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Title: Anti-arrhythmic agents/ some old, some new
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.
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Arrhythmias
Arrhythmia - 1 region of the heart out of step with another
Normal Heart beat:
Starts in SA node (dispersed zone of pacemaker cells)
If heart beat originates elsewhere, result of:
Abnormal pacemaking (automacity) (ectopic foci - other pacemaker areas)
Failure of conduction to stop at the end of a heart beat (reentry)
Caused by localised slow conduction
Wave-front meander and become ragged
Wave-front may split into two
May then circle around and re-enter its original pathway
Re-entry can initiate an arrhythmia if injury (ischaemia) causes localised slow conduction
Middle diagram: Slower wave working through injury can re-activate the faster 2 waves
which in turn can reactivate the slower wave (after their respective refractory periods)
Atrial Arrhythmias
---> 50-100 bpm
---> 250-350 bpm
---> 350-600 bpm
Ventricular Arrhythmias
Ventricular Tachycardia can lead to Ventricular Fibrillation
Fibrillation doesn't allow blood to flow properly --> end organ hypoxia and ischaemia etc
...
in anorexia)
Autonomic dysfunction
Parasympathetic/Sympathetic overdrive
Therapeutic (e
...
digitalis) and abuse drugs
HERG channel (Human Ether Agogo related Gene) - has a large open outer protein
mouth
Lots of drugs can block this and cause late repolarisation
Inherited mutations of cardiac ion channels
HERG mutated in 20% of arrhythmias (inherited)
Fever
Present agents (drugs) have side effects that limit use for arrhythmias
Paradoxical capacity to create more serious electrical disturbances
Unmet need for safer and more effective agents
Review emerging targets to develop new Anti-Arrhythmic agents
Targeting the pacemaker ie the SA node
...
Overcome existing channelopathies:
Novel Mechanisms I
Targeting the pacemaker (i
...
the SA
node)
Blockers of I(f) (HCN)
Ivabradine, Zatebradine
4 types of HCN (encodes I(f))
Increase HCN expression -->
Increase rhythm
Increase coronary perfusion time by
slowing heart down --> decreases
ischaemia risk and increases diastole
time
Region limited therapy - atrial fibrillation
Atrial fibrillation
Present in 2% population
Increases incidence in elderly
Can precipitate into ventricular fibrillation
Increased risk of pulmonary, coronary and cerebral
embolism
Present therapy:
Prevents re-entry by prolonging the refractory period
Blockers of I(kr) = ventricles - so pro-arrhythmogenic
Right diagram:
Na+ channel open - I(Na)
Calcium influx - I(CaL)
I(Kr) - these channels are also present in the ventricles (so is difficult as drugs can
affect ventricles as well)
Novel Mechanisms II
Atrial Repolarisation Delaying agents
Right diagram:
Light blue = things that aren't in both
Red = things only found in the atrium
Red Boxes = possible drug targets just for
atria (only) AP delay
Novel Mechanisms IIa
Targeting I(KUR) - see above diagram
Blocking I(KUR) will delay early
repolarisation
Phase 2 more depolarised
Greater activation of I(Kr) leading to rapid
repolarisation
AP duration will stay the same
NIP-141
High affinity for I(KUR) but also I(TO)
XEN-D0101
High affinity for I(KUR)
Efficacy of a pure Kv1
...
1/3
...
e
...
Discuss
...
Describe conventional treatment rationales for arrhythmias and why new strategies are
required
Title: Anti-arrhythmic agents/ some old, some new
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.
Description: This is a lecture on Anti-arrhythmic agents/ some old, some new as part of the St. Georges University Biomedical Science course in the Human Cardiovascular and Respiratory Pharmacology module.