Lignocaine blocks activated & inactivated Na gates mainly & thus mainly effects abnormally depolarised cells (eg. ischaemic foci) & rapidly firing cells where there is insufficient time in diastole for removal of drug from receptor → decr. automaticity of abnormal foci with minimal effect on normally repolarised cells.
ie. don't use phenytoin to Mx local anaesthetic induced convulsions as similar actions!!
If a drug exerted minimal effect on a quiescent fibre at normal resting potential, but could block a significant fraction of channels during one action potential, with slowing of the conversion from inactive to resting state, then channels would accumulate in the inactive state during repeated action potentials until a steady state was obtained with a decr. no. of channels open;
eg. all LA antiarryhythmics, some Ca-blockers;
"Tonic" Blockade:
Some drugs appear to cause “tonic” (ie. not use-depend.) block through interaction with channels in the resting state;
NB. a decr. in transmembrane voltage ⇒ inactivation of fast channels, thus the effects of drugs on iNa are enhanced in depolarised cells;
How anti-arrythmics are thought to work:
First, a brief outline of the cardiac muscle action potential:
There are 2 fundamentally different types of AP seen in mammalian heart:
1) Myocardium:
Initial rapid activation of inward movement of Na ions due to opening of the m gates of the fast Na channel ⇒ “activated” opened channel
⇒ initial up steep upslope in AP approaching E(Na) - phase 0.
Immediately on depolarisation, the h gates of the Na channel close ⇒ “inactivated” closed channel
⇒ brief downslope in AP - phase 1.
Activation of an inward flow of Ca via slow L-type calcium channels
⇒ maintenance of depolarised state → plateau of AP - phase 2.
⇒ influx of Ca activates the contractile mechanism
(contraction in proportion to Ca influx)
Gradually, the slowly opening K rectifying channels open allowing outflow of K, while the Ca channels slowly close
⇒ return AP towards resting membrane potential - phase 3
The final stage is electrical diastole - phase 4 with the negative resting membrane potential being maintained by:
K permeability » Na or Ca permeability ⇒ E(memb) approaches E (K)
2Na(out) - K(in) ATPase
3Na(in) - 1Ca(out) anti-port
2) Pacemaker cells of SA & AV nodes (Purkinje cells are also capable of this behaviour):
Phase 0 is ~100x slower because it is produced entirely by slow inward Ca flux.
⇒ very slow conduction velocity through sinus & AV nodes
⇒ delay between atrial & ventric. contraction to allow adequate ventricular filling to occur.
Phase 2 is indistinct & blends into phase 3 which is as for myocardium.
Phase 4 is very different due to complex & controversial mechanisms which involve a combination of steadily decling outward K flux & an increasing slow diastolic inward 'pacemaker' current probably mainly due to Na ions:
it exhibits spontaneous depolarisation (the prepotential) which eventually reaches 'threshold' voltage & fires off another AP.
⇒ automaticity
Cardiac Arrhythmia Mechanisms:
All tachyarrhythmias arise by one of a very few basic mechanisms which can be grouped into 2 groups (both groups may occur together):
A) Abnormal impulse generation:
All tend to be enhanced by hypoxaemia, ischaemia, catecholamines, hypokalaemia & hypomagnesaemia. Whether the resulting arrhythmia is a SVT}} or [[C_VT|VT depends only on the site of the focus.
i) pacemaker-type automaticity (eg. in ectopic foci such as Purkinjes)
ii) early after-depolarisations (EAD's):
are thought to be due to cyclic uptake & release of Ca ions from sarcoplasmic reticulum, leading to fluctuations in K permeability
non-sedating antihistamines esp. with erythromycin &/or people with hereditary prolonged QT syndrome
iii) delayed after-depolarisations (DAD's):
these may occur in any condition that causes intracellular Ca overload & thus causes diastolic depolarisations early in phase 4 due to the 3Na(in) - 1Ca(out) antiport attempting to expel the XS calcium ions:
ie. digitalis toxicity, ischaemia, catecholamines, hypokalaemia, hypomagnesaemia, fast HR
if these depolarisations reach threshold then they will cause triggered PVC's (bigeminy) which may lead to further Ca overload & a self-perpetuating process ⇒ tachycardia
AMI → central necrotic area surrounded by rim of slowly
conducting ischaemic cells ⇒ macro circuit
electrical disparity in ischaemic terminal Purkinjes ⇒ micro circuit
b) depolarising wave front must never 'catch up' to the repolarising tail, this depends upon:
duration of refractoriness in circuit (~APD)
anatomical length of circuit (eg. especially in dilated chambers such as LA ⇒ AF)
conduction velocity - usually very slow due to:
pacemaker-type phase 0, &/or
depressed Na current potentials
How drugs may abolish arrhythmias:
1) Automatic arrhythmias via depression of automaticity:
Class I drugs:
block the small but significant inward Na current which persists beyond phase 0 & 1.
lignocaine in particular, depresses automaticity of abnormally depolarised (eg. ischaemic) cells but with little effect on normally repolarised cells which become free of drug during diastole.
Class II & IV drugs:
depress inward Ca current during phase 4 & also reduce tendency to intracellular Ca overload & thus reduces risk of DAD's.
Class III drugs:
class III effect in its own right would have little effect except by prolonging the overall cycle length somewhat.However, amiodarone and sotalol have other actions that may decrease automaticity:
The ideal anti-reentry agent would simultaneously accelerate conduction velocity & prolong the refractory period, thus shortening or abolishing the 'window' or excitatory gap between the advancing wavefront & the refractory tail.
Unfortunately, none of the drugs do both & most slow conduction velocity
(class Ic » class Ia » classes Ib,II) but this may be adequately offset by the drugs ability to prolong ERP.
Drugs that prolong APD & ERP & slow cond. velocity:
Class Ia & III ⇒ may revert or may slow tachycardia & widen the excitatory gap ⇒ easier induction of tachycardia
Drugs that decrease APD & ERP with minimal slowing of cond. velocity:
Class Ib ⇒ minimal effectiveness in reverting VF
Drugs that have minimal effect on APD or ERP but slow cond. velocity ++:
Class Ic ⇒ may be pro-arrhythmic wrt re-entry
Class IV agents are a special case as they are of great value in abolishing re-entrant circuits dependant on inward Ca current - most SVT's but few VT's.