DRUGS FOR CHF AND ARRYHTMIAS

What is heart failure? Manifestation of Heart Failure

- It is a chronic, progressive disorder in  Systolic HF
which the heart muscle is unable to o Less blood pumped out of
pump enough blood to meet the body’s ventricles
needs o Ejection fraction <40%
- Decrease CO (Cardiac Output) o Weakened heart muscles
Frank-Starling Law  Diastolic HF
- Increased filling of the ventricle results o Less blood fills the
in greater contraction forces and thus a ventricles
rise in the cardiac output o Ejection fraction – normal
o Stiff heart muscle

- In the presence of HF, in order to

counteract the effect of falling CO and
thus reduced perfusion to vital organs,
the body will try to compensate via two
tightly regulated mechanisms
- The first one involves the increase in
sympathetic nervous system activity
- Second major compensatory
mechanism, which involves activation of
 the renin-angiotensin-aldosterone
system
Main role of natriuretic peptides is to counter
the effects of volume overload and adrenergic
activation by stimulation sodium and water
excretion, promoting myocardial relaxation,
inhibiting cardiac hypertrophy and fibrosis,
suppressing sympathetic outflow & stimulating
vasodilation.
Electrophysiology of Normal Cardiac Rhythm
- An electrophysiology (EP) study is a test
performed to assess your heart’s
electrical system or activity and is used
to diagnosis abnormal heartbeats or
arrhythmia
- The electrical impulse that triggers a
normal contraction originates at regular
intervals in the sinoatrial (SA) node
usually at a frequency of 60-100 bpm
- Cardiac electrical activity is determined
by transmembrane potential-the
potential, or voltage the difference
between the intracellular and
extracellular environments. These
potential differences can only exist
because of the selectivity-permeable
cardiac cell membranes. This
membrane is composed of a lipid
bilayer which are situated specialized
proteins that form channels that allow
passage of certain ions at specific times
between the intra- and extracellular
spaces.
- The initiation of a heartbeat is governed
by automaticity
- The sinus node controls the heart rate
most of the time because its rate of
discharge is faster than the His cells
- The bundle of His is a heart muscle that
takes part in electrical conduction in the
heart. Purkinje fibers are branched
 fibers that carry the electrical impulse
to the ventricles.
Schematic representation of the heart
and normal cardiac electrical activity
(intracellular recordings from areas
indicated and ECG). Sinoatrial (SA) node,
atrioventricular (AV) node, and Purkinje
cells display pacemaker activity (phase 4
depolarization). The ECG is the body surface
manifestation of the depolarization and
repolarization waves of the heart. The P
wave is generated by atrial depolarization,
the QRS by ventricular muscle
depolarization, and the T wave by
ventricular repolarization. Thus, the PR
interval is a measure of conduction time
from atrium to ventricle, and the QRS
duration indicates the time required for all
of the ventricular cells to be activated (ie,
the intraventricular conduction time). The
QT interval reflects the duration of the
ventricular action potential
• Transmembrane Potential (TMP) is the
electrical potential difference (voltage)
between the inside and the outside of
a cell. When there is a net movement
of +ve ions into a cell, the TMP
becomes more +ve, and when there is
a net movement of +ve ions out of a
cell, TMP becomes more –ve.
ACTION POTENTIAL: Electrical stimulation
created by a sequence of ion fluxes through
specialized channels in the membrane
(sarcolemma) of the cells responsible for
generating contractile force in the intact heart
that leads to cardiac contraction.
ACTION POTENTIAL IN CARDIOMYOCYTES
The action potential in typical
cardiomyocytes is composed of 5 phases (0-4),
beginning and ending with phase 4.
PHASE 0: DEPOLARIZATION
• An action potential triggered in a
neighboring cardiomyocyte or
pacemaker cell causes the TMP to rise
above −90 mV.
PHASE 1: EARLY REPOLARIZATION
• TMP is now slightly positive.
• Some K+ channels open briefly and an
outward flow of K+ returns the TMP to
approximately 0 mV.
PHASE 2: THE PLATEAU PHASE
• L-type Ca2+ channels are still open and
there is a small, constant inward
current of Ca2+. This becomes
significant in the excitation-contraction
coupling process described below.
• K+ leaks out down its concentration
gradient through delayed rectifier K+
channels.
• These two countercurrents are
electrically balanced, and the TMP is
maintained at a plateau just below 0
mV throughout phase 2.
PHASE 3: REPOLARIZATION
• Ca2+ channels are gradually inactivated.
• Persistent outflow of K+, now exceeding
Ca2+ inflow, brings TMP back towards
resting potential of −90 mV to prepare
the cell for a new cycle of
depolarization.
• Normal transmembrane ionic
concentration gradients are restored by
returning Na+ and Ca2+ ions to the
extracellular environment, and K+ ions
 to the cell interior. The pumps involved
include the sarcolemma Na+-Ca2+
exchanger, Ca2+-ATPase and Na+-K+-
ATPase.
PHASE 4: THE RESTING PHASE
• The resting potential in a cardiomyocyte
is −90 mV due to a constant outward
leak of K+ through inward rectifier
channels.
• Na+ and Ca2+ channels are closed at
resting TMP.
• TMP approaches −70mV, the threshold
potential in cardiomyocytes, i.e. the
point at which enough fast Na+
channels have opened to generate a
self-sustaining inward Na+ current.
• The large Na+ current rapidly
depolarizes the TMP to 0 mV and
slightly above 0 mV for a transient
period of time called the overshoot; fast
Na+ channels close (recall that fast Na+
channels are time-dependent).
• L-type (“long-opening”) Ca2+ channels
open when the TMP is greater than −40
mV and cause a small but steady influx
of Ca2+ down its concentration
gradient.
Mechanism of Arrhythmias
• Many factors can precipitate or
exacerbate arrhythmias: ischemia,
hypoxia, acidosis or alkalosis,
electrolyte abnormalities, excessive
catecholamine exposure, autonomic
influences, drug toxicity (eg. digitalis or
antiarrhythmic drugs), overstretching of
cardiac fibers, and the presence of
scarred or otherwise diseased tissue.
However, all arrhythmias result from (1)
disturbances in impulse formation, (2)
disturbances in impulse conduction, or
(3) both.
• Arrhythmias consist of cardiac
depolarizations that deviate from the
above description in one or more
aspects: there is an abnormality in the
site of origin of the impulse, its rate or
regularity, or its conduction.
Specific Anti-arrhythmic Agents
The most widely used scheme for the
classification of antiarrhythmic drug actions
recognizes four classes:
1. Class 1 action is sodium channel
blockade. Subclasses of this action
reflect effects on the action potential
duration (APD) and the kinetics of
sodium channel blockade. Drugs with
class 1A action prolong the APD and
dissociate from the channel with
intermediate kinetics; drugs with class
1B action shorten the APD in some
tissues of the heart and dissociate from
the channel with rapid kinetics; and
drugs with class 1C action have minimal
effects on the APD and dissociate from
the channel with slow kinetics.
2. Class 2 action is sympatholytic. Drugs
with this action reduce β-adrenergic
activity in the heart.
3. Class 3 action manifests as prolongation
of the APD. Most drugs with this action
block the rapid component of the
delayed rectifier potassium current, IKr.
4. 4. Class 4 action is blockade of the
cardiac calcium current. This action
slows conduction in regions where the
action potential upstroke is calcium
dependent, eg, the SA and AV nodes.