Pharmacology of

anti-arrhytmic drugs

Dr. DATTEN BANGUN MSc,SpFK

Dr. HASANUL ARIFIN

Bagian Farmakologi dan Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara
 What is an Arrhythmia ?

• Irregular rhythm
• Abnormal Rate
• Conduction abnormality
 What causes an arrhythmia?
• Changes in automaticity of the PM
• Ectopic foci causing abnormal APs
• Reentry tachycardias
• Block of conduction pathways
• Abnormal conduction pathways (WPW)
• Electrolyte disturbances and DRUGS
• Hypoxic/Ischaemic tissue can undergo
spontaneous depolarisation and become an
ectopic pacemaker
Normal heartbeat and atrial arrhythmia

Normal rhythm Atrial arrhythmia

AV septum
 Definition of arrhythmia
• Cardiac arrhythmia is an abnormality of the
heart rhythm
• Bradycardia – heart rate slow (<60 beats/min)
• Tachycardia – heart rate fast (>100 beats/min)

Clinical classification of arrhythmias

= Heart rate (increased/decreased)
= Heart rhythm (regular/irregular)
= Site of origin (supraventricular / ventricular)
= Complexes on ECG (narrow/broad)
 Mechanisms of arrhythmia
production
• Re-entry (refractory tissue reactivated due to
conduction block, causes abnormal continuous
circuit. eg accessory pathways linking atria and
ventricles in Wolff-Parkinson-White syndrome)
• Abnormal pacemaker activity in non-
conducting/conducting tissue (eg ischaemia)
• Delayed after-depolarisation (automatic
depolarisation of cardiac cell triggers ectopic beats,
can be caused by drugs eg digoxin)
 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 “ “ “ “
– K+ higher inside cell than outside

• Maintenance by ion selective channels, active pumps and

exchangers
Differences between nonpacemaker and pacemaker
cell action potentials
• PCs - Slow, continuous depolarization during rest
• Continuously moves potential towards threshold for a new
action potential (called a phase 4 depolarization)

Spontaneous
depolarisation
 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
 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
 Contraction of
ECG (EKG) ventricles
showing
wave segments

Repolarization of
Contraction
ventricles
of atria
Cardiac Na+ channels
 Therapeutic overview
• Na+ channel blockade
• β-adrenergic receptor blockade
• Prolong repolarization
• Ca2+ channel blockade

• Adenosine
• Digitalis glycosides
 Vaughan-Williams Classification
Class Mechanism Example

I Na channel blockers Lignocaine

Membrane Stabilisers
II Beta Blockers Metoprolol

III K channel blockers Amiodarone

IV Ca channel blockers Verapamil

Other Digoxin. Adenosine.

MgSO4. Atropine
Electrophysiological effects

Sodium Channel Rate of

Drug Class Example Affinity Dissociation
Class IA Quinidine Open > inactivated Slow

Class IB (Affect Lidocaine Inactivated > open Rapid

ischemic tissues)
Class IC (Affect Flecainide Open > inactivated Very slow
ventricular conduction)
 Classification of antiarrhythmics
(based on mechanisms of action)
• Class I – blocker’s of fast Na+ channels
– Subclass IA
• Cause moderate Phase 0 depression
• Prolong repolarization
• Increased duration of action potential
• Includes
– Quinidine – 1st antiarrhythmic used, treat both
atrial and ventricular arrhythmias, increases
refractory period
– Procainamide - increases refractory period but
side effects
– Disopyramide – extended duration of action, used
only for treating ventricular arrthymias
Kinidin
- prototip dari klas I A
Adalah d – isomer dari kinin, memiliki semua
sifat kinin seperti : - anitimalaria
- antipiretik
- oxitosik
- skeletal muscle relaxant
Kinidin juga memiliki efek antikholinergik, yang jelas
nyata pada awal terapi atau pada dosis rendah. Setelah
tercapai konsentrasi terapi  efek langsug(direct effect )
yang bekerja . Kinidin juga memiliki efek MSA
(membrane stabilizing activity)  sifat “ anestesi lokal”
Efek hemodinamik .
- negative inotropic effect → T.D. ↙
- vasodilatasi → α-adrenergik
blockade

ECG : P – R interval
Memanjang
QRS Comp
Q – T interval → torsade de pointes.

Farmakokinetik:
- diserap per-oral komplit
- 80 % berikatan dengan plasma protein
Kontra – Indikasi
 A.V Block
 C.H.F
 Hipotensi

Hati – hati :
 pemberian digitalis
 hiperkalemia
 miastenia gravis == why ?
Prokainamid :
- efek hampir = kinidin dengan perbedaan
- sumber
- antimuskarinik <<
- asetilasi dilever ada yang fast ada yang
rapid acetylator.
- menimbulkan lupus (80% akan mendapat
titer anti nuklear yang tinggi  30% 
lupus )., dose-related, biasanya pada yang
slow acetylator.
- dosis besar : agranulositosis.
 Classification of antiarrhythmics
(based on mechanisms of action)
– Subclass IB
• Weak Phase 0 depression
• Shortened depolarization
• Decreased action potential duration
• Includes
– Lidocane (also acts as local anesthetic) – blocks
Na+ channels mostly in ventricular cells, also
good for digitalis-associated arrhythmias
– Mexiletine - oral lidocaine derivative, similar
activity
– Phenytoin – anticonvulsant that also works as
antiarrhythmic similar to lidocane
 Lignocaine (Lidocaine)
• Class Ib (blocks Na+ channels, reduces AP duration)
• Ventricular arrhythmias (acute Rx)
• IV infusion only (2 hour half life, high first pass
metabolism)
• Hepatic metabolism (inhibited by cimetidine,
propranolol)
• SE mainly CNS - drowsiness, disorientation,
convulsions, hypotension
 Classification of antiarrhythmics
(based on mechanisms of action)
– 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

– Propafenone
» Also slows conduction
» Weak β – blocker
» Also some Ca2+ channel blockade
 Flecainide
• Class Ic (block Na+ channels, no change to AP)
• Slows conduction in all cardiac cells
• Acute Rx /prophylaxis
• Supraventricular tachycardias
• Paroxysmal atrial fibrillation
• Ventricular tachycardias
• Oral/IV
• Long acting (T1/2 14 hours)
• Hepatic metabolism, urinary elimination
 Flecainide
• CAST (Cardiac Arrhythmia Suppression Trial)
1989 – increased mortality post MI (VF
arrest)
• Side-effects:
= cardiac failure,= ventricular-
arrhythmias,blurred vision, abdominal
discomfort, nausea, paraesthesia, dizzyness,
tremor, metallic taste
 Classification of antiarrhythmics
(based on mechanisms of action)
• 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 Pindolo Stalol
• Timolol Esmolol
 Classification of antiarrhythmics
(based on mechanisms of action)

• Class III – K+ channel blockers

– Developed because some patients negatively sensitive to
Na channel blockers (they died!)
– Cause delay in repolarization and prolonged refractory
period
– Includes
• Amiodarone – prolongs action potential by delaying K+ efflux but
many other effects characteristic of other classes
• Ibutilide – slows inward movement of Na+ in addition to delaying
K + influx.
• Bretylium – first developed to treat hypertension but found to
also suppress ventricular fibrillation associated with myocardial
infarction
• Dofetilide - prolongs action potential by delaying K+ efflux with
no other effects
 Amiodarone
• Class III - increases refractory period and AP
• Major effect acutely is depression of AV node
• Acute Rx/prophylaxis
• Atrial and ventricular arrhythmias
• Oral or IV (central line)
• Loading and maintenance doses
• T1/2 ; 54 days
• Large volume of distribution
• Accumulates
• Hepatic metabolism- biliary and intestinal excretion
 Amiodarone – adverse effects
• Photosensitive rashes
• Grey/blue discolouration of skin
• Thyroid abnormalities 2%
• Pulmonary fibrosis
• Corneal deposits
• CNS/GI disturbance
• Pro-arrhythmic effects (torsade de pointes)
• Heart block
• Nightmares 25%
• Interacts with digoxin, warfarin (reduces clearance)
 Classification of antiarrhythmics
(based on mechanisms of action)

• 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
 Verapamil
• Class IV (calcium channel blocker)
• Prolongs conduction and refractoriness in AV node,
slows rate of conduction of SA node
• Used IV/oral
• SUPRAVENTRICULAR NOT VENTRICULAR
ARRHYTHMIAS (cardiovascular collapse)
• Do not use IV verapamil with ß- blocker (heart
block)
• T1/2 6-8 hours
 Verapamil- adverse effects
• Heart failure
• Constipation
• Bradycardia
• Nausea
 Adenosine
• Purine nucleoside
• Acts on A1 adenosine receptors
• Opens Ach sensitive K channels
• Inhibits Ca in current – Suppresses Ca dependent AP
(Nodal)
• Increases K out current – Hyperpolarisation
• Inhibits AVN > SAN
• Increases AVN refractory period
 ADENOSINE
• Interrupts re-entry and aberrant pathways through AVN
– Diagnosis and Treament
• Drug for narrow complex PSVT
• SVT reliant on AV node pathway
• NOT atrial flutter or fibrillation or VT
• Contraindications:
• VT – Hypotension and deterioration
• High degree AV block
• Poison or drug induced tachycardia
• Bronchospasm but short DOA
 ADENOSINE
• Carotid massage and vagal maneuvers first
• Rapid IV push 6mg – 12 mg – 12 mg
• Flush with 20ml N/S
• Record rhythm strip
• FLUSHING
• CHEST PAIN
• ASYSTOLE/BRADY
• VENTRICULAR ECTOPY
 Adenosine- adverse effects
• Feeling of impending doom!
• Flushing, dyspnoea, chest pain, transient
arrhythmias
• Contraindicated in asthma, heart block
 Digoxin
• Not in Vaughan Williams class

• Cardiac glycoside (digitalis, foxglove)

• Act on Na/K-ATPase of cell membrane (inhibits

Na+/K+ pump, increases intracellular Na+ and
calcium)/ increases vagal activity

• Increase cardiac contraction and slows AV

conduction by increasing AV node refractory period
 Digoxin
• Atrial fibrillation or flutter (controls ventricular rate)
• Acute Rx/prophylaxis
• Oral/IV
• Loading and maintenance doses
• T1/2 36 hours
• Excreted by kidneys
• Narrow therapeutic index
• Therapeutic drug monitoring
• Reduce dose in elderly/renal impairment
 Digoxin – adverse effects
• Arrhythmias, heart block, anorexia, nausea,
diarrhoea, xanthopsia, gynaecomastia,
confusion, agitation

• Adverse-effects potentiated by hypokalaemia

and hypomagnesaemia

• Overdose –Digibind (digoxin binding antibody

fragments), phenytoin for ventricular
arrhythmias, pacing, atropine
 Anti-bradycardia agents

1. ß-adrenic receptor activator

2. M-cholinergic receptor blocker
3. Non-specific activator
Dalam keadaan denyut jantung amat
melambat ( bradikardia ):

- atropin(M-cholinergic receptor blocker)

- β stimulator (ß-adrenic receptor activator)

- pacemaker (pacu jantung )

 Pacemakers
• Surgical implantation of electrical leads attached to a
pulse generator
• Over 175,000 implanted per year
1.Leads are inserted via subclavicle vein and advanced to
the chambers on the vena cava (right) side of the heart
2. Two leads used, one for right atrium, other for right
ventricle
3. Pulse generator containing microcircuitry and battery are
attached to leads and placed into a “pocket” under the
skin near the clavicle
4. 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
 Summary
• Anti-arrhythmic drugs are classified by their
effect on the cardiac action potential

• Not all drugs fit this classification

• In clinical practice treatment of arrhythmias is

determined by the type of arrhythmia (SVT, VT)
and clinical condition of the patient

• Anti-arrhythmic drugs are efficacious but may

have serious adverse effects
• Not all arrhythmias are treated with drug
therapy alone
 Take-Home Message
• Anti-arrhythmics are also pro-
arrhythmics
• Dangerous side effects
• If patient is unstable rather
cardiovert
• Enlist expert help
• Stick to drugs you know
• Limited choice in SA anyway