additional blood samples. The mean concentration
of chlorpheniramine in these cases was 1075 ng/g.
The combined mean of all liver samples in the ab-
sence of additional drugs was calculated to be 1412
ng/g (n = 12).

Chlorpheniramine was detected in seven urine
samples and two lung samples, as indicated in Table
1. A value of 478 ng/ml was found in spinal fluid in
one case. The drug was detected in muscle fluid in a
separate case.

As depicted in Figure 1, the median level of all
blood samples for chlorpheniramine in the absence of
other drugs was 94 ng/ml, with a range of 8-238 ng/
ml (n =4). It should be noted that the majority of
these blood samples fell at or below a concentration
of 50 ng/ml. The median level of all liver samples for
chlorpheniramine in these cases was 561 ng/g, with a
range of 153-4900 ng/g (n = 9). While the majority
of liver cases fell at or below 500 ng/g, a significant
number were above 2500 ng/g.

As given in Table 2, there were 31 cases (with and
without blood) in which chlorpheniramine was de-
tected in cases in which other drugs were also present.
Eighteen of these 31 cases had a chiorpheniramine drug
level at or above the assay detection limit of 5 ng/ml.
The mean blood concentration in these cases was 93 ng/
ml. The drug was detected in this tissue in an additional
five cases. In one case, unusually high concentrations of
this drug were found in various tissues (6100 ng/ml
blood; 4970 ng/ml liver fluid; and 47000 ng/g in lung).
These values were not used to calculate indicated aver-
ages but are included in the total number of cases.

iam Liver

‘ pan

Bool 30 100 0 i) J 220
Liver 500 woo 1800 0D 2500 2500

(Chlorphenirasnine (agit oc og't)
Figure 1. Chlorpheniramine Tissue Dis-
tribution in Absence of Other Drugs

Chlorpheniramine was also quantitated in nine
liver samples in which corresponding blood samples
were obtained; the mean value of chlorpheniramine
for these samples was 916 ng/g liver. The drug was
further quantitated in liver in another three cases
obtained in the absence of additional blood samples.
The mean concentration of chlorpheniramine in these
cases was 241 ng/g. The combined mean value for all
liver samples in the presence of other drugs was
calculated to be 747 ng/g (n = 12).

Table 2. Concentrations of Chlorpheniramine in Cases in
Which Other Drugs Were Also Present

Chlorpheniramine (Average; ng/ml (or g))
Blood Liver Lung _ Urine
With Blood 93 916*** 6483 Detected
(n=23)” | (10-493; n=18) (50-6299; n = 9) (365,12600; (n= 13)
n=2)
Without - 241 (24-600; n = 3) 731 (n= 1) | Detected (n = 5)

Blood
(n=8)

“Urine samples are routinely analyzed for qualitative analysis only. Therefore, detection simply means that

chlorpheniramine was present in the sample.

"In four blood samples, concentrations were below the limit of quantitation of the analytical procedure (< 5 ng/ml).
One additional sample in an abnormally high case was also excluded from calculation of average values.

***The mean value of all liver samples analyzed was 747 ng/g (n = 12).



CONCLUSIONS

In the time covered by this study, 2172 pilot
fatalities were received at CAMI. In 111 of these
fatalities, we found evidence for the presence of
various antihistamines. Therefore, 5.1% (111) of all
pilot fatalities involve antihistamines. Chlor-
pheniramine was involved in 47 of the 111 antihista-
mine related pilot deaths and accounts for 42% of all
such fatalities. This antihistamine was detected in
2.2% (47) of all pilot casualties. In 16 of these 47
cases, in which only chlorpheniramine was found, its
mean concentration in blood was 109 ng/mi and was
1412 ng/g in liver. The median concentrations in these
tissues were 94 ng/ml and 561 ng/g, respectively.

For the remaining 31 cases, in which other drugs
were also present, the mean chlorpheniramine con-
centration in blood was 93 ng/ml and was 747 ng/g
in liver. The median concentrations in these tissues
were 67 ng/ml and 126 ng/g, respectively. Ninety-
five percent of all quantitative blood values were at or
above the therapeutic (10 ng/ml) level, giving a 100
ng/ml blood mean level. The drug’s mean concentra-
tion in the liver of all the cases was 1080 ng/g. Thirty-
five of the 47 chlorpheniramine-related cases involved
only chlorpheniramine or other OTC medications.
These medications are commonly used in self-treat-
ment of allergies or upper respiratory infections.
Therefore, the total number of simple OTC cases is
35, or 74% of all cases.

The average chlorpheniramine blood value for all
observed cases was 100 ng/ml. This value was ap-
proximately 10 times higher than the therapeutic
value of 10 ng/ml. The mean and median values for
blood concentrations in the absence and presence of
other drugs did not vary significantly. Therefore, the

presence of other drugs did not appear to signifi-
cantly alter the blood level of chlorpheniramine. No
such correlation could be established, however, with
the hepatic value. The approximate 10-fold increase
in the mean liver concentration, as compared with
the blood value, was consistent with the general trend
of the distribution of drugs in the hepatic compart-
ment. However, the contribution of postmortem
redistribution of the drug to alter its concentration
cannot be entirely ruled out. The findings from this
study suggest that chlorpheniramine was present in
those aviation fatalities at levels higher than thera-
peutic perimortem levels

REFERENCES

(1) Gilman, A.G., Goodman, L.S., Rall, T.W., and
Mured F. (1985), pg. 623 “The Pharmacological
Basis for Therapeutics.” New York: Macmillan.

(2) Over the Counter Medications and Flying, Medi-
cal Facts for Pilots, Publication AM-400-92/1.
Oldahoma City, OK: FAA Civil Aeromedical
Institute.

(3) Gilliland, K., Schlegel, R.E. and Nesthus, T.E.
(1997). Workshift and Antihistamine Effects on
Task Performance (DOT/FAA/AM-97/25)
‘Washington, DC: Federal Aviation Administra-
tion, Office of Aviation Medicine.

(4) Home Guide to OTC Drugs at Internet site
<www.e-pharmacy.com>.

(5) Baselt, R-C. (1982), pg 162. “Disposition of Toxic
Drugs and Chemicals in Man” Davis, CA: Bio-
medical Publications.



PREVALENCE OF CHLORPHENIRAMINE IN AVIATION ACCIDENT
Prior Faraririss, 1991-1996

INTRODUCTION

Chiorpheniramine, a popular nonprescription
antihistaminic, is known to cause drowsiness (1).
Therefore, individuals are advised, not to operate
heavy machinery while using this drug (2). This side
effect has a potential to impair performance (3) and to
be a potentially significant factor in aircraft accidents.

In addition to direct effects of this drug on pilot
reaction time, the medical conditions for which this
drug is customarily taken may also impair pilot
performance. Since chlorpheniramine is one of the
most popular antihistamines (4), we conducted this
study to establish the prevalence of this drug in pilot
fatalities of aviation accidents.

METHODS

During fatal aircraft accident investigations, post-
mortem samples collected from the pilots at autopsy
are submitted to the Civil Aeromedical Institute
({CAMI) for toxicological evaluation. Analytical data
are collected for the presence of ethanol, over-the-
counter dtugs (OTCs) including antihistamines (e.g.,
chlorpheniramine), and sympathomimetic amines
(e-g., pseudoephedrine). Samples are also analyzed
for abused drugs and for various prescription medi-
cations. These drugs are analyzed according to cur-

rent laboratory procedure manuals, and the analyti-
cal findings are maintained in a computer database.
Those data were examined for the presence of
chiorpheniramine in fatalities that occurred during a
six-year (1991-1996) period.

RESULTS AND DISCUSSION

As shown in Table 1, there were 16 cases in which
only chlorpheniramine was found. In 6 of these cases
blood was received in the toxicological samples sub-
mitted for analysis, while in 10 additional cases there
was insufficient blood available for submission. There
was 2 total population of 47 chlorpheniramine-re-
lated Pilot fatalities that occurred during the six-year
period ranging from 1991-1996. The therapeutic
level of chlorpheniramine in blood is 10 ng/ml (5),
and the detection limit of the assay used was 5 ng/ml.
Four of these 16 cases had a total drug level in blood
at or above the detection limit of the assay. The mean
value of the blood concentration in these cases was
109 ng/ml. The drug was only detected in blood in an
additional two cases.

Chlorpheniramine was also quantitated in liver in
three cases in which corresponding blood samples
were obtained; the liver mean value in these cases was
2423 ng/g. The drug was further quantitated in liver
in another nine cases obtained in the absence of

Tabie 1. Concentrations of Chlorpheniramine in Cases in Which
Only This Antihistaminic Was Present

Chlorpheniramine (Average; ng/ml (or g)

Blood Liver Lung Urine”
With Blood 109 2423*** 3260 (n = 1) | Detected (n = 6)
(n= 6)" (8-238; n= 4) (1075-3674; n = 3)
Without - 1075 1160 (n= 1) | Detected (n = 1)
Blood (153-4900; n = 9)
(n= 10)

“Urine samples are routinely analyzed for qualitative analysis only. Therefore, detection simply means that

chlorpheniramine was present in the sample.

“In two blood samples, concentrations were below the limit of quantitation of the analytical procedure (< 5 ng/ml).
***The mean value of all liver samples analyzed was 1412 ng/g (n= 12).



Blood 50 10 1390 200 250 2250
‘Liver 500 1000, 190 ay 2300
Chidorpheniramine (agin o np't)

Figure 2. Chiorpheniramine Tissue Dis-
tribution in Presence of Other Drugs

Chlorpheniramine was detected in 18 urine samples
and three lung samples (Table 2). An average level of
43 ng/ml was obtained in two kidney fluids. A value
of 183 ng/ml was obtained in an additional heart
fluid sample.

As depicted in Figure 2, the median level of all
blood samples for all cases in which this antihistaminic
was present, in addition to other drugs, was 67 ng/ml,
with a range of 10-493 ng/ml (n= 18). Figure 2 shows
that the greatest number of cases involving blood fell

at or below 50 ng/ml, wich continually decreasing
numbers of cases thereafter. The median level of all
liver samples for chlorpheniramine in the presence of
other drugs was 126 ng/g, with a range of 24-6299
ng/g (n = 12). As with blood cases, the greatest
rumber of liver samples fell at the lowest concentra-
tion range recorded.

Table 3 presents data for the distribution of
chlorpheniramine in all cases in which the drug was
at or above 10 ng/ml (or g) in blood or liver. This
concentration is considered a therapeutic level in
blood (5). Thirty-six cases were found to have
chlorpheniramine present in blood or in other tissues
at a concentration at or above 10 ng/ml (or g). These
cases were taken from the total pool of all 47 cases.
They included all situations in which chlor-
pheniramine was found both in the absence and in
the presence of additional drugs. Twenty-one of
these cases had blood values above the therapeutic
level. The average value of these blood cases was 100
ng/ml, with a range of 10-493 ng/ml. Twenty-four of
the liver cases had values above 10 ng/g. The average
value of these cases was 1080 ng/g, with a range of 24-
6299 ng/g. Twelve of the 24 cases with liver values
had no corresponding blood samples available.

Table 4 presents data describing the number of
cases in which chlorpheniramine was found by itself,
as well as with additional compounds. The additional
compounds detected include other sedating
antihistaminics, over-the-counter (OTC) drugs, and
other pharmacologically active agents.

Table 3. Average Concentration of Chlorpheniramine
Found in Blood and Liver for All Cases

Chiorpheniramine (ng/ml (or g))
Tissue Type Average Value Range
Blood 10-493
(@=21)
Liver (n = 24) 1080 24-6299

*All blood and liver concentrations were at or above therapeutic levels of 10 ng/ml (or g).


DOT/FAA/AM-99/29

Office of Aviation Medicine
Washington, D.C. 20591

3 QUALITY DGPECTED 1

Prevalence of

Chlorpheniramine in
Aviation Accident Pilot
Fatalities, 1991-1996

John W. Soper

Arvind K. Chaturvedi

Dennis V. Canfield

Civil Aeromedical Institute
Federal Aviation Administration
Oklahoma City, Oklahoma 73125

December 1999

Final Report

This document is available to “he public
through the National Technical Information
Service, Springfield, Virginia 22161.

©

U.S. Department
of Transportation

Federal Aviation
Administration

0000114 051

t
|
|
i
|
i
i



Table 4. Distribution of Number of Cases in Which Additional Antihistaminics, Over-the-Counter
{OTC) Drugs, and Other Agents Were Present in Addition to Chiorpheniramine

Analysis | Chlorpheniramine | Chlorpheniramine | Chlorpheniramine | Chlorpheniramine
Type Only Plus Plus and Non-sedating
Diphenhydramine | Diphenhydramine OTC drugs
/Doxylamine /Doxylamine and
other agents”

Blood 5 3 2 10
Liver 9 1 1 1

| “Other 2 1 - 3
Types
Total 16 5 3 14
Cases

“Other agents include ethanol, prescription drugs, and controlled substances. Cases involving controlled substances

are summarized in Table 5.
“Other analysis types include urine, bile, and kidney.

Chlorpheniramine was found as the only drug
present in 16 cases (Table 4). Five cases were found in
which chlorpheniramine was present, along with the
sedating antihistaminics diphenhydramine and doxy-
lamine. These cases indicate the simple consumption
of OTC medications, where the only other sedating
drug was another antihistaminic. Three additional
cases involving these sedating antihistaminics also
involved various combinations of ethanol, prescrip-
tion drugs, and/or controlled substances. Non-sedat-
ing medications such as acetaminophen, salicylates,
and other sympathomimetic amines were also found
as the only additional compounds in conjunction
with chlorpheniramine. Fourteen cases are listed in
this category.

As can be seen from Table 4, there were 16 cases
involving chlorpheniramine alone, and there were 14
cases involving chlorpheniramine in the presence of
only non-sedating OTC agents. Finally, there were
five cases in which the only other sedating agents were

additional sedating antihistaminics. The summation
of these various categories yields 35 cases. In two
other cases, carbon monoxide or atropine was also
detected in blood. Ethanol was detected in six addi-
tional cases out. of the total drug population of 47
cases. In one of these cases, the antidepressant
fluoxetine and the calcium—channel blocker diltiazem
were also found in addition to ethanol.

Theze were seven cases in which chlorpheniramine
was detected in conjunction with controlled substances
(Table 5). Narcotic analgesics that were found in three
separate cases were hydrocodone, morphine, and
norpropoxyphene. Cocaine (benzoylecgonine) was de-
tected in one case, while butalbital was also detected in
a blood sample in conjunction with norpropoxyphene.
Benzodiazepines were detected in urine, liver, or blood
in three separate cases. Five cases involved various
combinations of ethanol, scheduled drugs, and sedating
antihistamines, while one case involved the simulta-
neous occurrence of all three classes of compounds.

Table 5. Distribution of Number of Cases in Which Controlled
Substances Were Present in Addition to Chlorpheniramine

Analysis Narcotic Cocaine* Barbiturates Benzodiazepines
Type Analgesics
Blood 2 = 1 2
Liver - 1 - -
Urine/Bile 1 : 1

*Cocaine was detected as its metabolite benzoylecgonine.



NOTICE

This document is disseminated under the sponsorship of
the U.S. Department of Transportation in the interest of
information exchange. The United States Government
assumes no liability for the contents thereof.



Technical Report Documentation Page

Fatalities, 1991-1996

1. Report No. ‘2. Government Accession No. ‘3. Recipient's Catalog No. }
DOT/FAA/AM-99/29

Tite and Subtiie 5. Report Date

Prevalence of Chlorpheniramine in Aviation Accident Pilot December 1999

6. Performing Organization Code

7. Author(s) . 8. Performing Organization Report No.
Soper, J.W., Chaturvedi, A.K., and Canfield, D.V.

9. Performing Orgenization Name and Address 10. Work Unit No. (THAIS)
FAA Civil Aeromedical Institue

P.O. Box 25082 11. Contract or Grant No.
Oldahoma City, Oklahoma 73125

12. Sponsoring Agency name and Address 13. Type of Report and Period
Office of Aviation Medicine

Federal Aviation Administration T4. Sponsoring Agency Code

800 Independence Ave., S.W.

| Washington, DC _20591
18. Supplemental Notes:

This work was accomplished under the approved task AM-B-98-TOX-202.

16. Abstract

Chlorpheniramine, a popular nonprescription antihistaminic, is known to cause drowsiness. This side effect has a
potential to impair performance and to be a factor in accidents. Therefore, this study was conducted to establish
the prevalence of this drug in pilot fatalities of aviation accidents. During fata) aircraft accident investigations,
postmortem samples collected from the pilots at autopsy are submitted to the Civil Aeromedical Institute for
toxicological evaluation, and the findings are maintained in a database. Those data were examined for the
presence of chlorpheniramine in the fatalities, which occurred during a 6-year (1991-1996) period. It was
determined that there were 47 (2.2%) accidents involving chlorpheniramine. In 16 of these cases, only chlor-
pheniramine was found, with the mean concentrations of 109 ng/ml (n = 4) in blood and 1412 ng/g (n = 12) in
liver. Other drugs were also present in the remaining 31 cases, wherein the mean chlorpheniramine concentrations
were 93 ng/ml (n = 18) in blood and 747 ng/g (n = 12) in liver. Ninety-five percent of all the quantitative blood
values were at or above the therapeutic (10 ng/ml!) level, giving a 100 ng/ml (n = 21) blood mean level. The drug's
mean concentration in the liver of all the cases was 1080 ng/g (n = 24). The average chlorpheniramine blood
value was approximately 10 times higher than its therapeutic value. The presence of other drugs did not appear to
Significantly alter the blood level of chlorpheniramine, but no such correlation could be established with the
hepatic value. The approximate 10-fold increase in the liver concentration, as compared with the blood value, was
consistent with the general trend of the distribution of drugs in the hepatic compartment. However, the
contribution of postmortem redistribution of the drug to alter its concentration cannot be entirely ruled ont. The
findings from this study suggest that chlorpheniramine was present in some aviation fatalities at levels higher than
therapeutic perimortem levels.

17. Key Words 76. Distribution Statement

Chlorpheniramine, Antihistaminics, Sedatives, OTC Document is available to the public through.

Medications, Post-mortem Drug Analysis, Abused Drugs, | the National Technical Information Service,

Aircraft Accident Investigation Springfield, Virginia 22161

19. Securtty Classi, (of this report) "20. Security Classi (of this page) @i. No. of Pages ZPrce |
Unclassified Unclassified 8

Form DOT F 1700.7 (8-72) Reproduction of completed page authorized