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The Afterlife of Drugs February Edition 2020


Introduction Today’s healthcare can do wonders, as it allows us to treat many illnesses which were previously untreatable. We can see a growing trend in the consumption of pharmaceuticals as these new treatments often rely on access to effective medicines. Unfortunately, at the same time, pollution caused by drugs is an emerging global problem with well-documented evidence of risks to the environment, wildlife and human health. This problem is the focus of many research projects, as well as many national and international regulatory authorities. This is the reason why EPSA decided to focus on this hot topic with the upcoming EPSA Annual Reception where the main topic for discussion shall be “Pharmaceuticals in the Environment”. This edition of Science! Monthly will give you an insight into the research done on this topic and prepare you for the Event.

Josef Kunrt EPSA Science Coordinator 2019/2020

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The routes of medicines to the environment Residues of several medicinal compounds have been found in surface/ground waters, soil and animal tissues across the world. Certain drugs, such as painkillers, antimicrobials, antidepressants, contraceptives, betablockers, cytostatics and antiparasitics are commonly found. In fact, over 80 pharmaceutical compounds have been identified in sewage water. Traces of some pharmaceuticals have even been found in drinking water. But what are the sources of pharmaceutical pollution in the environment? (1) The first and most common source of this waste is the treatment of people or animals. The major route by which pharmaceuticals enter the environment is widely accepted to be via urine or faeces, with each contributing different relative amounts depending on pharmacokinetics and structure of the individual pharmaceutical drug. (2) However, there are other routes that are often overlooked. Residues of drugs can be released from the skin, by bathing and washing, including laundering of clothing and bedding contaminated by dermal contact and by direct transfer via surface contact. This is generally a problem associated with topically administered drugs such as corticosteroids, sex hormones and antimicrobials, but chemotherapeutics can also be excreted via sweat, which might pose an environmental risk. (3) The influx of pharmaceutical residues into the environment is the highest from hospitals. On the top common groups of drugs as mentioned previously, hospital sewage water is polluted with anaesthetics, disinfectants and heavy metals mainly platinum, used in the form of platinum-based chemotherapy e.g. cisplatin and carboplatin for the treatment of malignancies and gadolinium (a rare-earth element) used as a contrast agent in magnetic resonance imaging (MRI) scans. (4) Another source of pharmaceutical pollution is due to the improper disposal of unused medicines. A survey carried out in the UK investigated the household disposal habits of unused and expired medicines. The acquired data were used for the design of a model aiming to assess the pathways of human pharmaceuticals into the environment. The model demonstrated that the disposal of unused pharmaceuticals, either by household waste or via the sewerage, may be a prominent route that requires greater attention. (5)Pharmaceuticals disposed to household waste end up landfills, where they may undergo degradation, adsorption and enter the groundwater. (6) Manufacturing of active pharmaceutical ingredients (APIs) is also a big source of pollution. Its degree is magnified by the fact that factories focused on the synthesis of APIs is very often located in countries such as India and China, where the standards of waste management might be lower compared to Europe or the US. Moreover, we lack systematic monitoring of API emissions from manufacturers worldwide and selfreporting by the manufacturing itself is probably under-reported. It is important to allow the publication of negative findings from adequately designed studies and to acknowledge the possibility of spreading environmental contaminants through solid waste or, for some drugs, possibly even air pollution. (7)

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The effect of pharmaceutical waste on wildlife Various pharmaceuticals are entering the environment continuously and although their concentration might seem negligible they may affect the wildlife. Aquatic animals are the most endangered group since most of the drugs end up in the groundwater, rivers or seas either directly or indirectly through elution from the soil. Sex hormones used as female contraception have been proven to disrupt the development of many aquatic animals, such as frogs and fishes. A study done by researchers from Uppsala University found out that when tadpoles of two frog species (Rana Temporaria and Xenopus tropicalis) are swimming in water with low concentrations of ethynylestradiol, all of them developed ovaries instead of the normal distribution when half of the tadpoles develop testicles and the other half ovaries. (8) A doctoral thesis done in Lund University showed that ethinylestradiol (EE2), an active ingredient in many birth control pills, affects salmons, trouts and roaches both on the behavioural and genetical level. Fish affected by EE2 found it more difficult to to catch food and also developed problems with procreation. This endangers whole fish populations and as a consequence the whole ecosystem. (9)

Although many isolated compounds might not have a great effect on the marine wildlife, the problem arises in real-life settings when many different pharmaceuticals are in one place. This can cause a so-called “cocktail effect” when the combined effect of low-level pollutants with other chemicals may lead to a larger, detectable effect on the animals. (10) The pharmaceuticals are not only influencing the aquatic animals but also their predators. A study done in Melbourne, Australia focused on insects living around selected streams. They have identified up to 69 different compounds and the insect tissues had drug concentrations that were orders of magnitude higher than concentrations measured in surface waters. They also identified a similar number of compounds in riparian spiders which predates river insects thus proving the movement of drugs through the food web. In the studied streams, platypus also fed on the aquatic insect and by pairing concentrations of pharmaceuticals found in stream insects with known dietary needs of platypus, the researchers were able to estimate drug exposure. They found out that platypus living in the river downstream of the water treatment plant could receive an equivalent of half the recommended human dose of antidepressants every day. (11) The use of drugs for humans is not the only reason for pharmaceuticals in the environment affecting wildlife. Veterinary use of a wide range of pharmaceutical compounds for the treatment of livestock has an effect on wild animals. For example, the use of diclofenac, prescribed to treat various inflammations in livestock was the reason for a dramatic decline in the vulture population to near-extinct levels in South Asia in the 1990s. Residues of diclofenac remained in livestock carcasses were eaten by vultures. Even very low concentrations of diclofenac then caused renal failure and death in some of the vultures. (12) There’s no doubt that pharmaceuticals released into the environment pose an ecological risk. This risk is not only posed to animals but also to plants. We have focused on the effect of drugs on plants in EPSA Science! Monthly August Edition, which we recommend you to read if you want to learn more about this topic.

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How to get rid of pharmaceuticals from wastewater Numerous studies have concluded that discharged water from wastewater treatment plants contains trace concentrations of various pharmaceuticals. A status report in the matter of the presence of pharmaceutical pollutants in the Baltic sea has evaluated the extent of the pharmaceutical presence in the environment. In general, the further away from the source the samples were acquired, the fewer pharmaceuticals which were found because of the gradual dilution and degradation of molecules. But despite that, they still found 30 - 40% of the studied pharmaceuticals relatively far from the source, in seawater, sediment and marine organisms. For example carbamazepine (an epilepsy medication) has been found in virtually every sample that was acquired. (13) As conventional water and wastewater treatment processes are unable to reliably remove some of the pharmaceuticals, it is necessary to introduce additional advanced treatment technologies prior to discharge into the environment. Currently, there are several approaches to reliably purify wastewater.

Researchers from the Lappeenranta University of Technology in Finland tested the removal of drug residues using membrane filtration and oxidation. The results show that these technologies remove 95% and, in some cases, up to 99% of contaminants and nutrients, such as phosphorus and nitrogen, two elements that are contributing to the overgrowth of algae. (14) Another study conducted at the University of Johannesburg focused on the use of titanium dioxide nanofibers to remove diazepam and similar compounds from wastewater which pass through the treatment facilities largely unchanged. The nanofibers can be used to remove industrial dyes and other organic pollutants as well. However, there is a need to optimize some important parameters on the fibre structure first. Nevertheless, it is an important step towards a simple and cost-efficient way to remove pharmaceutical pollutants from the wastewater. (15) Using powdered activated charcoal is another way to remove pharmaceutical pollutants large-scale in a costefficient manner. This approach has the benefit of avoiding the generation of unwanted breakdown products. The treatment facility was designed as a mixing tank for mixing wastewater with powdered activated carbon, followed by three sequential contact tanks, a sedimentation tank, and a sand filter. The results showed that recirculation design on average significantly improves the removal of pharmaceuticals. Researchers found that drugs such as clarithromycin may be removed to a greater extent than the average of all studied pollutants, whilst carbamazepine and diclofenac may be removed to a lesser extent than the average. As this was only a pilot study there is a need for further optimization of the parameters of the removal process. (16)

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Scientists are also looking into ways to detect pharmaceutical products in water. A multi-centric team of scientists from Germany has succeeded in developing cell-based biosensors for two classes of drugs, NSAIDs and beta-blockers. They were able to detect even very low concentrations of the drugs. These biosensors have many more advantages in contrast to previous approaches. After the biosensor cell lines are exposed to drugs in water samples, a fluorescence signal appears within seconds. In contrast to conventional sensors, the biosensors detect the effect of chemicals in the cell in real-time. (17)

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Re-dispensing of medication - a way to give unused medicines a second life In Europe, almost everything can be recycled, except for medication. It was estimated that the annual spendings on pharmaceuticals is more than 210 billion euros, with four-fifths spent on prescription medicines. Although not all of the sold medication is used. This creates an undesirable amount of medical waste which has economical and environmental consequences. A lot of people are returning unused medicines to pharmacies for safe disposal. Sometimes the drugs are even returned in their original packaging and still within the expiry date. Adam Mackridge, a pharmacist on the Betsi Cadwaladr University Health Board, has published research that suggests 25.3% of patient returns would meet criteria for reuse, which were defined as over six months remaining before expiry; complete and unadulterated patient pack; an unbroken security seal in the case of devices; no special storage requirements. (18) A similar study in the Netherlands found that 19.1% of medicines were eligible for re-dispensing (19) It might seem that the return of such medication to the supply chain would be easy. However, there are several reasons why it might be difficult. The most obvious hurdle is quality assurance. Every pharmacist is taught that medicines should not be reused after dispensing to a patient, as the conditions under which the products have been stored are unknown and, as such, the quality, safety and efficacy of the medicine cannot be guaranteed. This leads us to an interesting paradox. If we are so sure that patients frequently store medicines incorrectly, why are we not more concerned about the possible impact this may have on their health. Researchers from the University of WĂźrzburg assessed long-term stability of 50 drugs with an age of 20-30 years. The samples represented commonly used drug classes such as beta-blockers, anti-infectives, NSAIDs, antipsychotics and antihistamines. 44 were within the acceptance criteria of the respective pharmacopoeial monograph regarding the content and chromatographic purity. These findings are surprising as they show high chemical stability of the old drug substances. (20) Another obstacle might be the Falsified Medicine Directive (FMD). This European regulation mandates the manufacturers to label each package with a unique 2D code that is designed to make the pharmaceutical supply chain more secure by tracking medicines from the manufacturer to patients. Reintroduction of previously dispensed medicine back to the supply chain might undermine the benefits of FMD. Scientists from the University Medical Centre Utrecht in The Netherlands have focused on the economic aspect of re-disposing of medicine. They found out that it is most cost-beneficial when labour and material costs are taken into account if it is applied to expensive medications that require room temperature storage; for example, oral anti-cancer medicines. (21)

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Any new initiatives about re-dispensing of medicine would end quickly if pharmacists wouldn’t be willing to take part. A survey among primary care and community pharmacists concluded that there are several key criteria that would need to be met. They mentioned the need for liability arrangements for individual pharmacists and guidance from the regulator. In the matter of packaging, medicines would require tamperevident seals and only “as new” packaging. New technologies such as irreversible temperature-sensitive stickers should be used. It would be also needed to extensively educate the public about the safety of redispensing of pharmaceuticals. (22) When patients were interviewed about willingness to use unused medication that was returned to the pharmacy by another patient. Out of 2215 interviewed patients, 61.2% were willing to use returned medication. In general men, patients with higher education, regular users of medication, people who returned medication to pharmacy for disposal and those who ever had unused medication themselves were more willing to use returned medication. (23)

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References: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

https://www.sciencedirect.com/science/article/pii/S0378427402000413 https://www.sciencedirect.com/science/article/pii/S0048969708003410?via%3Dihub https://setac.onlinelibrary.wiley.com/doi/full/10.1897/08-382.1#bib4 https://www.sciencedirect.com/science/article/pii/S0022169410003409?via%3Dihub https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1314909/pdf/ehp0113-001705.pdf https://www.sciencedirect.com/science/article/pii/S030438940800784X?via%3Dihub https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2013.0571 https://www.sciencedaily.com/releases/2007/02/070228091721.htm https://www.sciencedaily.com/releases/2016/03/160304092230.htm https://www.sciencedaily.com/releases/2009/03/090324101612.htm https://dx.doi.org/10.1038/s41467-018-06822-w https://www.nature.com/news/2003/030616/full/news030616-14.html http://www.helcom.fi/Lists/Publications/BSEP149.pdf https://www.sciencedaily.com/releases/2015/03/150324084714.htm https://dx.doi.org/10.1016/j.molliq.2017.11.144 https://www.ncbi.nlm.nih.gov/pubmed/28214398 https://dx.doi.org/10.1016/j.watres.2017.02.036 https://academic.oup.com/jpubhealth/article/29/3/258/1591566 https://link.springer.com/article/10.1007%2Fs11096-018-0642-8 https://onlinelibrary.wiley.com/doi/abs/10.1002/dta.2593 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481041/pdf/12913_2019_Article_4065.pdf https://onlinelibrary.wiley.com/doi/pdf/10.1111/ijpp.122757 https://bmjopen.bmj.com/content/bmjopen/9/5/e024767.full.pdf

Picture sources: 1. https://www.ivtnetwork.com/sites/default/files/Drugging%20the%20Environment%20%20Scientist%20Magazine.jpg?1579810002 2. https://cdn.theatlantic.com/assets/media/img/2019/04/DIS_Animals_Giggs_Salmon/square .jpg?1554748585 3. https://live.staticflickr.com/2761/4515205247_9667c85dde.jpg 4. https://p0.piqsels.com/preview/702/8/44/various-capsules-doctor-doctors.jpg

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Science plays a very important part of the education of pharmaceutical students. It represents one of the main aspects of pharmaceutical education. Thing is, there are many aspects of pharmacy and pharmaceutical sciences, we as EPSA, want to enlighten our students with. Want to know more about them? In that case, visit LLeaP – Lifelong Learning Platform and be in charge of your education! All you need to do is REGISTER and start creating your own lifelong learning journey by filling this submission form and winning your Science Monthly Medal! Further, many interesting activities and medals are coming up this year!

So stay tuned and take a LLeaP of faith!

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EPSA Science Blog is an online platform that gathers all the EPSA Science projects together in one place and offers more for those who want it!

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EPSA Science! Monthly February Edition 2020  

EPSA Science! Monthly February Edition 2020  

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