11.27.2017 | John Addington
The oral LD 50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderay 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 desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up. J. D.
In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently. 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. The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer.
The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms. Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal.
Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam. 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. Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain. Baclofen or tizanidine is sometimes used as an alternative to diazepam. Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed.
Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.
Both of these kits deliver drugs using autoinjectors. The United States military employs a specialized diazepam preparation known as Convulsive Antidote, Nerve Agent (CANA), which contains diazepam. 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. 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.
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. 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. Very rarely dystonia can occur. Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.
This increased chloride ion influx hyperpolarizes the neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely. The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. Benzodiazepines are positive allosteric modulators of the GABA type A receptors ( GABAA ).
However, intravenous lorazepam has advantages over intravenous diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect. Intravenous diazepam or lorazepam are first-line treatments for status epilepticus. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures. 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.
The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). 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 has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. It has several pharmacologically active metabolites. Most of the drug is metabolised; very little diazepam is excreted unchanged. 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. 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.
Diazepam is mainly used to treat anxiety, insomnia, panic attacks and symptoms of acute alcohol withdrawal. Benzodiazepines have a relatively low toxicity in overdose. Diazepam is the drug of choice for treating benzodiazepine dependence with its long half-life allowing easier dose reduction. It is also used as a premedication for inducing sedation, anxiolysis, or amnesia before certain medical procedures (e.g., endoscopy ).
The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. Diazepam may impair the ability to drive vehicles or operate machinery.
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. People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug.
This drug is only used in cases with severe respiratory depression or cardiovascular complications. 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). Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Dialysis is minimally effective. Emesis is contraindicated. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Hypotension may be treated with levarterenol or metaraminol.
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 is stored preferentially in some organs, including the heart.
Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.
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. 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. Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration.
While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia ; information learned before using benzodiazepines is not impaired. 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. Drug tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours. Infusions or repeated intravenous injections of diazepam when managing seizures, for example, may lead to drug toxicity, including respiratory depression, sedation and hypotension. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia, and hangover effects, as well as falls. Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. Long-term use of benzodiazepines such as diazepam is associated with drug tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome. 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. Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. Benzodiazepines may also cause or worsen depression. Adverse effects such as sedation, benzodiazepine dependence, and abuse potential limit the use of benzodiazepines.
Sustained repetitive firing seems limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation. 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.
Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Long-term therapy in these people is not recommended. Therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms.
When diazepam is administered IM, absorption is slow, erratic, and incomplete.
Diazepam is marketed in over 500 brands throughout the world. It is supplied in oral, injectable, inhalation, and rectal forms.
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. 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.
Use of diazepam should be avoided, when possible, in individuals with:
GABAA receptors containing α2 mediate the anxiolytic actions and to a large degree the myorelaxant effects. Drugs like Flumazenil also bind to GABAA to induce their effects. The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines. GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). Diazepam is not the only drug to target these GABAA receptors.
During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.
Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Differences in rates of withdrawal (50–100%) vary depending on the patient sample.
Particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, opioids, and antidepressants. If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions.
These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable. Agents with an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism.
Diazepam was first synthesized by Leo Sternbach, and was first manufactured by Hoffmann-La Roche. It has been one of the most frequently prescribed medications in the world since its launch in 1963. In 1985 the patent ended, and there are now more than 500 brands available on the market. Diazepam is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about 0.01 USD per dose as of 2014. In the United States it was the highest selling medication between 1968 and 1982, selling more than two billion tablets in 1978 alone. In the United States it is about 0.40 USD per dose.
Improper or excessive use of diazepam can lead to dependence. At a particularly high risk for diazepam misuse, abuse or dependence are:.
The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.
About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation. Benzodiazepine treatment should be discontinued as soon as possible by 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.
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.
Diazepam has a number of uses including:
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 is highly protein-bound, with 96 to 99% of the absorbed drug being protein-bound. The duration of diazepam's peak pharmacological effects is 15 minutes to one hour for both routes of administration. The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The distribution half-life of diazepam is two to 13 minutes. 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. The bioavailability after oral administration is 100%, and 90% after rectal administration. When administered orally, it is rapidly absorbed and has a fast onset of action.
Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup of 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. It is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age. This use, however, is not typically recommended as the benefits are small and side effects are common.
An individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximay four hours immediay following a suspected overdose:
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 inhibits acetylcholine release in mouse hippocampal synaptosomes.
Diazepam has anticonvulsant properties. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate. Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations. It differs from some other anticonvulsive drugs with which it was compared. 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. Diazepam is a long-acting "classical" benzodiazepine.
Diazepam, first marketed as Valium, is a medication of the benzodiazepine family that typically produces a calming effect. It may also be used to cause memory loss during certain medical procedures. It is commonly used to treat a range of conditions including anxiety, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, seizures, trouble sleeping, and restless legs syndrome. When given into a vein, effects begin in one to five minutes and last up to an hour. By mouth, effects may take 40 minutes to begin. It can be taken by mouth, inserted into the rectum, injected into muscle, or injected into a vein.
Long term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Occasionally excitement or agitation may occur. It is not recommended during pregnancy or breastfeeding. Serious side effects are rare. They include suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy. After stopping, cognitive problems may persist for six months or longer. Common side effects include sleepiness and trouble with coordination. Abrupt stopping after long-term use can be potentially dangerous. Its mechanism of action is by increasing the effect of the neurotransmitter gamma -Aminobutyric acid (GABA).
Dosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have.
Diazepam has a range of side effects common to most benzodiazepines, including:
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, or soman (or other organophosphate poisons), lindane, chloroquine, physostigmine, or pyrethroids.
Diazepam can be administered orally, intravenously (must be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.
Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.
Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation), leading to respiratory arrest and death.Diazepam