DIAZEPAM DRUG PROFILE
Introduction
Manufacture of drugs
involves combination of various substances and chemicals using a predefined
chemical formula and for this reason a drug is given a chemical name. Usually
this chemical name is too long and hard to pronounce and it’s for this reason
that manufacturers give generic and brand names that are easier to pronounce. Diazepam
is a chemical drug belonging to the group Benzodiazepines as indicated above
and is very effective in treatment of depression. It is a colorless,
crystalline compound available in both liquid and tablet form. This drug has
three names, chemical name is 7-chloro-1, 3-dihydro-1- methyl-5-phenyl-2H-1,
4-benzodiazepin-2-one, generic name is diazepam, Brand name is Valium. Other
brand names include Diastat, Diastat AcuDail, Diastat Pediatric, and Dizac. Isojärvi, JI; Tokola RA. (December 1998 pp12)
In Australia, diazepam
drug is an approved drug by the medical practitioners and is usually a
prescriptive drug whose uses (indications) are varied depending on what the
patient is suffering from. This drug is prescribed to both the old and the
children as young as six months old.
Common uses of the drug include treating alcohol withdrawal especially
to the –patients showing agitation, shakiness. It also treats muscle spasms
especially those arising due to muscle and joint inflammation. In this case the
drug relieves the patient’s pain. Other diazepam uses include treatment of
anxiety (usually short term use), seizures especially when used with other
seizure drugs and sleep walking medically known as parasomnias. Sometimes
diazepam drug may be prescribed to treat underlying conditions of a disease
even if it is not approved to treat that particular disease. This is called off
label drug.
Sometimes when certain
drugs are used together with diazepam, may increase the side effects of the
drug and may lead to interactions that may prove fatal to the patient. The
drugs may also impair the general breakdown of the drug in the body thus
failing to take effect to the body. These are over- the – counter (OTC)
medicines and complementary alternative medicines (CAM’s) and prescription
medicines. Remember that diazepam when not carefully taken and depending on the
dosage may greatly impair your thinking thus it is advisable to tell your
doctor all the diseases and medications that you are undergoing to avoid the
contra- indications through drug- drug interactions . These drugs include the
HIV/AIDs drug like the reyataz, delavirdine, indinavir, antifungal medicines
like itraconazole, ketoconazole and voriconazole, anti depressant like
flouxetine, antibiotics like the erythromycin, heart or blood pressure
medications like the nicardipine, quinidine verapamil among others. Similarly
there are certain drugs that have similar combinations and drug components that
resemble diazepam and thus may cause improper drug breakdown.
Mechanism of action
of diazepam
Diazepam is a
benzodiazepine with the sedative, anxiety relieving and muscle relaxing
effects. When diazepam is taken, it travels to the brain where its receptors,
the GABA cells are located. Action of the drug on these receptors causes the
release of a chemical neurotransmitter GABA located in the brain nerve cells
and the nervous system. The drug intervention acts on the receptor cells by
either mimicking the natural transmitter or by binding to the receptors thus
preventing the action of the transmitter. The produced chemical helps in
transmitting messages between nerve cells and thus acts as a natural nerve
calming agent keeping the nerve activities in the brain in balance, reducing
anxiety and inducing sleep to the patient. As the activities of diazepam
increases in the brain, its effects also increase resulting in the patient
feeling sleepy and the general relaxation of muscle. According to Alcohol and alcoholism report form the
Warsaw Medical academy 1996, 51 patients suffering from alcohol withdrawal
syndrome were involved in the study through the administration of the diazepam
drug to determine the effect of the drug in maintaining the body balance of the
patients. In this study however, different people wit showing different
alcoholism and signs and symptoms level were examined and the drug administered.
The result indicated that there was a significant change in the patients who
had previously taken alcohol.
Drug Metabolism and
renal excretion
Diazepam drugs are
either taken in as solid through oral medication, through injection or gel
forms of the drug can be administered rectally. Whether oral of injected the
drug need to be broken down into its constituents to be able to elicit the
required function. This is called drug metabolism. Seddon T,
& Chenery RJ
(1989 pp56). The drug breakdown mostly
occur in the liver cells with the help of different cytochrome P450
metabolizing enzymes commonly refered to as CYP’s
Source: (Diazepam
Metabolism by human liver report by. T Anderson et al 1994)
The above diagram shows how diazepam drug is broken down into its constituent metabolites namely the temazepam, N- demethyldiazepam and oxazepam through use of enzymes. The C3- hydrolation of the diazepam is catalyzed by the enzyme CYP3A12 to form temazepam while the N1- methylation is catalyzed by CYP2D15. The breakdown of the diazepam can be inhibited by CYP2C19 and CYP3A4 whereby they bind to the enzymes thus reducing the overall concentration of enzymes to act on the diazepam substrate. In their report Urinary excretion of diazepam metabolites in healthy volunteers and drug users, A. Smith-Kielland & B. Skuterud (2005) noted that most of the diazepam taken into the body is metabolized. The metabolites are then conjugated with sulphate and glucoronide and excreted primarily in urine.
Sources of variability
in diazepam drug metabolism
For the effective
delivery of a drug into the body to elicit a reaction, the drug must be broken
down into constituent metabolites. The breakdown of diazepam occurs in the
liver cells called hepatocytes. Andreasen PB & Hvidberg EF (2001pp 45-48) noted that metabolism
rate can either be inhibited or increased depending on various factors. The health status of the patient plays a role
in the general breakdown of the disease, example giving depressed patient a
tablet when the patient has liver failure, it will inhibit the production of
the cytochrome enzymes to breakdown the drug thus the function of the drug will
not be achieved by the patient and the drug may be eliminated from the body as
a unit. Enzyme concentration determines the amount of diazepam broken down;
example if there is low production of enzymes compared to the amount of drug
available for metabolism. Other factors affecting diazepam metabolism include
enzyme inhibitors which compete with the substrates for the active sites on the
enzymes. This causes diazepam blood and urine concentration high thus elimination
of the drug from the body.
Drug – drug
interactions of diazepam
Sometimes a drug may be
administered to a patient who is under medication for another disease. In this
case, addition of other drugs into the body system may produce side effects in
addition to eliciting fatal body reactions to the body. According to Dresser GK
& Bailey DG (2002 pp191- 195), drug-drug interactions occur when the
effectiveness of one medication is altered by the administration of another
medicine for medicinal reasons. The drug interactions are categorized on basis
of the type of reaction produced by the drugs. They include major interactions
where the risk of interaction outweighs the benefit, moderate and minor
interactions where the risks are low but require monitoring plan incase of drug
combinations. The drugs that react with diazepam include vicodin, lyrica,
Lipitor, fish oil, ambient and nexium among others. Consider drug interaction
between aspirin/ caffeine with diazepam, both drugs act sedatives, muscle
relaxers and antidepressants thus administration of both drugs may prove a
dangerous combination to the patient. The aspirin increases plasma
concentration of iso- enzymes that inhibit diazepam reuptake. This means that
the increase in aspirin concentration increases the toxicity levels of the
diazepam in blood.
References
A. Smith-Kielland, B. Skuterud, K.
M. Olsen, J. Mørland (2005). Urinary
excretion of diazepam metabolites in
healthy volunteers and drug users (doi: 10.1080/003655101300133676). Read More: http://informahealthcare.com/doi/pdf/10.1080/003655101300133676
Andreasen PB, Hendel J, Greisen G,
& Hvidberg EF (2001)Pharmacokinetics of diazepam in disordered liver function. Eur. J. Clin. Pharmacol, 10:45-48
Dresser
GK, Bailey DG. A basic conceptual and
practical overview of interactions with highly prescribed
drugs. Can J Clin Pharmacol. Winter 2002;9(4):191-198.
Isojärvi,
JI; Tokola RA. (December 1998). "Benzodiazepines
in the treatment of epilepsy in people
with intellectual disability". J
Intellect Disabil Res. 42 (1): 80–92. PMID 10030438
Seddon T, Michelle I, Chenery RJ 1989: Comparative drug
metabolism of diazepam in hepatocytes
isolated from man, rat, monkey and dog. Biochem Pharmacol. May 15; 38(10):1657-65.
T Andersson, J O Miners, M E Veronese, and D J Birkett.(1994) Diazepam metabolism
by human liver microsomes is
mediated by both S-mephenytoin hydroxylase and CYP3A isoforms.
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