Study regarding the recreational use of benzodiazepines

Study regarding the recreational use of benzodiazepines

Author: Anca ButuceaCoauthors: Adriana Simion, Robert-Alexandru Vlad

Coordinator: Associate Professor Gabriel Hancu,PhD

Discovery of Benzodiazepines

Leo H. Sternbach – Hoffmann-LaRoche researcher

Chordiazepoxidum (Librium®)7-cloro-2-metilamino-5-fenil-3H-1,4-benzodiazepin-4-oxid

ON

N

C6H5

Cl

Cl

I

CH3NH2

ON

N

C6H5

NH-CH3

Cl

IICH3NH2

N

N

NH-CH3

Cl

C6H5 O

III

Chance as the counterpoint between failure and success

Structure-activity relationship of BZD

X

N

N

R2

R3

R4

R1

1 2

3

4567

8

9

2'

A B

C

X – electron-attracting substituentX – ClX – NO2 – sedato-hypnotics

The hydration of the 1-2 double bond –> increases activity

The hydration of the 4-5 double bond –> decreases activity

- H, -CH3

= O – lactamic BZD - OH- COOH- optic activity

Halogen elements (-Cl, -F)phenyl (exception: 2 piridil – bromazepam)

The introduction of additional cicles:- oxazolobenzodiazepines;- triazolobenzodiazepines;- imidazobenzodiazepines.

R1 – H, - CH3; R3 – H, - OH, - COOH,

R2 – 2H, = O, = S; R4 – H, - Cl, - F; X – Cl, - Br, - NO2

Mechanism of action

Major effects of Benzodiazepines

Adverse effects of BZDs

• Sedation• Apathy• Drowsiness• Depression• Anterograde amnesia• Difficulty in learning• Damage to the cognitive

function• Decrease of long-term

memory• Impaired motor

coordination

• Ataxia• Weakness• Headache• Visual disturbances• Vertigo• Nausea• Vomiting• Changes in taste• Diarrhea• Diminished libido• Menstrual disorders

Intoxication with BZDs

The chronic intoxication• Tolerance • Physical dependence• Abstinence syndrome

The acute intoxication• Lethargic state• Slurred speech• Ataxia• Hypotension• Coma • Respiratory depression• Exitus

Antidote: Flumazenil – a competitive antagonist of BZD on the GABAA receptor

Drug Addiction

A chronic, relapsing brain disease that is characterized by compulsive drug seeking and use, despite harmful consequences.

Alcohol, the oldest known Alcohol, the oldest known sedative - sedative - ““When Noah left the When Noah left the Ark he planted a vineyard, drank Ark he planted a vineyard, drank the wine, and was drunken, and the wine, and was drunken, and he was uncovered within his tent.”he was uncovered within his tent.”

Genesis Genesis

•http://www.emcdda.europa.eu•http://www.ana.gov.ro

Legislative framework

The law no. 143/2000 concerning the prevention and the combating illicit drug trafficking.(Tab. III - risk drugs)

The law no. 339/2005 regulates the legal regime of plants, drugs and psychotropic substances and compounds which are of interest in medicine, that are subject to strict control.

More and more recently discovered abused drugs are actually designed for the legal use as medicines

Alprazolam;Clonazepam;

Diazepam;Flunitrazepam;

Lorazepam;Phenazepam.

How can these drugs be obtained ?

the deviation of controlled drugs from the regulated market;

the import of unauthorized drugs from outside of EU; component drugs can be imported in bulk from

countries such as China or India, then processed and packed in the EU and sold directly on the illegal drug market, on the legal drug market or through the Internet.

0.00%

0.20%

0.40%

0.60%

0.80%

1.00%

Antidepressants Hypnotics Sedatives/tranquilizersM 0.30% 0.30% 0.30%F 0.30% 0.90% 0.60%

The prevalence of drug abuse among teenagers, aged 10-18 (100%=607)

Source: “The status of adolescents in Romania - UNICEF”

The highest prevalence for drug abuse was recorded among adolescents aged 14-18 for the consumption of sedatives/tranquilizers and hypnotics.

Source: “The status of adolescents in Romania - UNICEF”

According to the analysis, depending on the area of residence, drug abuse is rarer among the teens from the rural area.

Source: “The status of adolescents in Romania - UNICEF”

The characteristics of the population admitted to treatment due to drug abuse

In 2013, 1529 people requested assistance for hospitalization and ambulatory treatment due to drug abuse, from which:

• 821 were hospitalized and 708 were ambulatory cases• 632 were new cases and 825 were relapsed patients

From the 1529 admitted for treatment, 378 patients declared consumption of other drugs (secondary drug), other than the one they received treatment for. Hypnotics and sedatives (11,1%), were among the substances most utilized as a second drug, as well as methadone (34,8%), ethnobotanics (12%), cannabis (11,8%) and alcohol(10,5%).

The characteristics of the population admitted to treatment due to drug abuse

Source: The Central Laboratory of Analysis and Drug Profile, General Inspectorate of Romanian Police

Conclusions

• Based on the type of drug , the most frequent abuse was recorded for hypnotics, sedatives and opiates (approx. 2/3 from the 2013 treated patients admitted consumption on a daily basis).

• Iaşi county has recorded the highest number of cases of drug abuse with hypnotics and sedatives; although with smaller numbers, it was considered that a diversified consumption exists in Mureş, Sibiu, Timiş, where there were recorded treatment admissions for several types of drugs: hypnotics and sedatives, opiates and ethnobotanics.

• The area with the highest risk (regarding the no. of cases recorded) like in the previous years takes shape around the large universities and border districts: Bucharest, Iaşi, Cluj-Napoca, Sibiu, Tîrgu-Mureş, Timişoara and Constanţa.

• Compared with the previous year, we can distinguish a 13,00% increase in the no. of emergency cases in which there was declared a consumption of medicines exclusively, administered without medical prescription.

Characteristics of the reported cases in 2014 of BZD intoxication in Mureş county

Source: National Antidrug Agency– Mass-media statistics

BZD intoxication in Mureş county

• Methadone is combined with BZD and other drugs – Zolpidem, Citalopram, Topiramat (21 cases from the 23 cases of deaths associated with Methadone use);

• Alcohol is also added to this combinations (4 cases);• There is an increased incidence in the abuse of sedatives,

anxiolytics or antipsyhotics (possible due to the decrease of pharmacovigilance and the control of sales in pharmacies) with the relatively constant presence of BZD;

• The toxicological tests revealed the presence of BZD in 20 cases;

• Only in 3 cases death was due to the acute intoxication with prescription drugs (carbamazepine, barbiturates and BZDs) but the presence of these drugs was relevant in 24 cases, in general with the value of excipient or potentiator of the principal substance from the dose.

Conclusions

Benzodiazepine dependence

• BZDs are safe and effective for short-term treatment, however, long-term use is controversial due to the development of tolerance and their liability for physical dependence.

• The characteristic symptoms of intoxication with sedatives, hypnotics or anxiolytics includes inappropriate or aggressive sexual behavior, affective lability, deterioration of judgment, deterioration of social or professional function. These symptoms may appear in the course or after the use of these substances.

• These memory disorders (anterograde amnesy) or attention or coordination disorders may lead to accidents, stupor or even coma.