Self Directed Learning Assignment

Drug: Rohypnol (Flunitrazepam)

Movie: The Hangover (2009)
Gahlinger: Club Drugs: MDMA, Gamma-Hydroxybutyrate (GHB),
Rohypnol and Ketamine
Enhance social intimacy and sensory stimulation
Low cost, convenient distribution (pills, powders, liquids)
Usually taken orally, maybe in combination with each other,
with alcohol, with other drugs
Flunitrazepam = antidote is flumazenil
o OD = hyperthermia, hypertension, rhabdomyolysis,
serotonin syndrome
o Can occur w even small dose
Enhance social interaction = entactogens = physical
closeness, empathy, euphoria
Rohypnol = powerful sedative/hypnotic agent
People can assume that substances that appear as
pharmaceuticals are safe to use
Can be misrepresented, adulterated (made worse by adding
something else) or substituted for another substance without
knowledge of the user
o Also taken with other things
High risk of unanticipated effects and OD
Increase in use of club drugs in last decade and a half
Rohypnol
o Potent benzodiazepine
o Rapid onset
o Clinical uses
Pre-op anaesthesia, sedation, treatment of
insomnia
o Street uses 1990s ->
Recreational sedative and date rape drug
o mg dose
reduction in anxiety, inhibition, muscular tension
(10x more potent than valium diazepam)
o higher doses than mg
anterograde amnesia, lack of muscular control,
loss of consciousness
o effects
30 minutes after ingestion
peak @ two hours
last 8-12 hours
potentiated with concurrent ingestion of
alcohol/sedatives

hypotension, dizziness, confusion, visual

disturbances, urinary retention, aggressive
behaviour in some users

o withdrawal
headache, tension, anxiety, restlessness, muscle
pain, photosensitivity, numbness, tingling of
extremities, increased seizure potential
treatment
o due to being illicitly obtained/adulterated/substituted =
treat as unknown substances
o cardiorespiratory maintenance first concern
o basic management
cardiac monitoring
pulse oximetry
urinalysis
chem panel for electrolyte balance, renal tox,
underlying disorders
try and avoid seizures
o in taken in previous 60 minutes orally = GI
decontamination with activated charcoal and a cathartic
o with the exception of a massive dose, induction of
emesis seldom effective (if anything can increase
distress)
o hypertension and tachycardia will generally resolve with
management of anxiety/agitation
severe hypertension = labetalol, phentolamine,
nitroprusside
agitation = benzodiazepines
hyperthermia = tepid water bathing and fanning
serotonin syndrome = serotonin antagonists (e.g.
chlorpromazine and cyproheptadine)
detection
o rohypnol and active metabolite 7-amino-flunitrazepam =
gas chromatography/mass spectrometry testing up to
72 hours

Britt: A brief overview of the clinical pharmacology of club drugs

clinical pharmacology of stated club drugs including origins,
neurobiology, therapeutic and illicit uses, acute and chronic
effects, treatment of withdrawal and OD
Drug
Rohypnol
Manner of use
Tablet, typically ingested orally,
can be crushed and snorted,
easily dissolved in beverages
Therapeutic uses
Treat insomnia and as pre-op
anaesthetic
Clinical effects
Euphoria, anxiety reduction,

Toxic effects

Systems affected
Dependence liability
Long term sequelae

increased comfort in social

situations
Decreased body temperature
and blood pressure, cognitive
and psychomotor impairment,
visual disturbances, dizziness,
confusion, GI disturbances,
urinary retention
Chloride channels
Can produce physical
dependence
Unknown, but likely similar to
other benzodiazepines:
depression, memory loss, mental
confusion, stomach disorders,
aggressive behaviours

rohypnol
o pill form
o typically taken orally
neurobiology
o similar to other benzodiazepines
o GABA agonist
o Mediates inhibitory neurotransmission in brain and
spinal cord
Bind to GABA receptor
Open Cl- channels of neurons
Influx of chloride and hyperpolarisation of cell
Decrease in excitability of cell
Sedation, anticonvulsant, anxiety reduction
Clinical pharmacology
o Sedative/hypnotic benzodiazepine
o Approved for therapeutic use in some countries (not US)
o Treatment of insomnia and pre-surgery anaesthetic
o Profound sedation sexual assault
Anterograde amnesia
o Odourless and tasteless, easily dissolved in bevarages
Manufacturers now adding blue die to pill that will
be visible if added to a beverage?
o Misuse by individuals
Nightclubs and raves
High abuse liability
Faster onset (15-20 min) and longer duration
(12 or more hours)
More potent
o Illicit use
Feeing of relaxation
Enhance effects of heroin

Decrease experience of opiate withdrawal

symptoms
Enhance effect of other substances
Lessen adverse stimulant effects of cocaine
Reduces anxiety
Induces euphoria
Increases comfort in social situations
o Acute adverse effects
Decrease in body temperatire
Sedation
Impairment of cognitive and psychomotor tasks,
decreased blood pressure, visual disturbances,
dizziness, confusion, GI distrubances, urinary
retention
o Withdrawal
Headache
Tension
Anxiety
Restlessness
Muscle pain
Sensitivity to light
Numbness and tingling of extremities
Seizures
Treatment
o OD loss of consciousness and respiratory depression
(can be life threatening)
o Activated charcoal to absorb drug in GIT
o Respiratory support
o Flumazenil = specific benzodiazepine antagonist
(administered to reverse the effects of flunitrazepam
Issues
o Population that misuses these drugs relatively small
group of substance misusers
o Difficult to tease apart effects of individual substances
o Difficult to know purity and dose

Schwartz: Rohypnol, The date rape drug

Sedative-hypnotic benzodiazepine
Manufactured by Hoffman-La Roche company in Europe/Latin
America
Prescribed for treatment of anxiety and insomnia
o 10 times more potent than diazepam
smuggled and mailed into US
comes as individually bubble-wrapped 2 mg scored tablet
o embossed with name Roche and 2 in a circle
enhance disinhibition

rapidly effective
o effects begin within 30 minutes
o peak at 2 hours
o persist for up to 8 hours
o effects
reduction of anxiety
muscular relaxation
somnolence
fatal ODs rare unless mixed with alcohol
treatment
o activated charcoal
o benzodiazepine antagonist flumazenil IV 0.5mg/minute
up to 3-5mg
reduces coma
metabolite = 7-aminoflunitrazepam
o detected by immunoassay

Saum: Rohypnol Misuse in the United states

potent sedative hypnotic
illicit in US
gained popularity as cheap means of intoxication sexual
abuse of unsuspecting victims
patterns of misuse
in benzodiazepine family of CNS depressants
o render disinhibited and helpless
sold OTC for insomnia in Europe/mexico/south America
appeared in US early 90s
greatest quantities arrive into US from mexico and Columbia
legal 3 month supply allowed in if accompanied by
prescription from country where it is legal, but security on this
lax
DEA attempting to reclassify it from Schedule 4 (low abuse
potential) to Schedule 1 (no accepted medical use in US)
o As a schedule 1, would carry same severe penalties for
possession as do heroin and cocaine
Effects and patterns of misuse
o Intoxication characterised by sedative and other
potentially dangerous effects as extreme disinhibition,
severe memory impairment or amnesia, muscle
relaxation, GI disturbances, visual impediment, and
slowing of psychomotor performance
Some patients may have no recollection of any
awakenings occurring in the six to eight hours
during which the drug exerts its action

o When combined with other sedatives, antidepressants,

analgesics or other tranquilizers, sedative effect is
intensified
However, although rohypnol is classified as a
depressant, it induces excitability or aggressive
behaviour in some users
o Long lasting effects peak 1-2 hours after ingesting
1mg dose
Fall to one-half peak after 16-35 hours
o Occasionally used as primary intoxicant
Misused more often when ingested with alcohol
Can be fatal due to enhanced NS depression
Greatly increased disinhibition
Blackouts lasting several hours
o 7-10 times more potent than diazepam
o unlikely to be fatal when taken alone even when ODing
o Date rape drug of choice = adversaries
o Mind eraser = users
o Once placed into liquid = colourless tasteless dissolves
easily
o Amnesia
Difficult to prosecute crimes
Also used by prostitutes in Europe so they can
steal their clients things but honestly good
o Inexpensive
o Ability to increase effectiveness of other drugs
o Long lasting effects
o Mistaken ideas of youth
Unadulterated (pre sealed bubble packs)
Cannot be detected by urinalysis testing
o Heroin users
Enhance effects of low quality heroin or
methadone
Relieve withdrawal symptoms
o Cocaine users
Ease intensity of crash following cocaine/crack
binges
Post script
o for professionals involved in prevention, the challenge
is how to warn young girls about the predatory use of
Rohypnol without teaching young boys how to do it
o US took measures to prevent it entering
o Impaired drivers how screen for flunitrazepam intox
when they appear drunk but register low BAC
o Testing for rohypnol in drug related deaths
o More severe penalties for rape cases which involve
rohypnol drugging

Labianca: Rohypnol: profile of the date-rape drug

Criminal use of rohypnol in a chemical context
Historical background and pharmacology
o A 1, 4-benzodiazepine
o CNS depressants noted for sedative-hypnotic activity
o Sedative: diminishes activity and excitement, calming
recipient
o Hypnotic: produces drowsiness and sleep
Presence of nitro group at C7 of rohypnol molecule
and o-fluoro substituent of phenyl group at C-5
o Not sanctioned by US FDA
Smuggled from Mexico and South America
o Mechanism of action and consequent effects
Selectively affects synaptic processes in the brain
mediated by the CNS NT GABA
Processes involve transmission of nerve
impulses between neurons, and ultimately
to effector cells (cells of the organ, gland or
muscle activated by impulse)
GABA = major inhibitor of NTmission
o Release blocks arousal of higher brain
centres
Benzodiazepines increase affinity of GABA
for its receptors produce diminished
excitation for nerve systems and
accompanying reduction in anxiety and
alertness
Also produces amnesia
o Alters rate of peptide chain formation
of certain neurons
o Advantageous in clinical setting
o Amnesia Bad in criminal setting
Amnesic effects and depressant
effects potentiated when taken
in conjunction with alcohol
OD can cause fatal depression of
respiratory reflex center of brain
(rare unless taken with another
CNS depressant)
Biotransformation
o Biotransformation Catalysed by liver enzymes (Figure 1)
o Principal products = N-demethyl (4), 3-hydroxy (5) and
7-amino (6) derivatives
N-demethyl derivative product of initial and most
rapid phase of biotransformation

Hydroxylation at C-3 and reduction at C-6 proceed

more slowly
Inactivation = glucuronidation displacement of
uridine diphosphate (UDP) from uridine
diphosphate-alpha-D-glucuronate (UDP-GA) which
is derived from UDP-glucose
Consistent with Sn2 displacement process
involves configuration at anomeric carbon
C1 of glucuronate GA moiety
Resulting O- and N-glucuronides have beta
configuration of the UDP-GA precursor
o Presence of carboxylate group in each of the
glucuronide conjugations products 8 and 9 promotes
their aqueous solubility, facilitating their excretion,
which occurs primarily through the kidneys

Schechter: Rohypnol (Roofies) Control of drug discrimination:

effect of coadministered ethanol or flumenazol
Introduction
o Anxiolytic flunitrazepam
o Typical benzodiazepine
o Commercially available in 1 and 2 mg tablets
o Acts as effective short-term sedative-hypnotic used for
insomnia
Also used as preanaesthetic medication
o Rarely leads to death taken alone
Combined with alcohol can lead to blackouts that
last 8 to 24 hours, depending on dose
Behavioural disinhibition coupled with amnesia
(anterograde)
Date rape
Now as super duper illegal as heroin and stuff
o Drug discrimination tests to train animals to
differentially respond to administration of a dose of R vs.
its vehicle in an effort to see if this centrally
psychoactive drug is capable of controlling differential
discriminative responding
To evaluate the dose-effect relationship as a
discriminative performance gradient
To determine the discriminative time course of this
drug
To allow for experiments to indicate any possible
additive or potentiating effects when this drug in
low dose is combined w ethanol
To explore if R, like most other benzodiazepines
used to train discriminative performance in rats, is

attenuated by pretreatment with the

benzodiazepine receptor blocker flumenazil
o Discussion
First to test rohypnol
Ability of any drug to produce differential
responding in a drug discrimination task is based
upon its state-dependent nature
Rohypnol previously been shown to produce
state-dependent learning deficits in humans
as a dose of 2mg R in volunteer subjects
was reported to have disruptive effects
inherent in anterograde memory loss
suggests involvement of state dependent
learning
Therefore, benzodiazepines appear to
produce performance deficits in humans in
going from drug-state learning to the blah
idk

Druid: Flunitrazepam: an evaluation of use, abuse and

toxicity
Fast acting hypnotic drug
Primary indications = insomnia and premedication
before anaesthesia
Toxicity