Groot JAN, Ten Bokum L, van den Oever HLA Late presentation of torsades de pointes related to fluoxetine following a multiple drug overdose. J Intensive Care. 2018; 6 https://doi.org/10.1186/s40560-018-0329-1
Shah RR Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?. Br J Clin Pharmacol. 2013; 75:347-358 https://doi.org/10.1111/j.1365-2125.2012.04415.x
Wilde AAM, Amin AS, Postema PG Diagnosis, management and therapeutic strategies for congenital long QT syndrome. Heart. 2022; 108:332-338 https://doi.org/10.1136/heartjnl-2020-318259
Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G Prevalence of the congenital long-QT syndrome. Circulation. 2009; 120:1761-1767 https://doi.org/10.1161/CIRCULATIONAHA.109.863209
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Drug-induced prolongation of the qt interval: implications for dental prescribing Rachel Botrugno E Anne Field Christine Randall Dental Update 2025 52:4, 270-274.
Authors
RachelBotrugno
BDS, MFDS RCPS(Glasg), Specialist Registrar in Oral Medicine, Liverpool University Dental Hospital
Prolongation of the QT interval, as measured on an electrocardiogram, can result in a ventricular arrhythmia known as torsade de pointes (TdP), which can be fatal. Individual drugs and interactions between drugs can pose a risk of QT interval prolongation. Some antimicrobial drugs on the Dental Practitioners' Formulary are associated with a risk of QT interval prolongation. An awareness of QT interval prolongation is critical for safe dental prescribing, particularly for patients with recognized risk factors, including cardiac disease and hepatic/renal impairment.
CPD/Clinical Relevance: For patients at risk of QT interval prolongation, certain antimicrobials that can be prescribed by general dental practitioners have the potential to cause life-threatening cardiac arrhythmias.
Article
Warnings have been issued over the past few years about drugs that are known to cause prolongation of the QT interval, which can result in a potentially life-threatening cardiac arrhythmia.1,2,3
Dentists treating NHS patients can prescribe from an approved list of drugs: the Dental Practitioners' Formulary (DPF).4 Some of the antimicrobial drugs on the DPF are associated with a risk of QT interval prolongation. This article has three aims:
To provide a brief overview of the QT interval and its clinical significance;
To identify patients particularly at risk of developing QT prolongation; and
To provide guidance for dentists prescribing antimicrobial drugs that may affect the QT interval.
QT interval and torsade de pointes
The QT interval, as measured on an electrocardiogram (ECG), represents the time between the start of the Q wave to the end of the T wave. This corresponds to the start of ventricle depolarization to the end of ventricle repolarization (Figure 1). The QT interval varies with the patient's heart rate; as the heart rate increases, the QT interval shortens.
Figure 1. Electrocardiogram trace indicating the QT interval.
Prolongation of the QT interval can result in a ventricular arrhythmia known as torsade de pointes (TdP), which can be fatal. Torsade de pointes is translated as ‘twisting of peaks' owing to its distinct characteristics on an ECG, which were first described in 1966.
Most patients experiencing an episode of TdP will return spontaneously to a normal sinus rhythm.5 However, if this tachycardia is rapid or sustained, it can progress to ventricular fibrillation in 15–20% of cases and may result in sudden death.6 Symptoms include palpitations, light-headedness and fainting.7 In the US, around 5% of 300,000 sudden cardiac deaths per year have been attributed to TdP.8
Causes of QT interval prolongation can be inherent, acquired or congenital. Acquired prolongation of the QT interval may result from structural defects in the heart, for example, owing to myocardial infarction and left ventricular hypertrophy, as well as bradycardia and other cardiac diseases. Other acquired risk factors include electrolyte disturbances, impaired hepatic/renal function, diabetes and thyroid disease. Concomitant use of more than one drug that prolongs the QT interval, and genetic variations are also risk factors. Inherent risk factors include a family history of sudden death, female sex and age ≥65 years (Table 1).9
Congenital long QT syndrome
Cardiac disease (of multiple origin, including congestive heart failure, ventricular hypertrophy, myocardial infarction, recent conversion from atrial fibrillation)
Bradycardia
Impaired hepatic/renal function (owing to effects of drug metabolism/excretion)
Electrolyte disturbances, in particular hypokalaemia, hypomagnesaemia and, more rarely, hypocalcaemia. Consider the risk of electrolyte disturbance if the patient has gastrointestinal upset
Thyroid disease: more common with hypothyroidism and usually normalizes with treatment
Concomitant use of more than one drug that prolongs the QT interval
Family history of sudden death
Genetic variations affecting the medicine's therapeutic or adverse effects
Diabetes
Female sex
Aged ≥65 years
Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome without structural heart disease or other factors.10 LQTS is rare and thought to affect around 1 in 2000 individuals.11 This syndrome is characterized by QT interval prolongation and life-threatening, and can lead to syncope and sudden death.10 Many patients are asymptomatic and investigated only because of a positive family history or an incidental finding on an ECG. Patients with LQTS can develop their first symptoms around the age of puberty.10
Drug-induced prolongation of the QT interval
Drugs can be categorized according to their potential to cause QT interval prolongation and TdP. However, recognized risk categories differ depending on the source reviewed.
The US-based CredibleMeds website is internationally accepted as a reliable reference source and is used in this article.7 CredibleMeds divides drugs into three main categories: those with a known risk of TdP, a possible risk of TdP and a conditional risk of TdP. The descriptors of these risk categories are given in Table 2. There is also a fourth category: drugs that should not be used in patients with LQTS. These include medications found within the other three risk categories as well as additional drugs.
Risk category
Definition
Known risk
Drugs that prolong the QT interval and are clearly associated with a known risk of TdP, even when taken as recommended
Possible risk
Drugs that can cause QT prolongation, but currently lack evidence of TdP risk when taken as recommended
Conditional risk
Drugs that are associated with TdP but only under certain conditions of their use, such as excessive dose or when combined with risk factors outlined in Table 1.
Drugs to avoid in congenital long QT
Drugs within known risk, possible risk and conditional risk categories, as well as additional drugs that have a special risk for those with congenital long QT syndrome owing to their actions
In the UK, a drug's summary of product characteristics (SmPC) describes the approved conditions of use and properties of a medicine, including the risk of drug interactions and its effect on QT prolongation.
Dental prescribing and QT interval prolongation
Although many drugs have the potential to prolong the QT interval, dentists have a comparatively small number of drugs available for NHS prescribing. Table 3 lists antimicrobial drugs in the Dental Practitioners' Formulary known to affect the QT interval and their risk category assigned by Credible Meds.
*The BNF highlights a predisposition to QT interval prolongation for all macrolides. However, these medications will not be flagged on the BNF interaction checker regarding QT interval prolongation when entered with other medications that share this risk, such as citalopram.
Macrolide antibiotics
The British National Formulary (BNF) cautions that all macrolides have a predisposition to prolong the QT interval.12
Clarithromycin is a second-choice antimicrobial and can be used as a first-line antibiotic for penicillin-allergic patients or those who have completed a recent course of penicillin-based antibiotics.13 Clarithromycin is in the known risk category for QT interval prolongation as categorized by CredibleMeds. In 2023, the BNF reviewed its criteria for including pharmacodynamic interactions and, consequently, the BNF interaction tables and checker no longer flag up an interaction between clarithromycin and other drugs with a known risk of QT interval prolongation. A dentist considering clarithromycin for the treatment of a dental infection needs to be aware that a potential risk remains to patients who are already taking a drug known to prolong the QT interval, as noted in the SmPC, or to those who have significant risk factors outlined in Table 1. The SmPC for clarithromycin highlights precautions on concomitant prescribing of medications associated with prolongation of the QT interval.14
Azithromycin is a recognized antimicrobial for antibiotic prophylaxis against infective endocarditis for those allergic to penicillin and unable to swallow capsules.15 Azithromycin is in the known risk category according to CredibleMeds.
Erythromycin is not recommended as an antimicrobial of choice by the Faculty of General Dental Practice.13 It is in the known risk category according to CredibleMeds. Erythromycin is listed within drugs that prolong the QT interval within the BNF interactions appendix.16
Table 4 covers guidance for dentists when prescribing an antimicrobial drug that has the potential to prolong the QT interval.
An updated medical history is essential for all patients. A detailed history is particularly important for those who are elderly/frail and for patients with cardiac conditions
A full list of current medications should be obtained from the patient or their GP
If a patient reports having congenital long QT syndrome, seek advice from the patient's GP, cardiologist or the Specialist Pharmacy Service before prescribing any drug
Special consideration should be given to patients who present with risk factors for QT prolongation (Table 1) and an allergy to penicillin. Appropriate antimicrobials should be considered for any future oral or dental infections in this cohort of patients
Avoid prescribing macrolide antibiotics or fluconazole to patients who are already taking drugs that are known to have the potential to prolong the QT interval
If the patient reports palpitations, dizziness and/or light-headedness while taking any of antimicrobials listed in Table 3, they should be instructed to stop the prescribed drug and advice from the GP should be sought
Metronidazole
Metronidazole is a first and second choice antimicrobial used within dentistry.13 CredibleMeds lists metronidazole within the conditional risk category. These conditional risks are stated as hypokalaemia, hypomagnesaemia and use of concomitant drugs that affect the QT interval prolongation risk.
The SmPCs for the Flagyl brand and Aurobindo generic metronidazole report a potential for QT interval prolongation when metronidazole is prescribed alongside drug/s that also have an associated risk of QT interval prolongation.17
The SmPCs for other generic metronidazole preparations on the UK market do not all include warnings for QT prolongation. The QT interval warning for metronidazole is not found within the BNF or Stockley's Drug Interactions/Stockley's Interactions Checker (comprehensive UK resources for drug interactions).18,19
In conclusion, if a patient has multiple risk factors for prolonged QT interval (Table 1), including taking drugs known to prolong the QT interval, it may be prudent to consider whether metronidazole is a suitable choice. If in doubt, advice should be sought from the Specialist Pharmacy Service Dental Medicines Advice Service (SPSDMAS) (Table 5).
SPSDMAS provides advice to dentists and other dental professionals concerning the use of medicines and medical devices in dental practice including prescribing, administering and dispensing
Warnings related to drug contraindications and aspects of drug safety can change, and up-to-date sources should always be consulted
SPSDMAS provides advice via telephone Monday–Friday, 0830–1700 and aims to give answers during the initial call, within a short time or within a longer timescale, depending on the question and the urgency
Antifungals
Fluconazole and miconazole are used in the management of oral candidosis.13,20
Fluconazole is listed within the known risk CredibleMeds category (Table 3) and is contraindicated in patients who are already taking drug/s associated with a risk of QT interval prolongation and metabolized by cytochrome P450 (CYP) 3A4 (e.g. lithium).21 Fluconazole should also be used with caution in patients with other recognized risk factors, including drugs known to prolong the QT interval but not metabolized by CYP3A4 (Table 1).
The SmPC for Daktarin (miconazole) oral gel contraindicates the use of miconazole with drugs metabolized by the enzyme CYP3A4 and known to prolong the QT interval.22 However, neither the BNF, Stockley's Interaction Checker nor CredibleMeds include this potential interaction.7,18,23 Prolongation of the QT interval is dose dependent and, although the dose from systemic absorption of miconazole is unlikely to be high, dentists need to be aware of this potential drug interaction risk, albeit small.
Resources to help clinicians answer questions on drug interactions are available (Table 6). Readers are reminded that warnings related to drug contraindications and aspects of drug safety can change and up-to-date sources should always be consulted.
Free resources
British National Formulary website/app
Includes an A–Z of drug interactions via the Interactions tab
Specialist Pharmacy Service website for dental medicines information
www.sps.nhs.uk/home/about-sps/get-in-touch/medicines-information-services-contact-details/dental-medicines-advice-service/
email: nwmedinfo@nhs.nettelephone: 0151 794 8206The website has information on:
Drug interactions: resources to support answering questions
Understanding drug interactions
Identifying risk factors for developing a long QT interval
Summary of product characteristics (SmPC)
Information on QT interval may appear under ‘Contraindications’, ‘Special warnings and precautions for use’ or ‘Interaction with other medicinal products and other forms of interaction’
CredibleMeds
A free website, registration required. A US site with a searchable database of medicines that cause a long QT interval and/or induce torsade de pointes
Resources requiring a subscription
Stockley's Interactions Checker
Stockley's Drug Interactions
Prescribing guidance for dentists regarding QT interval prolongation
The authors appreciate that consideration of drug-induced QT interval prolongation and its application within dentistry are not straightforward, and this is compounded by sources giving different information.
The case study in Table 7 highlights factors to consider for a patient who is taking citalopram (in the known risk category for prolongation of the QT interval), is penicillin allergic and requires antibiotics for a dental infection.
Clinical presentation and medical history
A 30-year-old female patient presented with an acute peri-apical infection requiring antibiotics as an adjunct to operative dental treatment
This patient takes 40 mg of citalopram once daily for depression. She reported no other medications, but is allergic to penicillin; the rest of her medical history is clear. She is a non-smoker and does not drink alcohol
Antibiotic considerations
Owing to the patient's penicillin allergy, an antibiotic such as metronidazole or a macrolide would be considered
Prescribing considerations
The QT interval prolongation risk for both citalopram and the antibiotic to be prescribed should be reviewed, along with any relevant risk factors
The patient is young and has no other risk factors for prolongation of the QT interval, except being on citalopram
CredibleMeds states that citalopram, clarithromycin and other macrolides are in the known risk category. Metronidazole is in the conditional risk category
Under cautions and contraindications for citalopram on the BNF, QT interval prolongation is mentioned
The BNF mentions the predisposition for QT interval prolongation under cautions for all macrolides
Management
On balance, metronidazole appears to have fewer potential risks for QT interval prolongation than macrolides. The patient should be warned to report side effects such as palpitations, dizziness and/or light-headedness
When treating patients with known LQTS, advice should be sought from the patient's GP or cardiologist, or the SPSDMAS, before prescribing any drug that may have a risk of QT interval prolongation.
If a dentist prescribes a drug with a recognized risk for QT interval prolongation to a patient with risk factors, then the patient should be advised to report any palpitations, light-headedness or dizziness.7
Table 4 summarizes general guidance for dentists when prescribing drugs that may prolong the QT interval.
Conclusion
Dentists need to be aware of the potential risk of QT interval prolongation when prescribing antimicrobial drugs and be able to initiate action to manage any adverse reactions.
