Diazepam: History, Chemistry and Future Trends

Diazepam

Historical Developments and Discovery

 Barbiturates were developed in the first half of the 20^th century but had limited use because of the high risk for abuse and dependence.  They had fatal consequences and raised controversy.  In 1954, pharmaceutical companies wanted a safer alternative to these barbiturates. Chemist and pharmacist, Leo Sternbach, was tasked with developing this safer alternative.  Sternbach had created forty new compounds, but none had any kind of effects when he tested them on animals (Medline Plus, 2005).  He finally modified a white powdered compound, Ro 5-0690, and placed it on a random shelf where he had later forgotten it.  After a year, the compound was found accidentally during a clean-up.  Sternbach sent it out for testing and the results showed the compound had similar effects to meprobamate.  The same compound he had been trying to discover for three years (Ban, 2006).  This compound was put on the market in 1960 as an anxiolytic drug named Librium.  This was the first clinically used benzodiazepine (Medline Plus, 2005).

After Librium was released, the market wanted more benzodiazepines.  Diazepine became the second successful benzodiazepine.  It was introduced in 1963 and received the trade name of Valium.  Diazepam quickly gained interest and for over thirteen years, it was the most prescribed drug in the United States.  Sales peaked in 1978 with over two million pills sold (Ban, 2006).  It quickly gained popularity because it had the same effects as the barbiturates people were used to but had a significantly lower chance of abuse and overdose.  Over time though, the use of benzodiazepines became controversial.  Their potential for abuse and dependence had increased and doctors were overprescribing them.  The Rolling Stones even wrote a song about diazepam called “Mother’s Little Helper” because many people viewed it as a habit-forming, dangerous drug (Ban, 2006).  Benzodiazepines has continued to decline in popularity due to the new hypnotics and anxiolytics.

Pharmacological Characteristics

Diazepam is a benzodiazepine; a person can tell by the ending of the word (epam).  The chemical name is 7-chloro-1, 3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one.  The structure formula is:

(American Society of Health Systems of Pharmacists. AHFS Drug Administration, pg. 2578, 2010.)

It is a white to light yellow compound.  Diazepam is administered orally as 2 mg, 5 mg, or 10 mg tablets.  It is used to treat many forms of anxiety disorders, alcohol withdrawal, muscle spasms, and seizures (Rxlist).  The most common side effects are drowsiness, fatigue, and muscle weakness.

In order to maximize the benefits of diazepam, dosages need to meet the needs of patients.  There will be some patients who may require a higher dosage due to the issue they are having.  For management of anxiety disorders, dosages vary from two to ten milligrams, two to four times daily.  Alcohol withdrawal requires ten milligrams, three to four times daily, reducing to five milligrams, three or four times daily.  Muscle spasm treatment can be treated with two to ten milligrams, three to four times daily.  Epileptic patients take diazepam in dosages of two to ten milligrams, two to four time daily (FDA).

Diazepam exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnesic effects (Roche Group).  This results from a facilitation of the action of Gamma-amino butyric acid (GABA), a neurotransmitter in the central nervous system.  When a receptor is empty (no agonists), the chloride channel is closed and inactive.  When GABA binds to a receptor, the chloride ion channel opens which leads to hyperpolarization of the cell.  The binding of GABA is enhanced by benzodiazepines, resulting in a greater entry of chloride ions.  The benzodiazepine does not bind to the GABA receptor, but to the actual receptor (Steemit, 2017). The entry of chlorine ions hyperpolarizes the cell, making it more difficult to depolarize.  This reduces neural excitability.  GABA inhibits excitatory stimulation which controls emotional behavior and has effects that suppresses seizure activity.

After administration, over ninety percent of diazepam is absorbed.  The time to achieve peak plasma concentration is approximately one to one and a half hours.  Absorption can be delayed or decreased if a person eats a meal with moderate fat before taken.  Diazepam is highly bound to plasma proteins (Roche).  The initial distribution phase has a half-life of approximately one hour but can range up to three hours.  The elimination phase has a half-life up to forty-eight hours (Roche).  Diazepam is excreted mainly in the urine.  It accumulates after multiple dosing, and there for the elimination half-life can be slightly prolonged.

Diazepam is a drug that has a high subject to drug dependence and abuse.  It is a Schedule IV control drug (DEA, 2013).  Addiction-prone patients must be under careful surveillance when taking diazepam.  Once dependence has taken place, treatment will depend on the subject and the symptoms.  Abuse is more likely to take place in patients who have taken the medication for more than four months.  The warning signs for diazepam abuse includes change in appearance, slow movement, change in eating habits, and excessive sleeping.  Warning signs for addiction are strong cravings, self-isolation, and ignoring obligations (Iliades, 2014). 

Dependence is likely in patients with long-term therapy because their body builds a tolerance to it.  This means that your body needs more of the drug to feel the same effects. People then take more of the drug, and abuse is likely to follow.  Tolerance can develop at different rates depending on the patient, how much of the drug the patient takes, and how often a patient takes it (National Institute on Drug Abuse, 2007).  Pre-existing health conditions also effects how rapidly a patient can become dependent on a drug then addiction.  A patient feels like the drug is the only thing to make you feel good or function.  What a patient doesn’t realize is the drug is causing most of the negative thoughts and feelings.

An addiction forms once a person continues to use diazepam even when there are negative effects present.  A person’s perception of drug abuse changes after they become addicted to a drug.  “Addiction is not defined as how long a person has been taking a drug; it is the inability to stop despite consequences or even being able to notice the consequences (American Society of Addiction Medicine, 2011).

Future Trends

The future for diazepam is focused around tolerance.  Scientists are trying to develop new forms of this drug to decrease the chance a person will abuse the drug.  Many benzodiazepines have been developed in order to try and fix this problem.  Some of these include alprazolam, clonazepam, and lorazepam (Hoffman, 2015).  Treatments are also available for people who need some extra help.

Not everyone who gets prescribed diazepam becomes addicted.  People can decrease their chances and slow the progression of tolerance.  People need to understand risk factors.  A family history can increase your chances of becoming addicted and developing an addiction faster.  “Genetic factors account for half of the likelihood that an individual will develop addiction” (American Society of Addiction Medicine, 2011).

There are many different treatments a person can attain.  Medically assisted detoxification is the first step in treating addiction.  This allows the drug to be completely removed from the body while a professional medical team assesses vitals and manages any complications that arise.  Medical treatment can include gradually weaning a person off diazepam, switching to another benzodiazepine that has a lower potential for abuse, or switching to a long-acting barbiturate (Substance Abuse and Mental Health Services Administration, 2015).

Once detoxification has terminated, a patient can go through behavioral interventions (Scruggs, Meyer, Kayo, 2014).  One is motivational nurturing and interviewing.  This works to develop natural, self-motivation instead of family and friends (outside sources) convincing them to quit.  Another is extrinsic reward factors.  This treatment focuses on patients attending appointments, participating in community events, and taking drug tests periodically.  The last one is communication-based family therapy (Substance Abuse and Mental Health Services Administration, 2015).  Families will be involved to address communication and the proper overall family functions. 

Diazepam triggers a very rewarding and pleasurable feeling.  Patients can abuse this drug more often than other drugs.  Diazepam isn’t as prescribed as it was when it was first developed.  Other drugs have been developed to replace diazepam, but it depends on each patient and how the drug interacts to find the best drug for that patient.  Diazepam is not meant to be taken for an extended amount of time, so if a patient takes it as prescribed there shouldn’t be an ample amount of problems.  Anyone can become addicted, but patients can take steps to gradually wean themselves off or go through different interventions.  Diazepam was a great start to developing other benzodiazepines, and the market is still on the rise for a safer alternative.

References

• American Society of Addiction Medicine. Definition of Addiction, 2011.
• American Society of Health System Pharmacists. AHFS Drug Information, 2578, 2010.
• Ban TA. The role of serendipity in drug discovery. Dialogues Clinical Neuroscience, 8(3), 335-44, 2006.

         Bryan, J. Landmark drugs: The discovery of benzodiazepines and the adverse publicity that followed, The Pharmaceutical Journal, 2009.

• Iliades, C. What is Diazepam?, 2014.
• MacKlon, A., Barton, M., James, O., The Effect of Age on the Pharmacokinetics of Diazepam, 59(6), 1980.
• Medline Plus Drug Information. Diazepam, 2016.
• National Institute on Drug Abuse. Definition of Dependence, 2007.
• Roche Group. Valium (brand of diazepam) Tablets, 1-12, 2015.
• RxList. Valium (Diazepam Tablets): Side Effects and Interactions, 2018.
• Steemit. Anti-Anxiety Drugs, 2017.
• Substance Abuse and Mental Health Services Administration. Prevention of Substance Abuse and Mental Illness, 2016.