF) Demeton Demeton-S-Methyl Diazinon Dichlorvos Dicrotophos Diisopropyl Fluorophosphate (Guthion) Diisopropylphosphate Dimethoate Dioxathion Disulfoton EA-3148 Echothiophate Ethion Ethoprop Fenamiphos Fenitrothion Fenthion Fosthiazate GV Isofluorophate Isoxathion Malaoxon Malathion Methamidophos Methidathion Metrifonate Mevinphos Monocrotophos Naled Novichok Agent Omethoate Oxydemeton-Methyl Paraoxon Parathion Parathion-Methyl Phorate Phosalone Phosmet Phostebupirim Phoxim Pirimiphos-Methyl Sarin (GB) Soman (GD) Tabun (GA) Temefos Terbufos Tetrachlorvinphos Tribufos Trichlorfon VE VG VM VR VX; Others: Demecarium Onchidal (Onchidella Binneyi)

BChE Inhibitors

Many of the acetylcholinesterase inhibitors listed above act as butyrylcholinesterase inhibitors.

Others

Precursors

Choline (Lecithin) Citicoline Dimethylethanolamine Glycerophosphocholine Phosphatidylcholine Phosphatidylethanolamine Phosphorylcholine

Cofactors

Acetic Acid Acetyl-L-Carnitine Acetyl-Coenzyme A Vitamin B5 (Pantothenic Acid, Pantethine, Pantetheine, Panthenol)

Others

Acetylcholine Releasing Agents: -Latrotoxin -Bungarotoxin; Acetylcholine Release Inhibitors: Botulinum Toxin (Botox); Acetylcholinesterase Reactivators: Pralidoxime obidoxime

v  d  e

Histaminergics

Receptor

Ligands

H1

Agonists: 2-Pyridylethylamine Betahistine Histamine HTMT UR-AK49

Antagonists: 1st Generation: 4-Methyldiphenhydramine Alimemazine Antazoline Azatadine Bamipine Benzatropine (Benztropine) Bepotastine Bromazine Brompheniramine Buclizine Captodiame Carbinoxamine Chlorcyclizine Chloropyramine Chlorothen Chlorpheniramine Chlorphenoxamine Cinnarizine Clemastine Clobenzepam Clocinizine Cyclizine Cyproheptadine Dacemazine Deptropine Dexbrompheniramine Dexchlorpheniramine Dimenhydrinate Dimetindene Diphenhydramine Diphenylpyraline Doxylamine Embramine Etybenzatropine (Ethylbenztropine) Etymemazine Histapyrrodine Hydroxyethylpromethazine Hydroxyzine Iproheptine Isopromethazine Isothipendyl Meclizine Mepyramine (Pyrilamine) Mequitazine Methafurylene Methapyrilene Methdilazine Moxastine Niaprazine Orphenadrine Oxatomide Oxomemazine Phenindamine Pheniramine Phenyltoloxamine Pimethixene Promethazine Propiomazine Pyrrobutamine Talastine Thenalidine Thenyldiamine Thiazinamium Thonzylamine Tolpropamine Tripelennamine Triprolidine; 2nd Generation: Acrivastine Astemizole Azelastine Cetirizine Clemizole Clobenztropine Dimebolin Ebastine Emedastine Epinastine Ketotifen Levocabastine Loratadine Mebhydrolin Mizolastine Olopatadine Rupatadine Setastine Terfenadine; 3rd Generation: Desloratadine Fexofenadine Levocetirizine; Miscellaneous: Tricyclic Antidepressants (Amitriptyline, Doxepin, Trimipramine, etc) Tetracyclic Antidepressants (Mianserin, Mirtazapine, etc) Serotonin Antagonists and Reuptake Inhibitors (Trazodone, Nefazodone) Typical Antipsychotics (Chlorpromazine, Thioridazine, etc) Atypical Antipsychotics (Clozapine, Olanzapine, Quetiapine, etc)

H2

Agonists: Amthamine Betazole Dimaprit Histamine HTMT Impromidine UR-AK49

Antagonists: Cimetidine Famotidine Lafutidine Metiamide Niperotidine Nizatidine Ranitidine Roxatidine

H3

Agonists: -Methylhistamine Cipralisant Histamine Imetit Immepip Immethridine Methimepip Proxyfan

Antagonists: A-349,821 A-423,579 ABT-239 Betahistine Burimamide Ciproxifan Clobenpropit Conessine GSK-189,254 Impentamine Iodophenpropit JNJ-5,207,852 MK-0249 NNC-38-1,049 SCH-79,687 Thioperamide Tiprolisant VUF-5,681

H4

Agonists: 4-Methylhistamine Histamine VUF-8,430

Antagonists: JNJ-7,777,120 Thioperamide VUF-6,002

Reuptake

Inhibitors

Plasmalemmal

.....

Vesicular

VMAT Inhibitors

Ibogaine Reserpine Tetrabenazine

Enzyme

Inhibitors

Anabolism

HDC Inhibitors

-FMH Brocresine Catechin Cyanidanol-3 McN-A-1293 ME Meciadanol Naringenin Thiazol-4-yimethoxyamine Tritoqualine Zy-15,029

Catabolism

HNMT Inhibitors

Amodiaquine BW-301U Diphenhydramine Harmaline Metoprine Quinacrine SKF-91,488 Tacrine

DAO Inhibitors

1,4-Diamino-2-butyne Aminoguanidine

Others

Precursors

L-Histidine

Cofactors

Vitamin B6 (Pyridoxine, Pyridoxamine, Pyridoxal Pyridoxal Phosphate)

v  d  e

Piperazines

1-Cyclohexylpiperazine  2C-B-BZP  Acaprazine  Almitrine  Alnespirone  Aminoethylpiperazine  Amoxapine  Antrafenine  Aripiprazole  Atevirdine  Azaperone  Azimilide  Befuraline  Bifeprunox  Binospirone  BRL-15572  Buclizine  Buspirone  BZP  Chlorbenzoxamine  Chlorcyclizine  Cinepazet  Cinnarizine  Ciprofloxacin  Clocinizine  Clopenthixol  Clozapine  CPPene  Cyclizine  Dasatinib  DBL-583  DBZP  Dibenzylpiperazine  Diethylcarbamazine  Dimethylphenylpiperazinium  Dotarizine  DPI-3290  Dropropizine  EGIS-12233  Eltoprazine  Ensaculin  Etoperidone  Fipexide  Flesinoxan  Flibanserin  Flupentixol  Fluphenazine  Fluprazine  GBR-12935  Gepirone  HEPPS  Hexocyclium  Hydroxyzine  Imatinib  Indinavir  Ipsapirone  Itraconazole  JNJ-7777120  Ketoconazole  Levodropropizine  Lidoflazine  Loxapine  Lurasidone  Manidipine  MBZP  mCPP  MDBZP  Meclizine  MeOPP  Nefazodone  Niaprazine  Olanzapine  Opipramol  Oxatomide  Oxypertine  PB28  Perazine  Perospirone  Perphenazine  pFPP  Piberaline  Piperazine  PIPES  Pirenzepine  Piribedil  Posaconazole  Prochlorperazine  PRX-00023  Quipazine  Ranolazine  S-15535  SA 4503  SB-258,585  SB-271,046  SB-357,134  SB-399,885  Sildenafil  Tandospirone  TFMPP  Thiethylperazine  Thiothixene  Tirilazad  Trazodone  Trelibet  Trifluoperazine  Trimazosin  Trimetazidine  Vanoxerine  Vardenafil  Vesnarinone  Vilazodone  VUF-6002  WAY-100,135  WAY-100,635  Zalospirone  Zipeprol  Ziprasidone  Zuclopenthixol

Categories: Drugboxes which contain changes to watched fields | Analgesics | Antiemetics | Anxiolytics | H1 receptor antagonists | Sedatives | Piperazines | Organochlorides | Ethers | AlcoholsHidden categories: Articles needing additional references from August 2009 | All articles needing additional references | All articles with unsourced statements | Articles with unsourced statements from October 2009