Drug Interactions in Dermatological Practice. What Should be Considered when Treating Patients with Multimorbidity?

Introduction

Dermatologists are increasingly treating multimorbid patients undergoing polypharmacy. This highlights the need for a thorough understanding of potential interactions between patients’ existing medications and prescribed dermatological treatments. Data from registries of drug-induced complications indicate that adverse reactions commonly associated with adverse events often involve medications used in polytherapy. This article compiles the most frequent interactions encountered in dermatological practice [1–4]. Table 1 presents the most significant factors contributing to the occurrence of drug interactions in clinical practice.
In clinical practice, four main types of interactions are most typically encountered. These are summarized and described in table 2 [1, 2].

Clinically significant interactions of antihistamines

Among antihistamine agents, pharmacokinetic interactions – particularly those involving cytochrome P450 isoenzyme-mediated metabolism – are of the greatest clinical relevance. When selecting an antihistamine drug, it is advisable to consider the potential risk of adverse interactions with other medications the patient is taking concurrently. This risk significantly rises when the selected antihistamine undergoes metabolism involving cytochrome P450. To prevent drug interactions and their clinical consequences – and thereby reduce the need for treatment modifications – it is preferable to select drugs whose metabolism is not mediated by CYP 450. Indeed, in the context of polypharmacy, the potential for drug interactions may be one of the most critical factors in antihistamine selection [3–7].

Interactions of loratadine

Food delays the absorption of the drug. Adverse effects may include dry mouth, hair loss, liver dysfunction, allergic reactions, supraventricular arrhythmias, and sedation (which may be more pronounced than with desloratadine). The drug is metabolized via CYP3A4 and CYP2D6, which presents a real risk of pharmacokinetic interactions with CYP3A4 inhibitors (such as azole antifungals, clarithromycin, or grapefruit juice). These interactions may increase the risk of cardiac arrhythmias. There is also a risk of interactions with CYP2D6 inhibitors, which is particularly significant in individuals classified as poor CYP2D6 metabolizers. In the Polish population, the prevalence of poor metabolizers is estimated to range from 6% to 14%.

Interactions of desloratadine

In individuals with hepatic or renal impairment, the drug concentration may increase by up to 2.5 times. Both the half-life and the drug’s ability to bind to blood proteins are clinically relevant for the quantitative and qualitative (severity of adverse effects) assessment of drug interactions. Potential adverse effects include headache, dry mouth, dizziness, and very rarely, sedation. The drug does not potentiate the negative impact of ethyl alcohol on the central nervous system (CNS). No interactions with other concurrently administered drugs have been identified to date, and the risk of pharmacokinetic interactions is considered minimal. This is particularly important in patients undergoing polypharmacy, where the risk of harmful interactions between concurrently used medications is increased.

Interactions of cetirizine

Cetirizine is the active metabolite of hydroxyzine, formed through an oxidation reaction. The penetration of cetirizine into the CNS is lower than that of hydroxyzine; however, its sedative effect is more pronounced compared to other second-generation antihistamines. Theophylline slightly decreases the clearance of cetirizine. Caution should be exercised during the concurrent use of CNS depressants. No clinically significant interactions have been observed with pseudoephedrine, azithromycin, diazepam, or glipizide. Ritonavir increases exposure to cetirizine. No clinically significant interactions with alcohol have been reported; however, alcohol consumption should be avoided during cetirizine treatment due to the potential for increased CNS-related adverse effects. Cetirizine has anticholinergic properties, which may be additive when used concurrently with other medications.

Interactions of levocetirizine

Levocetirizine (the (R)-enantiomer of cetirizine) has twice the affinity for the H1 receptor compared to cetirizine. This allows for a 5 mg dose to be used, which in turn reduces the frequency of adverse reactions such as sedation and anticholinergic symptoms. Both cetirizine and levocetirizine can enhance the depressant effects of other concurrently used medications (such as tranquilizers, hypnotics, sedative antidepressants, antipsychotics, and opioid analgesics). Both drugs can potentially impair the ability to drive or perform complex tasks.

Interactions of fexofenadine

Fexofenadine is a metabolite of the antihistamine drug terfenadine, but it does not exhibit the adverse reactions associated with its parent drug. Fexofenadine should not be taken with strong CYP3A4 inhibitors or with antacids, as they can reduce the absorption of the drug from the gastrointestinal tract.

Interactions of rupatadine

Rupatadine is an antihistamine agent that also inhibits platelet-activating factor (PAF). This additional mechanism may be clinically relevant for the action of the drug in the treatment of allergic rhinitis. Rupatadine produces no sedative effects and has no impact on the QTc interval. Due to its pharmacokinetic profile, dose adjustment is not required in patients with hepatic or renal impairment. Rupatadine is metabolized via the CYP3A4; therefore, it should be used with caution in patients taking strong CYP3A4 inhibitors or statins metabolized by this isoenzyme (e.g. simvastatin, atorvastatin). Caution is also advised when using rupatadine concurrently with moderate CYP3A4 inhibitors, such as fluconazole or diltiazem. It should not be taken with grapefruit juice, as co-administration increases systemic exposure to rupatadine by approximately 3.5 times. Dose adjustment may be necessary for drugs sensitive to the CYP3A4 isoenzyme (atorvastatin, simvastatin) and drugs with a narrow therapeutic index that are CYP3A4 substrates (e.g., cyclosporine A, tacrolimus, sirolimus, everolimus), as rupatadine may increase their plasma concentrations. Caution should be exercised when co-administering rupatadine with other metabolized drugs that have a narrow therapeutic index, as limited information is available regarding its interactions with other medications. Rupatadine at a dose of 20 mg taken concurrently with alcohol significantly intensifies alcohol-induced psychomotor impairment; at a dose of 10 mg, the impairment was found to be similar to that observed after alcohol consumption alone.

Interactions of bilastine

Bilastine is a drug with high affinity for the H₁ receptor. It does not act on muscarinic receptors and produces no sedative effects. Food impairs the absorption of the drug from the gastrointestinal tract. Since bilastine bypasses hepatic metabolism, it does not engage in adverse interactions with other concurrently used drugs. It is excreted unchanged in the feces, with a small amount eliminated via kidneys. No dose adjustment is required in patients with hepatic or renal impairment. It can be safely used by individuals operating motor vehicles. Bilastine does not affect the QTc interval and, therefore, may be safely administered to patients with cardiovascular diseases. Concomitant use of drugs affecting the activity of P-glycoprotein or organic anion-transporting polypeptides, or those that are their substrates, may alter bilastine levels. Co-administration of ketoconazole or erythromycin increases the AUC and Cmax of bilastine, while diltiazem increases its plasma concentration. Ritonavir and rifampicin may decrease bilastine plasma levels. Bilastine does not potentiate the depressant effect of lorazepam on the CNS nor does it exacerbate impairments caused by alcohol.

Caution: hydroxyzine – a drug subject to safety warning

Hydroxyzine is a medication that delivers primarily calming and sedative effects by suppressing the activity of subcortical centers within the CNS. It has antihistamine properties and exhibits antipruritic effects, which is why it is still commonly used in dermatological practice. It reduces nervous tension, alleviates anxiety and its somatic symptoms, and also has a sleep-inducing effect. Hydroxyzine is widely prescribed for its strong symptomatic effects rather than its intrinsic efficacy, which is directly attributable to its pharmacokinetic parameters. Unfortunately, when used in inappropriate combination therapy, the drug can cause numerous complications, including sudden cardiac death. In 2015, hydroxyzine became the subject of a safety communication, which significantly limited the possibilities for its safe use. However, in practice, the provisions of this safety communication are often ignored or unknown. According to the safety communication, hydroxyzine should be used at the lowest effective dose, and treatment duration should be as short as possible due to the risk of drug accumulation and the increasing risk of complications over time. Hydroxyzine is contraindicated in patients with known acquired or congenital QT interval prolongation, as well as in those with known risk factors for QT prolongation, i.e. patients who are concurrently taking other medications with a potential risk of causing ventricular arrhythmias. Furthermore, hydroxyzine is not recommended in elderly patients, as in this population the risks associated with adverse reactions outweigh the therapeutic benefits. In young adults, the maximum daily dose is 100 mg, while in children with a body weight up to 40 kg, the maximum daily dose is 2 mg/kg body weight per day. In practice, hydroxyzine is very often used in populations of patients with clear contraindications to treatment with the drug. The most common risks associated with unreasonable prescribing are summarized in table 3 [1, 5–7].

Cardiac safety of antihistamines

Second- and third-generation antihistamines are characterized by an optimal risk profile with regard to the cardiovascular system. This stems from their receptor selectivity and the use of centralized electrocardiogram (ECG) evaluation by expert cardiologists during all phases of clinical trials for new drugs. The first drug that sparked increased interest in the effects of antihistamines on the heart was astemizole. Only later, clinical studies in humans and experimental research in animals demonstrated that astemizole and terfenadine strongly inhibit potassium channels in cardiac muscle cells. A consequence of this effect is delayed repolarization of the ventricular muscle. Clinically, this is associated with prolongation of the QTc interval. This phenomenon directly leads to a substantial rise in the risk of life-threatening ventricular arrhythmias, referred to in clinical practice as the risk of torsadogenicity. The drugs listed above were withdrawn from the pharmaceutical market due to the relatively high risk of cardiovascular adverse effects, particularly affecting the heart’s conduction system. The risk of torsadogenicity does not apply to antihistamines other than those mentioned above, so it is not a class effect. Since then, the impact of all antihistamines on the QTc interval has been evaluated in clinical trials. New guidelines for the treatment of chronic urticaria have shifted perspectives on the potential and actual safety of antihistamine agents. The established protocol of increasing the standard antihistamine dose to fourfold (quadruple dosing) may prolong the QTc interval. It is important to note that this risk should be assessed on an individual basis. Among antihistamines, bilastine has relatively the most robust study data on cardiovascular safety. When used at doses ranging from 20 to 100 mg (i.e. five times the registered dose), it showed no impact on ECG morphology or QTc interval duration. Importantly, in all conducted clinical studies, bilastine was found to have no effect on ECG morphology or QTc duration, which is particularly important in the context of patients with coexisting risk factors for ventricular arrhythmias.

Use of antihistamines and road traffic safety

Antihistamines that cross the blood–brain barrier and penetrate the CNS may impair psychomotor performance, a concern particularly relevant for drivers. Adverse effects associated with centrally acting antihistamines that can compromise driving safety include drowsiness, headache, dizziness, and diplopia (table 4). Notably, due to their pharmacokinetic properties, certain antihistamines may pose a greater risk to road traffic safety than alcohol [1, 5, 7]. A detailed overview of specific impairments and their impact on driving performance is presented in table 5.

Interactions of glucocorticosteroids

In the case of drugs from the glucocorticosteroid (GC) group, it should be noted that interactions observed in clinical practice may arise through both pharmacokinetic and pharmacodynamic mechanisms. In patients treated with GCs, the risk of adverse interactions depends on the pharmacological profile of these drugs (e.g. anti-inflammatory activity, mineralocorticoid effect). The pharmacokinetic parameters of individual agents are also significant [7]. Table 6 lists the interactions of hydrocortisone with drugs from various pharmacological groups, while table 7 summarizes agents commonly used in clinical practice that inhibit or induce CYP3A4 activity. Table 8 provides an overview of drugs and drug classes that may interact with prednisone and methylprednisolone, along with the potential clinical consequences of such interactions.
It is important to be aware that when prednisone or methylprednisolone is used alongside cyclosporin A, the patient should not concurrently take medications that lower the seizure threshold [7]. These medications are listed in table 9. Additionally, table 10 includes interactions of dexamethasone with drugs from other pharmacological groups.

Interactions of immunosuppressive drugs used in dermatology

The most important pharmacokinetic interactions that may occur in patients undergoing polytherapy with tacrolimus and cyclosporin A are summarized in table 11.
In contemporary clinical practice, adverse interactions between immunosuppressive agents and herbal products or dietary supplements are increasingly reported. Table 12 presents the most commonly observed interactions of tacrolimus and cyclosporin A with herbal preparations and dietary supplements [1, 7].

Tacrolimus, cyclosporin A, and analgesics

In patients treated with tacrolimus and cyclosporin A, drugs including dihydrocodeine, buprenorphine, oxycodone, and fentanyl should be used with caution due to the risk of pharmacokinetic interactions involving CYP3A4. In turn, NSAIDs can modify the excretion of immunosuppressive drugs; therefore, such combinations should be avoided whenever possible. When NSAID use is required, preference should be given to drugs with a minimal risk of pharmacokinetic interactions and a short peripheral half-life. Examples of such agents include dexketoprofen and ketoprofen, especially its lysine salt [1–3, 7].

Interactions of dapsone

Table 13 details the interactions of dapsone with various other drugs, outlining potential pharmacokinetic and pharmacodynamic considerations relevant to clinical practice.

Interactions of antibacterial drugs used in dermatology

Interactions of clindamycin

Clindamycin has relatively few clinically significant interactions. Due to antagonistic effects, clindamycin should not be used concurrently with macrolide antibiotics. Systemic antibacterial drugs, including clindamycin, should be avoided during intravesical BCG therapy for bladder cancer, as they may weaken the immunomodulatory effects of BCG. The immunogenicity of BCG vaccination may also be reduced when systemic antibiotics – including clindamycin − are used. Clindamycin enhances the effect of skeletal muscle relaxants that cause reactions at the neuromuscular junction. The effect of clindamycin may be diminished by concurrent use of strong CYP3A4 isoenzyme inducers, which include St. John’s wort extracts, enzalutamide, phenobarbital, phenytoin, carbamazepine, dexamethasone, rifabutin, and rifampicin. Clindamycin significantly lowers the concentration of mycophenolic acid – the active metabolite of mycophenolates – likely due to its impaired enterohepatic circulation. This results in reduced immunosuppressive efficacy. Also, clindamycin, like many other antibacterial agents, may adversely affect Lactobacillus bacteria, a component of probiotics [7].

Interactions of fluoroquinolones

Fluoroquinolones (FQs) are antibacterial drugs that may cause the greatest number of interactions in patients hospitalized in the ICU (most commonly pharmacokinetic or related to the additive effects of adverse reactions). In clinical practice, it is important to be aware of fluoroquinolone interactions in patients undergoing polypharmacy [5, 7]. It should be noted that the highest risk of pharmacokinetic interactions is associated with the use of ciprofloxacin and norfloxacin, while the risk is the lowest with levofloxacin and moxifloxacin. Ciprofloxacin has the ability to inhibit the activity of the CYP1A2 and CYP3A4 isoenzymes.

Prolongation of the QTc interval and cardiac arrhythmias

The absolute risk of torsades de pointes associated with the use of FQs is low, which in practice corresponds to 160 additional cases of cardiac arrhythmia per 1,000,000 courses of FQ therapy. The risk rises significantly when other medications potentially prolonging the QTc interval on an ECG are given concurrently, and also when hypokalemia or hypomagnesemia is present. In terms of the risk of torsadogenicity, moxifloxacin represents a particularly significant concern. The risk of torsadogenic effects is 2–6 times greater with moxifloxacin than with ciprofloxacin or levofloxacin. This adverse reaction is caused by the impact of FQs on the potassium channels in cardiac muscle [10].
Due to ciprofloxacin’s inhibitory effect on the CYP1A2 and CYP3A4 isoenzymes, it should not be used in combination with the agents listed in table 14, as this poses a very high risk of complications resulting from pharmacokinetic interactions.
FQs used concurrently with serotonin reuptake inhibitors, fentanyl, and anticholinergic agents potentiate each other’s effect in inducing peripheral neuropathy.

Interactions of tetracyclines

Concurrent administration of lymecycline, doxycycline, and tetracycline with systemic retinoids elevates the risk of intracranial hypertension; therefore, this drug combination is contraindicated. There is also a risk of intracranial hypertension associated with the interaction of tetracyclines and vitamin A at doses above 10,000 IU/day. Antacids containing magnesium, aluminum, or calcium compounds, bismuth compounds, as well as iron, zinc, magnesium, and calcium salts may reduce the absorption of tetracyclines. Consequently, a 2-hour interval between their administration should be maintained. Inducers of cytochrome P450 isoenzymes, such as barbiturates, carbamazepine, and dexamethasone, may accelerate the metabolism of tetracyclines. Tetracyclines enhance the effects of anticoagulant agents (warfarin, acenocoumarol). Cases of pregnancy or breakthrough bleeding have been reported during concurrent use of tetracyclines and oral combined contraceptives.

Interactions of linezolid

Linezolid, as a monoamine oxidase (MAO) inhibitor, should not be used in combination with serotonergic drugs due to the heightened risk of serotonin syndrome. Concurrent use of linezolid and serotonergic agents may also lead to hypothermia, which is frequently misinterpreted as fever. Table 15 lists the drugs used concurrently in patients hospitalized in the ICU that increase the risk of excessive serotonergic stimulation.
Linezolid should not be combined with digoxin. The combination increases the levels of both medications. Linezolid levels decrease when used concurrently with rifampicin and thiopental. Combining linezolid with medications known to cause thrombocytopenia as an adverse reaction is not advised [5, 7].

Interactions of metronidazole

Metronidazole is a CYP3A4 inhibitor; therefore, it increases the levels of drugs metabolized by this isoenzyme, enhances the effect of phenytoin, and amplifies the muscle-relaxing action of vecuronium bromide. It increases lithium serum levels and enhances its toxic effects. Phenytoin, phenobarbital, and thiopental reduce serum levels of metronidazole. When used concurrently with amiodarone, QT interval prolongation and torsade de pointes-type arrhythmias have been observed. Consequently, QT interval monitoring may be necessary when amiodarone is combined with metronidazole. Metronidazole increases serum levels of cyclosporin A. It reduces the clearance of 5-fluorouracil, thus potentially elevating its toxicity.

Interactions of azole antifungal drugs

Interactions within this group of drugs are mainly pharmacokinetic in nature. In practice, cumulative adverse effects from other concurrently administered medications may also occur, leading to hepatopathies. Table 16 summarizes information regarding the pharmacokinetic profiles of individual azole antifungals [4, 7].

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The author declares no conflict of interest.

References