Pharmacology: interactions and adverse effects in Sports

Skaistys Ana¹, Späni Selina², Leuppi-Taegtmeyer Anne^3,4
1 University Department of Medicine, Clinical Research, Cantonal Hospital Baselland, Rheinstrasse 26, Liestal, ­Switzerland
² Hospital Pharmacy, Cantonal Hospital Baselland, Rheinstrasse 26, Liestal, Switzerland
³ Medical Directorate, University Hospital Basel, Spitalstrasse 22, Basel, Switzerland
⁴ Hospital Pharmacy, Cantonal Hospital Baselland, Rheinstrasse 26, Liestal, Switzerland

Abstract

Due to pharmacokinetic and pharmacodynamics effects, there are numerous interactions between medications. Athletes and their healthcare providers must be mindful of ­potential drug-drug interactions, and it is essential to avoid adverse effects that could compromise performance.
Certain drug combinations can create complexes, substantially diminishing bioavailability and possibly resulting in undertreatment. Special caution is therefore warranted when taking antacids containing Ca2+, Mg2+, or Al3+, and trace elements such as iron and zinc, with certain classes of antibiotics like quinolones and tetracyclines concurrently, as their interaction may result in complex formation. It is advisable to space these medications 2-3 hours apart. In addition to conventional medications, it’s important to highlight St. John’s Wort, often taken for depression. When used concomitantly with other medications, it can significantly reduce their effectiveness. Conversely, grapefruit juice can substantially potentiate the effects of certain medications by inhibiting intestinal CYP3A4, the enzyme responsible for drug metabolism in the small intestine. This inhibition boosts drug absorption into the bloodstream and prolongs their presence in the body, resulting in increased medication levels, over­exposure, and potential adverse reactions. Furthermore, non-steroidal anti-inflammatory agents such as ibuprofen – often used by atheletes – can increase the risk of bleeding when used in combination with platelet inhibitors and anticoagulants.
In this article we address the mechanisms of drug interactions in detail, the adverse effects these may cause and how they can be avoided.

Zusammenfassung

Aufgrund pharmakokinetischer und pharmakodynamischer Effekte gibt es zahlreiche Wechselwirkungen zwischen Medikamenten. Athleten und ihre Gesundheitsdienstleister müssen sich der potenziellen Wechselwirkungen zwischen Medikamenten bewusst sein, und es ist wichtig, unerwünschte Wirkungen zu vermeiden, die die Leistung beeinträchtigen könnten.
Bestimmte Medikamentenkombinationen können Komplexe bilden, die die Bioverfügbarkeit erheblich verringern und möglicherweise zu einer Unterbehandlung führen. Besondere Vorsicht ist daher geboten, wenn Antazida, die Ca²⁺, Mg²⁺ oder Al³⁺ enthalten, sowie Spurenelemente wie Eisen und Zink gleichzeitig mit bestimmten Antibiotikaklassen wie Chinolonen und Tetracyclinen eingenommen werden, da ihre Wechselwirkung zur Komplexbildung führen kann. Es wird empfohlen, diese Medikamente im Abstand von 2 bis 3 Stunden einzunehmen. Neben konventionellen Medikamenten ist es wichtig, auf Johanniskraut hinzuweisen, das oft zur Behandlung von Depressionen eingenommen wird. Wenn es gleichzeitig mit anderen Medikamenten verwendet wird, kann es deren Wirksamkeit erheblich verringern. Umgekehrt kann Grapefruitsaft die Wirkung bestimmter Medikamente erheblich verstärken, indem er das intestinale CYP3A4, das für den Arzneimittelstoffwechsel im Dünndarm verantwortliche Enzym, hemmt. Diese Hemmung erhöht die Aufnahme des Medikaments in den Blutkreislauf und verlängert dessen Verweildauer im Körper, was zu erhöhten Medikamentenspiegeln, Überexposition und potenziellen Nebenwirkungen führt. Darüber hinaus können nichtsteroidale Antirheumatika wie Ibuprofen – häufig von Sportlern verwendet – das Blutungsrisiko erhöhen, wenn sie in Kombination mit Thrombozytenaggregationshemmern und Antikoagulanzien verwendet werden.
In diesem Artikel befassen wir uns ausführlich mit den Mechanismen von Arzneimittelwechselwirkungen, den möglichen Nebenwirkungen und den Massnahmen, mit denen sie vermieden werden können.

Schlüsselwörter: Arzneimittelwechselwirkungen, Nebenwirkungen, Sportler

Introduction

Medications can affect all aspects of sports performance: skill, strength, endurance, and recovery. However, interactions between drugs, foods, and beverages can alter their ­effectiveness, either enhancing or reducing their effects. ­Athletes should be cautious about potential interactions and work closely with healthcare professionals to optimize their medication use for performance and safety. In this article, we will address these issues and illustrate them with case­studies.

Drug-drug interactions and how they arise

Interactions between medications arise through changes in a drug’s pharmacokinetic or pharmacodynamics properties. Pharmacokinetics (PK) refers to the effect of the body on the drug, which is the sum of the following biological processes: absorption, distribution, metabolism and elimination (Fig. 1). All of these processes can be affected by the presence of other drugs, hence the phenomenon of drug-drug interactions. On the other hand, pharmacodynamics (PD) refers to the effect of the drug on the body due to molecular, biochemical, and physiological effects or actions. Understanding both pharmacokinetic and pharmacodynamic interactions is essential for managing medication use effectively and safely, especially in the context of sports performance.
When certain medications are ingested together, they can form large, non-absorbable complexes in the gastrointestinal tract. This substantially reduces the bioavailability of the drug. An example of drug interactions involving complexes is seen with ciprofloxacin and magnesium. When taken alone, ciprofloxacin reaches its peak concentration of around 3 μg/ml approximately 3 hours after ingestion. However, if ciprofloxacin is taken together with magnesium, the peak plasma concentration of ciprofloxacin may decrease significantly to only 0.25 μg/ml [1]. As a result, the antibiotic effect of ciprofloxacin may be substantially reduced when taken with magnesium. This can compromise the effectiveness of the antibiotic treatment and lead to inadequate management of the underlying infection, potentially prolonging the course of the disease.

Not only magnesium, but also calcium, iron, aluminium and zinc form complexes with other medication, namely: quinolones (e.g., ciprofloxacin, levofloxacin), tetracyclines (e.g., doxycycline), levodopa, methyldopa and levothyroxine [2]. For this reason, it is advisable to observe an interval of at least two to three hours between the intake of these substances and other medications. For example, levothyroxine could be taken in the morning on an empty stomach and iron in the afternoon or evening, or the other way around. It should be noted that magnesium, aluminium and calcium are present in certain over-the-counter antacid medication [3].
Other drug-drug interactions can involve inhibition or induction of the drug-metabolizing enzymes or transporters. For example, the enzyme cytochrome P450 3A4 (CYP3A4) plays a crucial role in metabolizing various substances in the liver and intestine. It oxidizes small foreign organic molecules, including drugs, facilitating their elimination from the body. Some drugs bind to CYP3A4 and alter its activity by reducing or increasing its function, which in turn affects the metabolism and effectiveness of medications, leading to potential changes in their efficacy or toxicity.
Additionally, there may be competition for renal or hepatic excretion routes, which can impact the elimination of medications from the body. Understanding these complex interactions is essential for optimizing medication regimens and minimizing adverse effects, particularly in the context of sports performance where precise dosing and timing are ­critical.
To better understand enzyme and transporter interactions, let’s consider an example involving a 77-year-old woman who experienced weakness a few days after being discharged from the hospital, where she was treated for pneumonia. Her main diagnoses included coronary artery disease and arterial hypertension, for which she was prescribed acetylsalicylic acid (100 mg), bisoprolol (2.5 mg), irbesartan/hydrochlorothiazide (150/12.5 mg), and simvastatin (20 mg for the past 5 years). During her hospital stay, she received a 7-day course of therapy with clarithromycin and amoxicillin to treat community-acquired pneumonia. Upon laboratory testing, it was found that the patient’s creatine kinase (CK) levels were significantly elevated at 4160 U/l, compared to the normal levels (< 200 U/l) measured two weeks prior. This drastic increase in CK levels indicated rhabdomyolysis, a condition characterized by the breakdown of muscle tissue.
An interaction between clarithromycin and simvastatin likely contributed to the rhabdomyolysis. Clarithromycin is a potent inhibitor of both the CYP3A4 enzyme and the ­OATP1B1 transporter. Clarithromycin’s inhibition of the OATP1B1 transporter and the CYP3A4 enzyme led to increased systemic uptake and decreased metabolism of ­simvastatin, resulting in elevated plasma concentrations of simvastatin. This increased exposure to simvastatin significantly potentiated its myotoxic effects, leading to muscle breakdown and the subsequent elevation of CK levels.
This case highlights the importance of understanding enzyme and transporter interactions in pharmacotherapy. Healthcare professionals should be vigilant in identifying potential drug interactions, especially when prescribing medications with known inhibitory effects on metabolizing enzymes or transporters, to prevent adverse events like rhabdomyolysis.
Avoid co-administration of medications such as atorvastatin, lovastatin and simvastatin with clarithromycin [4]. If clarithromycin is necessary, discontinue the statin for the duration of the antibiotic treatment and for two weeks after clarithromycin is stopped. Alternatively – if the clinical ­situation allows it – consider using another antibiotic such ­as azithromycin, which does not interact with statins.
Statin-induced muscle toxicity (myalgia, creatin kinase elevation, rhabdomyolysis) may be more noticeable during periods of physical exertion. However, currently there is no evidence that statins consistently reduce muscle strength, overall exercise performance, or endurance [5].
Another example is grapefruit juice, which can significantly enhance the effects of certain medications by inhibiting the action of intestinal CYP3A4, an enzyme responsible for drug metabolism in the small intestine [6]. This inhibition leads to increased drug absorption into the bloodstream and prolonged presence in the body, resulting in elevated drug levels and thus excessive drug effects and potential adverse reactions. Grapefruit juice can amplify exposure to various CYP3A4 substrates, including some calcium channel blockers, statins, antiarrhythmics, central nervous system acting agents, as well as drugs like ciclosporin, tacrolimus, sildenafil and ticagrelor.
Hypericum perforatum, commonly known as St. John’s Wort, is a widely used herbal remedy for conditions like anxiety, depression, and sleep disorders. It contains several biologically active compounds, including hypericin, an antidepressant, and hyperforin, an enzyme inducer. Due to its strong enzyme-inducing effects, St. John’s Wort can diminish the effectiveness of hormonal contraceptives, coumarins, direct oral anticoagulants (DOACs), ciclosporin, digoxin, antiretroviral drugs, and certain antitumor therapies like irinotecan and imatinib. Examples of other potent enzyme inducers are rifampicin and carbamazepine. Drug-drug interactions checks should always be performed when these medications are prescribed.
An example of a pharmacodynamic interaction is the combination of low dose aspirin (acetylsalicylic acid) used as platelet aggregation inhibitor and ibuprofen. When ibuprofen is given together with or before acetylsalicylic acid, it prevents acetylsalicylic acid-induced platelet inhibition, thereby increasing the risk of an in-stent thrombosis, for example. If unavoidable, ibuprofen should be taken at least 2 hours after aspirin to minimize this risk [7]. Furthermore, ibuprofen is associated with gastric ulceration and patients taking both ibuprofen and acetylsalicylic acid are at increased risk of gastrointestinal bleeding. Other drugs that are known to interact with NSAIDs are oral anticoagulants, antihypertensive agents, lithium, and corticosteroids [9].

Medication for symptom-relief during and after sport activities

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely utilized by both elite and non-elite athletes, comprising approximately 30-50% of all medications [10]. These drugs are employed to alleviate inflammation and pain, facilitating a swift return to sports activities. NSAIDs have fever-reducing, pain-relieving, and anti-inflammatory effects, making them a preferred choice in sports medicine. However, it is crucial to consider potential adverse effects, notably gastrointestinal issues resulting from the impact of cyclooxygenase-1 (COX-1) enzyme inhibition on gastric mucosa, kidneys, vascular endothelium, and platelets. COX-1 inhibition is caused by non-COX-selective NSAIDS (for example ibuprofen, naproxen). Cyclooxygenase-2 (COX-2) on the other hand – which is inhibited by both non-COX-selective NSAIDs and coxibes (for example celecoxib, etoricocib) – is involved in the synthesis of prostaglandins that mediate inflammation, fever, and pain in response to tissue injury. Long-term use of NSAIDs may also impede the healing process of fractures, muscles, and tendons. In his SEMS article “A sensible approach to the use of NSAIDs in sports medicine”, Philippe Tscholl underscores the critical relationship between inflammation and healing when prescribing NSAIDs and other anti-inflammatory drugs [10].

Avoiding and minimising interactions

To minimize or avoid drug interactions, healthcare providers can employ several strategies. Firstly, they should gather a thorough medication history from patients, which includes details about prescription drugs, over-the-counter medications, herbal supplements, dietary supplements, and intake of any illicit substances. Regular reviews of the patient’s medication list should be conducted to identify any potential interactions or changes in therapy that may impact drug interactions. Patients should also be educated about the importance of discussing their medication use with healthcare providers, including any changes or additions to their regimen. Encouraging patients to consistently use one pharmacy and to avoid sharing medications with others can also help minimize the risk of interactions. Additionally, healthcare providers can utilize reliable resources such as the product information or computerized decision support systems (CDSS) and specific online databases dedicated to drug interactions (for example those provided by Liverpool University, UK, which are free of charge) to identify potential interactions and guide clinical decision-making [11,12]. Patients should feel empowered to contact healthcare providers or pharmacists for further information or clarification if needed. By implementing these strategies, healthcare providers can minimize the risk of drug interactions and optimize patient safety and therapeutic outcomes.

Conclusion

Medication’s role in sport is multifaceted. Athletes and their healthcare providers must be mindful of potential drug-drug interactions, and it is essential to avoid adverse effects that could compromise performance. While medication can offer benefits, it is crucial to weigh the risks and benefits carefully. Further research is necessary to fully understand the impact of medication on athletic performance and overall health.

Correspondence

Anne Barbara Leuppi-Taegtmeyer, PhD; Prof. Dr. med.
FMH Klinische Pharmakologie und Toxikologie, MRCP (UK)
Leiterin Abteilung Patientensicherheit, Universitätsspital Basel
Leitende Ärztin Klinische Pharmakologie, Kantonsspital Baselland
Spitalstrasse 22, 4031 Basel
Phone: 061 328 68 48
anne.leuppi-taegtmeyer@usb.ch

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