*2.2. Consumption Patterns*

The presence of pharmaceuticals in the environment generally correlates well with the amount used in human medicine. Therefore, these data can be used to identify pharmaceuticals that may pose a risk to the environment [30]. An accurate estimate of the extent of drug exposure in a population is di fficult in most countries, as precise consumption data are often lacking. In addition, the statistics frequently cover prescription drugs only and do not include over-the-counter medicines or hospital use of pharmaceuticals [31].

Nevertheless, for several reasons, consumption of pharmaceuticals is expected to increase and, thus, increase the burden of their presence in the environment. First, as the number of older people is rising, with frequent therapeutic regimes of five or more medicines, the extensive use of pharmaceuticals will also increase. In addition, with a rise in living standards and with a decrease in pharmaceuticals price, their usage will escalate throughout the world [9].

Bearing in mind the available data on antidepressants and lipid regulators provided by the Organization for Economic Cooperation and Development (OECD), in defined daily dose (DDD), which is calculated per 1000 inhabitants per day, the increased consumption from 2000 to 2015 is clear, with an increase of 30.7 to 60.6 DDD and of 28.1 to 100.7 DDD in antidepressants and lipid regulators, respectively [32].

However, the correlation between consumption data and environmental contamination is related to the amount consumed per year (kg y<sup>−</sup>1), which may not correspond to a higher DDD, that varies widely between pharmaceuticals. For example, in 2000, approximately 100 million women worldwide were current users of combined hormonal contraceptives; however, since the DDD is very low for hormones, this will not correlate with the amount sold in kg [33].

When observing the pharmaceuticals consumption data on European countries (Table 2), namely, the amount consumed per year, we can realize that the amount used in Switzerland and Sweden is lower than the rest of the countries. This is explained by the fact that they have a significantly lower population when compared to the other countries referred to in Table 2 (Germany, France, Italy and Spain).


**Table 2.** International consumption of the selected pharmaceuticals.


**Table 2.** *Cont.*

Anx—anxiolytics, Antib—antibiotics, Lip reg—lipid regulators, Antiepi—antiepileptics, Anti-inf—anti-inflammatories, Horm—hormones, NA—not available, DDD—defined daily dose and SSRIs—selective serotonin reuptake inhibitors. a Estimated consumption. Data on ZOL, GEM and CIT was not possible to obtain.

Besides the differences in population, different patterns are also observed between countries, even within each therapeutic group; however, some trends are clear regarding the global consumption of therapeutic groups. Anti-inflammatories are clearly the group with higher consumption (in kg), being PARA the pharmaceutical with the highest consumption. This group is followed by the antiepileptic CAR, with particularly high values in Germany. Antibiotics and lipid regulators have similar consumption patterns; nonetheless, these groups have grea<sup>t</sup> variations within them, showing distinct trends in different countries. Anxiolytics, SSRIs and hormones, in decreasing order, were the therapeutic groups with the lowest consumptions.

One should note that there are often discrepancies between pharmaceuticals sold and those actually consumed, due to delays between sales and actual use of medication. Moreover, patterns of local consumption might differ from those observed on a national scale [34,35].

#### *2.3. Mechanism of Action, Metabolization and Excretion*

Pharmaceuticals have different mechanisms of action resulting in several therapeutical indications, which differ between therapeutic groups. However, within each group, some variations can also occur, since there is more than one class of pharmaceuticals in each group.

The therapeutic group of anxiolytics include pharmaceuticals from the class of benzodiazepines like ALP and LOR, which are used for numerous indications, including anxiety, insomnia, muscle relaxation, relief from spasticity caused by central nervous system pathology and epilepsy. They act by binding to gamma-aminobutyric acid, increasing its activity, reducing the excitability of neurons and promoting a calming effect on the brain [36]. Although the hypnotic ZOL is not a benzodiazepine, it also acts on gamma-aminobutyric acid, promoting a shorter effect than benzodiazepines [37].

The selected antibiotics belong to two different classes, fluoroquinolones (CIP) and macrolides (AZI, CLA and ERY), which inhibit bacterial growth. Fluoroquinolones act by inhibiting bacterial DNA synthesis, and macrolides link to the bacterial ribosomes, inhibiting protein biosynthesis [38,39].

Lipid regulators drugs are used to treat dyslipidaemias; primarily, raised cholesterol. Statins like SIM have the capacity to reduce the endogenous cholesterol synthesis by inhibiting the principal enzyme involved. The fibrates (BEZ and GEM) increase the expression of some proteins in the liver, which results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in cholesterol concentrations [40,41].

The antiepileptic CAR has been extensively used in the treatment of epilepsy, as well as in the treatment of neuropathic pain and affective disorders, mainly due to the inhibition of sodium channel activity [42].

The SSRIs (CIT, ESC, FLU, PAR and SER) are antidepressants that, via inhibition of the serotonin reuptake mechanism, induce an increase in serotonin concentration within the central nervous system [43]. It should be noticed that CIT is a racemic mixture of *R*-citalopram and *S*-citalopram enantiomers with different potencies, but since *S*-citalopram is more potent, it is also marketed as the single *S*-enantiomer formulation ESC [44].

The anti-inflammatories DIC, IBU and NAP are non-steroids, and their mechanism of action is through inhibition of cyclooxygenase (1 and 2) in the periphery and central nervous system, reducing pain and inflammation but also other physiologic processes [45]. As for PARA, it acts on cyclooxygenase (2 and 3) in the central nervous system and only reduces pain and fever [46].

Finally, the hormones E1 and E2 are estrogen sex hormones, mainly female, and although they regulate the reproductive system, they also act in very different endocrine systems. As pharmaceuticals, E2 is mostly used in hormone replacement therapy, and EE2, a synthetic hormone more potent than E2, is primarily used in oral contraception [47,48].

According to other authors, pharmacokinetic data could provide a better knowledge of the environmental fate of pharmaceuticals, especially in the water compartment [30,49].

After consumption, pharmaceuticals are metabolized and primarily excreted in urine and feces as a mixture of the parent compound and its metabolites. The elimination in urine and/or feces is driven by two mechanisms, Phase I and Phase II metabolites. The first one uses the hepatic metabolism and, through biochemical oxidations, reductions and hydrolysis, increases the polarity and water solubility of the metabolites. Phase II metabolites are produced by a biochemical reaction through a conjugation step (i.e., glucuronidation and sulphation), where polar groups are transferred to parent compounds or metabolites, allowing these conjugated metabolites to become enough hydrophilic and water soluble to be eliminated through urine and/or feces [1,50,51]. These processes usually promote the loss of pharmaceutical activity of the compound. However, there are pharmaceuticals that are only active after metabolic activation by enzymatic system(s) of the parent compound (pro-drugs) to metabolite(s) [1].

To determine this pharmacokinetic feature, the proportion of the unchanged active molecule excreted in urine and/or in feces and the proportion of the parent molecule excreted as conjugates (glucuronide and sulphate) was included when available [52,53] (Table 3). The excretion rate, in addition to the consumption data, contributes to either a greater or lesser environmental impact and is related to the reported occurrence of the parent compound and its metabolites in the aquatic compartment [30,54]. Therefore, the excretion features were revised and are presented in Table 3.


**Table 3.** Excretion rates of the selected pharmaceuticals.

Anx—anxiolytics, Antib—antibiotics, Lip reg—lipid regulators, Antiepi—antiepileptics, SSRIs—selective serotonin reuptake inhibitors, Anti-inf—anti-inflammatories and Horm—hormones.

While several publications are available on the metabolism of pharmaceuticals, the results of these studies can vary. The observed di fferences are probably explained by genomically distinct metabolizing capacities, as well as di fferences in race, sex, age and health status of the studied subjects, which are all known to a ffect the route and rate of metabolism [54,72]. SSRIs are clearly the therapeutic group with lower excretion rates, ranging from 0.2% to 23%, whereas the other groups present higher variability. The compounds with higher excretion rates are CIP (84%), PARA (80%), LOR (73%), BEZ (72%), E2 (68%) and GEM (50%).

#### **3. Physicochemical Properties and Fate**
