DiazepamDiazepam is a colorless, crystalline compound. Available primarily in tablet or liquid form.
Synonyms: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; Valium®, Valrelease®, Vazepam®, Diaz Intensol®, Diastat®, Dizac®.
Sources: Diazepam is a Schedule IV controlled substance and is available by prescription in tablet, gel and injectable form. Valium® tablets are white (2 mg), yellow (5 mg) or blue (10 mg) round tabs with a cut out “V” design. Valium® Injectable is available in 5 mg/mL strength liquid.
Drug Class: Tranquilizer, sedative, CNS depressant.
Medical and Recreational Uses: Used medicinally in the management of anxiety disorders, as an adjunct for the relief of skeletal muscle spasm and for convulsive disorders/status epilepticus, and as a minor tranquilizer or sedative. Also used to suppress or dampen acute alcohol withdrawal, and anxiety-related gastrointestinal disorders such as stress ulcers. Diazepam is used recreationally as a sedative or to enhance the effects of alcohol or opioids. For example, administration of diazepam 30 minutes after a dose of oral methadone reportedly produces an augmented high. Diazepam is used by cocaine users to increase seizure threshold and by heroin users to enhance the effects of heroin, and by both of these users to reduce the impact of withdrawal symptoms between doses.
Potency, Purity and Dose: Commonly prescribed doses of Valium® are 5-40 mg daily. For anxiety, 2-10 mg is taken twice to four times daily; for alcohol withdrawal symptoms 10 mg is taken three to four times daily. For the injectable form, 2-20 mg is administered intramuscularly or intravenously. Street doses may consist of several tablets administered at once.
Route of Administration: Usually oral, but intravenous injection is possible after preparing a solution from crushed tablets. Commercially available liquid Valium® can be injected, and gel forms can be rectally administered.
Pharmacodynamics: Diazepam is a 1,4-benzodiazepine, which binds with high affinity to the GABA A receptor in the brain to reduce arousal and to affect emotions. Diazepam’s action causes an increase in affinity of the major inhibitory neurotransmitter, GABA. GABA binds mainly to the a subunit while diazepam binds to the b subunit. The g subunit is also essential for modulation of chloride transport by benzodiazepines. Diazepam increases chloride transport through ion-channels and ultimately reduces the arousal of the cortical and limbic systems in the CNS. Diazepam depresses the electrical after-discharge in the amygdala and hippocampus regions of the limbic system that affect emotions.
Pharmacokinetics: Diazepam is rapidly absorbed. Oral bioavailability is approximately 100%, and close to 99% is bound in plasma. The half-life of diazepam is 43±13 hours, but ranges from 40-100 hours if the contribution from active metabolites is included. Diazepam is metabolized to nordiazepam which is an active metabolite with a half-life of 40-99 hours. Temazepam and oxazepam are minor active metabolites of diazepam. Diazepam is excreted in urine mainly as oxazepam conjugate (~33 %), and temazepam conjugate, with only traces of diazepam and nordiazepam.
Molecular Interactions / Receptor Chemistry: Diazepam is demethylated to nordiazepam via P450 2C19 and 3A4; and 3-hydroxylation to temazepam and oxazepam occurs via P450 3A4. Potential inhibitors of 2C19 and 3A4 could decrease the rate of diazepam elimination if administered concurrently, while potential inducers of these isoenzymes could increase the rate of elimination.
Blood to Plasma Concentration Ratio: 0.55 and 0.70 reported; 0.59 for nordiazepam.
Interpretation of Blood Concentrations: Simple interpretation of blood concentrations without any knowledge of drug-taking history is ill advised. Given changing responses with repeated use and variability in response, blood concentrations will not provide a good indication of likely behavioral effects. Additionally, the long half-life of diazepam may cause accumulation to occur with repeated use. Blood concentrations may be several-fold higher after chronic use compared to single use, and there are significant increases in blood levels in the elderly
Therapeutic blood concentrations typically range from 0.1-1.0 mg/L. Single oral doses of 10 mg result in diazepam concentrations of 0.2-0.6 mg/L at 0.5-2 hours, while chronic doses of 30 mg produce steady state diazepam concentrations of 0.7-1.5 mg/L and nordiazepam concentrations of 0.35-0.53 mg/L. Plasma concentrations of 0.3-0.4 mg/L are recommended for anxiolytic effects, and > 0.6 mg/L for control of seizures. Higher concentrations might suggest misuse or abuse.
Interpretation of Urine Test Results: Urine concentrations of metabolites are detectable for several days to weeks after last use. Urinary excretion of unchanged drug is less than 1%.
Effects: At low doses, diazepam is a moderate tranquilizer, causing sleepiness, drowsiness, confusion, and some loss of anterograde memory. At high doses, excitement, disinhibition, severe sedation, and effects on respiration occur, particularly if respiration is impaired by other drugs or by disease. Diazepam can produce a state of intoxication similar to that of alcohol, including slurred speech, disorientation, and drunken behavior.
Side Effect Profile: Side effects may include dry mouth, blurred or double vision, headache, vertigo, urinary retention, excessive perspiration, nausea and vomiting, ataxia, tremor, depression, hypotension and diminished reflexes. The elderly are more likely to develop significant adverse CNS effects from the use of diazepam. In overdose, paradoxical reactions of anxiety, insomnia, stimulation, hallucination, and acute hyperexcited state may occur. Shallow breathing, clammy skin, dilated pupils, weak and rapid pulse, coma, and death are possible.
Duration of Effects: Dose-dependent, however, with therapeutic doses onset of effects occurs within 30 minutes and significant effects can last for 12-24 hours.
Tolerance, Dependence and Withdrawal Effects: Regular use will produce tolerance to most of the sedative and adverse effects, but tolerance may not occur for the anxiolytic benefits of diazepam. Tolerance may take several weeks or months to develop depending on dose and frequency of administration. Diazepam is capable of causing mild physical and psychological dependence and is regarded as having a significant abuse potential. Abstinence or abrupt withdrawal may produce excitement, restlessness, dysphoria, anxiety, apprehension, fearfulness, dizziness, headache, muscle stiffness, tremors, insomnia, and sensitivity to light and sound. More severe symptoms may include intense rebound nausea, vomiting, abdominal cramps, delirium, hallucinations, hyperthermia, sweating, panic attacks, confusional or paranoid psychoses, tachycardia, increased blood pressure, and occasionally seizures or convulsions.
Drug Interactions: Other benzodiazepines, alcohol, phenothiazines, narcotic analgesics, barbiturates, MAOI’s, and other CNS depressants may potentiate action of diazepam. Alcohol enhances such effects as drowsiness, sedation, and decreased motor skills, and can also exacerbate the memory impairing effects of diazepam. Cimetidine delays clearance of diazepam. Valproate may potentiate the CNS depressant effects. Theophylline has an antagonistic action to some of the deleterious effects of diazepam.
Performance Effects: Laboratory studies have shown that single doses of diazepam (5-20 mg) are capable of causing significant performance decrements, with maximal effect occurring at approximately 2 hour post dose, and lasting up to at least 3-4 hours. Decreases in divided attention, increases in lane travel, slowed reaction time (auditory and visual), increased braking time, decreased eye-hand coordination, and impairment of tracking, vigilance, information retrieval, psychomotor and cognitive skills have been recorded. Lengthened reaction times have been observed up to 9.5 hours post dose. Lethargy and fatigue are common, and diazepam increases subjective perceptions of sedation. Such performance effects are likely to be exacerbated in the elderly. In drug users, diazepam has greater behavioral changes, including subjects’ rating of liking and decrements in psychomotor and cognitive performance. Reduced concentration, impaired speech patterns and content, and amnesia can also be produced, and diazepam may produce some effects that may last for days. Laboratory studies testing the effect of ethanol on subjects already using benzodiazepines demonstrate further increases in impairment of psychomotor and other driving skills, compared to either drug alone.
Effects on Driving: The drug manufacturer suggests patients treated with diazepam be cautioned against engaging in hazardous occupations requiring complete mental alertness such as driving a motor vehicle. Simulator and driving studies have shown that diazepam produces significant driving impairment over multiple doses. Single doses of diazepam can increase lateral deviation of lane control, reduce reaction times, reduce ability to perform multiple tasks, decrease attention, adversely effect memory and cognition, and increase the effects of fatigue. Significant impairment is further increased when diazepam is combined with low concentrations of alcohol (0.05 g/100 mL). A number of epidemiological studies have been conducted to evaluate the risk of crashes associated with the use of diazepam and other benzodiazepines. These show a range of relative risk, but most demonstrate increases in risk compared to drug free drivers. These increases have been twice to several fold. The elderly may have an increased risk of a motor vehicle crash.
DEC Category: CNS depressant
DEC Profile: Horizontal gaze nystagmus present; vertical gaze nystagmus present in high doses; lack of convergence present; pupil size normal; reaction to light slow; pulse rate down; blood pressure down; body temperature normal. Other characteristic indicators may include behavior similar to alcohol intoxication without the odor of alcohol, staggering and stumbling, lack of balance and coordination, slurred speech, disorientation, and poor performance on field sobriety tests.
Cognitive Functioning: The incidences of diazepam in drivers involved in road crashes and in drivers suspected of being under the influence, suggest an adverse effect of diazepam on road safety. Data are available to demonstrate that single therapeutic doses of diazepam can significantly impair psychomotor skills associated with safe driving, with some effects still observable the morning after a nighttime dose.
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