Rhythm and BluesDrugs and QT Prolongation

Dr Martin Quinn

St Vincents University Hospital

Irish Medication Safety Network conference

Farmleigh 18 Oct 2013

Drugs and QT Prolongation

• Anti-psychotic, antidepressant, anti-histamine, antiarrhythmic and antibiotics are the commonest

• The risk of arrhythmia is increased x 3-8 fold

• Up to 3% of prescription are for medication with the potential to prolong the QT interval

QT prolongation with medicationNa channel blockade

QT prolonging medications

Cardiac Ion ChannelsAction potential

Torsade de Pointes

Measuring QT interval-ECG

• Effected by heart rate and sex

• Normal for males <440ms

• Females <460 ms

Relationship of QT to heart rate

Congenital Long QT Syndrome

• 5-20% of patients with drug induced prolongation have previously unrecognized long QT

• Usually diagnosed in patients with aborted SCD or family member with SCD

• Examination – normal, occasional deafness or skeletal and cardiac abnormalities

Long QT syndrome

• 100 of mutations in 10 genes have been identified

• Mutations in 3 genes encoding a cardiac ion channel account for the majority.

• Some have multiple mutations which increases the risk of SCD

• Syncope/SCD usually due to torsades de pointes

• Sometimes associated with bradycardias

Long QT syndrome

• Romano-Ward the autosomal dominant form

• Often variable penetrance

• Usually a disease of young and syncope and SCD rare in those over 40 years

• Post mortem usually normal

• Jervell-Lange-Neilson autosomal recessive with deafness

LQT-3 Na channel

Common forms of LQTS

Uncommon forms of LQTS

Disease gene Functional effect Other features

LQT4 ANK2

Altered intracellular calcium control and subcellulartargeting of calcium control proteins

Atrial fibrillation, sinus node dysfunction

LQT5 KCNE1 Decreased IKs Similar to LQT1

LQT6 KCNE2 Decreased IKr

No formal linkage in a family to date; isolated mutations in drug-associated QT prolongation

LQT7 KCNJ2 Decreased inward rectifier potassium current (IK1)

Anderson-Tawil syndrome, including neurological symptoms and unusual facies

LQT8 CACNA1C Increased L-type calcium current

Timothy syndrome: syndactyly, unusual facies, neurological defects

LQT9 CAV3 Increased plateau INa Similar to LQT3

LQT10 SCN4B Increased plateau INa Similar to LQT3

AKAP9 Decreased IKsPreliminary report only

SNTA1 Increased plateau INa

Jervell-Lange- Nielsen KCNQ1 Loss of IKs

Congenital deafness,

Risk of long QT

• Most powerful predictor of risk is length of QTc

• The incidence of syncope or SCD over 10 years in 647 patients with LQT1-3 was <20% with QTc<446 and 70% with QTc>498

Factors to watch out for

History of syncope

Family history

• SCD

• Drowning

• SIDS

• Death while driving

Anti-psycotics and QT prolongationAdjusted Incidence-Rate for Sudden Cardiac Death

Ray et al NEJM 2009

Effect is dose related

Adjusted Rate of Sudden Cardiac Death among Current

Users of Antipsychotic Drugs, According to Dose

QT prolongation with newer antipsychotics

• 478 events per 166,324 patient years of use (Ray et al 2009) or 2.9/1000

• With higher doses the rate is 3.3/1000

• 3% of patients with schizophrenia (mean age 40 years) who were treated with risperidone or quetiapine had prolongation of the QT interval

• The risk was doubled in older patients with dementia (6%)

QT Prolongation with Azithromycin

• HR for cardiovascular death 2.8 during 5 days of therapy

• 47 extra deaths per million prescriptions

• 1 for every 21,000

• Increasing to 245 per million in patients with highest risk

Ray et al 2012

Important drug interactions

Isozyme QT prolonging drugs Inhibitor

CYP3A4 HaloperidolPimozide

Erythromycin

Clarithromycin

KetoconazoleItraconazoleDiltiazem

CYP1A2 Imipramine Ciprofloxacin

CYP2D6 ThioridazineImipramineAmitryptyline

FluoxetineAmiodarone

Prevention

• History

• Other medications

• Check pulse/BP

• ECG at baseline and within a few days of increase in dose

Conclusion

• QT prolongation with medications is common (3-6%)

• QT interval prolongation is dose related

• The risk of ventricular tachycardia/SCD is related to the degree of prolongation of the QT interval

• With up to a 3 to 4 fold increase in the risk of SCD

• Drug interactions are particularly important in increasing the risk