Cardiac complications of systemic drugs used in dermatology

INTRODUCTION

Cardiovascular disease are one of the primary cause of morbidity and mortality in many developed countries all over the world. This makes it crucial to understand the potential effects of the drugs on the cardiovascular system.¹ There are many dermatological conditions with cardiac involvement. Certain conditions affect both the skin and the heart. And then there are drugs that are used in treating the skin conditions causing cardiac side effects. This underscores the importance of dermatologist being aware of the potential side effects of these medications.

RETINOIDS

Retinoids are known to cause dyslipidemia. Though not commonly encountered there are case reports of isotretinoin induced atrial tachycardia, pericardial effusion.² Acitretin can cause acute myocardial infarction and bexarotene is reported to accelerate coronary atherosclerosis.^3,4 The cardiovascular birth defects due to teratogenic action are explained by inhibition of mesoderm formation during cardiac differentiation, dysregulation of genes associated with mesoderm differentiation during cardiomyocyte differentiation and disruptions in signalling pathways during mesoderm formation.⁵

METHOTREXATE

Methotrexate use presents with both benefits and potential risks. Reduction in tetrahydrofolate results in homocysteinemia. Though there are factors that places cardiovascular system at risk some actions reduce the cardiovascular risk as discussed in Table 2.

AZATHIOPRINE

Azathioprine, though the cardiac risk is very low, cases of hypotension, cardiogenic shock and atrial fibrillation are reported.^8,9

MYCOPHENOLATE MOFETIL

Mycophenolate mofetil (MMF) is said to reduce the progression of atherosclerosis due to decreased vascular oxidative stress and its anti-inflammatory action.¹⁰ In contrast, there have been case reports documenting MMF-induced supraventricular tachycardia.¹¹

CYCLOSPORINE

Animal studies have demonstrated a correlation between cyclosporine use and adverse cardiovascular effects, including coronary vasospasm and ventricular hypertrophy.^12,13 Additionally, clinical case reports have documented instances of atrial fibrillation associated with cyclosporine toxicity in human subjects.¹⁴

BLEOMYCIN

Bleomycin use has been associated coronary artery disease, myocardial ischemia, myocardial infarction and rarely pericarditis and acute chest pain syndrome. These adverse events are not associated with any consistent signs and symptoms.¹⁵

CYCLOPHOSPHAMIDE

Cyclophosphamide, when given in low doses not induce cardiotoxicity. High dose cyclophosphamide use in the management of Mycosis fungoides, lymphoma etc has been associated with tachyarrhythmias, decreased amplitude of QRS complex, heart block and nonspecific T wave or ST segment abnormalities.¹⁶

ANTIFUNGALS

Itraconazole has been linked to adverse cardiovascular events, encompassing congestive heart failure, premature ventricular contractions, systemic hypertension and, in severe cases, ventricular fibrillation.^17-21 Fluconazole is known to prolong the QT interval and result in Torsade de pointes (TDP) even at low doses, necessitating the need of serial electrocardiographic monitoring in patients with increased risk of ventricular arrythmias.^18,22 Griseofulvin causes peripheral vasodilation and decreases the blood pressure when given intravenously. It also acts directly on the myocardial fibres and vessel wall resulting in increased heart rate.²³ Ketoconazole can also prolong the QT interval and cause TDP.²⁴ Amphotericin B is associated with ventricular arrhythmias, bradycardia, hypokalaemia. Though cardiac toxicity is rare with liposomal preparation of Amphotericin B bradycardia, Atrioventricular block (AV block) are reported.²⁵

ERTHYROMYCIN

Erythromycin is reported to increase the risk of ventricular arrhythmias, QT prolongation and Torsades de pointes. In addition, patients who are on erythromycin with concomitant CYP3A inhibitors has five times more risk of sudden death due to cardiac causes than those who are not on these drugs.²⁶

FOSCARNET

It’s mainly used in acyclovir resistant Herpes simplex infection and cytomegalo virus infection. Foscarnet forms drug-calcium ion complex resulting in hypocalcemia, hypomagnesemia (hypoparathyroid state) and hypokalaemia (renal wastage of potassium). This in turn leads to cardiac arrythmias. Hypokalaemia is commonly seen during the induction phase of Foscarnet therapy.²⁷

ANTIHISTAMINES

Due to profound cardiac adversities two first generation antihistamines, astemizole and terfenadine are banned from use.²⁸ First generation H1 antihistamine is associated with higher risk of cardiovascular events like arrhythmias especially in pediatric population.²⁹

TRICYCLIC ANTIDEPRESSANTS

Amitriptyline, doxepin, nortriptyline are associated with life threatening rhythm abnormalities especially wide QRS complex tachycardia and hypotension.¹

HYDROXYCHLOROQUINE

Hydroxychloroquine (HCQ) causes cardiomyopathy with the electron microscopic changes similar to that seen Fabry disease. HCQ induced cardiomyopathy may manifest as ventricular hypertrophy, valvular dysfunction, hypokinesia and potentially pulmonary arterial hypertension.³⁰ Acute intoxication of HCQ can lead to QTc prolongation, ventricular tachycardia, ventricular fibrillation, rarely prolonged QRS and Torsades de pointes. However prolonged use of over 10 years results higher incidence of arrhythmias and cardiomyopathies than in acute intoxication. Atrial fibrillation, bundle branch block, left-sided heart failure and QT prolongation are seen with prolonged use of HCQ.³¹

CORTICOSTEROIDS

Corticosteroids are widely used in day to day practice. They exert their action via genomic action or via non genomic action such as activating the membrane bound glucocorticoid receptor or via direct physiochemical interaction with the cell wall elements.³² While the genomic effects pose the cardiac related adverse effects, the non-genomic effects are responsible for the beneficial effects of steroids on vascular inflammation, inhibiting the leucocyte endothelial interaction and also activating the endothelial nitric oxide synthase.^33,34 The common adverse effect of glucocorticoids on Cardiovascular system is dyslipidemia and hypertension, atrial fibrillation and also pose a significant risk of heart failure.^35-37 Though it was of the belief that low dose steroids was comparatively safer, its now been proved that doses even less than 5 mg of prednisolone doubles the risk of cardiovascular diseases.³⁶

Pulse therapy with corticosteroids is used in the management of autoimmune disorders. Sinus tachycardia, the most common cardiac event is followed by atrial fibrillation, sinus bradycardia and ventricular tachycardia.³⁸ Arrhythmias occur in 1% to 82% patients on intravenous methylprednisolone pulse.³⁹ One study suggests the mean time for development of bradycardia as 42-80hours from the initiation of the pulse.⁴⁰

ORAL MINOXIDIL

Minoxidil, a systemic vasodilator, triggers myocardial ischemia by reflex tachycardia and fluid retention by modulating renal hemodynamics. Thus, making it contraindicated in patients with angina or recent history of myocardial ischemia, heart failure and left ventricular hypertrophy.⁴¹ There are case reports of Pericardial effusions due to low dose oral minoxidil.⁴²

RITUXIMAB

Rituximab is a chimeric human/murine IgG monoclonal antibody that binds specifically to CD 20 antigen on normal and malignant B lymphocytes. In patients aged more than 60 years with a known history of cardiovascular disease are at a higher risk of developing arrythmias. Cardiac adverse effects of rituximab include arrythmias, hypotension, cardiogenic shock, reduction in ejection fraction, non-ischemic cardiomyopathy, Takotsubo’s cardiomyopathy During infusion reaction, side effects like angina, acute coronary syndrome (ACS), and arrhythmias are reported.^43,44 Benign cardiac side effects of rituximab include hypertension (between approximately 6%-12% of patients) and transient hypotension (approximately 10% of patients).⁴⁵

OMALIZUMAB

Omaliuzmab is a humanized monoclonal antibody that prevents activation by allergens and reduces chronic inflammation. Cardiomyopathy, MI (myocardial infarction), arrythmias, heart failure, syncope, Arterial and venous thrombosis have been reported in patients on omalizumab compared to untreated group.^46,47 Exposure to omalizumab is associated with an increased risk of arterial thrombotic events in asthmatic patients, predominantly cardiovascular death and stroke.⁴⁶ Omalizumab may be a cause of Takotsubo syndrome, a reversible form of dilated cardiomyopathy mimicking acute MI associated with sympathetic stimulation.⁴⁸

ETANERCEPT

It’s a tumor necrosis factor α (TNF-α) antagonist. Etanercept blocks the deleterious effects of TNF at the level of cell surface receptors. TNF can dissociate from this cytokine-drug complex leading to increased peripheral bioactivity that adversely affect the cardiomyocytes.⁴⁹ Though it is claimed to be safe from cardiac front, there are case reports of heart failure, non-ischemic cardiomyopathy.^50-52

ADALIMUMAB

In vitro studies showed improvement in congestive heart failure (CHF) symptoms in mice cardiomyocytes. There are no large scale human studies to support this finding. There are case reports of CHF due to adalimumab.⁵³ However among etanercept, infliximab and adalimumab, adalimumab has better cardiac safety.⁵⁴

INFLIXIMAB

A popular clinical trial on the effects of infliximab in class III-IV heart failure has been stopped prematurely with a conclusion that there was increased hospitalization and deaths. This was seen in patients on a dose of 10 mg/kg, while 5 mg/kg showed no evidence of reduction in cardiac symptoms.⁵⁵ Therefore infliximab should be avoided in symptomatic moderate to severe congestive heart failure.

INTERFERON

Interferon therapy is associated with arrythmias, dilated cardiomyopathy, hypotension, ischemic heart disease and pericarditis.^56,57

INTRAVENOUS IMMUNOGLOBULIN THERAPY

Intravenous immunoglobulin therapy (IVIg) infusion is associated with high risk for cardiac arrest and supraventricular tachycardia. It can also result in sick sinus syndrome, atrial flutter, atrial fibrillation and bradycardia.^58,59

CONCLUSION

Dermatologist should be aware of the cardiac side effects of the drugs as well as the cardiac involvement in a particular condition. It always starts with eliciting a proper history to rule out any pre-existing cardiac conditions and starting on the appropriate dose according to the age and weight of the patient. In instance of adverse events prompt intervention from withholding the drug to taking a cardiologist opinion is paramount in preventing morbidities.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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