Drugs Acting on the

Cardiovascular System
Antiarrhythmic Drugs
Types of cardiac cells:

 The mechanical component that pumps

the blood (cardiac myocytes) Refer to
Heart failure
 The electrical component lecture
The electrical component controls the pump rhythm by:

• generating rhythmical electrical impulses

• conducting these impulses rapidly through the heart

rhythmical contraction of the heart muscle

Conducting system of the heart
Pacemakers cells

Sinoatrial node
(SA node) at the junction
of the superior vena cava
with the right atrium

Atrioventricular node
(AV node) in the interatrial
septum

Ventricular conducting
system: bundle of His,
bundle branches, &
Purkinje fibers
Normal conduction pathway

SA node initiate impulses;

SA node The cardiac impulse travels
from SA node
atria contract.
The impulse passes

AV node  AV node
 ventricular conducting
system

ventricular  ventricles  contract

conducting
system
Sympathetic & parasympathetic fibers innervate SA & AV nodes
 Action potential of cardiac cells
SA node unstable membrane potential

Phase 0: Rapid depolarisation Phase 3: repolarization:

Due to Ca++ influx Due to K+ efflux

Phase 4: pacemaker potential

Slow spontaneous
depolarisation
Na+ & Ca++ influx, K+ efflux Threshold potential
until the cell reaches threshold (minimum potential needed to
trigger an action potential)
 Conducting system of the heart
Pacemakers cells
Phase 4: Slow spontaneous depolarization during rest,
continuously moves potential towards threshold for a new action potential
accounting for automaticity of the cardiac conduction system

Automaticity:
ability to depolarize above a threshold voltage in a rhythmic fashion

SA node
fastest rate of Phase 4 depolarization
 Normal heart pacemaker
 sets myocardial contraction pace

Latent pacemakers
• in the cells of the AV node & ventricular conducting system
• depolarized by impulses coming from SA node because discharge rate
of the SA node is faster than their natural self-excitatory discharge rate
Non-pacemakers Cells

Atrial & ventricular myocytes:

These cells contract in response to depolarization
Other types of
conduction that
occur between
myocardial cells:
Ions move with
ease in the
intracellular fluid
along the
longitudinal axes
of the cardiac
muscle fibers
When a cell is
depolarized 
adjacent cell
depolarizes
 Action potential of cardiac cells
Ventricular action potential is divided into 5 phases (0-4):

Phase 1: partial repolarization Phase 2: plateu

K+ out Ca2+ in
K+ out

Phase 0: Phase 3:
depolarisation repolarization
Na+ in K+ out

Phase 4: resting
membrane potential
Action potential of cardiac cells

Refractory period:
A protective mechanism to ensure that the heart has
sufficient time to pump blood from its chambers

Time during which another action potential cannot occur

From initiation of action potential  repolarization phase
 Electrocardiogram (ECG)
Electrical activity is recorded
by electrocardiogram
• P wave corresponds to
atrial depolarization
• QRS complex
corresponds to
ventricular depolarization
• T wave corresponds to
ventricular repolarization
• Atrial repolarization
record is masked by the
larger QRS complex

https://www.ncbi.nlm.nih.gov/books/NBK2214/
Electrocardiogram (ECG)

https://www.youtube.com/watch?v=RYZ4daFwMa8
Cardiac Conduction System and Understanding ECG, Animation.
Arrhythmia
Arrhythmia

Most arrhythmias arise either from

• abnormality in impulse generation
(abnormal automaticity)
• or from defect in impulse conduction
Arrhythmia: Abnormal automaticity

cardiac sites other than the SA node show enhanced automaticity

 generate competing stimuli
 Arrhythmia

If myocardial cells are damaged

 cells may remain partially depolarized during diastole
 abnormal automatic discharges (Abnormal automaticity)
 Arrhythmia

Antiarrhythmic agents: suppress automaticity by:

blocking either Na+ or Ca2+ channels
 reduce the ratio of these ions to K+
Arrhythmia: Abnormal impulse conduction:

Normal cardiac function requires A phenomenon called

unobstructed & timely propagation
of an electrical impulse through the
cardiac myocytes.
Impulses from higher pacemaker
centers are normally conducted
down bifurcating pathways
reentry can occur if a
unidirectional block
results in an abnormal
conduction pathway
Arrhythmia: Abnormal impulse conduction:

e.g. Purkinje fiber with 2 conduction pathways to ventricular muscle.

An impulse normally travels down both limbs of the conduction path
 Arrhythmia: Abnormal impulse conduction:

5 retrograde impulse
reenters point (a)
1 Myocardial injury
refractory period
of bifurcation
of cells in pathway2
is prolonged so
forward conduction
is prohibited.
 ventricular muscle
6 reexcitation
premature contraction
4
impulse conducts At point (b):
2 through pathway1 cells in pathway2
are no longer
refractory 
impulse conducts
in backwards in
pathway 2
3 impulse proceeds to point (b)
Arrhythmia: Abnormal impulse conduction:

Antiarrhythmic agents prevent reentry by:

Slowing conduction and/or increasing the refractory period

(so both pathways have long refractory period)
 convert unidirectional block  bidirectional block
Arrhythmia

Arrhythmias can be organized into groups according to the

anatomic site of the abnormality;
the atria, the AV node, or the ventricles.

Abnormalities can be further divided into subgroups

depending on the electrocardiogram findings.

https://www.youtube.com/watch?v=6LrptveKYus&list=PLJIs8ZcKXHUwdmQ
l1hxgtiTrKS1mOoVSi&index=4
Cardiac Arrhythmias
Arrhythmia

Atrial flutter
• Electrical signal travels as a single large wave always in
one direction around & around the atrial muscle mass
• Atrial rate: 280 - 300 beats/min.
• Pace of atrial firing is so rapid  some impulses from
the atria reach the AV node during its refractory period
 not transmitted to the ventricles  ventricular rate is
slower; (2-3 beats of the atria for single beat of the
ventricles)

Atrial fibrillation
rapid reentry & chaotic movement of impulses
through the tissue of the atria
Arrhythmia

Supraventricular tachycardia
A reentrant arrhythmia that travels through the AV node; may also be
conducted through atrial tissue as part of the reentrant circuit

Ventricular tachycardia
Abnormal automaticity or abnormal conduction.
Ventricular rates: 100 - 250 beats/min

Ventricular fibrillation
rapid reentry & chaotic movement of impulses
through the tissue of the ventricles
Antiarrhythmic
Drugs
Antiarrhythmic Drugs

Class I: Na channel blockers

Class II: β-blockers

Class III: K channel blockers

Class IV: Ca channel blockers

Miscellaneous

https://www.youtube.com/watch?v=OnLsLByuo0E&list=PLJIs8ZcKXHUwdmQl
1hxgtiTrKS1mOoVSi&index=5
Antiarrhythmic Drugs, Animation
Antiarrhythmic Drugs

State-dependent ion channel block

Antiarrhythmic drugs have different affinities for the different

conformational states of the ion channel

This type of binding is referred to as:

“state-dependence” or “use-dependence”
Antiarrhythmic Drugs
Class I: sodium channel blockers
Na+ channel undergoes 3 state changes during an action potential

Drugs bind to (& block) open or inactivated channels

 selectively depress frequently depolarizing tissue
Antiarrhythmic Drugs
Class I: sodium channel blockers

Blocking of Na+ channels  ↓ Na+ influx

• SA node:
extend phase 4 duration
 ↓ heart rate

• Cardiac tissue:
slows the rate of rise of Phase 0
 ↓ conduction velocity (↑ conduction time)
Antiarrhythmic Drugs
Class I: sodium channel blockers

Blocking of Na+ channels  ↓ Na+ influx

Class IA: Class IB: Class IC:

intermediate rate Rapid rate Slow rate
 Antiarrhythmic Drugs
Class I: sodium channel blockers
Class IA:
• Block Na+ channels; intermediate rate
Slows Phase 0 depolarization in ventricular muscle fibers
• Block K+ channels (class III activity)
↓K+ efflux  ↑ repolarization & refractory period
 Antiarrhythmic Drugs
Class I: sodium channel blockers
Class IA Quinidine (prototype) Procainamide Disopyramide
Uses atrial & ventricular I.V. formulation only ventricular
arrhythmias - acute atrial and arrhythmias
ventricular arrhythmias

Adverse - Cinchonism: -Hypotension -marked

effects a syndrome with -Lupus erythematosus antimuscarinic
headache, vertigo & (autoimmune disease) effects
tinnitus -negative inotropic
- Inhibitor of p-gp; effect and may
competes with digoxin precipitate heart
for renal excretion failure
-Antimuscarinic
 Antiarrhythmic Drugs
Class I: sodium channel blockers
Class IB:
Block Na+ channels ;
Rapidly associate to & dissociate from channels
rapidly unbind during diastole Channels recover quickly from blockade
 there is little residual Na channel block by the time of the next action
potential at normal heart rates
Shorten Phase3 repolarization
 Antiarrhythmic Drugs
Class I: sodium channel blockers
Class IB Lidocaine (lignocaine) (prototype) Mexiletine

PK given IV, IM due to first-pass Analog of lidocaine; modified to

transformation by the liver
Uses - Local anesthetic
- Acute ventricular arrhythmias
reduce first-pass hepatic
metabolism & permit chronic
oral therapy
Chronic ventricular arrhythmias

Adverse CNS effects: Tremor and nausea

effects Nystagmus (early indicator of toxicity),
Slurred speech,
Tremor,
Altered levels of consciousness
convulsions
Antiarrhythmic Drugs
Class I: sodium channel blockers
Class IC:
Block Na+ channels ;
Slowly dissociate from resting Na+ channels during diastole
 Markedly slows Phase 0 depolarization
 prominent effects even at normal heart rates
Antiarrhythmic Drugs
Class I: sodium channel blockers

Class IC Flecainide (prototype) Propafenone

Uses Atrial flutter or fibrillation Atrial arrhythmias

Refractory ventricular arrhythmias

Adverse Dizziness Dizziness

effects Blurred vision Blurred vision
Nausea Nausea
Bronchospasm due to
β-blocking effects (class
II activity)
 Antiarrhythmic Drugs
Class II: β-blockers
Sympathetic stimulation releases norepinephrine
binds to β1 receptors in SA & AV nodes  increase Ca2+

β-blockers: Propranolol, Metoprolol, Esmolol

block sympathetic stimulation of β1-receptors in SA & AV nodes
 decrease the rate of phase 4 depolarization

Uses:
• Arrhythmias caused by increased sympathetic activity
• Atrial arrhythmias & AV-nodal reentrant tachycardia
• Metoprolol prophylactic in patients who have had a myocardial
infarction.
• Esmolol: very-short-acting for intravenous administration in acute
arrhythmias that occur during surgery or emergency situations
Antiarrhythmic Drugs
Class III: potassium channel blockers
Block K+ channels
 reduce K+ efflux
prolong repolarization and refractory period
Antiarrhythmic Drugs
Class III: potassium channel blockers
Amiodarone
• Contains iodine & structurally related to thyroxine
• Useful in most types of arrhythmias; most efficacious
antiarrhythmic drug
broad spectrum of action: mainly class III, but has class I,
class II, & class IV effects as well as α-blocking activity
alters the lipid membrane in which ion channels & receptors
are located
• Adverse effects: pulmonary fibrosis, hepatotoxicity,
neuropathy, optic neuritis, corneal deposits, thyroid
dysfunction (hypo- or hyperthyroidism) , and blue skin
discoloration caused by iodine accumulation in the skin
Antiarrhythmic Drugs
Class III: potassium channel blockers

Dronedarone,
• Amiodarone analog; less toxic

Sotalol
d-sotalol  class III ; l-sotalol  β-blocker
The clinical preparation contains both isomers
 Antiarrhythmic Drugs
Class IV: calcium channel blockers
Verapamil & diltiazem
• SA & AV nodes (potential upstroke is Ca2+ dependent)
 ↓ rate of phase 4 spontaneous depolarization
• Cardiac myocytes: ↓ contractility
Uses:
• treating reentrant supraventricular tachycardia
• reducing ventricular rate in atrial flutter & fibrillation

Adverse effects:
↓↓↓ cardiac contractility, AV conduction, & blood pressure
(other adv effects: refer to previous lectures)
Antiarrhythmic Drugs
Other agents

Digoxin
• Uses:
 Atrial fibrillation & flutter: digoxin ↓ conduction velocity
protects ventricles from excess atrial rate
(parasympathomimetic action)
Refer to
 Heart failure Heart failure
lecture
• Intoxication:
 Acute : cardiac depression  cardiac arrest
(parasympathomimetic action)
 Chronic : ectopic ventricular beats  ventricular
arrhythmias (due to enhanced automaticity caused by
excessive Ca2+ accumulation in cardiac cells)
Antiarrhythmic Drugs
Other agents

Adenosine

In the AV node
• ↓ automaticity
• ↓ conduction velocity
• ↑ refractory period

Uses: AV nodal arrhythmia.

Thank you