Arrhythmias are one of the leading causes of death in the UK, most notably by ventricular fibrillation.

Arrhythmias can be the result of a variety of reasons such as acute myocardial infarction, heart
failure, inherited cardiac ion channel mutations, abuse of drugs and low potassium plasma levels.
The two main types of arrhythmias are ventricular premature beat and ventricular fibrillation.
Ventricular premature beat is mild and usually goes untreated, however ventricular fibrillation is
extremely dangerous and lethal.

The initiation of an arrhythmia is by origin of heartbeat somewhere other than the sinoatrial node
which contains the pacemaker cells. If heartbeat originates elsewhere in the heart it is due to
abnormal pace making called automaticity or failure of conduction at the end of the heartbeat, also
known as re-entry.

Abnormal automaticity can initiate ventricular tachycardia in myocardial infarction. This is because
there are few surviving purkinje fibres after an episode of acute MI so this region of surviving
purkinje fibres fire action potentials away from focus which causes abnormal automaticity induced
cardiac arrhythmias. Re-entry of action potentials in the heart is also another cause of arrhythmias
and is the main reason of arrhythmia persistence. It is caused by localised slow conduction due to
depolarisation, which results in the wave front splitting in 2 which can then circle round and re-enter
the original pathway. Injury and ischaemia result in localised slow conduction or blocked conduction.
Initially the conduction block is only in one direction so the normal wave cannot pass through the
damaged tissue. However the adjacent wave fronts to the conduction block find excitable tissue and
then propagates back up through the damaged tissue, and this is called slow retrograde conduction.
The wavefront then enters its original pathway. This slow retrograde conduction can result in a loop
of activity in a small section of tissue which can trigger a fast rhythm. Slow conduction also causes a
ragged wave front which leads to spiral wave re-entry.

Due to the two mechanisms that cause arrhythmias there are two potential targets of antiarrhythmic
treatment. However, because automaticity is what initiates arrhythmias and re-entry is what
maintains the arrhythmias it is more efficient to target inhibition of re-entry and preventing
conduction of the re-entry wave. There are four classes of drugs that were defined by the Vaughan
Williams antiarrhythmic drug classification. Class 1 was the Na+ channel blockers, class 2 were the B1
adrenoceptor antagonists and class 3 were the drugs delaying repolarisation and class 4 which were
the calcium antagonists. Class 1 is involved with the direct block of re-entry by localised blocking of
ion channels involved with depolarisation, this will result in the tissue being unexcitable. Class 1
drugs should target channels directly in the affected area to only block local conduction, however
most of them are not selective enough so cause slow conduction through all the tissue including
healthy tissue. The overall slowing of conduction can facilitate re-entry of wave fronts leading to
further arrhythmias. However there is a class 1 drug which is selective for ischaemic tissue meaning
it doesn’t produce effects in healthy tissue. This drug is lidocaine and it is highly selective for the
sodium channel and doesn’t increase risk of re-entry. Then there are the class 3 drugs which block
re-entry indirectly. Class 3 drugs block re-entry by blocking potassium channels and delaying
repolarisation which prolongs the refractory period so the ragged or split wave fronts encounter
fewer excitable cells meaning wave re-entry is blocked. They are called indirect drugs because there
is indirect block of Na channels and conduction. The effects of class 3 drugs need to be selective for
abnormal rhythm, they should not be active during normal rhythm and they do not need ischaemic
region selectivity.

The general rule for antiarrhythmic drugs is the prolong the QT interval so that the period of
excitability is shorter so there is lower chance of wave front re-entry which triggers arrhythmias.