Drug Induced Long QT Syndromes: Lethal Reactions to ‘Benign Drugs’ - May/2005 Dr. R.G.Williams

Long QT syndrome (LQTS)

¾ A disorder of myocardial repolarization characterized by a prolonged QT interval on ECG. ¾ ↑ risk of a characteristic life-threatening cardiac arrhythmia, known as torsade de pointes (TdP) VT. ¾ Drug induced usually with bradycardia ¾ Short-long cycles 2o VPBs ¾ Present with: z Palpitations z Syncope z Seizures z Sudden cardiac death (SCD) ¾ Congenital – 2 phenotypes z Romano – Ward: more common, purely cardiac • Autosomal dominant z Jervell + Lange-Nielsen: sensorineural deafness • Autosomal recessive ¾ At least 7 genes described LQTS 1 - 7 ¾ Affect Na and K channels ¾ Acquired LQTS may be a ‘forme fruste’

Acquired LQTS ¾ Commonest causes z Medications z Electrolyte disorders ¾ Others z Structural heart disease z Stroke + brain injury z HIV z Eating disorders

May, 2005 1 Talk edited into handout by RAS Long QT of Hypocalcemia

May, 2005 2 Talk edited into handout by RAS Drug Induced LQTS ¾ First recognized in 1920s – quinidine syncope ¾ Monitoring identified typical sequences in TdP in 1960s ¾ In the past decade, the single most common cause of the withdrawal or restriction of the use of drugs that have already been marketed has been the prolongation of the QT interval associated with polymorphic ventricular tachycardia, or torsade de pointes. ¾ Nine structurally unrelated drugs removed or severely restricted due to QT ↑ + TdP.

Risk Factors for TdP ¾ Drug regimen: z Not usually an idiosyncratic event z ↑drug dose or concentration (except quinidine) z Rapid IV infusion z Concurrent drugs • That ↑ QT • ↓ metabolism: cytochrome P450 inhibition • Erythromycin does both! ¾ Metabolic factors z Electrolytes: ↓K, ↓ Mg, (↓ Ca) z Impaired hepatic or renal function ¾ Other z Heart disease: CHF, LVH z Recent conversion from atrial fibrillation z ♀ gender ¾ ECG abnormalities z Baseline QT ↑ or T wave lability z The development of marked QT ↑, T wave lability, or T wave morphologic changes during therapy z Bradycardia → ↓extracellular K, → ↑ drug-induced inhibition of IKr z Congenital long QT syndrome or "silent" mutations in LQTS genes ¾ Drugs include: z terfenadine, astemizole, grepafloxicin, terodiline, droperidol, lidoflazine, sertindole, levomethadyl, and cisapride.

May, 2005 3 Talk edited into handout by RAS Methadone-induced QTS

Acquired LQTS ¾ Drugs block outward IKr current ¾ IKr responsible for phase 3 repolarization, ¾ ↑ phase 3 repolarization → QT↑ ¾ QT ↑ → ↑ spatial dispersion of repolarization

Why the IKr Channel in LQTS? ¾ ↑ inner cavity size in IKr channel ¾ → trapping of large molecules ¾ Aromatic residues bind large aromatic drugs ¾ APD prolongation with IKr blockade is non-uniform → QT dispersion throughout the myocardium ¾ “reverse frequency dependent”

So What? ¾ Early after-depolarizations (EAD) can induce triggered beats. ¾ EADs can infringe on the underlying substrate of inhomogeneous repolarization (M cells) to initiate re-entrant excitation →TdP

Drugs + Acquired LQTS ¾ Among 761 cases of drug-induced TdP reported to the World Health Organization Drug Monitoring Centre between 1983 and 1999, the most common drugs were sotalol and cisapride (17 and 13 percent) ¾ Antiarrhythmic drugs: class I + III; responsible in ¾ cases

May, 2005 4 Talk edited into handout by RAS ¾ Nonsedating antihistamines ¾ Macrolide antibiotics z Erythromycin: 2 fold ↑ in SCD z Metabolized by CYP3A4 system z Patients taking diltiazem, verapamil, troleandomycin, azole antifungals →5x risk of SCD if taking erythromycin. ¾ Antipsychotics + antidepressants ¾ Drugs recently d/c due to ↑ QT: z Cisapride In Children: ¾ N = 35,mean age 5.2 years, rx for reflux. ¾ ↑QT in 31%, TDP in 5.7% z Terfenadine ¾ Very potent IKr blocker ¾ Nearly completely biotransformed by the CYP3A before entering the systemic circulation. ¾ Its major metabolite, fexofenadine, is noncardioactive, marketed as Allegra. ¾ Problems occur with: ¾ Inhibition of CYP3A - erythromycin or ketoconazole ¾ CYP3A overwhelmed ie. an overdose ¾ Reduced activity by disease (such as cirrhosis) ¾ Terfenadine levels ↑ markedly, → ↑↑ QT z Astemizole

VT in Acquired LQTS ¾ Usually bradycardia or frequent pauses precede VT, ie ‘pause-dependent’ ¾ VT commonly ‘short – long’ RR intervals ¾ VPB → pause → further ↑ QT ¾ Next VPB in longer QT → VT ¾ LQTS drugs → ‘reverse use dependence’ ie ↓rate → >>↑QT

May, 2005 5 Talk edited into handout by RAS

What about quinidine syncope? ¾ TdP occurs at sub-therapeutic levels: 1st dose ¾ Low levels: potent IKr blocker ¾ Higher levels: Na channel blocker dominates which may protect against TdP

‘Reduced repolarization reserve’ ¾ A spectrum of ‘normal’ repolarization, not apparent in the basal state. ¾ Exposure to QT↑ drugs, ∆metabolic state → marked QT↑ in susceptible individuals. ¾ TdP risk also varies for similar degrees of QT prolongation. ¾ QTC > 500 ms, should prompt consideration of medication change.

May, 2005 6 Talk edited into handout by RAS

What’s different about females? ¾ ♀ have: z longer QT z greater response to drugs blocking IKr z estrogen potentiates bradycardia induced ↑QT z androgens ↓QT and → less drug responsive

When prescribing drugs affecting QT ¾ Caution when 1> risk factors present

May, 2005 7 Talk edited into handout by RAS z Consider alternative agents ¾ Baseline and interval ECG for QTc ¾ Instruct pts to report z Palpitation, syncope, near syncope z Report changes that → ↓ K+ (ie. GI ∆s , diuretics

QT measurement ¾ Lead II: beginning of QRS to end of T wave ¾ Corrected to rate with Bazett’s formula z QTc = QT interval ÷ √RR interval (in sec) z Normal QTc: • ♂ ≤ 440 ms • ♀ ≤ 460ms

Rx for Drug-induced TdP ¾ Unstable pt: nonsynchronized DC cardioversion ¾ Stable or to prevent recurrence z MgSO4:2 g / 1-2 min with repeat or infusion, correct K+ z Isoproterenol: 2g/500 to ↑ HR ~100bpm z Overdrive pacing: atrial or ventricular, ↓QT+dispersion z Screen family members for congenital LQTS

May, 2005 8 Talk edited into handout by RAS

The Bad News ¾ Torsade de pointes (TdP) ventricular tachycardia is often unhearalded and fatal. ¾ TdP often occurs without apparent structural heart disease. ¾ TdP often occurs in young healthy patients. ¾ TdP can occur with commonly Rx drugs.

The Good News ¾ TdP can be prevented with good Rx habits and heightened level of awareness. ¾ Most TdP occurs in presence of risk factors. ¾ Close monitoring can prevent most cases.

May, 2005 9 Talk edited into handout by RAS