1. Dr Laith M Abbas Al-Huseini
Antiarrhythmic Drugs
Dr Laith M Abbas Al-Huseini
M.B.Ch.B, M.Sc., M.Res., Ph.D.

2. Antiarrhythmics ???? In a textbook  Interesting but sedative.
Try it if you have insomnia
In the lecture  Confusion ??????????
As always
In the exam hall  Panic!
Don’t worry rarely asked but it
could happen!!!!!

3. Background
To function efficiently, heart needs to contract sequentially (atria, then ventricles) and in synchronicity
Relaxation must occur between contractions (not true for other types of muscle [exhibit tetany  contract and hold contraction for certain length of time])
Coordination of heartbeat is a result of a complex, coordinated sequence of changes in membrane potentials and electrical discharges in various heart tissues

4. Mechanisms of Cardiac Arrhythmias
Results from:
Faulty impulse initiation
Faulty impulse conduction
Combination of the above
Results in rate and/or timing of contraction of heart muscle that is insufficient to maintain normal cardiac output (CO)
To understand how anti-arrhythmic drugs work, need to understand electrophysiology of normal contraction of heart

5. Ventricular arrhytmia
ARRHYTHMIAS
Sinus arrythmia
Atrial arrhythmia
Nodal arrhythmia
(junctional)
Ventricular arrhytmia
SVT

6. Ventricular Arrhythmia
Ventricular arrhythmias are common in most people and are usually not a problem but…
VA’s are most common cause of sudden death
Majority of sudden death occurs in people with neither a previously known heart disease nor history of VA’s
Medications which decrease incidence of VA’s do not decrease (and may increase) the risk of sudden death treatment may be worse then the disease!

7. Electrophysiology-resting potential
A transmembrane electrical gradient (potential) is maintained, with the interior of the cell negative with respect to outside the cell
Caused by unequal distribution of ions inside vs. outside cell
Na+ higher outside than inside cell
Ca+ much higher outside than inside cell
K+ higher inside cell than outside
Maintenance by ion selective channels, active pumps and exchangers

8. ECG showing wave segments
Contraction of ventricles
Repolarization of ventricles
Contraction of atria

9. Rapid Repolarization phase
Early repolarization
Inactivated
Plateau phase
+30 mV 1 2
0 mV
Rapid Repolarization phase
Na+
Phase zero depolarization
open 3
Phase 4
resting membrane
Resting 4
-80 mV
RMP IS -90 MV
Cardiac bounded by a lipoprotein membrane which has receptor channels crossing it
WHEN AN ATRIAL OR VENTRICULAR CELL RECIEVES An action potential it starts depolarising in response to it..and sodium starts entering it
Intracellular negativity starts diminishing
When such depolarisation reaches a threshold potential, the sodium channels open abruptly
Na enters cell in large quantities
CELL MEMBRANE ACTION POTENTIAL CHANGES FROM -90 TO ALMOST +30MV
Phase 0: rapid depolarisation…fast selective inflow of na ions
During latter part, ca ions also enter the cell via na channels
Frther in phase 1 and 2 ca ions enter thru slow ca channels
THE CONFORMATION OF THE SODIUM CHANNELS HENCE CHANGES TO INACTIVE STATE
The ca which enters the cell in dis manner causes release of ca from sarcoplasmic reticulumraising the conc of ca within the cells
This intracellular free ca interacts with actin myocin system and causes contraction of heart
Afetr this, phase 1: short rapid repolarisation due to beginning of outflow of potassium and entry of cloride ions into the cells, MEMBRANE CHARGE CHANGES FROM +30 TO ALMOST 0 MV IN VERY SHORT TIME
Phase 2 : prolonged plateau phase.. Balance bw ca enterin the cell and k leavin the cell..VOLTAGE SENSITIVE SLOW l type CA CHANNELS OPEN …SLOW INWARD CA CURRENT BALANCED BY SLOW OUTWARD K CURRENT..DEPOLARISATION = REPOLARISATION
Phase 3 : rapid repolarisation.. CA CHANNELS CLOSE…K CHANNELS OPEN..Contimued extrusion of k…RESUMES INITIAL NEGATIVITY
FROM PHASE 0 TO 3 THERE HAS BEEN A GAIN OF NA AND A LOSS OF K ..THIS IS NOW REVERTED AND BALANCED BY NA K ATPASE
Phase 4: resting phase..ELECTRICALLY STABLE… Ionic reconstitution of cell is reachieved by na k exchange pump
RMP MAINTAINED BY OUTWARD K LEAK CURRENTS AND NA CA EXCHANGERS
The cycle is then repeated
Inactivation gates of sodium channels in resting membranes close over the potential range of -75 to -55mv
Cardiac sodium channel protein shows 3 different conformations
Depolarisation to threshold voltage results in opening of the activation gates of sodium channel thus causing markerdly increased sodium permeability
Brief intense sodium current , conductance of fast sodium channel suddenly increases in response to depolarising stimulUs
Very large influx of na accounts for phase 0 depolarisation
Clusure of inactivation gates result
Remain inactivated till mid phase 3 to permit a new propagated response to external stimulus…refractory period..
Cardiac calcium channels are L type
Phase 1 and 2 : turning off nodium current, waxing and waning of calcium curent, slow development of repolarising potassium current, calcium enters ..potassium leaves..
Phase 3: complete inactivation of sodium and calcium currents and full opening of potassium
2 types of main potassium currents involved in phase 3 : ikr and iks
Certain potassium channels are open at rest also…”inward rectifier” channels
In addition there are 2 energy requiring exchange pumps in cardiac myocyte cell membrane…na k exchange pump…and and na-ca exchange pump
Normally na ions concentrated extracellularly and vice versa for k cions
Thus have a tendency odf diffusion along concentration gradient
This diffusion is opposed by na k pump
This pump operates contimuously and does not switch on and off during action potential of cardiac cells
-90 mV
Ca++ K+ K+
Na+ K+ K+
OUTSIDE
Na+
Ca++
ATP
MEMBRANE
INSIDE K+
Na+

10. Cardiac Action Potential
Divided into five phases (0,1,2,3,4)
Phase 4 - resting phase (resting membrane potential)
Phase cardiac cells remain in until stimulated
Associated with diastole portion of heart cycle
Addition of current into cardiac muscle (stimulation) causes
Phase 0 – opening of fast Na+ channels and rapid depolarization
Drives Na+ into cell (inward current), changing membrane potential
Transient outward current due to movement of Cl- and K+
Phase 1 – initial rapid repolarization
Closure of the fast Na+ channels
Phase 0 and 1 together correspond to the R and S waves of the ECG

11. Cardiac Action Potential (con’t)
Phase 2 - plateau phase
sustained by the balance between the inward movement of Ca+ and outward movement of K +
Has a long duration compared to other nerve and muscle tissue
Normally blocks any premature stimulator signals (other muscle tissue can accept additional stimulation and increase contractility in a summation effect)
Corresponds to ST segment of the ECG.
Phase 3 – repolarization
K+ channels remain open,
Allows K+ to build up outside the cell, causing the cell to repolarize
K + channels finally close when membrane potential reaches certain level
Corresponds to T wave on the ECG

12. Causes of arrhythmias Cardiac ischemia
Excessive discharge or sensitivity to autonomic transmitters
Exposure to toxic substances
Unknown etiology

13. Anti-arrhythmic drugs
Biggest problem – anti-arrhythmics can cause arrhythmia!
Example: Treatment of a non-life threatening tachycardia may cause fatal ventricular arrhythmia
Must be vigilant in determining dosing, blood levels, and in follow-up when prescribing anti-arrhythmics

14. Classification of anti-arrhythmics (Vaughan-Williams-Singh) (based on mechanisms of action)
Class I – Na+ channel blockers
Subclass IA
Increased duration of action potential and Prolong repolarization
Includes
Quinidine – 1st anti-arrhythmic used, increases refractory period, treats both atrial and ventricular arrhythmias, maintains sinus rhythm in patients with atrial flutter or atrial fibrillation, prevents recurrence of ventricular tachycardia or VF.
SE: Diarrhea, thrombocytopenia, cinchonism , skin rashes, QT-interval prolongation, torsades de pointes, HOT and drug interactions.

15. Classification of anti-arrhythmics
Subclass IA (con’t)
Procainamide - increases refractory period, uses for supraventricular and ventricular arrhythmias.
SE: less anticholinergic effects, cardiac adverse effects like quinidine, can cause SLE not recommended > 6 months
Disopyramide – extended duration of action, well absorbed orally, negative ionotropic action, used only for treating ventricular arrhythmias,
SE: prominent anticholinergic actions and heart failure.

16. Classification of anti-arrhythmics
Subclass IB
Shortened depolarization & Decreased action potential duration
Includes
Lidocane (also acts as local anesthetic) – blocks Na+ channels mostly in ventricular cells, extensive 1st pass metabolism.
Used in arrhythmias associated with digitalis toxicity, MI and
open heart surgery. SE: CNS like: drowsiness and convulsions.
Mexiletine - oral lidocaine derivative, similar activity and uses
Phenytoin – anticonvulsant and also works as anti-arrhythmic similar to lidocane
Tocainide – Structurally similar to lignocaine but can be administered orally. Serious non cardiac side effects like pulmonary fibrosis limits its use.

17. Classification of anti-arrhythmics
Subclass IC
Strong Phase 0 depression & No effect of depolarization
No effect on action potential duration
Includes
Flecainide (initially developed as a local anesthetic)
Slows conduction in all parts of heart, also inhibits abnormal automaticity
Potent blocker of Na+ & K+ channels
Used in life-threatening arrhythmias like sustained VT
Propafenone
Slows conduction
Weak β–blocker and also some Ca2+ channel blockade
Reserve drug for persistent ventricular arrhythmias
Side effects: metallic taste, constipation and is proarrhythmic!

18. Classification of anti-arrhythmics
Class II – β–adrenergic blockers
Based on two major actions
1) blockade of myocardial β–adrenergic receptors
2) Direct membrane-stabilizing effects related to Na+ channel blockade
Includes
Propranolol
causes both myocardial β–adrenergic blockade and membrane-stabilizing effects
Slows SA node and ectopic pacemaking
Can block arrhythmias induced by exercise or apprehension
Other β–adrenergic blockers have similar therapeutic effect
Metoprolol, Nadolol, Atenolol, Acebutolol, Pindolol, Sotalol, Timolol, Esmolol

19. Classification of anti-arrhythmics
Class III – K+ channel blockers
Cause delay in repolarization and prolonged refractory period
Includes
Amiodarone – Iodine containing long acting drug acts by
blocking K+ channels. Slow onset with t1/ days.
Used for SVT and VT. SE: cardiac e.g. bradycardia and A-V
block, reversible pulmonary fibrosis and goiter.
Bretylium – first developed to treat hypertension but found to
also suppress resistant VF associated with myocardial
infarction. SE: orthostatic HOT.
Ibutilide – slows inward movement of Na+ in addition to
delaying K+ influx. indicated for chemical cardioconversion
of AF and atrial flutter of a recent onset to sinus rhythm. SE: can
lead to arrhythmia and MI.
Dofetilide - prolongs action potential by delaying K+ efflux
with no other effects. Use in AF to convert or maintain sinus
rhythm. May cause QT prolongation.

20. Classification of anti-arrhythmics
Class IV – Ca2+ channel blockers
slow rate of AV-conduction in patients with atrial fibrillation
Includes
Verapamil – blocks Na+ channels in addition to Ca2+; also slows SA node in tachycardia
Diltiazem

21. Other anti-arrhythmics
Adenosine:
Purine nucleoside having short and rapid action
IV suppresses automaticity, AV conduction and dilates coronaries
Drug of choice for Paroxysmal supraventricular tachycardia (PSVT)
Adverse events: Nausea, dyspnoea, flushing, headache. CI in asthma.
Atropine: Used in sinus bradycardia
Digitalis: Atrial fibrillation and atrial flutter
Magnesium SO4: digitalis induced arrhythmias

22. Drugs of choices S. No Arrhythmia Drug 1 Sinus tachycardia Propranolol2
Atrial extrasystole
Propranolol, 3
AF/Flutter
Esmolol, verapamil ,digoxin 4
PSVT
Adenosine ,esmolol 5
Ventricular Tachycardia
Lignocaine , procainamide , Amiodarone 6
Ventricular fibrillation
Lignocaine, amiodarone 7
A-V block
Atropine , isoprenaline

23. Extra information

24. Impulse generation and transmission

25. Disorders of impulse formation
No signal from the pacemaker site
Development of an ectopic pacemaker
May arise from conduction cells (most are capable of spontaneous activity)
Usually under control of SA node  if it slows down too much conduction cells could become dominant
Often a result of other injury (ischemia, hypoxia)
Development of oscillatory after depolariztions
Can initiate spontaneous activity in nonpacemaker tissue
May be result of drugs (digitalis, norepinephrine) used to treat other cardiopathologies

26. Disorders of impulse conduction
May result in
Bradycardia (if have AV block)
Tachycardia (if reentrant circuit occurs)
Reentrant circuit

27. Pacemakers
Surgical implantation of electrical leads attached to a pulse generator
Over 175,000 implanted per year
Leads are inserted via subclavicle vein and advanced to the chambers on the vena cava (right) side of the heart
Two leads used, one for right atrium, other for right ventricle
Pulse generator containing microcircuitry and battery are attached to leads and placed into a “pocket” under the skin near the clavicle
Pulse generator sends signal down leads in programmed sequence to contract atria, then ventricles
Pulse generator can sense electrical activity generated by the heart and only deliver electrical impulses when needed.
Pacemakers can only speed up a heart experiencing bradycardia, they cannot alter a condition of tachycardia