IKr blockade
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IKr blockade hERG cardiac arrhythmia
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IKr Blockade
What is IKr?
IKr (the rapid component of the delayed rectifier potassium current, IK(rapid)) is carried through cardiac ion channels encoded by the KCNH2 gene (also called hERG - human Ether-a-go-go Related Gene), producing the protein KV11.1. It is one of the two main outward repolarizing currents (along with IKs, the slow component) that terminate the cardiac action potential during phase 3 repolarization.
- IKr flows outward (K⁺ leaving the cell), driving the membrane back toward resting potential
- It is the dominant repolarizing current at physiological heart rates
- The hERG channel has a unique pharmacological vulnerability: it contains a large inner vestibule with aromatic amino acid residues that make it highly susceptible to drug binding
Physiological Role in the Action Potential
| Phase | Event | IKr contribution |
|---|---|---|
| 0 | Rapid depolarization (Na⁺ influx) | Minimal |
| 1 | Early rapid repolarization | Small |
| 2 | Plateau (Ca²⁺ influx balanced by outward currents) | Growing |
| 3 | Rapid repolarization | Major - IKr peaks here |
| 4 | Resting membrane potential | Closed |
Consequences of IKr Blockade
1. Prolongation of Action Potential Duration (APD)
Blocking IKr slows repolarization, extending the APD. On the surface ECG this manifests as QT interval prolongation (specifically the JT portion, reflecting direct IKr antagonism).
2. Drug-Induced Long QT Syndrome (DI-LQTS) and Torsades de Pointes (TdP)
This is the cardinal danger. Prolonged repolarization creates conditions for early afterdepolarizations (EADs), which can trigger the polymorphic ventricular tachycardia known as torsades de pointes (TdP), potentially degenerating into ventricular fibrillation and sudden cardiac death.
"The specific prolongation of the segment from the end of ventricular depolarization to the end of repolarization ('JT' interval) is characteristic of toxic exposures that directly antagonize the IKr potassium channel." - Washington Manual of Medical Therapeutics
Vaughan Williams Classification
IKr blockade is the principal mechanism of Class 3 antiarrhythmic action - action potential prolongation:
"Class 3 action manifests as prolongation of the APD. Most drugs with this action block the rapid component of the delayed rectifier potassium current, IKr." - Katzung's Basic and Clinical Pharmacology, 16e
Drugs that Block IKr
Intended IKr blockers (Class 3 antiarrhythmics)
| Drug | Notes |
|---|---|
| Dofetilide | Pure IKr blocker - dose-dependent, no IKs or INa blockade; TdP risk ~1-3%; initiated in hospital with QTc monitoring |
| Ibutilide | IKr blockade + late INa activation; IV only; cardioversion of AF/flutter |
| Sotalol | IKr blockade (both D/L isomers) + beta-blockade (L-isomer); TdP risk approaches 6% at highest doses |
| Amiodarone | Blocks IKr along with INa, ICa, and beta receptors (all 4 classes); paradoxically low TdP risk despite significant QT prolongation |
Class 1A drugs (secondary IKr blockade)
- Quinidine - blocks INa primarily + IKr secondarily
- Procainamide - INa primary + IKr secondary
- Disopyramide - similar profile
Non-antiarrhythmic drugs (off-target IKr blockade - high clinical concern)
These cause drug-induced TdP as an adverse effect:
- Antibiotics: macrolides (azithromycin, erythromycin), fluoroquinolones (moxifloxacin)
- Antipsychotics: haloperidol, droperidol, chlorpromazine, prochlorperazine
- Antidepressants: TCAs, citalopram (dose-dependent)
- Antihistamines: terfenadine, astemizole (withdrawn from market due to TdP)
- Antifungals: ketoconazole (especially when combined with above drugs)
- GI drugs: metoclopramide, domperidone
Repolarization Reserve Concept
A key principle from Braunwald's: the cardiac system has "repolarization reserve" - the heart can tolerate some reduction in IKr because IKs and other currents provide redundancy. TdP only typically occurs when multiple hits reduce this reserve simultaneously:
- Genetic background (KCNH2/hERG polymorphisms, e.g., p.K897T-KCNH2 reduces channel function)
- Electrolyte disturbances (hypokalemia and hypomagnesemia are potent risk amplifiers - dofetilide's IKr blockade actually increases in hypokalemia)
- Female sex (women have intrinsically longer QTc at baseline)
- Drug interactions (CYP3A4 inhibitors raising plasma levels of IKr-blocking drugs)
- Pre-existing LQTS (subclinical mutations unmasked by drug challenge)
- Bradycardia (reverse use-dependence: IKr blockers are more potent at slow rates)
"10-15% of patients with DI-TdP host rare ion channel mutations... multiple genetic and environmental hits to the 'repolarization reserve' are involved in the pathogenesis of DI-LQTS/DI-TdP." - Braunwald's Heart Disease
Beyond hERG Blockade: Additional Mechanisms
Recent evidence shows hERG/KV11.1 IC50 alone may underestimate TdP risk. Drugs like dofetilide, sotalol, and azithromycin also inhibit PI3K signaling, which:
- Reduces IKs further
- Increases late/sustained Na⁺ current (I
NaL)
This synergy makes them more torsadogenic than drugs that only block hERG.
Key Risk Factors for Drug-Induced TdP
- Baseline QTc >450 ms (women) / >440 ms (men)
- Hypokalemia or hypomagnesemia
- Bradycardia (<50 bpm)
- Congenital LQTS (even subclinical)
- Female sex
- Combination of QT-prolonging drugs
- Hepatic/renal impairment (alters drug clearance)
- IV administration vs oral (faster/higher peak levels)
Clinical Monitoring for IKr Blockers
For drugs like dofetilide and ibutilide, guidelines require:
- Baseline QTc measurement
- Serum K⁺ and Mg²⁺ before and during loading
- Continuous ECG monitoring during hospital initiation
- Dose reduction or discontinuation if QTc rises to ≥500 ms (or ≥550 ms with intraventricular conduction delay)
Sources:
- Katzung's Basic and Clinical Pharmacology, 16th Ed., Ch. 14 (Antiarrhythmic Drugs)
- Braunwald's Heart Disease, 2-Vol Set, Ch. 63 (hERG/K
V11.1 Channel Blockade and Cardiac Repolarization Reserve) - Washington Manual of Medical Therapeutics (Electrocardiography - QT interval)
- Maudsley Prescribing Guidelines in Psychiatry, 15th Ed.
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