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The following message was posted to: PharmPK
I'm new to the list and I don't know the first thing about
pharmacokinetics. Sorry! I subscribed because I urgently need to
know more about the pharmacokinetics of one drug - DROPERIDOL.
I was hoping that you guys might be able to help me. What I've
learnt so far is at the bottom of this email. (Yeah, it's
pathetic - I could probably write it on the back of a postage
stamp.) I'm still trying to learn all I can, but I'm running out
of time. I desperately need to do a calculation. So if anybody
out there can spare a few minutes to help me, I'd be so
incredibly grateful. *Gulp!* Here goes....
Let's say - hypothetically speaking - that a male patient is
admitted to a psychiatric hospital. He's in his mid 20's, about
6' 5" tall, of lanky, athletic build. He usually weighs about
63kg, but today he's malnourished, dehydrated and has walked more
than 20 miles. He weighs barely 54 kg. He's very tired, not very
talkative and he wants to be left alone. Skipping the fuss and
bother of tiresome medical examinations - this is the night
shift, after all - the staff insist that he have a single dose of Droperidol
10mg intramuscularly (gluteus maximus) and a 2mg shot
of Lorazepam, lest he should decide to abscond and create more
work for them. Finally, he is allowed to go to bed.
Unfortunately, at some time during the evening, the patient
suddenly - and through no fault of his own - stops metabolising
the drugs. By the time they notice his blatant disobedience of
hospital policy, it is too late to do anything about it. This
greatly inconveniences the staff, who are now faced with the
prospect of having to make several phone calls and hastily
correct some errors in their paperwork. Fortunately, a kind
pathologist steps in and firmly suggests that they let him take
over from there. He painstakingly examines the patient (at his
leisure, since the patient's plans have been cancelled for the
foreseeable future) and obtains some blood samples. He records
blood plasma levels of Droperidol in the left femoral artery (24
nanograms/ml) and right femoral artery (29 nanograms/ml). He runs
some tests and - correctly - determines that the single doses of
Lorazepam and Droperidol are the only drugs in the patient's
system. He would like more information, but the patient isn't in
any position to talk and, not surprisingly, the forgetful staff
at the hospital have sort of 'lost track' of his medical notes.
So what I need, folks, is the best possible estimate of the time
elapsed between the injections and the point at which the patient
stopped er... metabolising. Can anybody help me?
(pharmacokinetically-challenged but not giving up!)
P.S. This is what I have learnt so far:
o Droperidol is an antipsychotic of butyrophenone group
o Initial plasma half-life = 10 minutes
o Terminal plasma half life = 2 hours
(Therefore it must be biphasic, right?)
o Its Vd = 2.4 L/kg (I'm a bit dubious about the accuracy
of this figure)
o I read somewhere that there's little to choose between the
im and iv route so far as Droperidol's action is concerned
o Additionally, the Drug Data Sheet says:
"The action of a single intramuscular or intravenous dose
commences 3-10 minutes after administration, although
the peak effect may not be apparent for up to 30 minutes.
The tranquillising and sedative effects tend to persist for
2 to 4 hours, although alertness may be affected for up
to 12 hours."
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The following message was posted to: PharmPK
This poor patient admitted in hospital then died at that night. Since I was
a clinical pharmacist before, I would like to rule out the relationship
between the death and medications.
Droperidol may cause hypotension due to its central nervous system and
alpha-adrenergic blocking properties. Especially, in patients (like this
patient) who are hypovolemic or who are receiving vasodilator therapy,
droperidol could induce a profound hypotension (Ellenhorn's medical
toxicology 2nd ED(1997),Section IV Chemicals). Another concern is lorazepam
has additive CNS effects when used concomitantly with droperidol. Such
combinations, or IV lorazepam used alone in higher than recommended doses,
can produce excessive sedation that may result in partial airway
obstruction. In my opinions, these reasons probably cause the death of this
Base on the limited pharmacokinetic data, I would like to trace the time of
death of this patient. Using the population pharmacokinetic data, the Vd of
this patient is 129.6 L (2.4 L/kg=B454kg), Ke of this patient is 0.3465 hr-1
(t1/2 =3D 2hr).
To simplify this case, assume it's an IV bolus administration instead of IM
Because it's IM administration, so we have to know there was the lag time
for absorption (assume 30min). So, I try to predict the death time of this
patient was 4hrs after administration of droperidol.
>From the limited data, I would like to provide one possibility to predict
the death time of the patient based on my limited knowledge. And also form
this case, we learn droperidol should be used carefully in hypovelemic
Not related to the calculation, my question is why the pathologist ordered
two blood samples from left femoral artery and right femoral artery. These
data stand for different clinical meanings?
Look forward to seeing your commends!
Li-Jiuan Margarita Shen
Department of Pharmaceutical Sciences
University of Southern California, School of Pharmacy
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Thank you for your contribution. You calculate the patient's time
of death to be approximately 4 hours after the administration of
the Droperidol injection. Well done, this is highly consistent
with the estimate that was arrived at by the County
Coroner/Toxicology team. You must have both used the same maths.
However, there is one slight problem.
Exactly 3 hours and 45 minutes after the injection, the patient's
body was seen by a number of witnesses who state that it was
cold, hard, clammy to the touch, and in an advanced state of
rigor mortis. The body's limbs were totally stiff, so stiff that
the ankles and toes could not be manipulated without breaking the
rigor mortis. So we're back to the drawing board.
Obviously, our mathematical models are wrong. My research into
the Pharmacokinetics of Droperidol has unearthed two very
interesting experimental papers (see below). The first, published
in 1973 proposed a two-compartment bi-phasic model, with an
initial (absorption) half-life of just 10 minutes. The
experimenters found that there was very little difference between
the absorption and elimination of Droperidol by intramuscular and
intravenous routes; both were astonishingly fast. The second
paper, published in 1986, looked at absorption by intravenous
bolus only. They refined the older theory into a 3-compartment
tri-exponential equation, with three separate half-lives. They
also determined that about 90% of the Droperidol had left the
plasma within 1 hour.
It seems we don't need to allow a time lag of 30 minutes for the
complete absorption of the intramuscular injection. The drug
begins to act within 3 to 10 minutes and maximum sedative effect
is seen within 30 minutes, REGARDLESS of IM or IV route.
As far as the mechanism of death is concerned, you are absolutely
right, excessive sedation leading to partial airway obstruction
is one possibility. In autopsy, the patient was found to have an
apparent 'flattening of the convolutions of the surface of the
brain' (Cerebral Oedema?) and 'the lungs and trachea were full of
a bloody, frothy fluid' (Pulmonary Oedema?). This certainly ties
in with your theory. However, there are a number of other
An acute dystonic reaction to the medication can cause a nasty
case of Laryngeal Dystonia which chokes the patient to death.
Drug-induced Long QT Syndrome (LQTS) can rapidly lead to Torsades
de Pointes, cardiac fibrillation and death. This is a frequent
cause of sudden death in psychiatric patients. Neuroleptic
Malignant Syndrome (NMS) is another, but more remote,
possibility. NMS can kill in as little as an hour, but it
generally takes much longer.
In answer to your question about the blood samples, I made a
small error. The samples were actually taken from the left and
right femoral veins. I'm sure it makes no difference. I think the
reason the pathologist took two samples was probably to ensure a
more accurate estimate of plasma concentration in the whole body.
You can average the values.
Cressman WA; Plostnieks J; Johnson PC "Absorption, metabolism and
excretion of Droperidol by human subjects following
intramuscular and intravenous administration." Anesthesiology
1973 Apr;38(4):363-9 ISSN: 0003-3022
Fischler M; Bonnet F; Trang H; et al "The pharmacokinetics of
Droperidol in Anaesthetised Patients" Anesthesiology 1986 64:
486-489 ISSN: 0003-3022
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About the Droperidol injection problem. Postmortem serum drug
concentrations, or blood concentrations in general, may be quite
different postmortem than premortem, as the distribution of the drug
may well change, and the binding to various serum and other proteins
may well change. Postmortem serum digoxin concentrations, for example
(I believe) can be significantly higher than premortem ones. This
might make one think the patient had died sooner after an injection
than was actually the case. It is difficult to extrapolate from
premortem to postmortem serum concentration data unless the
relationship is well known.
Also, why average the 2 values from each femoral vein? You
lose data points to fit if you do that, and you may well be better
off using all the individual data points you can get. It is also
useful, when fitting, to start with the known error pattern of the
assay, then to supplement this with an extra parameter (gamma, in our
terminology) of intraindividual variability (environmental noise),
using, for example, the iterative Bayesian (IT2B) program in the
USC*PACK collection, and then, having gamma, using a nonparametric
approach to get the full, and most likely, parameter distributions.
In this way, each data point can be fitted according to its
credibility. More info is available on our web site (www.lapk.org),
under teaching topics, then under population modeling, both
parametric and nonparametric, and also under assay error patterns, in
sections 12 and 14.
Very best regards,
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.aaa.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
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