Fluorinated Medications - Revisited

I wrote a post a few years ago on the issue of fluorinated medications.  It was based on and investigation of the Fathead minnow (Pimephales promelas) and the possible induction of autism like illness from increasing amounts of fluoxetine in the water system.  The authors of this article looked at concentrations about 10 times what they currently are in wastewater. Medications of all kinds can be detected ins wastewater with the primary sources being ingested medications and excreted medications and metabolites and wasted medications.  There has been a suggestion that “wasted medications” – like full prescriptions that were either never used or only a few tablets were used should be incinerated in a plasma furnace.  That type of incineration destroys the chemical structure of medications and any chance that they could have unexpected secondary effects. 

The first fluorinated compound was the mineralocorticoid fludrocortisone or Florinef in 1955. I recall prescribing it for people with autonomic disorders (Shy-Drager Syndrome) and orthostatic hypotension from tricyclic antidepressants before the era of SSRI-type antidepressants.  Recently 45% of all FDA approved small molecule drugs (2018-2019) were fluorinated (3).  On the illicit side, in South Korea the percentage of seized synthetic cannabinoids that were fluorinated went from 0% in 2010 to 90% in 2013 (6).  Agricultural chemicals have had a similar increase in fluorinated compounds.  The medications at the top of this post are from my collection of standard psychiatric medications.  That list currently contains 144 medications across all therapeutic classes. After looking at all of the chemical structures only the 15 at the top were fluorinated and most of them have been around for a long time.

The FDA’s current position on medications in general is that there are no demonstrated problems with medications in wastewater.  They encourage the use of safe disposal sites.  They provide details on medications that should not be added to wastewater (No Flush List) that is basically a default based on the Flush List. Consumers are instructed to mix the no flush medications with inert substances that would render them unusable and dispose of them in the trash.  That typically would mean a landfill and the possibility of groundwater contamination. The issue of pharmaceuticals in freshwater is loosely regulated at this time.  There is existing research that some of these compounds can be measured, persist, and in some cases can damage aquatic life.  There is also the case of what can happen if bioaccumulating pharmaceuticals are detected in tap water as well as illegal drugs.  The total number of compounds detected are at the highest levels in the United States and Europe (see graphic on page 2 of this OECD document).

The organic chemistry of fluorinated compounds is detailed in the Science review (1). The authors of that review do a good job of looking at the advantaged of fluorination – specifically how it affects the physical properties of fluorinated molecules and their activity in biological systems. There is probably a lot more detail in that review than most people unfamiliar with organic chemistry need to know. The basic concept is that fluorination can alter the physicochemical properties of a molecule based on its electronegativity and that can later metabolism and how a drug interacts with the site of action.  As an example, fluorinated compounds tend to be more lipophilic or fat soluble than their non-fluorinated counterparts.  The authors of the Science article also take a look at how common fluorinated compounds like atorvastatin bind to an active site in 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase to inhibit cholesterol biosynthesis.

A more recent review (3) suggests that fluoride is used to block the metabolism of molecules and that the number of fluorinated compounds continues to increase.   They also describe more widespread use of fluorine in pesticides, herbicides, and fungicides that incorporate anywhere from 2.5 to 4 halogen atoms per molecule.  These authors also describe fluorine toxicity and make the following relevant points.  First, that fluorine can accumulate in bone and teeth and if it occurs in excess can cause fluorosis.  A case report in the New England Journal of Medicine (4) describes a woman who developed fluorosis from excessive tea consumption (100-150 tea bags per day or an estimated >20 mg/day of fluoride). Radiographs showed spinal changes consistent with fluorosis (forearm and spine). She also had brittle teeth to the point they were all extracted. Fluorine toxicity can also occur at the level of metabolism specifically the Krebs cycle when fluorinated small molecules like fluoracetic acid can block metabolism.  Fluorine toxicity at this level is potentially lethal.  The LD 50 of fluoracetic acid is listed as 10 mg/kg and the toxic intake of fluoride is estimated to be > 10 mg/day.

An important consideration by these authors is that some fluorinated compounds can be metabolized freeing up fluoride in toxic levels.  They describe reactions including oxidation, nucleophilic substitution, and glutathione displacement (5) as reactions that can result in liberating fluorine from some of these compounds. Their example of toxicity is voriconazole – a tri-fluorinated antifungal compound that can undergo metabolism over time and lead to excess fluorine levels.  400 mg doses were estimated to liberate 17.5 mg/day of fluoride.  That leads the authors to conclude that fluoride metabolism of many of the new compounds needs investigation to reduce the risk of toxicity.  Pan has also stressed the importance of follow-up studies of these compounds to investigate how they are metabolized.

As an addiction psychiatrist, there is an additional group of fluorinated compounds that are less likely to be investigated and they are street drugs in this case fluorinated JWH compounds or synthetic cannabinoids (see Figure 1 below for the location of fluorination).  Bannister, et al noted that a design trend in these synthetic cannabinoids was to incorporate a terminal fluorine into these compounds.  Potency at the CB1 receptor was enhanced by this process. The authors describe concern over fluorine toxicity since it can be mobilized in these molecules by thermolytic defluorination by smoking as well as metabolic oxidative defluorination. 

At present time, the fate of fluorine in human metabolism and the ecosystem seems to be in a state of flux.  The trend in producing fluorinated human medications, pesticides, herbicides, fungicides, and synthetic cannabis compounds seems to be increasing at an unprecedented rate.  Understanding the toxicology of these compounds does not seem to have kept pace and that may be because many of them have been around for a long time and have not caused any significant problems. There was also a lot of theoretical reasons to think that the carbon-fluoride bond was very stable and difficult to break.  Now that we have plausible chemical paths for the metabolism of these compounds – physicians probably need to be more aware of fluorosis as a side effect and hopefully there will be more studies focused on metabolites and their possible toxicities.  Fluorination of street drugs is a real wild card because of the different paths of administration and potential impurities in these compounds some of which may contain fluorine precursors.

 

George Dawson, MD, DFAPA

 

References:

1:  Müller K, Faeh C, Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science. 2007 Sep 28;317(5846):1881-6. doi: 10.1126/science.1131943. PMID: 17901324.

2:  Benotti MJ, Trenholm RA, Vanderford BJ, Holady JC, Stanford BD, Snyder SA. Pharmaceuticals and endocrine disrupting compounds in U.S. drinking water. Environ Sci Technol. 2009 Feb 1;43(3):597-603. doi: 10.1021/es801845a. PMID: 19244989.

3:  Kyzer JL, Martens M. Metabolism and Toxicity of Fluorine Compounds. Chem Res Toxicol. 2021 Jan 29. doi: 10.1021/acs.chemrestox.0c00439. Epub ahead of print. PMID: 33513303.

4:  Kakumanu N, Rao SD. Images in clinical medicine. Skeletal fluorosis due to excessive tea drinking. N Engl J Med. 2013 Mar 21;368(12):1140. doi: 10.1056/NEJMicm1200995. PMID: 23514291.

5:  Pan Y. The Dark Side of Fluorine. ACS Med Chem Lett. 2019 Jun 20;10(7):1016-1019. doi: 10.1021/acsmedchemlett.9b00235. PMID: 31312400; PMCID: PMC6627733.

6:  Banister SD, Stuart J, Kevin RC, Edington A, Longworth M, Wilkinson SM, Beinat C, Buchanan AS, Hibbs DE, Glass M, Connor M, McGregor IS, Kassiou M. Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135. ACS Chem Neurosci. 2015 Aug 19;6(8):1445-58. doi: 10.1021/acschemneuro.5b00107. Epub 2015 May 8. PMID: 25921407.

 

Permissions:

Table 1 is reprinted with permission from Banister SD, Stuart J, Kevin RC, Edington A, Longworth M, Wilkinson SM, Beinat C, Buchanan AS, Hibbs DE, Glass M, Connor M, McGregor IS, Kassiou M. Effects of bioisosteric fluorine in synthetic cannabinoid designer drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135. ACS Chem Neurosci. 2015 Aug 19;6(8):1445-58. doi: 10.1021/acschemneuro.5b00107. Epub 2015 May 8. PMID: 25921407. Copyright 2015 American Chemical Society."