Physiological basis of action of antiaarhythmic drugs

There are 4 classes of antiarrhythmic drugs depending on which channels or receptors they block.

Class I drugs block sodium channels
Class II drugs are beta blockers
Class III drugs block K+ channels and
Class IV drugs are calcium channel blockers

 We should know first where on the cardiac action potentials, different classes of antiarrhthymic drugs will act…

Class I antiarrhythmic drugs: Sodium channel blocker i.e class I anti arrhythmic drugs increase the threshold for phase 0 of contractile cell action potential increases, …it also decreases the slope of phase 0. 
In class I there are 3 subclasses of drugs..
   There are different states of sodium channels …closed, open and inactivated.
        Class Ia drugs block sodium channels in open state
        Class Ib drugs block sodium channels in inactivated state… most important effect on already depolarised tissue as seen in ischemia
        Class Ic drugs block sodium channels in open state and also prolong the recovery time of channels 

Class II antiarrhythmic drugs: act on phase 4 of pacemaker action potential

Class III drugs i.e potassium channel blockers will act on the repolarization phase and prolong the duration of action potential

Class IV drugs i.e L type calcium channel blockers will act in phase 0 of action potential of pacemaker cells.

Tachyarrhythmias may occur either due to
Enhanced automaticty
Triggered automaticity
Reentry

Physiological basis of treatment of arrhythmias

 1. Enhanced automaticity: In arrhythmias due to enhanced automaticity, the slope of the prepotential becomes steeper may be due to enhanced sympathetic activity or the maximum diastolic potential becomes less negative


Basically to treat these arrhythmias you will want to decrease the rate of generation of impulse either by:
 a. decreasing the slope of this drift of phase 4 : beta blockers (Class II)
 b. Increasing the threshold for excitation… so phase 0 will start much above than usual threshold: Class IV for pacemaker cells or class I for contractile cells
c. Prolonging action potential duration: by potassium channel blockers
d. Increasing the negativity of RMP: by acetylcholine and adenosine

Mechanisms of cardiac arrhythmias | Fundamentals

The arrhythmias are an abnormality in rate and rhythm of heart.

They may be either bradyaarhythmias or tachyarrhythmias.

There are 3 basic mechanisms by which tachyarrhythmias may occur 
1. Enhanced automaticity 
2. Triggered automaticity 
3. Reentry 

 Enhanced automaticity 

This type of arrhythmias may poccur due to abnormality in the pacemaker cells. Enhanced automaticity may occurif there is increase in slope of the pacemaker potential or the Resting membrane potential becomes less negative. This may happen in case of excessive sympathetic stimulation and mild kyperkalemia

Triggered automaticity 

This occurs in cells which are not having automaticity but automaticy is being triggered by someting. It involves due to generation of after-depolarization
After depolarizations are of two types:

Early after depolarization which occurs during the repolarization phase of cardiac action potential. It occurs whenever action potential gets prolonged. QT interbal prolonation is a sign of prolonationof action potential duration and thus it may lead to early after depolarization and hence predisposes a person to arrhythmias.

Delayed after depolarization occur after the repolarization ends i.e in phase 4 of cardiac action potentia. These after depolarization can lead to generation of impulse before the normal impulse reaches the contractile cells.

Reentry circuits 

Third mechanism for arrhythmias is reentry or movement of an impulse in a circus movement. If an impulse has 2 paths through which it can pass and these conducting paths differe electrically such that one is fast conducting path and th eother is slow conducting path, in that case of renetry of impulse may occur. Reeentry may occur due to an anatomical defect (anatomical reentry) or may be due to functional difference in the electrical propery of the cells (functional reentry).

Wolff-Parkinson syndrome is a type where arrhthmias occur due to anatomical reentry.

Absolute and Relative Refractory period in cardiac muscle cells | States...

The absolute and relative refractory period

Refractory means the cells are unresponsive to stimulus. It may be either absolute or relative.

In the absolute refractory period, the cells are unresponsive to any stimulus no matter how strong it is.

In the relative refractory period, the cells are unresponsive to threshold stimulus but respond to a suprathreshold stimulus that is a higher strength of the stimulus is required than usual to stimulate the cell.

Refractory period occurs due to different states of sodium channels. 

States of sodium channels 

Sodium channels can be in 3 states:
1. Closed (at RMP)
2. Open (as depolarization occurs, lot o channels open at threshold)
3. Inactivated: From the open state, channels become inactivated.

Channels go back to the closed state from the inactivated state as repolarization occurs. At RMP, all become closed. These channels can only open from the closed state and not from the inactivated state. So for the next action potential to occur, channels should go back to the closed state. So till the time, channels are in an inactivated state, the next action potential cannot occur.

Cause of Absolute/Effective refractory period 

From phase 0 to half of phase 3 of the cardiac action potential is the absolute refractory period. It occurs because sodium channels are in the inactivated state during this time.

Cause of relative refractory period 

After half of phase 3 to RMP is the relative refractory period. It occurs because some channels have changed their state to closed state so few channels are available which can open.


 

Ventricular action potential | Ionic basis | Cardiovascular physiology

 Phases of ventricular action potential and its ionic basis

Stable resting membrane potential (phase 4)

Phase of rapid depolarisation (phase 0): Due to opening of voltage gated sodium channels and entry of sodium inside the cells

 Phase of early rapid repolarisation (phase 1): Due to opening of voltage gated potassium channels and exit of potassium outside the cells

 Plateau phase (phase 2) where there is hardly any change in potential: Both voltage gated potassium channels and voltage gated calcium channels are open. Potassium moves out of the cells while calcium moves into the cells. This balances the potenetial and the potential is recorded as a plateau.

Phase of delayed rapid repolarization (phase 3): Calcium channels close while potassium channels remain open. Potassium continues to moves out of the cells causing repolarization.

Total duration of ventricular action potential is approximately 250 ms.


 

Mechanism of change in heart rate by autonomic nervous system (chronotropy)

Sympathetic and parasympathetic stimulation affect the nodal action potential to change the heart rate

Sympathetic stimulation increases heart rate

Stimulation of sympathetic system releases noradrenaline which binds with beta 1 receptor. Due to this G alpha S gets activated and it causes activation of adenyl cyclase which in turn leads to formation of cAMP. The HCN channels which are responsible for prepotential.. their opening and closing is affected by the concentration cAMP inside the cells. When cAMP increases, the probability of opening of these channels increases. So, in short sympathetic activation leads to more opening of HCN channels, causing more entry of sodium inside the cells leading to faster change in the potential towards threshold. So there is a change in the slope of the prepotential which becomes steeper and due to this SA node generates more number of impulses in the same time and hence it increases heart rate.

Parasympathetic stimulation decreases heart rate

Acetylcholine released from vagus causes activation of G i type of proteins which inhibits adenyl cyclase leading to decreased production of cAMP. Thus is leads to decreased opening of HCN channels and also T type channels. Hence the slope of pre-potential decreases leading to decrease in the number of impulses generated and hence decreased heart rate. Parasympathetic activation has one more effect. It delays the closure of these potassium channel which are responsible for phase 3. So more potassium moves out which leads to hyperpolarization. that is more negative maximum diastolic potential.


 

Pacemaker potential I SA node action potential I Cardiovascular physiology

In this video, we differentiate between SA node action potential and ventricular action potential. 

 SA node action potential is responsible for automaticity of heart. It consists of 3 phases : phase 4, phase 0 and phase 3.

Phase 4 is due to: Hyperpolarization gated cyclic nucleotide channels (HCN channels) and T type voltage gated calcium channels.

Phase 0 is due to opening of L type voltage gated calcium channels and entry of calcium inside the cells

Phase 3 is due toopening of voltage gated potassium channels and exit of potassium from the cells.

(Where are phases 1 and 2 ?) 😮

Phase 4 is also known as prepotential or pacemaker potential. The slope of the phase 4 determines the number of impulses which are generated in 1 minue. Steeper slope means more impulses, less steep slope means less impulses.

 

Waves, 3 segments and 5 intervals in ECG (EKG) | ECG basics

ECG Waves, 3 segments and 5 intervals in ECG (EKG) | ECG basics 

ECG waves: P waves, QRS complex, T wave

Segments: Do not include waves (PR segment, ST segment and TP segment )

Do you know the importance of TP segment ? It is used to find whether ST segment elevation or depression is present or not..

Intervals: PR interval, ST interval, QT interval, RR interval (used to calculate heart rate in case of sinus rhythm), P-P interval (used to calculate atrial rate in case sinus rhythm is not present)