FLUNITRAZEPAM
Pharmacology CHEM8005
Brugha Fitzpatrick – R00133434
TABLE OF
CONTENTS
DISCOVERY 1
ACTIVE INGREDIENT 2
ROUTES OF ADMINISTRATION 3
PHARMACOKINETICS……………….…………………………………………4
PHARMACODYNAMICS……………………………………………………….5
MECHANISMS OF ACTION……………………………………..………….6
TOXICOLOGY………………………………………………………………………7
REFERENCES………………………………………………………………………8
References
1. UK Parliament. (2016). Dr. Reg Peart Class-Action-Lawsuit [online] Available at: https://publications.parliament.uk/pa/cm199899/cmselect/cmhealth/549/99072723.htm [Accessed 24 Oct. 2017].
2. Drugbank.ca. (2017). Flunitrazepam – DrugBank. [online] Available at: https://www.drugbank.ca/drugs/DB01544 [Accessed 24 Oct. 2017].
3. Kangas L, et al. (2017). A pharmacokinetic and pharmacodynamic study of flunitrazepam. – PubMed – NCBI. [online] Ncbi.nlm.nih.gov. Available at: https://www.ncbi.nlm.nih.gov/pubmed/6130046 [Accessed 2 Nov. 2017].
4. Fitzgerald, P. and Geitskell Philips, G. (2004). Rohypnol – Molecule of the Month – June 2004. [online] Chm.bris.ac.uk. Available at: http://www.chm.bris.ac.uk/motm/rohypnol/rohypnolh.htm [Accessed 2 Nov. 2017].
5. Project Know. (2017). Flunitrazepam Overdose Symptoms and Treatment. [online] Available at: https://www.projectknow.com/research/flunitrazepam-overdose/ [Accessed 6 Nov. 2017].
6. Lippincott Williams Wilkins (2004). Substance Abuse: A Comprehensive Textbook [Novel] Available at: https://books.google.ie/books?id=HtGb2wNsgn4C&pg=PA305&lpg=PA305&dq=flunitrazepam+misuse&source=bl&ots=jok8sltRYF&sig=WSalg0V7wH8d_2PkXufpoReM_X4&hl=en&sa=X&ved=0ahUKEwjT8Pi9h6rXAhUCLcAKHRTZCbgQ6AEIXjAF#v=onepage&q&f=false
7. Insomnia.net. (2017). Learn About the Types of Medications Used to Treat Insomnia. [online] Available at: https://www.insomnia.net/medications/ [Accessed 6 Nov. 2017].
8. Ecstasy.com.ua. (2012). Controlled Substances » Pharmacokinetics of Flunitrazepam. [online] Available at: http://ecstasy.com.ua/pharmacokinetics-of-flunitrazepam#Absorption_Distribution_and_Plasma_Levels [Accessed 6 Nov. 2017].
9.
DISCOVERY
Flunitrazepam is a drug that is part of the benzodiazepine family. These are a class of psychoactive drugs, they contain a fusion of a benzene ring and a diazepine ring as their core chemical structure. The first of the benzodiazepine drugs that was discovered was chlordiazepoxide (Librium) by Leo Sternbach in 1955 and was made available on the market in by Hoffmann-La Roche in 1960. They have also marketed another benzodiazepine diazepam (Valium) since 1963. They were, globally, the most prescribed drug in 1977. They are commonly referred to as minor tranquilizers.
IN fact, the first benzodiazepine drug was discovered accidentally. The initial pharmacological properties of the compounds prepared were obsolete, Sternbach abandoned the project. Two years on, in 1957, Earl Reeder, a co-worker of Sternbach, noticed a “nicely crystalline” compound left over from the discontinued project whilst cleaning in the lab.
Benzodiazepines were initially greeted with optimism by the medical profession, but gradually concerns grew; in particular, the risk of dependence became evident in the 80s.
“Benzodiazepines have a unique history in that they were responsible for the largest-ever class-action lawsuit against drug manufacturers in the UK, involving 14,000 patients and 1,800 law firms that alleged the manufacturers knew of the dependence potential but intentionally withheld this information from doctors.” 1
Flunitrazepam, also known as Rohypnol or its street name “Rophie”, is an intermediate acting benzodiazepine used in some countries to treat chronic insomnia and earlier in anesthesia.
Flunitrazepam was discovered at Hoffman-La Roche as part of the benzodiazepine work led by Leo Sternbach. There was a patent applied in 1962 and in 1974; it was first put on the market.
ACTIVE INGREDIENT
Flunitrazepam is a nitrodiazepine. It is the fluorinated N-methyl derivative of nitrazepam.
ROUTES OF ADMINISTRATION
There are two routes of administration. It can be taken via the mouth (orally) or via the rectum in suppository action. Orally is the best method as it usually observed 64-77% of the time. The suppository method has only a 50-50 chance of being absorbed. Therefore, it is recommended that it’s taken orally either by swallowing or sub-lingually. This explains why it is used as a Class C drug for either recreational use or as the most popular “date rape drug”. It is easy to administrate and is far more potent than diazepam.
PHARMACOKINETICS
Absorption:
Flunitrazepam is administered orally, intravenously, suppository or intramuscularly. In doses of about 0.5-2mg. Flunitrazepam is lipophilic and is absorbed very quickly at physiological pH. It is almost completely absorbed orally. Flunitrazepam undergoes first-pass metabolism in the liver, resulting in a systemic bioavailability of 85-90%. 6
The absorption rate of the drug from the gastrointestinal tract is directly linked to the onset of action. This usually occurs for most if not all benzodiazepines.
Distribution:
Flunitrazepam absorption and distribution follow first-order kinetics after single- and multiple-dose oral administration. The distribution is biphasic and lasts up to 20 hrs.2
The initial half-life of flunitrazepam is between 2-4 hours. The brain takes up the metabolites very rapidly and the distribution throughout the brain from the central compartment is equally as quick.
Plasma Levels:
When flunitrazepam is administered orally a twin compartment model is used to describe the plasma concentration. After a single 2mg concentration dose, plasma concentration peaks at 8.8ng/ml with a 3.0ng/ml standard deviation over 1.9 1.38 hours after administration. If a chronic dose is administered then accumulation can be seen. A steady state is recorded 5-7 days after administration with N-desmethyl-flunitrazepam being the primary metabolite in the body. The volume of distribution after 5-7 days is 2.2-4.1L/kg.
When flunitrazepam is administered intravenously it is grouped into three-compartments. More than 95% of flunitrazepam is bound to plasma proteins, with the ratio of blood to plasma being 0.65-0.8.
Flunitrazepam is detectable in whole blood but 7-amino-flunitrazepam is detectable in both the plasma and the blood but higher concentration in plasma. Flunitrazepam is detectable in blood for 4 hours and 7-amino-flunitrazepam is detectable 12 hours post-injection.
The therapeutic range for flunitrazepam in the blood is 0.005mg/L-0.015mg/L with 0.020mg/L being the upper limit. This explains why 2 mg tablets are so popular in rape cases. The health of the liver needs to be good enough to eliminate the drug from the body.8
Half-Life vs Duration of Action
Although benzodiazepines are similar in every way they have varying half-lives. Oxazepam has a short half-life and diazepam has a long half-life. Flunitrazepam is an Intermediate-acting benzodiazepine with a half-life of 10-24hrs. Half-life is the time it takes for half the concentration of a certain molecule to be eliminated from the body.
PHARMACODYNAMICS
As previously mentioned flunitrazepam is a benzodiazepine derivative. It is a powerful sedative that has hypnotic, sedative, anxiolytic and skeletal muscle relaxant effects. In the United States of America, flunitrazepam has not been approved by the Food and Drug Association and therefore is illegal. However, in some countries in Europe like Spain and Germany it is verified and in other developing countries it is used due to its availability and price. Up until recently it was legal in the UK (even up to the date this reference was written), it is now illegal and is the most popular drug in “date-rape” cases due to its sedative and mild amnesia effects.2
In a flunitrazepam pharmacodynamics study done by the NCBI, 12 patients were dosed with flunitrazepam before being put under anesthesia for an operation. 75% of the 12 patients could not recall events leading up to the anesthesia being applied. An anterograde amnesia was noted.3
MECHANISM OF ACTION
Before mentioning flunitrazepam’s mechanism of action, the action of the gamma-aminobutyric acid – A molecule and its corresponding receptor.
When the GABA molecule is introduced into a system where the receptors are present they attract and bind the GABA receptor. This receptor acts on chloride-ion specific channels. The massive rush of negative ions into the neurons hyperpolarizes the cells to approximately -65mV to restrict the continuation of a signal from neuron to neuron or the firing of new signals.
Flunitrazepam enters the brain rapidly and efficiently with very little loss of active ingredient. It binds specifically to a receptor protein in the brain; benzodiazepine receptors, BNZ1 and BNZ2. Which are widely spread in the nerve cell groups involved in anxiety, sedation, memory loss and coordination. These receptors also bind a very important protein produced in the body; ɣ-amino butyric acid. The GABA receptors bind both the GABA and the flunitrazepam. The binding of the flunitrazepam enhances the activity of the GABA hyperpolarizing the brain’s nerve cells which shuts down brain activity more effectively.
USES AND MISUSES
Throughout the world Rophies are known only for the misuses in the western world. It is known that the USA citizens attain the drug by postage from countries like Cuba and Columbia. They are available in these countries as drugs that can be used to treat anxiety, depression, insomnia and many other mental disabilities.6
The misuse is mainly found in Florida and Texas. These are very popular party areas and quite backward thinking in their culture. These are two main reasons why it is the common “date-rape” drug in the US.
Although flunitrazepam is widely regarded as a dangerous drug it is also a very important drug for mental illnesses in countries that cannot afford drugs that are less potent and dangerous. South American countries and Africa’s cannot afford more modern drugs like Lunesta or Rozerem. To compensate they have to use this violent drug to treat very basic cases of insomnia. This means people can easily access the drugs and ship it worldwide in small parcels without detection.
The US Department of Justice has reported that two thirds of 18-25 year olds abuse Rohypnol both for recreational use and as a “date-rape” drug, and it is only worsening.
TOXICOLOGY
Flunitrazepam on its own is not a very toxic drug but when it is induced with CNS depressant drugs like alcohol and heroin, can abuse severe sedation, unconsciousness, slower heart rate, and suppression of respiration which can be fatal. Single IV doses of aminophylline 1-2mg/kg may reverse the sedation.
Signs of overdose include; excessive drowsiness, slurred and loss of coordination. These symptoms occur due to the GABA gates being constantly open leaving the ion channels in overdrive and the brain in a constant state of sedation.
Overdose can occur when 2 milligrams of flunitrazepam is consumed, this can be enhanced by simultaneous consumption of opiates as previously mentioned.
Alcohol is one of these opiates, this is why it is the most common “date-rape” drug. The drug is odorless, flavorless and completely dissolves in liquid. The effects of flunitrazepam are fast and long lasting due to the ease at which one can overdose.
If the overdose occurred recently, vomiting can be induced to clear the drug from the system of the patient. If the patient is unconscious their stomach may be pumped to force the toxin out of their system. Receptor antagonists like Romazicon can be used to medicate the patient and cancel the effects of flunitrazepam.