Lec 26- Anti-dysrhythmic drugs Flashcards
The ECG
- P wave= atrial depolarization
- QRS= conduction through AV node and bundle
- T wave= ventricular repolarization
Refractory period
- Absolute refractory period, because all of the voltage gated channels are open there is no way of causing another action potential
- Relative refractory period- Depolarisation has just finished so gated channels have just closed and repolarisation is occurring meaning that we can excite the cells again but it has to be a large excitation
SA Node potentials
- Slow Ca2+ dependant upstroke
- K+- dependant repolarisation
- No resting membrane potential- because it is never resting -Looking at the AV node the K+ repolarisation is slower showing heart rate is based on the SA node
AV node
- Similar to SA node
- Latent pacemaker- if SA fails it can take over as pacemaker
- Slow Ca2+- dependant upstroke (L-type VGCC)
- Slow conduction (DELAY)
- K+- dependant repolarisation
Atrial muscle potential
- Resting membrane potential (-80 to -90) this is very negative, this is to allow a big Ca2+ gradient meaning lots of Ca2+ will enter atrial cells
- Rapid Na+ dependant upstroke
- Similar to SA node -Ca2+ Shoulder
- K-dependant repolarisation -Involved in conduction and contraction
Purkinje fibre action potential
- Another latent pacemaker
- Rapid Na+ dependant upstroke
- Ca2+ sensitive plateau
- K-dependant repolarisation
- Rapid conduction
Ventricular muscle action potential
- Resting membrane potential (-80 to-90)
- Rapid Na+- dependant upstroke
- Ca2+ sensitive plateau
- K- dependant repolarisation
Cardiac network organisation
-Cells connected by gap junction channels (NOT synapse)
The main dysrhythmias
Mechanism of dysrhythmogenesis
- 4 main mechanism
1) Afterdepolarisation (abnormal impulse generation)
2) Ectopic pace maker activity (Abnormal impulse generation)
3) Heart block (abnormal conduction)
4) Re-entry (abnormal conduction)
Early after depolarisation (EAD)
- AP becomes abnormally prolonged
- Allows L-type VGCC to recover from inactivation during plateau phase 2
- Leads to abnormally early depolarisation
Delayed afterdepolarisation
- ventricular problem
- Rasied Ca2+ in ventricular myocytes triggers depolarisation
- Seen in HF
- Often results in ventricular tachycardia
Delaid afterdepolarisation mechanism
- T tuble, depolarisation happens through Ca2+ channels within here
- Sarcoplasmic reticulum has ryanodine receptors which sense Ca2+ and open sarcoplasmic reticulum
- The cells become loaded with Ca2+ which changes the biochemistry within cell
- Phosphorylated Ca2+ and ryanodine receptors affecting the receptor
- Causes leak of Ca2+ from ryanodine, which increases background Ca2+
- This causes an increase in Ca2+ exporter proteins meaning greater efflux of Ca2+ -Leading to decreased contraction shown in HF
Delayed afterdepolarisation continued
- Increased Ca2+ levels activates transient inward current (TIC) which makes latent pacemaker become active (cause contraction and arrythmias)
- TIC is due to chronic increased Ca2+ level upreagulating Na+-Ca2+ exchanger
- Too much Na+ is pumped into the cell
Heart block
- Fibrosis or ischaemic damage to conducting system
- Usually AV node
- Atria and ventricles may beat independently
Ectopic pacemaker activity
- Pacemaker activity in parts of heart other than SA node and conducting system
- Caused by increased catecholamine action/depolarisation as can occur after ischemic action
- B1 adrenoreceptor agonist can increase rate of phase 4 depolarisation uncovering latent pacemakers
- If block SAN action, reveal latent pacemaker activity in AVN and Purkinje fibres
- SAN fires faster than AVN, and Purkinje, we get overdrive suppression of other pacemakers because there slower than SAN
- SA node normally fires faster than AVN, bundles of His and Purkinje fibres
- known as overdrive suppression of other pacemakers because SA node dominates pacemaker activity to higher rat of firing
Re-entry
- Re-excitation of previously existed heart muscle (Atrial or ventricular) that would normally be refractory
- Leads to constant cycle of excitation
- Can be caused by fibrosis or schematic damage to conducting system of muscle
- Can be purely ‘functional’- some myocytes may have abnormally slow conduction and rapid refractory period
- Can be thought of as electrical vortices ‘rotors’
- Requires a substrate (damage myocardium) and a trigger (ectopic firing)
Re-entry- mechanism
- Normally AP’s will travel through the hearth cells in 2 pathways (2 semi circles), the AP can’t carry on because of refractory periods
- In damaged heart if there is a serious block which stopes one of the pathways, the other AP will carry all the way round because there is no depolarisation and so refractory period
- This can lead to abnormal pathways around the heart
- If you allow slowing of the conduction then you can enter the relative refractory period (damage to cardiac muscle, change in ion channel expression)
- Anything that shortens width of AP so it is over faster and can be re-exited faster change to vortex activity
- Change in the size of the heart
Re-entry- atrial fibrosis
- Damage where there Are islands of muscle surrounded by collagen
- This will cause lots of independent electrical circuits giving rise to AF
- lots of little vortex’s
- bombarding the AV node with many signals
Electrical remodelling
- Abnormal activity or infarction causes changes in gene expression -Ion channels and gap junction proteins affected
- Can lead to permanent change in electrical function of a region of a heart
- connexin-43 is a gap junction protein, you give it a heart attack, the protein is then spread out across the myocytes after the infarction, this makes it unregulated giving irregular impulses -Same with K channels, they get spread out and distributed out throughout the myocytes after AMI meaning it gives abnormal activation and rhythm
Electrical remodelling continued- atrial tachycardia remodelling
- Atrial tachycardia remodelling (ART) -AF due to ECTOPIC focus causes increased Ca2+ loads
- Connexin-40 expression depressed
- L-type VGCC expression down regulated to depress [Ca2+]i (as a compensatory response)
- K+ channels conductance increased via gene changes
- Results- slower conductance; shorter phase 3= shorter RP -Slow conductance and short RP= ideal for re-entrance (vortex)
- Re-enternace causes AF so AF predisposes the heart to have more AF
Electrical remodelling- mechanism
-Prolonged Ca2+ entry causes remodelling by decreasing transcription and translation (GENE EXPRESSION) of ion channels -this leads to re-entry
Wolff-Parkinson-White syndrome
-W-P-W is a congenital abnormality associated with supra ventricular tachycardia (SVT) -
Involves an activation of ventricles that occurs earlier than expected called pre-excitation
-Occurs because of conductance of an atrial impulse not by means of normal conduction system, but via an extra atrioventricular (AV) muscular connection, termed accessory pathway, that bypasses the AV node
Anti-dysrhythmic drugs- sodium channel blockers
1) Sodium channel blockers -1A) quinidine, procainamide -1B) Lidocaine, phenytoin (Both A and B have widened QRS and prolonged QT waves) -1C) Flecainide, propafenone (Prolonged PR, widened QRS) -1(miscellaneous)= moricizine
Anti-dysrhythmic drugs
2) Beta blockers- propranolol (Prolonged PR wave, bradycardia) 3)K channel blockers- amiodarone (Prolonged QT) 4) Ca channel blocker- verapamil, diltiazem (Prolonged PR, bradycardia) 5)Miscellaneous- Adenosine, digoxin (prolonged PR, bradycaridas)
Class 1 ADD
- Block Na channels like local anaesthetics (bind a-subunit of Na channels)
- Slows the heart so used in tachycardia conditions
- 1a) intermediate dassociation from channel
- 1b) Fast dissociation
- 1c) Slow dissociation
- Use dependant channel block- they only block open or refractory channels (similar to anti-epileptic drugs)
Class 1
- 1a- quinidine, procainamide; the oldest drugs, slow phase 0 and prolong phase 4
- 1b- lidocaine: very fast association and dissociation with Na+ channels
+Bind during phase 0 without slowing phase 0
+By time AP reaches peak many channels are blocked
+Channels unblock in time for next AP, but a premature beat will be blocked by lidocaine still bound to Na+ channels
-1C- Flecanide, encainide: very slow association and dissociation +Reach steady-state level of block through the AP
+Reduce excitability, especially of re-entrant rhythms
+Reduce excitability of His bundle and Purkinje fibres markedly
Class 2 ADD
-B-adrenoreceptor antagonists (propranolol)
+sympathetic activation increases HR and force of contraction (FOC)
+B1- adrenoceptors increase Ca2+ level in myocytes= increased FOC -Increased Ca2+ makes pacemaker currents switch on earlier (steeper phase 4)
+Increased Ca2+ level activates transient inward current (TIC), which makes latent pacemakers become active
- B-adrenoceptor antagonists block all of these effects e.g. used in AF which is due to sympathetic activation
- B-adrenoceptor antagonists also slow AV node conduction and increase refractory period= slower rhythm
Class 3 ADD
- Prolong the cardiac AP (phase 3) by inhibiting K+ channels -Increase the refractory period, interrupt re-entrant tachycardia and ectopic pacemakers
- Prolong the QT interval
- Examples: amiodarone, sotalol NB- prolonged AQ intervals is itself dangerous and if Class 3 ADD are given with another drug which prolongs AQ, there is a risk of torsade de pointes
Torsade de pointes
-This is a ventricular rhythm which is incredibly irregular and will result in death if not treated
Class 4 ADD
- Block L-type Ca2+ channels, thus shortening phase 2
- Slow conductance in SVN and AVN where AP propagation depends on a slow Ca2+ current
- Terminate supraventricular tachycardia through partial Av node block
- Reduced Ca2+ entry blocks ectopic pacemakers through decreased afterdepolarisation -verapamil and diltiazem
Summary; where do different drugs intervene
0= class 1 1= 2= class 4 and class 2 3= class 3 and 1A 4= class 2
Clinical uses of ADD class 1
Class 1a (Disopyramide)
- Ventricular dysrhythmias
- prevention of recurrent AF due to vagal overactivity
Class 1B (IV lidocaine)
-treatment and prevention of VT and VF after AMI
Class 1C (flecanide)
- Prevention of paroxysmal AF
- Treatment of recurrent arrhythmias due to abnormal conducting pathways (WPW syndrome)
Clinical uses of ADD
Class 2 (propranolol, timolol)
- To reduce mortality after MI
- To prevent recurrent AF due to sympathetic overactivity
Class 3
- Amiodarone used to treat tachycardia associated with WPW syndrome
- Drug of last respired due to side effects
- Racemic sotalol combines class 2 and 3 effects, used in SVT, ventricular ectopic bears and short bursts of VT
Class 4 (verapamil)
- Prevention of paroxysmal SVT
- Reduction of ventricular rate in patients with AF
- as long as not WPW
- Termination of SVT (Obsolete, now use adenosine)
Unclassified ADD
- Atropine- used in sinus bradycardia
- Adrenaline- used in cardiac arrest
- Isoprenaline- used to relieve heart block
- Digoxin- used in AF
- CaCl2- used in VT due to hyperkalaemia
- MgCL2- used in VF, digoxin toxicity
Treatment with class I agents like flecanide is limited by inotropic effects and by ventricular pro arrhythmic effects- why
-Block I(Na) means slow conduction and increased refractoriness in the atrial = good same thing in damaged ventricles facilitates re-entry
Anti dysrythmic drugs
