CARDIOVARCULAR CLINICAL

PHARMACOLOGY
DR.MED.dr.WIDHARTO PH,SpFK
Pharamacology & Therapy Dept
Faculty of Medicine
UNIVERSITAS GADJAH MADA
 Arrhythmia
• Heart condition where disturbances in
– Pacemaker impulse formation
– Contraction impulse conduction
– Combination of the two

Results in rate and/or timing of contraction of heart

muscle that is insufficient to maintain normal
cardiac output (CO)

To understand how antiarrhythmic drugs work, need

to understand electrophysiology of normal
contraction of heart
Normal heartbeat and atrial arrhythmia

Normal rhythm Atrial arrhythmia

AV septum
 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!
 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
Typische Ruhe bzw. Aktionspotentiale in verschiedenen Myokardabschnitten

1. sinusknoten

2. vorhof

3. AV - Knoten

4. His - Bundel

5. Kammerschenkel
6. Rechte Kammer

7. linke Kammer
 Contraction of
ECG (EKG) showing wave ventricles
segments

Repolarization of
Contraction of
ventricles
atria
 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
• 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
 Mechanisms of Cardiac Arrhythmias

• Result from disorders of impulse formation,

conduction, or both

• Causes of arrhythmias
– Cardiac ischemia
– Excessive discharge or sensitivity to autonomic
transmitters
– Exposure to toxic substances
– Unknown etiology
 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 depolarizations

– Can initiate spontaneous activity in nonpacemaker tissue
– May be result of drugs (digitalis, norepinephrine) used to treat other
cardiopathologies
 Antiarrhythmic drugs
• Biggest problem – antiarrhythmics 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
antiarrhythmics
 Classification of antiarrhythmics
(based on mechanisms of action:Vaugham William
Classification)
• 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
 Classification of antiarrhythmics
(based on mechanisms of action)

– Subclass IB
• Weak Phase 0 depression
• Shortened depolarization
• Decreased action potential duration
• Includes
– Lidocaine (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
 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
 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
• Pindolol
• 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
 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
The classic four types of antiarrhythmic agents
 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
 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
Implantation of Pacemaker
 3 (three) Major Underlying Mechanisms
 Enhanced Automaticity
 Triggered Automaticity
 Re-entry

A drugs may block arrhythmias owing to DADs or

EADs by 2 (two) major mechanisms :
1. Inhibition of the development of after
depolarization's
2. Interference with the inward current (usually
through Na+ or Ca2+ channels), which is responsible
for the upstroke
Thus, arrhythmias owing to digitalis-induced DADs may be
inhibited
 By verapamil (which block the development of DAD).
 By quinidine (which block Na+ channels, thereby
elevating the threshold required to produce the
abnormal abstroke)

DC (direct current) cardioversion

 The application of a large electric current across the chest
 This technique also can be used to immediately restore
rhythm in less serious cases.
 If the patient is conscious, a brief period of general
anesthesia is required
 VF (ventricular fibrillation) is the best case to treat with this
ICDs (Implantable Cardioverter Defibrillators) :

 Are capable of detecting VF.

 Automatically delivering a defibrillating schock
 Are used increase ingly in patients judged to be at high
risk for VF
An alternative-approached to classify arrhythmia
mechanisms and then to target drug therapy (to
terminate or prevent the arrhythmia)
 Na+ channel Block
 Na+ channel Block Toxicity
 Action Potential Prolongation
 Toxicity of Drugs that Prolong QT Interval
Na+ Channel Block
 Depends critically on heart rate and membrane potential
 At the rapid heart rate in disseased tissue with Lidocaine (a
rapid – recovery drug)
 At the normal tissues with flecainide (a slow – recovery drug)

When Na+ channels are blocked :

 Threshold for exitability is decreased (i-e., greater membrane
depolarization is required to bring Na+ channels from the rest
to open states).
 This change in threshold probably constributes to the clinical
findings that Na+ channel blockers tent to increase
 Pacing threshold
 The energy required to defibrillate the fibrillating heart
Na+ Channel Block
 Depends critically on heart rate and membrane potential
 At the rapid heart rate in disseased tissue with Lidocaine (a
rapid – recovery drug)
 At the normal tissues with flecainide (a slow – recovery drug)

When Na+ channels are blocked :

 Threshold for exitability is decreased (i-e., greater membrane
depolarization is required to bring Na+ channels from the rest
to open states).
 This change in threshold probably constributes to the clinical
findings that Na+ channel blockers tent to increase
 Pacing threshold
 The energy required to defibrillate the fibrillating heart
Na+ Channel – Blocker Toxicity
 Is caused by the conduction slowing in potential re-entrant
circuits
 Example : Na+ channel block decreases conduction velocity &
hence slow a trial flutter rate
Action Potential Prolongation
• Most drugs that prolong the action potential do so by blocking
K+ channels, although enhanced inward Na+ current also can
cause prolongation (QT Prolongation)
Toxicity of Drugs That Prolong QT-interval
• Most of these agent prolong … action potentials when underlying
heart rate is slow.
• Cause torsades de pointes
(More common in women)?
Adenosine

 Is a naturally occurring nucleoside

 Is administered as a rapid intravenous bolus for the
acute termination of re-entrant supra ventricular
arrhythmias (Lerman & Belardinelli, 1991)
 Can terminate VT (Ventricular tachycardia)
 Also has been used to produce controlled
hypotension during some surgical procedures and in
the diagnosis of coronary artery disease.
 IV ATP (intravenous) appears to produce affects
similar to those of adenosine
Pharmacological Effects
 Are mediated by its interaction with specific G-protein-
coupled adenosine receptors
 Activates acetylcholine-sensitive K+ current in the atrium and
sinus and AV nodes.
– Shortening of action potential duration
– Hyper polarization
– Slowing of normal automaticity
 Also inhibits the electrophysiological effect of increased
intracellular cyclic AMP that occur with sympathetic
stimulation
 Reduces Ca++ currents by :
– Increasing AV nodal refractoriness
– Inhibiting DADs elicited by sympathetic stimulation
Pharmacokinetic

 Is eliminated by carrier-mediated uptake in most call

types, including the endothelium.
 Is metabolized by deaminase
 Whose officacy require a rapid bolus dose through a
large central intravenous line
 Are potentiated in patients receiving dipyridamole (an
adenosine-uptake inhibitor) & in patient with cordiac
transplants owing to denervation hypersensitivily
 Interact with methyl xanthines (theophylline caffeine)
– Because these drug block adenosine receptors.
– …. adenosine doses are required to produce an anti
arrhythmic effect in patients who have consumed
these again in Geverages
 Pharmacokinetics of Anti arrhythmic Drug

Bioavailability Primary Route Protein Therapeutic

Drug Substrate Inhibitor VD (L/kg) T½
(%) of Elimination Binding (%) Rage (mg/L)

Quinidine 70 – 80 H CYP3A4 CYP2D6 2 – 3,5 80 – 90 5 – 9h 2–6

P-GP
Procainamide 75 – 95 H/R NAT - 1,5 – 3 10 – 20 5 – 6h (SAs) 4 – 45
CYP2D6 2 – 3h (FAs) -

Disopyamide 70 – 95 H/R CYP3A4 - 0,8 – 2 50 – 80 4 – 8h 2–6

Lidocaine 20 – 40 H CYP3A4 - 1–2 65 – 75 1 – 3h 1,5 – 5
CYP2D6
Mexilentine 80 -95 H CYP2D6 CYP1A2 5 – 12 60 – 75 12 – 20h (PMs) 0,8 – 2
CYP1A2 7 – 11h (EMs)

Tocainide 90 – 95 H PH 11, gluC - 1,5 – 3 10 – 30 12 – 15h 4 – 10

Moricizine 34 – 38 H CYP1A2? - 6 – 11 92 – 95 2 – 4h -
Flecainide 90 – 95 H/R CYP2D6 - 8 – 10 35 – 45 14 – 20h (PMs) 0,3 – 2,5
10 – 14h (EMs)

Propafenone 11 – 39 H CYP2D6 - 2,5 – 4 85 – 95 10 – 25h (PMs)

CYP3A4 3 – 7h (EMs)
CYP1A2
Amiodorone 22 – 88 H CYP3A4 CYP1A2 70 – 150 95 - 99 15 – 100d 1,0 – 2,5
CYP2C8 CYP2C9 C
YP2D6
CYP3A4
P-GP
Sotalol 90 – 95 R 1,2 – 2,4 30 – 40 10 – 20h -
Dofrtilide 85 – 95 R/H CYP3A4 2,5 – 3,5 60 – 70 6 – 10h -
Ibutilide - H - 6 – 12 40 – 50 3 – 6h -
Bretyliuun 15 – 20 R - 4–8 5 – 10h 0,5 – 2
Verapamil 20 – 40 H CYP3A4 CYP3A4 1,5 – 5 95 – 99 4 – 12h >0,05
CYP1A2 P-GP
Diltiazem 35 -50 H CYP3A4 CYP3A4 3–5 70 – 85 4 – 10h >0,05
P-GP

H : hepatic P-GP : P-glycoprotein EMs : Extensive metabolizers

CYP : cytochrome p450 isoenzyme PII, gluc : Phase II glucoronedation SAs : Slow acetylator
NAT : N-acetyl transferase PMs : Poor metabolizers FAs : Fast acetylator