Aerospace Medicine Technical Reports

FAA Office of Aerospace Medicine
Civil Aerospace Medical Institute

Report No: DOT/FAA/AM-04/15

Title and Subtitle: Gas Chromatographic/Mass Spectrometric Differentiation of Atenolol, Metoprolol, Propranolol, and an Interfering Metabolite Product of Metoprolol

Report Date: October 2004

Authors: Angier MK, Lewis RJ, Chaturvedi AK, and Canfield DV

Abstract: Pilots who successfully control their hypertension with medications, diet, and/or exercise can be medically certified to fly an aircraft. At the present time, approximately 8% of active pilots are designated as "hypertensive with medication" by the Federal Aviation Administration (FAA). One of the groups of antihypertensives is the beta-blocker. Of this group, atenolol, metoprolol, and propranolol are commonly prescribed, and they also have chemical and structural similarities.

The FAA’s Civil Aerospace Medical Institute (CAMI) toxicologically evaluates postmortem biological samples collected from pilots involved in fatal civil aviation accidents. Over the 10-year period, 1993-2002, CAMI has identified 50 pilot fatalities wherein atenolol was found in 24 pilots, metoprolol in 19 pilots, and propranolol in 7 pilots, which is consistent with the fact that these drugs have been in the lists of the top 200 most-prescribed drugs in the United States. In a few of the 50 pilot fatality cases, initial analysis suggested the presence of atenolol and metoprolol.

However, there was no medical history with these cases supporting the use of both of these drugs, and it is also unusual for a patient to be prescribed atenolol together with metoprolol and/or propranolol. Therefore, further examination of the cases, wherein atenolol and metoprolol were apparently present, was undertaken. Atenolol, metoprolol, and/or propranolol, with their possible metabolite(s), were extracted from the selected case specimens, derivatized with pentafluoropropionic anhydride (PFPA), and analyzed by gas chromatography/mass spectrometry (GC/MS).

The MS spectra of the PFPA derivatives of these 3 antihypertensives and a metoprolol metabolite are nearly identical. All of the PFPA derivatives had baseline GC separation, with the exception of a metoprolol metabolite product, which co-eluted with atenolol. There were 4 primary mass fragments (408, 366, 202, and 176 m/z) found with all of the PFPA-beta-blockers and with the interfering metabolite product.

Therefore, this metabolite product could be misidentified as atenolol. However, atenolol has 3 unique fragments (244, 172, and 132 m/z), metoprolol has 2 unique fragments (559 and 107 m/z), propranolol has 4 unique fragments (551, 183, 144, and 127 m/z), and the metoprolol metabolite product has 2 unique fragments (557 and 149 m/z). These distinctive fragments were further validated by (i) using a computer program that predicts logical mass fragments and (ii) performing GC/MS of deuterated PFPA-atenolol and PFPA-propranolol and of the PFPA-alpha-hydroxy metabolite of metoprolol.

By using the unique mass fragments, none of the re-examined pilot fatality cases were found to contain more than 1 beta-blocker. Several unique mass fragments reported in this study can be used for the positive identification of the 3 commonly used and chemically/structurally similar beta-blockers and a co-eluting interfering metabolite product of metoprolol. Therefore, these mass ions can be used for differentiating and simultaneously analyzing these beta-blockers in biological samples.

Key Words: Forensic Science, Toxicology, Gas Chromatography/ Mass Spectrometery, Atenolol, Metoprolol, Propranolol, Interfering Metoprolol Metabolite Product

No. of Pages: 9