safety testing for antiarrhythmic drugs€¦ · safety testing for antiarrhythmic drugs michael j....
TRANSCRIPT
![Page 1: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/1.jpg)
Safety testing for antiarrhythmic drugs
Michael J. Curtis PhD
Cardiovascular Division, King’s College London, The Rayne Institute, St Thomas’ Hospital
London, UK
![Page 2: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/2.jpg)
Background
Antiarrhythmic drug discovery was damaged by CAST and SWORD (1989-1992)
• Clinical trials of antiarrhythmic drugs: flecainide and D-sotalolol
• ‘Expectation’ of a reduction in sudden cardiac death (SCD)
These drugs caused a doubling of death rate
• Proarrhythmia from antiarrhythmic drugs? • Deeply unsettling, badly explained
![Page 3: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/3.jpg)
Background
Antiarrhythmic drug discovery was damaged by CAST and SWORD (1989-1992)
• Clinical trials of antiarrhythmic drugs: flecainide and D-sotalolol
• ‘Expectation’ of a reduction in sudden cardiac death (SCD)
These drugs caused a doubling of death rate
• Proarrhythmia from antiarrhythmic drugs? • Deeply unsettling, badly explained
![Page 4: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/4.jpg)
Background
Antiarrhythmic drug discovery was damaged by CAST and SWORD (1989-1992)
• Clinical trials of antiarrhythmic drugs: flecainide and D-sotalolol
• ‘Expectation’ of a reduction in sudden cardiac death (SCD)
These drugs caused a doubling of death rate
• Proarrhythmia from antiarrhythmic drugs? • Deeply unsettling, badly explained
![Page 5: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/5.jpg)
Background
Antiarrhythmic drug discovery was damaged by CAST and SWORD (1989-1992)
• Clinical trials of antiarrhythmic drugs: flecainide and D-sotalolol
• ‘Expectation’ of a reduction in sudden cardiac death (SCD)
These drugs caused a doubling of death rate
• Proarrhythmia from antiarrhythmic drugs? • Deeply unsettling, badly explained
![Page 6: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/6.jpg)
Background
Antiarrhythmic drug discovery was damaged by CAST and SWORD (1989-1992)
• Clinical trials of antiarrhythmic drugs: flecainide and D-sotalolol
• ‘Expectation’ of a reduction in sudden cardiac death (SCD)
These drugs caused a doubling of death rate
• Proarrhythmia from antiarrhythmic drugs? • Deeply unsettling, badly explained
![Page 7: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/7.jpg)
Background
Antiarrhythmic drug discovery was damaged by CAST and SWORD (1989-1992)
• Clinical trials of antiarrhythmic drugs: flecainide and D-sotalolol
• ‘Expectation’ of a reduction in sudden cardiac death (SCD)
These drugs caused a doubling of death rate
• Proarrhythmia from antiarrhythmic drugs? • Deeply unsettling, badly explained
![Page 8: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/8.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 9: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/9.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 10: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/10.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 11: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/11.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 12: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/12.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 13: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/13.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 14: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/14.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 15: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/15.jpg)
Drug-induced torsades de pointes (TDP)
Independently, by 1996
• Terfenadine recognised to be proarrhythmic
• Risk of TDP
• Responsible for at least 50 deaths
• Statistical association with QT prolongation
• Extremely rare
• ‘Unexpected’
• QT prolongation went from ‘hallmark of class III antiarrhythmic activity’ to anathema
![Page 16: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/16.jpg)
TDP in the ECG, and the underlying action potential (AP) abnormalities
![Page 17: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/17.jpg)
Antiarrhythmic drugs can cause TDP Dofetilide DL-sotalol
![Page 18: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/18.jpg)
How can it be that an antiarrhythmic drug can be proarrhythmic?
• There is no consensus view in the literature
![Page 19: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/19.jpg)
How can it be that an antiarrhythmic drug can be proarrhythmic?
• There is no consensus view in the literature
![Page 20: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/20.jpg)
Objective of webinar • To explain how an antiarrhythmic can be
proarrhythmic
• To suggest ways of minimising risk
![Page 21: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/21.jpg)
Objective of webinar • To explain how an antiarrhythmic can be
proarrhythmic
• To suggest ways of minimising risk
![Page 22: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/22.jpg)
Objective of webinar • To explain how an antiarrhythmic can be
proarrhythmic
• To suggest ways of minimising risk
![Page 23: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/23.jpg)
Key issues • Arrhythmias are caused by electrophysiology
changes, caused in turn by biochemical changes
• Injury current, re-entry and abnormal automaticity are the electrophysiological mechanisms
• Accumulation and depeletion of biochemicals
‘mediate’ the electrophysiological changes
• Electrophysiological mechanisms and mediator identities differ according to pathology: ischaemia vs infarction vs heart failure etc.
![Page 24: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/24.jpg)
Key issues • Arrhythmias are caused by electrophysiology
changes, caused in turn by biochemical changes
• Injury current, re-entry and abnormal automaticity are the electrophysiological mechanisms
• Accumulation and depeletion of biochemicals
‘mediate’ the electrophysiological changes
• Electrophysiological mechanisms and mediator identities differ according to pathology: ischaemia vs infarction vs heart failure etc.
![Page 25: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/25.jpg)
Key issues • Arrhythmias are caused by electrophysiology
changes, caused in turn by biochemical changes
• Injury current, re-entry and abnormal automaticity are the electrophysiological mechanisms
• Accumulation and depeletion of biochemicals
‘mediate’ the electrophysiological changes
• Electrophysiological mechanisms and mediator identities differ according to pathology: ischaemia vs infarction vs heart failure etc.
![Page 26: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/26.jpg)
Key issues • Arrhythmias are caused by electrophysiology
changes, caused in turn by biochemical changes
• Injury current, re-entry and abnormal automaticity are the electrophysiological mechanisms
• Accumulation and depeletion of biochemicals
‘mediate’ the electrophysiological changes
• Electrophysiological mechanisms and mediator identities differ according to pathology: ischaemia vs infarction vs heart failure etc.
![Page 27: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/27.jpg)
Key issues • Arrhythmias are caused by electrophysiology
changes, caused in turn by biochemical changes
• Injury current, re-entry and abnormal automaticity are the electrophysiological mechanisms
• Accumulation and depeletion of biochemicals
‘mediate’ the electrophysiological changes
• Electrophysiological mechanisms and mediator identities differ according to pathology: ischaemia vs infarction vs heart failure etc.
![Page 28: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/28.jpg)
Pathology: consider ischaemic phase 1 and 2
(Data for conscious rat, Curtis, 1993)
0 20
40 60
80 100
VF in
cide
nce
(%)
hours after onset of ischaemia
Phase 1 Phase 2
0-0.5 0.5-1 1-2 2-3 3-4
Change in timescale
![Page 29: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/29.jpg)
Pathology: consider ischaemic phase 1 and 2
(Data for conscious rat, Curtis, 1993)
0 20
40 60
80 100
VF in
cide
nce
(%)
Change in timescale
hours after onset of ischaemia
Phase 1 Phase 2
0-0.5 0.5-1 1-2 2-3 3-4
![Page 30: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/30.jpg)
Phase 1 and 2 VF respond differently to drugs
e.g., Conscious rat 20 mg/kg i.v. verapamil:
0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil 0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil
Phase 1 VF Phase 2 VF
(Curtis et al., 1984)
*
![Page 31: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/31.jpg)
Phase 1 and 2 VF respond differently to drugs
e.g., Conscious rat 20 mg/kg i.v. verapamil:
0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil 0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil
Phase 1 VF Phase 2 VF
(Curtis et al., 1984)
*
![Page 32: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/32.jpg)
Phase 1 and 2 VF respond differently to drugs
e.g., Conscious rat 20 mg/kg i.v. verapamil:
0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil 0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil
Phase 1 VF Phase 2 VF
(Curtis et al., 1984)
* 0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil
Phase 1 VF
*
![Page 33: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/33.jpg)
Phase 1 and 2 VF respond differently to drugs
e.g., Conscious rat 20 mg/kg i.v. verapamil:
0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil 0
20
40
60
80
100
Inci
denc
e (%
)
Control Verapamil
Phase 1 VF Phase 2 VF
(Curtis et al., 1984)
*
![Page 34: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/34.jpg)
Antiarrhythmic mechanisms & proarrhythmia
• Ion channels are targets for antiarrhythmic drugs:
• IKr for class III
• INa for class I
• ICaL for class IV
• Mechanisms by which targeting leads to effects on rhythm are not well understood
• Even these antiarrhythmic drugs can be proarrhythmic
![Page 35: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/35.jpg)
Antiarrhythmic mechanisms & proarrhythmia
• Ion channels are targets for antiarrhythmic drugs:
• IKr for class III
• INa for class I
• ICaL for class IV
• Mechanisms by which targeting leads to effects on rhythm are not well understood
• Even these antiarrhythmic drugs can be proarrhythmic
![Page 36: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/36.jpg)
Antiarrhythmic mechanisms & proarrhythmia
• Ion channels are targets for antiarrhythmic drugs:
• IKr for class III
• INa for class I
• ICaL for class IV
• Mechanisms by which targeting leads to effects on rhythm are not well understood
• Even these antiarrhythmic drugs can be proarrhythmic
![Page 37: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/37.jpg)
Antiarrhythmic mechanisms & proarrhythmia
• Ion channels are targets for antiarrhythmic drugs:
• IKr for class III
• INa for class I
• ICaL for class IV
• Mechanisms by which targeting leads to effects on rhythm are not well understood
• Even these antiarrhythmic drugs can be proarrhythmic
![Page 38: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/38.jpg)
Antiarrhythmic mechanisms & proarrhythmia
• Ion channels are targets for antiarrhythmic drugs:
• IKr for class III
• INa for class I
• ICaL for class IV
• Mechanisms by which targeting leads to effects on rhythm are not well understood
• Unfortunately all antiarrhythmic mechanisms can be proarrhythmic:
![Page 39: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/39.jpg)
Antiarrhythmic mechanisms & proarrhythmia
• Ion channels are targets for antiarrhythmic drugs:
• IKr for class III
• INa for class I
• ICaL for class IV
• Mechanisms by which targeting leads to effects on rhythm are not well understood
• Unfortunately all antiarrhythmic mechanisms can be proarrhythmic:
![Page 40: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/40.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 41: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/41.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 42: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/42.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 43: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/43.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 44: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/44.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 45: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/45.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 46: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/46.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 47: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/47.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 48: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/48.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 49: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/49.jpg)
Antiarrhythmic mechanisms can be proarrhythmic
• IKr block by class III drugs inhibits re-entry
• BUT IKr block facilitates abnormal automaticity
• TDP
• INa block by class I drugs can block re-entry
• This requires total local block in damaged region
• Partial block will facilitate re-entry
• Ventricular fibrillation (VF)
• ICaL block by class IV can block AV node re-entry
• Excess block, AV dissociation
![Page 50: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/50.jpg)
Arrhythmia mechanisms themselves vary according to pathology
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• During infarct evolution the mechanisms differ
• Abnormal automaticity and re-entry are important
• Heart failure, hypertrophy, different again
• No reason to expect proarrhythmia risk is the same in each setting
![Page 51: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/51.jpg)
Arrhythmia mechanisms themselves vary according to pathology
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• During infarct evolution the mechanisms differ
• Abnormal automaticity and re-entry are important
• Heart failure, hypertrophy, different again
• No reason to expect proarrhythmia risk is the same in each setting
![Page 52: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/52.jpg)
Arrhythmia mechanisms themselves vary according to pathology
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• During infarct evolution the mechanisms differ
• Abnormal automaticity and re-entry are important
• Heart failure, hypertrophy, different again
• No reason to expect proarrhythmia risk is the same in each setting
![Page 53: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/53.jpg)
Arrhythmia mechanisms themselves vary according to pathology
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• During infarct evolution the mechanisms differ
• Abnormal automaticity and re-entry are important
• Heart failure, hypertrophy, different again
• No reason to expect proarrhythmia risk is the same in each setting
![Page 54: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/54.jpg)
Arrhythmia mechanisms themselves vary according to pathology
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• During infarct evolution the mechanisms differ
• Abnormal automaticity and re-entry are important
• Heart failure, hypertrophy, different again
• No reason to expect proarrhythmia risk is the same in each setting
![Page 55: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/55.jpg)
Arrhythmia mechanisms themselves vary according to pathology
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• During infarct evolution the mechanisms differ
• Abnormal automaticity and re-entry are important
• Heart failure, hypertrophy, different again
• No reason to expect proarrhythmia risk is the same in each setting
![Page 56: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/56.jpg)
Arrhythmia mechanisms themselves vary according to pathology
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• During infarct evolution the mechanisms differ
• Abnormal automaticity and re-entry are important
• Heart failure, hypertrophy, different again
• No reason to expect proarrhythmia risk is the same in each setting
![Page 57: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/57.jpg)
Example of complexity, consider acute ischaemia
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• Underlying these mechanisms are complex changes in Em, APD and conduction velocity
![Page 58: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/58.jpg)
Example of complexity, consider acute ischaemia
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• Underlying these mechanisms are complex changes in Em, APD and conduction velocity
![Page 59: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/59.jpg)
Example of complexity, consider acute ischaemia
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• Underlying these mechanisms are complex changes in Em, APD and conduction velocity
![Page 60: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/60.jpg)
Example of complexity, consider acute ischaemia
• In acute ischaemia two mechanisms operate
• These are flow of injury current and re-entry
• Underlying these mechanisms are complex changes in Em, APD and conduction velocity
![Page 61: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/61.jpg)
Potential for flow of injury current
Ischaemic Normal adjacent
![Page 62: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/62.jpg)
Potential for flow of injury current
Ischaemic Normal adjacent
Flow of current between regions initiates VPB
![Page 63: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/63.jpg)
Potential for flow of injury current
Ischaemic Normal adjacent
Janse MJ, et al., Circ Res. 1980;47:151-165.
![Page 64: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/64.jpg)
Potential for flow of injury current
Ischaemic Normal adjacent
And by diastolic depolarization
Caused by APD shortening
Janse MJ, et al., Circ Res. 1980;47:151-165.
![Page 65: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/65.jpg)
Facilitated by ischaemic conduction delay
Ischaemic Normal adjacent
Delayed AP
Janse MJ, et al., Circ Res. 1980;47:151-165.
![Page 66: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/66.jpg)
Facilitated by ischaemic conduction delay
Ischaemic Normal adjacent
Delayed AP
Janse MJ, et al., Circ Res. 1980;47:151-165.
![Page 67: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/67.jpg)
Ischaemic AP also facilitates re-entry
Re-entry occurs when wavelength of a propagating VBP is smaller than available pathlength • Wavelength equals conduction velocity
times refractory period (ω = θ x RP)
• Slowing θ (m/s) and reducing RP (s) reduces ω (m) and so facilitates re-entry
![Page 68: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/68.jpg)
Ischaemic AP also facilitates re-entry
Re-entry occurs when wavelength of a propagating VPB is smaller than available pathlength • Wavelength equals conduction velocity
times refractory period (ω = θ x RP)
• Slowing θ (m/s) and reducing RP (s) reduces ω (m) and so facilitates re-entry
![Page 69: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/69.jpg)
Ischaemic AP also facilitates re-entry
Re-entry occurs when wavelength of a propagating VBP is smaller than available pathlength • Wavelength equals conduction velocity
times refractory period (ω = θ x RP)
• Slowing θ (m/s) and reducing RP (s) reduces ω (m) and so facilitates re-entry
![Page 70: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/70.jpg)
Ischaemic AP also facilitates re-entry
Re-entry occurs when wavelength of a propagating VBP is smaller than available pathlength • Wavelength equals conduction velocity
times refractory period (ω = θ x RP)
• Slowing θ (m/s) and reducing RP (s) reduces ω (m) and so facilitates re-entry
![Page 71: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/71.jpg)
Ischaemia
Diastolic depolarisation causes partial inactivation of iNa
VPB more likely to initiate VF
AP upstroke slowed
θ slowed RP reduced
APD shortened
due to ↑IKATP and ∆INa/Ca
ω therefore reduced
Ischaemic AP facilitates re-entry
![Page 72: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/72.jpg)
VPB more likely to initiate VF
θ slowed RP reduced
APD shortened
due to ↑IKATP and ∆INa/Ca
ω therefore reduced
Ischaemic AP facilitates re-entry
Ischaemia
Diastolic depolarisation causes partial inactivation of iNa
AP upstroke slowed
![Page 73: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/73.jpg)
VPB more likely to initiate VF
θ slowed RP reduced
ω therefore reduced
Ischaemic AP facilitates re-entry
APD shortened
due to ↑IKATP and ∆INa/Ca
Ischaemia
Diastolic depolarisation causes partial inactivation of iNa
AP upstroke slowed
![Page 74: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/74.jpg)
Complexity increased by molecular pathology: consider acute ischaemia again
• Numerous chemicals accumulate or are depleted in the ischaemic region
• Some are proarrhythmic, some antiarrhythmic
• They have independent effects, and interact
• A drug may be proarrhythmic by blocking or facilitating generation or actions of these ‘mediators’
![Page 75: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/75.jpg)
Complexity increased by molecular pathology: consider acute ischaemia again
• Numerous chemicals accumulate or are depleted in the ischaemic region
• Some are proarrhythmic, some antiarrhythmic
• They have independent effects, and interact
• A drug may be proarrhythmic by blocking or facilitating generation or actions of these ‘mediators’
![Page 76: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/76.jpg)
Complexity increased by molecular pathology: consider acute ischaemia again
• Numerous chemicals accumulate or are depleted in the ischaemic region
• Some are proarrhythmic, some antiarrhythmic
• They have independent effects, and interact
• A drug may be proarrhythmic by blocking or facilitating generation or actions of these ‘mediators’
![Page 77: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/77.jpg)
Complexity increased by molecular pathology: consider acute ischaemia again
• Numerous chemicals accumulate or are depleted in the ischaemic region
• Some are proarrhythmic, some antiarrhythmic
• They have independent effects, and interact
• A drug may be proarrhythmic by blocking or facilitating generation or actions of these ‘mediators’
![Page 78: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/78.jpg)
Complexity increased by molecular pathology: consider acute ischaemia again
• Numerous chemicals accumulate or are depleted in the ischaemic region
• Some are proarrhythmic, some antiarrhythmic
• They have independent effects, and interact
• A drug may be proarrhythmic by blocking or facilitating generation or actions of these ‘mediators’
![Page 79: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/79.jpg)
X VF
X VF
Y VF
Z VF
Mediators may act in series, and in parallel, and may interact
Clements-Jewery, et al., Current Opinions in Pharmacology 9:146-153, 2009
![Page 80: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/80.jpg)
X Y Z VF
X VF
Y VF
Z VF
Mediators may act in series, and in parallel, and may interact
Clements-Jewery, et al., Current Opinions in Pharmacology 9:146-153, 2009
![Page 81: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/81.jpg)
And the role of a mediator may change as ischaemia progresses to infarction
Time after ischaemia onset (min) 0 30
Phase 1 Phase 2
Clements-Jewery, et al., Current Opinions in Pharmacology 9:146-153, 2009
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And the role of a mediator may change as ischaemia progresses to infarction
Time after ischaemia onset (min)
X
Y
Z
VF
X
VF
Y
VF
Z
VF
X
Y
Z
VF
X
VF
Y
VF
Z
VF
X
VF
X
VF
Y
VF
Y
VF
Z
VF
Z
VF
Y
VF
Y
VF
0 30
Phase 1 Phase 2
Y
Z
VF
Clements-Jewery, et al., Current Opinions in Pharmacology 9:146-153, 2009
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Putative proarrhythmic mediators
Other lipids
K+ Endothelin
PAF Palmitoylcarnitine
Angiotensin-II
Other prostaglandins
Leukotrienes Thromboxane A2 5-HT
Histamine Noradrenaline "X"
Aldosterone
Opioids
H+
VF
Clements-Jewery et al., Current Opinions in Pharmacology 9:81-83, 2009
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And some protective mediators
Prostacyclin
Magnesium
cGMP
Nitric oxide
Blood K+
(acts in uninvolved region)
Endocannabin- oids "X"
Adenosine
↓VF
Clements-Jewery, H. Curtis, MJ. In: MK Pugsley [Ed] Cardiac Drug Development Guide The Humana Press Inc., Totowa, NJ, USA, pp 203-226, 2003
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Evidence for mediator involvement: potassium Very rapid local increase during ischaemia
Hirche et al., 1980
![Page 86: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/86.jpg)
Concentration dependence studies
• Isolated rabbit heart (Langendorff perfusion)
• Epicardial cannulation of LAD
• Independent perfusion of LAD
• Local infusion of K+- supplemented Krebs (no ischaemia)
• Electrogram recorded from LAD and RV territory
Evidence for mediator involvement: potassium Local (intracoronary) injection of potassium: arrhythmogenic
![Page 87: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/87.jpg)
Concentration dependence studies
• Isolated rabbit heart (Langendorff perfusion)
• Epicardial cannulation of LAD
• Independent perfusion of LAD
• Local infusion of K+- supplemented Krebs (no ischaemia)
• Electrogram recorded from LAD and RV territory
Evidence for mediator involvement: potassium Local (intracoronary) injection of potassium: arrhythmogenic
![Page 88: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/88.jpg)
Concentration dependence studies
• Isolated rabbit heart (Langendorff perfusion)
• Epicardial cannulation of LAD
• Independent perfusion of LAD
• Local infusion of K+- supplemented Krebs (no ischaemia)
• Electrogram recorded from LAD and RV territory
Evidence for mediator involvement: potassium Local (intracoronary) injection of potassium: arrhythmogenic
![Page 89: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/89.jpg)
Concentration dependence studies
• Isolated rabbit heart (Langendorff perfusion)
• Epicardial cannulation of LAD
• Independent perfusion of LAD
• Local infusion of K+- supplemented Krebs (no ischaemia)
• Electrogram recorded from LAD and RV territory
Evidence for mediator involvement: potassium Local (intracoronary) injection of potassium: arrhythmogenic
![Page 90: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/90.jpg)
Concentration dependence studies
• Isolated rabbit heart (Langendorff perfusion)
• Epicardial cannulation of LAD
• Independent perfusion of LAD
• Local infusion of K+- supplemented Krebs (no ischaemia)
• Electrogram recorded from LAD and RV territory
Curtis, Cardiovasc Res 25: 1010-1022, 1991
Evidence for mediator involvement: potassium Local (intracoronary) injection of potassium: arrhythmogenic
![Page 91: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/91.jpg)
Curtis 1991
Regional K+ elevation can cause VF
![Page 92: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/92.jpg)
Arrhythmias most severe with 15 mM K+ and reduced by small K+ increase in adjacent bed
Curtis 1991
![Page 93: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/93.jpg)
How can you anticipate how a drug will affect rhythm?
• Test
• Test in all conditions in which the drug
will be used
• Ischaemia, infarction, heart failure .etc.
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How can you anticipate how a drug will affect rhythm?
• Test
• Test in all conditions in which the drug
will be used
• Ischaemia, infarction, heart failure etc.
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How can you anticipate how a drug will affect rhythm?
• Test
• Test in all conditions in which the drug
will be used
• Ischaemia, infarction, heart failure etc.
![Page 96: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/96.jpg)
How can you anticipate how a drug will affect rhythm?
• Test
• Test in all conditions in which the drug
will be used
• Ischaemia, infarction, heart failure etc.
![Page 97: Safety testing for antiarrhythmic drugs€¦ · Safety testing for antiarrhythmic drugs Michael J. Curtis PhD Cardiovascular Division, King’s College London, The Rayne Institute,](https://reader034.vdocuments.us/reader034/viewer/2022043008/5f9946223911fb756f6d7775/html5/thumbnails/97.jpg)
If you are not sure your drug is safe
• Then you don’t know that it is safe….
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If you are not sure your drug is safe
• Then you don’t know that it is safe….
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Drug for lethal indication
Drug for innocuous indication
Basis for decision to proceed to man
Basis for decision to not proceed to man
Incr
easi
ng a
mou
nt o
f dat
a
‘Good’ discovery
data
‘Bad’ safety
data
Key:
Increasing amount of time
1 3
2 4
Data required for Pharma decision making: the risk benefit continuum
Drug for lethal indication
Drug for innocuous indication Data
threshold for decision to
proceed
Data threshold for
decision to not proceed
Brit J Pharmacol 154:1282, 2008
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Reading Pugsley MK, Authier S, MJ Curtis Principles of Safety Pharmacology Br J Pharmacol 154: 1382-1399, 2008
Pugsley MK, Hancox JC, MJ Curtis Perception of validity of clinical and preclinical methods for assessment of torsades de pointes liability Pharmacology and Therapeutics 119: 115-117, 2008
Shah RR If a drug deemed ‘safe’ in nonclinical tests subsequently prolongs QT in phase 1 studies, how can its sponsor convince regulators to allow development to proceed? Pharmacology and Therapeutics 119: 215-221, 2008