Valium tradename.
A medicine of the benzodiazepine family that typically produces a calming effect.
Its mechanism of action is by increasing the effect of the neurotransmitter gamma-aminobutyric acid (GABA).
Commonly used to treat anxiety, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, seizures, trouble sleeping, and restless legs syndrome.
It may cause memory loss during certain medical procedures.
It can be administered orally by mouth, by rectum, inntramuscularly or intravenously.
When given into a vein, effects begin in one to five minutes and lasts up to an hour.
Orally its effects may take 40 minutes to begin.
Pregnancy category US: D (Evidence of risk).
It is supplied in oral, injectable, inhalation, and rectal forms.
Bioavailability 76% by mouth, 81% rectally.
Liver metabolism with CYP2B6 is a minor route, to desmethyldiazepam, CYP2C19 a major route to inactive metabolites, CYP3A4 a major route to desmethyldiazepam.
Elimination half-life 20–100 hours and 36–200 hours for main active metabolite desmethyldiazepam.
A long-acting benzodiazepine.
Excretion by renal.
Common side effects: sleepiness, incoordination.
Serious side effects are rare and include: suicide, decreased breathing, and an increased risk of seizures.
Rarely, it can cause excitement or agitation may occur.
Long term use of diazepam can result in tolerance, dependence, and withdrawal symptoms on dose reduction.
It is not recommended during pregnancy or breastfeeding.
Diazepam tablets come in 2, 5, and 10 mg sizes.
Used mainly to treat anxiety, insomnia, panic attacks, agitation, and symptoms of acute alcohol withdrawal, as a premedication for inducing sedation, anxiolysis, or amnesia before certain medical procedures.
It is the drug of choice for treating benzodiazepine dependence with its long half-life allowing easier dose reduction.
Diazepam has a number of uses including:
Treatment of symptoms associated with vertigo.
Treatment of the symptoms of alcohol, opiate, and benzodiazepine withdrawal.
Short-term treatment of insomnia.
Treatment of muscle spasms
Treatment of tetanus.
Treatment of spastic muscular paresis caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, or spinal cord injury.
Palliative treatment of stiff person syndrome.
Pre- or postoperative sedation, anxiolysis or amnesia.
Treatment of complications from a hallucinogen crisis and stimulant overdoses and psychosis, such as LSD, cocaine, or methamphetamine.
It is one of the first-line treatments for status epilepticus.
It 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.
Its anticonvulsant effects can help in the treatment of seizures due to a drug overdose or chemical toxicity.
Sometimes used for the prevention of febrile seizures that may occur in children under five years of age.
Can be used for the emergency treatment of seizures associated with eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed.
Has no pain-relieving properties, but can be used for muscle-relaxant properties to alleviate pain caused by muscle spasms.
The drug should be avoided with:
Ataxia
Hypoventilation
Acute narrow-angle glaucoma
Severe hepatic deficiency.
Severe renal deficiencies
Sleep apnea
Severe depression, particularly when accompanied by suicidal tendency
Psychosis
Pregnancy or breast feeding
Caution required in elderly or debilitated patients
Coma
Abrupt discontinuation.
Acute intoxication with alcohol, narcotics, or other psychoactive substances.
History of alcohol or drug dependence
Myasthenia gravis, an autoimmune disorder causing marked fatiguability
Benzodiazepine abuse and misuse should be guarded against when prescribed to those with alcohol or drug dependencies or who have psychiatric disorders.
It is usually not indicated, except for treatment of epilepsy, and pre- or postoperative treatment.
The safety and effectiveness have not been established for infants under 6 months.
In the elderly and very ill, they can possibly suffer apnea or cardiac arrest.
The concomitant use of other central nervous system depressants increases this risk of apnea and cardiac arrest.
The metabolism of the drug in the elderly is much slower than younger adults.
The elderly also more sensitive to the effects of benzodiazepines, even at similar blood plasma levels, than in younger adults.
In the elderly doses are recommended to be about half of those given to younger people, and treatment limited to a maximum of two weeks.
Long-acting benzodiazepines such as diazepam are not recommended for the elderly.
Associated with a significant increased risk of falls.
Benzodiazepines are lipophilic and rapidly penetrate membranes, so rapidly cross over into the placenta with significant uptake of the drug.
When used in late pregnancy, especially high doses, can result in floppy infant syndrome..
When taken late in pregnancy, during the third trimester, causes a definite risk of a severe withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apneic spells, cyanosis, and impaired metabolic responses to cold stress.
Symptoms of floppy infant syndrome may occur and the neonatal withdrawal syndrome have been reported to persist from hours to months after birth.
Adverse effects include: amnesia, confusion and sedation.
The elderly are more prone to adverse effects of: confusion, amnesia, ataxia, hangover effects, as well as falls.
Long-term use is associated with drug tolerance, dependence, and benzodiazepine withdrawal syndrome.
Can impair short-term memory and learning of new information.
Can cause anterograde amnesia, but does not cause retrograde amnesia.
Cognitive-impairing effects does not tend to develop with long-term use.
Cognitive-impairing effects are greater in the elderly.
Cognitive deficits may persist for at least six months after stopping the drug.
Benzodiazepines such as diazepam may cause or worsen depression.
Repeated intravenous injections when managing seizures, may lead to drug toxicity, including respiratory depression, sedation and hypotension.
If infusions of diazepam if it is given for longer than 24 hours, drug tolerance may also develop.
Adverse effects such as sedation, dependence, and abuse potential limit its use as with other benzodiazepines.
When used as a sleeping aid, associated with an increased risk of death.
Side effects common to most benzodiazepines, including diazepam:
Suppression of REM sleep and Slow wave sleep
Impaired motor function
Impaired coordination
Impaired balance
Dizziness
Depression
Reflex tachycardia
Paradoxical side effects, which are less common include: nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido, and in some cases, rage and violence.
Adverse reactions are more likely to occur in children, elderly, and individuals with a history of drug or alcohol abuse and or aggression.
Rarely, may increase, propensity toward self-harming behaviors and suicidal tendencies or acts.
It may impair the ability to drive vehicles or operate machinery, and the impairment is worsened by consumption of alcohol
Tolerance to the sedative effects usually develops over time, but does develop to the anxiolytic and myorelaxant effects.[
Higher doses of 5 mg or more causes significant deterioration in alertness performance combined with sleepiness.
It can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome.
The higher the dose and the longer the drug is taken, the greater the risk of withdrawal symptoms.
Withdrawal symptoms can occur from standard dosages and also after short-term use.
It should be discontinued as soon as possible by a slow and gradual dose reduction regimen.
Tolerance develops to the anticonvulsant effects and is not generally recommended for the long-term management of epilepsy.
Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam
It is recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems,
Its use increases craving for alcohol in problem alcohol consumers, and increases the volume of alcohol consumed.
People with severe personality disorders, such as borderline personality disorder, can abuse the drug and develop dependence.
Overdose symptoms appear approximately four hours after a suspected overdose.
Symptoms include:
Drowsiness
Confusion
Hypotension
Impaired motor functions
Impaired reflexes
Impaired coordination
Impaired balance
Dizziness
Coma
Flumazenil is the antidote, as for all benzodiazepines, for an overdose.
Overdoses along with alcohol, opiates or other depressants may be fatal.
Its effects are potentiates by barbiturates, phenothiazines, opioids, and antidepressants.
It does not alter hepatic enzyme activity, or alter the metabolism of other compounds.
No evidence would suggest diazepam alters its own metabolism with chronic administration.[23]
Drugs with hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism.
It increases central depressive effects of alcohol, other hypnotics/sedatives,, other muscle relaxants, certain antidepressants, sedative antihistamines, opioids, and antipsychotics, as well as anticonvulsants.
Drugs that prolong the action of diazepam by inhibiting its elimination: Cimetidine, omeprazole, oxcarbazepine, ticlopidine, topiramate, ketoconazole, itraconazole, disulfiram, fluvoxamine, isoniazid, erythromycin, probenecid, propranolol, imipramine, ciprofloxacin, fluoxetine, and valproic acid.
Alcohol in combination with diazepam may cause a synergistic enhancement of the hypotensive properties.
Oral contraceptives significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.
Its metabolism is increased by rifampin, phenytoin, dexamethasone, carbamazepine, and phenobarbital, decreasing drug levels and effects.
It increases the serum levels of phenobarbital, and may block the action of levodopa.
Theophylline may inhibit its action.
Foods that acidify the urine can lead to faster absorption and elimination of the drug, reducing its levels and activity.
Foods that alkalinize the urine can lead to slower absorption and elimination of the drug, and increase its levels and activity.
Has anticonvulsant properties, with no effect on GABA levels, glutamate decarboxylase activity, but has a slight effect on gamma-aminobutyric acid transaminase activity.
Benzodiazepines, such as diazepam, are positive allosteric modulators of the GABA type A receptors (GABAA).
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, such as diazepam, to this receptor complex promotes binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane.
The increased chloride ion influx hyperpolarizes the neuron’s membrane potential, making firing is less likely, reducing the arousal of the cortical and limbic systems in the central nervous system.
The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ).
For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3).
GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and some anticonvulsive effects of diazepam.
GABAA receptors containing α2 mediate the anxiolytic actions and some of the myorelaxant effects.
GABAA receptors containing α3 and α5 also contribute to myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines.
It appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects, and increases the inhibitory processes in the cerebral cortex.
Its anticonvulsant properties may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors.
The muscle relaxant properties of are produced by the inhibition of polysynaptic pathways in the spinal cord.
Diazepam can be administered orally, intravenously, intramuscularly or as a suppository.
When given by mouth, it is rapidly absorbed with a fast onset of action.
The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration.
Peak pharmacological effects is 15 minutes to one hour for oral and parenteral routes of administration.
The bioavailability after oral administration is 100%, and 90% after rectal administration.
The half-life is 30–56 hours.
Peak plasma levels occur between 30 and 90 minutes after oral administration.
Peak plasma levels occur between 30 and 60 minutes after intramuscular administration; and after rectal administration, peak plasma levels occur after 10 to 45 minutes.
Highly protein-bound, at 96 to 99%.
The distribution half-life of diazepam is two to 13 minutes.
When administered IM, its absorption is slow, erratic, and incomplete.
It is highly lipid-soluble, and is widely distributed throughout the body after administration.
It crosses both the blood–brain barrier and the placenta, and is excreted into breast milk.
Continual daily doses of diazepam quickly build to a high concentration in the body, mainly in adipose tissue.
It is stored preferentially in some organs, including the heart.
The risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified.
It undergoes oxidative metabolism by demethylation, hydroxylation and glucuronidation in the liver as part of the cytochrome P450 enzyme system.
It has several pharmacologically active metabolites, as most of the drug is metabolized.
Very little of the drug is excreted unchanged.
The elimination half-life of diazepam increases significantly in the elderly.
It may be measured in blood or plasma to confirm a diagnosis of poisoning, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation.
Blood or plasma concentrations are usually in a range of 0.1–1.0 mg/l in persons receiving the drug therapeutically, 1–5 mg/l in those arrested for impaired driving, and 2–20 mg/l in victims of acute overdose.
Death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or opioids.
Drug misuse can occur either through recreational misuse, or when the drug is continued long term against medical advice.
About 29% of drug-related suicide attempts involve benzodiazepines, making them the most frequently represented class in drug-related suicide attempts.