Considerations for laxatives in terms of their interactions with other drugs

KEYWORDS:

• Duchenne muscular dystrophy
• accelerated transit
• constipation
• drugs
• laxatives
• pharmacologic interactions

1. Introduction

Laxatives represent the main treatment for constipated subjects since ancient times [1], are among the most frequently used drugs worldwide, and impose a substantial economic burden on both patients and health-care systems [2]. Although the use of laxatives is generally perceived as safe in the public opinion, an important issue to take into account is that constipation increases in frequency with age and that aged subjects are those with the major consumption of drugs. This increases the risk of potentially harmful pharmacologic interactions.

A significant problem in evaluating this aspect of laxatives is due to the fact that many (probably, most) constipated patients often escape the physicians’ prescription and self treat their symptoms by means of over the counter (OTC) products [3]. Of note, these products are frequently not disclosed to the caring physicians probably because OTCs are not considered as actual drugs, and their use is often strictly linked to person to person (friends, neighbors, etc.) suggestions or pharmacist’s advice. It is also extremely important to remember that many OTC products are represented by herbal formulations (often composed of different and heterogeneous substances, employed for multiple dissimilar pathological conditions) and that these may interact with laxatives [4].

Thus, there is a concrete possibility that, especially in elderly subjects and/or in those treated with multiple drug regimens, the widespread use of laxatives (including the OTC ones) could cause potential interactions with other drugs. Unfortunately, this aspect has been almost neglected by researchers. Therefore, the literature evidence on this topic is relatively scarce, and these interactions are rarely detailed or are based on single-case reports [5].

2. Use of laxatives and interactions with other drugs

Laxatives can potentially interfere with the adsorption/function of other drugs by several different mechanisms, such as decrease of the intestinal or colonic transit time, modifications of the gastric pH, or inhibition of cytochrome P450 enzyme activity [6].

As stated above, however, it is quite disappointing that relatively little attention has been paid by researchers to the issue of drug interactions with laxatives. In fact, notwithstanding the lack of high quality studies investigating these aspects, there is scattered evidence that laxatives, including the OTC ones, may be involved in drug–drug interactions (DDI) [7]. Some of these evidences will be briefly discussed here. For instance, a study conducted in healthy volunteers demonstrated that the concomitant administration of macrogol 4000 and of a single dose of digoxin reduced the intestinal adsorption of digoxin, even though there were no consequences on heart rate and atrioventricular conduction [8]. Another study, conducted in patients with heart failure, showed that the combined use of sennosides and digoxin was associated with a modest increased risk of digoxin toxicity, requiring hospital admission, in these patients [9].

One of the most widely used OTC laxative, also thanks to its relatively low costs and good efficacy, is represented by magnesium oxide; however, it must be kept in mind that there is some evidence that the administration of this drug increases the gastric pH, leading to decreased concentrations of antipsychotic drugs, when co-administered [10].

Although there is some concern on the simultaneous use of laxatives and coumarin anticoagulants, the scientific evidence supporting this claim is scarce; however, a moderate but significant risk of increased anticoagulation has been demonstrated only for the concomitant administration of lactulose [11].

Of interest, it is worth noting that the DDI has not specifically been assessed for the newer, recently commercialized drugs (e.g. prucalopride, linaclotide, plecanatide, lubiprostone, and elobixibat). The DDI for these drugs are often mentioned in a generic manner in the trials, and to date there is a general belief that they are considered safe and almost devoid of significant such interactions [1,12]. This is likely due to the fact that these new drugs have been developed and approved following strict regulations by government agencies, and their safety profile has been evaluated in a very rigorous manner. In addition, these drugs are to date not marketed as OTC, are not available in all countries, are considerably more expensive compared to the commonly used laxatives and are usually prescribed in more severe cases of constipation [1]. Therefore, the knowledge of their potential interactions seems to be under a more strict control, especially compared to older laxative and OTC products.

3. Expert opinion

In recent years, many countries worldwide have constantly improved their health-care systems, with better patients’ assistance and the availability of a great number of drugs to treat pathological conditions. This is likely one of the main factors leading to an increased lengthening of life expectancy. The other side of the coin, however, is a progressive and steady increase in aging subjects, which aggravates the economic burden on the national health systems and raises the pro capite number of drug prescriptions. Owing to the fact that constipation becomes progressively more frequent with advancing age, the issue of the potential DDI assumes a certain relevance, since the use of laxatives, potentially interfering with other drugs, also becomes more frequent. Thus, some thoughts on this issue are mandatory.

A first consideration is that evaluating DDI between laxatives and other drugs is particularly complex, since most constipated patients self-medicate by means of OTC drugs, and this fact (if not specifically searched) may be missed by the caring physicians. In fact, in terms of medical information, the patients often regard OTC use as negligible, and do not consider these as proper drugs (of interest, most herbal laxatives are actually described as ‘home/familiar remedies’). Moreover, laxatives may be contained in herbal preparations employed for other pathological conditions, such as anti-obesity products [13]; thus, health-care professionals should be aware of this fact and warn their patients on the heterogeneous nature of these products and of their potential risk of interfering with other medications.

A second point is that, regrettably, there is only scarce literature evidence specifically addressing the actual impact of DDI between laxatives and other drugs, as reported above. However, the few available data seem to suggest that, overall, the use of laxatives appears to be quite safe concerning DDI and that most of the reported interactions (in particular those with the concomitant use of sennosides or lactulose) are of some clinical value only for selected groups of patients (e.g. those with heart failure using digoxin, those using coumarin anticoagulants, or those under antipsychotic drug treatments) [12]. Of course, the available data on DDI are even scarcer for the new, recently commercialized drugs (prucalopride, linaclotide, plecanatide, lubiprostone, and elobixibat) that so far, however, seem not to display important interactions with other drugs [1,12]. Thus, in the absence of more robust data on this issue, we feel that a thorough drug history (including OTC products) is mandatory, especially in elderly subjects or in those in whom multiple drugs are needed, in order to assess the potential risk of DDI before prescribing a laxative. This is particularly important in some groups of patients, such as those residing in nursing homes, in whom potentially inappropriate multiple-drug prescriptions (especially in subjects with dementia) are often reported [14].

As a practical suggestion, it is recommended on an empirical ground to pay attention when administering laxatives concomitantly with diuretics, corticosteroids, antiarrhythmics, and drugs prolonging the QT interval [12]. Again, a wise suggestion is that of administering laxatives for at least 30 minutes apart from other drugs [12]. This suggestion is based on the consideration that most drugs are mainly absorbed in the small intestine and to a lesser extent in the large bowel and that many laxatives exert their effect on the water content/motor activity of both the small and large intestines. Most of the new secretagogues, for instance, increase water secretion in the small intestine and accelerate colonic transit. However, it should also be recognized that the above recommendations are mostly unsubstantiated by solid scientific data and are generally based on personal belief/experience.

A third point is that, in our opinion, given the enormous global diffusion regarding the prescription and self-prescription of laxatives, most of the DDI related to these substances go unnoticed or under-reported. This is likely because the majority of these DDI are probably mild, self-limiting, and of little clinical importance and that the OTC and herbal products often escape the physicians’ control.

In conclusion, although DDI between laxatives and other drugs are relatively infrequent, there is the need for a more rigorous scientific approach toward the definition of this issue, together with a greater awareness by physicians on the fact that laxatives, although generally safe, may interact with other drugs with potentially harmful consequences. In fact, although research data suggest a good overall safety profile for laxatives at the recommended doses, real-life data indicate that dose over recommendation is common [12]. These above points are of paramount importance especially in elderly patients, in whom the World Health Organization has recognized medication-related harm as a global public health issue [15]. Prescribing physicians should also be aware of the potential safety hazards consequent to interactions with OTC products, and with herbal medications not necessarily labeled as laxatives (e.g. herbal teas or infusions), but containing substances with laxative effects. As future perspectives, there is no doubt that more sound scientific information is needed on whether laxatives interfere with the absorption of other drugs, whether their safety is influenced by the administration of other drugs, and whether the combination of more than one laxative interferes with their effect or increases adverse events.

Finally, the bi-directional effects of drug responses and efficacy on gut microbioma are a new road still waiting to be paved. Indeed, the recent evidence that several commonly used drugs, including laxatives, are associated with the gut microbiome is intriguing [16] and will surely yield further useful information in the field of DDI.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

This paper is dedicated to the memory of Professor Albano Del Favero

Additional information

Funding

This paper was not funded.