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Diazepam 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.
Panel’s Assessment of Driving Risks: 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.
References and Recommended Reading:
Baselt RC. Drug effects on psychomotor performance. Biomedical
Publications, Foster City, CA; pp 127-36; 2001.
de Gier JJ, Hart BJ, Nelemans FA, Bergman H. Psychomotor performance
and real driving performance of outpatients receiving diazepam. Psychopharmacology 1981;73(4):340-4.
Drummer OH. Benzodiazepines - Effects
on Human Performance and Behavior. Forens Sci Rev 2002;14(1/2):1-14.
Korttila K, Linnoila M. Psychomotor skills related to driving after
intramuscular administration of diazepam and meperidine. Anesthesiology 1975;42(6):685-91.
Korttila K, Linnoila M. Recovery and skills related to driving after
intravenous sedation: dose- response relationship with diazepam. Br
J Anaesth 1975;47(4):457-63.
Kozena L, Frantik E, Horvath M. Vigilance impairment after a single
dose of benzodiazepines. Psychopharmacol (Berl) 1995;119(1):39-45.
Mattila MJ, Aranko K, Kuitunen T. Diazepam effects on the performance
of healthy subjects are not enhanced by treatment with the antihistamine
ebastine. Br J Clin Pharmacol 1993;35(3):272-7.
Mattila MJ, Palva E, Seppala T, Ostrovskaya RU. Actions and interactions
with alcohol of drugs on psychomotor skills: comparison of diazepam and
gamma-hydroxybutyric acid. Arch Int Pharmacodyn Ther 1978;234(2):236-46.
Morland J, Setekleiv J, Haffner JF, Stromsaether CE, Danielsen A, Wethe
GH. Combined effects of diazepam and ethanol on mental and psychological
functions. Acta Pharmacol Toxicol 1974;34(!):5-15.
Moskowitz H, Smiley A. Effects of chronically administered buspirone
and diazepam on driving- related skills performance. J Clin Psychiatry 1982;43(12
Pt 2):45-55.
O'Hanlon JF, Haak TW, Blaauw GJ, Riemersma JB. Diazepam impairs lateral
position control in highway driving. Science 1982;217(4554):79-81.
O'Hanlon JF, Vermeeren A, Uiterwijk MM, van Veggel LM, Swijgman HF.
Anxiolytics' effects on the actual driving performance of patients and
healthy volunteers in a standardized test. An integration of three studies. Neuropsychobiology 1995;31(2):81-8.
Physicians’ Desk Reference, Medical Economics Company,
Montvale, NJ, 2002.
Seppala K, Korttila K, Hakkinen S, Linnoila M. Residual effects and
skills related to driving after a single oral administration of diazepam,
medazepam or lorazepam. Br J Clin Pharmacol 1976;3(5):831-41.
Smiley A, Moskowitz H. Effects of long-term administration of buspirone
and diazepam on driver steering control. Am J Med 1986;80(3B):22-9.
van Laar MW, Volkerts ER, van Willigenburg AP. Therapeutic effects and
effects on actual driving performance of chronically administered buspirone
and diazepam in anxious outpatients. J Clin Psychopharmacol 1992;12(2):
86-95.
Willumeit HP, Ott H, Neubert W, Hemmerling KG, Schratzer M, Fichte K.
Alcohol interaction of lormetazepam, mepindolol sulphate and diazepam
measured by performance on the driving simulator. Pharmacopsychiatry 1984;17(2):36-43. |
