CARDIAC MUSCLE PHYSIOLOGY

& CARDIAC GLYCOSIDES

DR W.A. BADRU
INTRODUCTION

• Cardiac muscle tissue is only found in the heart.

• Highly coordinated contractions of cardiac muscle pump blood into
the vessels of the circulatory system.
• Similar to skeletal muscle, cardiac muscle is striated and
organized into sarcomeres, possessing the same banding
organization as skeletal muscle
• However, cardiac muscle fibers are shorter than skeletal muscle
fibers and usually contain only one nucleus, which is located in the
central region of the cell.
INTRODUCTION

• Cardiac muscle fibers also possess many mitochondria and

myoglobin, as ATP is produced primarily through aerobic
metabolism.
• Cardiac muscle fibers cells also are extensively branched and are
connected to one another at their ends by intercalated discs.
• An intercalated disc allows the cardiac muscle cells to contract in a
wave-like pattern so that the heart can work as a pump.
• Intercalated discs are part of the sarcolemma and contain two
structures important in cardiac muscle contraction: gap junctions
and desmosomes
INTRODUCTION

• A gap junction forms channels between adjacent cardiac muscle

fibers that allow the depolarizing current produced by cations to
flow from one cardiac muscle cell to the next.
• This joining is called electric coupling, and in cardiac muscle it
allows the quick transmission of action potentials and the
coordinated contraction of the entire heart.
• This network of electrically connected cardiac muscle cells
creates a functional unit of contraction called a syncytium.
CARDIAC MUSCLE PHYSIOLOGY

• The remainder of the intercalated disc is composed of desmosomes.

• A desmosome is a cell structure that anchors the ends of cardiac muscle
fibers together so the cells do not pull apart during the stress of individual
fibers contracting.
• Contractions of the heart (heartbeats) are controlled by specialized cardiac
muscle cells called pacemaker cells that directly control heart rate.
• Although cardiac muscle cannot be consciously controlled, the pacemaker
cells respond to signals from the autonomic nervous system (ANS) to speed up
or slow down the heart rate.
• The pacemaker cells can also respond to various hormones that modulate
heart rate to control blood pressure.
• The wave of contraction that allows the heart to work as a unit, called a
functional syncytium, begins with the pacemaker cells.
• This group of cells is self-excitable and able to depolarize to threshold
and fire action potentials on their own, a feature called auto-rhythmicity.
• They do this at set intervals which determine heart rate.
• Because they are connected with gap junctions to surrounding muscle
fibers and the specialized fibers of the heart’s conduction system, the
pacemaker cells are able to transfer the depolarization to the other
cardiac muscle fibers in a manner that allows the heart to contract in a
coordinated manner.
• Another feature of cardiac muscle is its relatively long action
potentials in its fibers, having a sustained depolarization “plateau.”
• The plateau is produced by Ca++ entry though voltage-gated calcium
channels in the sarcolemma of cardiac muscle fibers.
• This sustained depolarization (and Ca++ entry) provides for a longer
contraction than is produced by an action potential in skeletal muscle.
• Unlike skeletal muscle, a large percentage of the Ca++ that initiates
contraction in cardiac muscles comes from outside the cell rather than
from the SR.
SUMMARY

• Cardiac muscle is striated muscle that is present only in the heart.

• Cardiac muscle fibers have a single nucleus, are branched, and
joined to one another by intercalated discs that contain gap junctions
for depolarization between cells and desmosomes to hold the fibers
together when the heart contracts.
• Contraction in each cardiac muscle fiber is triggered by Ca++ ions in a
similar manner as skeletal muscle, but here the Ca++ ions come from
SR and through voltage-gated calcium channels in the sarcolemma.
• Pacemaker cells stimulate the spontaneous contraction of cardiac
muscle as a functional unit, called a syncytium.
HEART FAILURE

• Serious cardiac condition associated with high mortality rate.

• The fundamental physiologic defect in heart failure is a decrease
in cardiac output relative to the needs of the body.
• Major manifestations are dyspnoea and fatigue.
• The causes of heart failure are not completely understood.
• It can be ascribed to simple loss of functional myocardium, as in
myocardial infarction.
HEART FAILURE

• It is frequently associated with chronic hypertension, valvular

disease, coronary artery disease and a variety of
cardiomyopathies.
• In about one third of cases of heart failure, the primary defect is a
reduction of cardiac contractile force and ejection fraction that is
detected during systole (systolic failure).
• In another third, the primary defect is stiffening or other changes
of the ventricles that prevent adequate filling during diastole,
ejection fraction may be normal though stroke volume is
decreased (diastolic failure)
HEART FAILURE

• The remainder of cases can be attributed to a combination of

systolic and diastolic dysfunction.
• The body response in heart failure include tachycardia, increased
peripheral vascular resistance, retention of salt and water by the
kidney and cardiomegaly (enlargement of the heart).
• Although these compensatory responses can temporarily improve
cardiac output, they also increase the load on the heart, and the
increased load contributes to further long term decline in cardiac
function.
THERAPEUTIC STRATEGIES

• Current clinical evidence suggests that acute heart failure should

be treated with a loop diuretic, if severe, a prompt acting positive
ionotropic agent such as a beta agonist or phosphodiesterase
inhibitor and vasodilators should be used.
• Chronic failure is best treated with diuretics (often a loop agent
and spironolactone) plus an ACE inhibitor.
• Digitalis may be helpful if systolic dysfunction is prominent.
CARDIAC GLYCOSIDES

• The cardiac glycosides are often called “digitalis” because several

come from the digitalis (foxglove) plant.
• All cardiac glycosides include a steroid nucleus and a lactone ring,
most also have one or more sugar residues.
• Digoxin is the prototype agent.
• Digitoxin is a very similar molecule, also frm foxglove.
• Digoxin has an oral bioavailability of 65-70% and a half life of 36-40
hour.
• Elimination is by renal excretion (60%) and hepatic metabolism (40%)
MECHANISM OF ACTION

• Primary biochemical mechanism of action is inhibition of Na+/K+

ATPase of the cell membrane.
• This comes with a small increase in intracellular sodium.
• Increased sodium alters the driving force for sodium-calcium
exchange so that less calcium is removed from the cell.
• This calcium is stored in the sarcoplasmic reticulum (SR) and upon
release increases contractile force.
• Digitalis also modifies autonomic outflow and this action has
effects on he electrical properties of the heart.
CLINICAL USES

Congestive Heart failure: Digitalis is the traditional positive ionotropic

agent used in the treatment of chronic heart failure.
• Clinical studies however, indicate that while it may improve
functional status (reducing symptoms), it does not prolong life.
• It accumulates significantly in the body because its half lives are long.
• Dosing regimen must be carefully designed and monitored.
• Other agents (diuretics, ACE inhibitors, vasodilators) are equally
effective and less toxic.
• Some of these alternative therapies do prolong life.
Atrial fibrillation: In atrial flutter and fibrillation, it is desirable to
reduce the conduction velocity or increase the refractory period of
the AV node so that ventricular rate is controlled within a range
compatible with efficient filling and ejection.
• Digitalis parasympathetic action often accomplishes this
therapeutic objective, although high doses of may be required.
INTERACTIONS

• Quinidine causes a well-documented reduction in digoxin clearance

and can increase the serum digoxin level if its dosage is not
adjusted,
• Amiodarone, verapamil and other drugs have same effect but
interactions with these drugs are not clinically significant,
• Hypokalemia, hypomagnesemia and hypercalcemia increase digitalis
toxicity especially arrhythmogenesis.
• Loop diuretics and thiazides, which are always included in the
treatment of heart failure, may significantly reduce serum
potassium and thus precipitate digitalis toxicity.
DIGITALIS TOXICITY

• Major signs of digitalis toxicity are arrhythmias, nausea, vomiting

and diarrhoea
• Rarely, confusion and hallucination and visual aberrations may
occur.