APPLIED PHARMACOLOGY DRUG PROFILE

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.