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Describe the structure and functional significance of the excitatory,
conductive and contractile elements of the heart
(Structure see next question)
Functional significance of excitatory & conductive elements:
Functional significance of contractile elements:
describe the anatomy of the heart and pericardium
Size.—The heart, in the adult, measures about 12 cm. in length, 8 to 9 cm. in breadth at the
broadest part, and 6 cm. in thickness. Its weight, in the male, varies from 280 to 340 grams; in
the female, from 230 to 280 grams. The heart continues to increase in weight and size up to an
advanced period of life; this increase is more marked in men than in women.
Cardiac Chambers
Right atrium
The SVC & IVC open into the posterior wall. The coronary sinus drains coronary venous blood into the
anteroinferior portion. The thebesian valve is located at the orifice of the coronary sinus. On the medial wall, the
limbus of the fossa ovalis circumscribes the septum primum of the fossa ovalis anteriorly, posteriorly, and
superiorly. The right auricle is separated from the right atrium internally, by a vertical crest ie, the crista terminalis.
The crista terminalis separates the right atrium into trabeculated and nontrabeculated portions. The right atrium is
larger than the left, but its walls are somewhat thinner, measuring about 2 mm.; its cavity is capable of containing
about 57 c.c.
Left atrium
The 4 pulmonary veins drain into the left atrium. The flap valve of the fossa ovalis is located on the septal
surface. The appendage of the left atrium is consistently narrow and long & is the only trabeculated structure in
the left atrium.
Right ventricle
Tricuspid valve is located in the large anterolateral portion (sinus) of the right ventricle. Pulmonic (semilunar)
valve is located in the outflow tract (infundibulum). Internally, both the sinus area and infundibulum contain
coarse trabeculations. The septal portion of the right ventricle has 3 components: (1) the inflow tract, which
supports the tricuspid valve; (2) the trabecular wall, which typifies the internal appearance of the right ventricle;
and (3) the outflow tract. The tricuspid valve is supported by a large anterior papillary muscle, which arises from
the anterior free wall and the moderator band, and by several small posterior papillary muscles. The wall of the
right ventricle is thinner than that of the left, the proportion between them being as 1 to 3; it is thickest at the
base, and gradually becomes thinner toward the apex. The cavity equals in size that of the left ventricle, and is
capable of containing about 85 c.c.
Left ventricle
The left ventricle can be divided into 2 primary portions, namely, the large sinus portion containing the mitral
valve and the small outflow tract that supports the aortic (semilunar) valve. The free wall and apical half of the
septum contain fine internal trabeculations. The septal surface is divided into a trabeculated portion (sinus) and a
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smooth portion (outflow). The outflow tract is located anterior to the anterior mitral leaflet and is part of the
atrioventricular (AV) septum. The mitral valve is supported by 2 large papillary muscles (ie, anterolateral,
posteromedial) attached to the free wall. The anterior papillary muscle is attached to the anterior portion of the
left ventricular wall, and the posterior papillary muscle arises more posteriorly from the ventricle's inferior wall. 1
Septi
Ventricular septum
The ventricular septum is divided into a muscular section (inferior) and a membranous section (superior). The
muscular portion comprises the left and right ventricular walls. The membranous septum, also termed the pars
membranacea, is a fibrous structure partially separating the left ventricular outflow tract from the right atrium and
ventricle.
Atrioventricular septum
The atrioventricular (AV) septum, located behind the right atrium and left ventricle, is divided into 2 portions: a
superior portion (membranous) and an inferior portion (muscular). Inside the left ventricle, the muscular
component comprises part of the outlet septum. The AV node lies in the atrial septum, juxtaposed to the
membranous and muscular portions of the AV septum.
Conduction System
The conduction system is composed for the most part of modified cardiac muscle that has fewer striations and
indistinct boundaries. The SA node and, to a lesser extent, the AV node, also contain small round cells with few
organelles, which are connected by gap junctions. These are probably the actual pacemaker cells, and therefore
they are called P cells.
Sinus node
The sinoatrial (SA) node occupies a 1-cm2 area on the lateral surface of the junction of the superior vena cava
and right atrium near the crista terminalis.
Internodal pathways
The spread of electrical activation from the sinus node extends toward the atrioventricular (AV) node via Purkinje
like pale cells in atrial muscle bundles. There are three bundles: the anterior internodal tract of Bachman, the
middle internodal tract of Wenckebach, and the posterior internodal tract of Thorel. Conduction also occurs
through atrial myocytes, but it is more rapid in these bundles.
Atrioventricular node
The AV node is situated directly on the right atrial side of the central fibrous body in the muscular portion of the
AV septum, just superior and anterior to the ostium of the coronary sinus. Measuring approximately 0.1 cm X 0.3
cm X 0.6 cm.
His bundle and bundle branches
The AV node continues onto the His bundle which follows a course along the inferior border of the membranous
septum and, near the aortic valve, gives off fibers that form the left bundle branch. The left bundle branch divides
into an anterior fascicle and a posterior fascicle. The branches and fascicles run subendocardially down either
side of the septum and come into contact with the Purkinje system, whose fibers spread to all parts of the
ventricular myocardium.
Cardiac Valves
Mitral valve
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bicuspid AV valve of the left ventricle. The AV valve has a large anterior leaflet (septal or aortic) and a smaller
posterior leaflet (mural or ventricular). The anterior leaflet is triangular with a smooth texture. The posterior leaflet
has a scalloped appearance. The chordae tendineae to the mitral valve originate from the 2 large papillary
muscles of the left ventricle and insert primarily on the leaflet's free edge.
Tricuspid valve
The AV valve of the right ventricle has anterior, posterior, and septal leaflets. The orifice is larger than the mitral
orifice and is triangular. The tricuspid valve leaflets and chordae are more fragile than those of the mitral valve.
The anterior leaflet, largest of the 3 leaflets, often has notches. The posterior leaflet, smallest of the 3 leaflets, is
usually scalloped. The septal leaflet usually attaches to the membranous and muscular portions of the ventricular
septum. The right atrioventricular orifice is the large oval aperture of communication between the right atrium and
ventricle. Situated at the base of the ventricle, it measures about 4 cm. in diameter and is surrounded by a fibrous
ring.
Aortic valve
The aortic valve has 3 leaflets composed of fragile cusps and the sinuses of Valsalva. Thus, the valve apparatus
is composed of 3 cuplike structures that are in continuity with the membranous septum and the mitral anterior
leaflet. The aortic sinuses of Valsalva are 3 dilations of the aortic root that arise from the 3 closing cusps of the
aortic valve. The right and left sinuses give rise to the right and left coronary arteries; the noncoronary sinus has
no coronary artery. The sinus of Valsalva walls are much thinner than the aortic wall, which is a factor of surgical
significance; therefore, aortotomies are typically performed away from this region.
Pulmonary valve
As with the aortic valve, the pulmonary valve has 3 cusps, with a midpoint nodule at the free end and lunulae on
either side; a sinus is located behind each cusp.
Coronary Arteries
4 main arteries: the left main, the left anterior descending, and the left circumflex (LCX) arteries (which are all
branches of the left coronary artery) and the right coronary artery (RCA). The RCA and LCXs form a circle
around the atrioventricular (AV) sulci. The left anterior descending and posterior descending arteries form a loop
at right angles to this circle; these arteries feed the ventricular septum. The LCX gives off several parallel, obtuse,
marginal arteries that supply the posterior left ventricle. The diagonal branches of the left anterior descending
artery supply the anterior portion of the left ventricle.
The term dominance is used to refer to the origin of the posterior descending artery (PDA). When the PDA is
formed from the terminal branch of the RCA (>85% of patients), it is termed a right-dominant heart. A left-
dominant heart receives its PDA blood supply from a left coronary branch, usually the LCX. This is often referred
to as a left posterolateral branch (LPL).
Left main coronary artery
Typically is 1-2 cm in length. When it reaches the left AV groove, the LCA bifurcates into the left anterior
descending (LAD) and the LCX branches. The LCA supplies most of the left atrium, left ventricle, interventricular
septum, and AV bundles.
Left anterior descending artery
runs along the anterior interventricular sulcus and supplies the apical portion of both ventricles. Gives rise to 4-6
perpendicular septal branches which supply the interventricular septum. toward the apex, it turns sharply to
anastomose with the posterior interventricular branch of the RCA. As the LAD artery courses anteriorly along the
ventricular septum, it sends off diagonal branches to the lateral wall of the left ventricle.
Left circumflex artery
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The LCX artery courses in the coronary groove around the left border of the heart to the posterior surface of the
heart to anastomose to the end of the RCA. The atrial circumflex artery, the first branch off the LCX artery,
supplies the left atrium. The LCX artery gives off an obtuse marginal (OM) branch at the left border of the heart
near the base of the left atrial appendage to supply the posterolateral surface of the left ventricle. In fewer than
40% of patients, the sinus node artery may originate from the LCX artery.
Right coronary artery
The RCA is a single large artery that courses along the right AV groove. The RCA supplies the right atrium, right
ventricle, interventricular septum, and the SA and AV nodes. In 60% of patients, the first branch of the RCA is the
sinus node artery. As the RCA passes toward the inferior border of the heart, it gives off a right marginal branch
that supplies the apex of the heart. After this branching, the RCA turns left to enter the posterior interventricular
groove to give off the PDA, which supplies both ventricles.
The AV node artery arises from the "U-turn" of the RCA at the crux (ie, the junction of the AV septum with the AV
groove). Terminal branches of the RCA supply the posteromedial papillary muscle of the left ventricle. (The LAD
artery supplies the anterolateral papillary muscle of the right ventricle.)
Cardiac innervations:
The SA node develops from structures on the right side of the embryo and the AV node from
structures on the left. This is why in the adult the right vagus is distributed mainly to the SA node
and the left vagus mainly to the AV node. Similarly, the sympathetic innervation on the right side is
distributed primarily to the SA node and the sympathetic innervation on the left side primarily to the
AV node. On each side, most sympathetic fibers come from the stellate ganglion. Noradrenergic
fibers are epicardial, whereas the vagal fibers are endocardial. However, connections exist for
reciprocal inhibitory effects of the sympathetic and parasympathetic innervation of the heart on
each other. Thus, acetylcholine acts presynaptically to reduce norepinephrine release from the
sympathetic nerves, and conversely, neuropeptide Y released from noradrenergic endings may
inhibit the release of acetylcholine. The parasympathetic system acts via M2 receptors & decreases
cAMP while sympathetic system acts via β1 receptors & increases cAMP. The parasympathetic
nerves are distributed mainly to nodes, to a lesser extent to atria and very little directly to the
ventricles. The sympathetic nerves are distributed to all parts of the heart.
Pericardium
The heart is separated from the rest of the thoracic viscera by the pericardium. The myocardium
itself is covered by the fibrous epicardium. The pericardial sac normally contains 5-30 mL of clear
fluid, which lubricates the heart and permits it to contract with minimal friction. The pericardium is a
conical fibro-serous sac, in which the heart and the roots of the great vessels are contained. It is
placed behind the sternum and the cartilages of the third, fourth, fifth, sixth, and seventh ribs of the
left side, in the mediastinal cavity.
In front, it is separated from the anterior wall of the thorax, in the greater part of its extent, by the
lungs and pleuræ; but a small area, somewhat variable in size, and usually corresponding with the
left half of the lower portion of the body of the sternum and the medial ends of the cartilages of the
fourth and fifth ribs of the left side, comes into direct relationship with the chest wall. The lower
extremity of the thymus, in the child, is in contact with the front of the upper part of the
pericardium. Behind, it rests upon the bronchi, the esophagus, the descending thoracic aorta, and
the posterior part of the mediastinal surface of each lung. Laterally, it is covered by the pleuræ, and
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is in relation with the mediastinal surfaces of the lungs; the phrenic nerve, with its accompanying
vessels, descends between the pericardium and pleura on either side.
Although the pericardium is usually described as a single sac, an examination of its structure shows
that it consists essentially of two sacs intimately connected with one another, but totally different in
structure. The outer sac, known as the fibrous pericardium, consists of fibrous tissue. The inner sac,
or serous pericardium, is a delicate membrane which lies within the fibrous sac and lines its walls; it
is composed of a single layer of flattened cells resting on loose connective tissue. The heart
invaginates the wall of the serous sac from above and behind, and practically obliterates its cavity,
the space being merely a potential one.
The fibrous pericardium forms a flask-shaped bag, the neck of which is closed by its fusion with the
external coats of the great vessels, while its base is attached to the central tendon and to the
muscular fibers of the left side of the diaphragm.
Above, the fibrous pericardium not only blends with the external coats of the great vessels, but is
continuous with the pretracheal layer of the deep cervical fascia. By means of these upper and lower
connections it is securely anchored within the thoracic cavity. It is also attached to the posterior
surface of the sternum by the superior and inferior sternopericardiac ligaments; the upper passing to
the manubrium, and the lower to the xiphoid process.
The serous pericardium is, as already stated, a closed sac which lines the fibrous pericardium and is
invaginated by the heart; it therefore consists of a visceral and a parietal portion. The visceral
portion, or epicardium, covers the heart and the great vessels, and from the latter is continuous with
the parietal layer which lines the fibrous pericardium. The portion which covers the vessels is
arranged in the form of two tubes. The aorta and pulmonary artery are enclosed in one tube, the
arterial mesocardium. The superior and inferior venæ cavæ and the four pulmonary veins are
enclosed in a second tube, the venous mesocardium, the attachment of which to the parietal layer
presents the shape of an inverted U. The cul-de-sac enclosed between the limbs of the U lies behind
the left atrium and is known as the oblique sinus, while the passage between the venous and arterial
mesocardia—i.e., between the aorta and pulmonary artery in front and the atria behind—is termed
the transverse sinus.
describe the normal pressure and flow patterns (including velocity profiles)
of the cardiac cycle
The figure shows electrical and mechanical events of cardiac cycle:
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The cardiac events that occur from the beginning of one heartbeat to the beginning of the next are
called the cardiac cycle. Duration of one cardiac cycle is usually 0.8 sec, & consist systole & diastole
which are further divided as follows:
Phases of systole:
1. Isovolumetric contraction (0.05 sec) – lasts from mitral valve closure until opening of aortic
valve. Immediately after ventricular contraction begins, the ventricular pressure rises abruptly,
causing the A-V valves to close. Then an additional 0.02 to 0.03 second is required for the
ventricle to build up sufficient pressure to push the semilunar (aortic and pulmonary) valves
open against the pressures in the aorta and pulmonary artery. Therefore, during this period,
contraction is occurring in the ventricles, but there is no emptying.
1. Isotonic contraction (0.18 sec) – separated into phase of rapid ejection (0.1) & phase of
reduced ejection (0.08 sec). When the left ventricular pressure rises slightly above 80 mm Hg
(and the right ventricular pressure slightly above 8 mm Hg), the ventricular pressures push
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the semilunar valves open. Immediately, blood begins to pour out of the ventricles, with about
70 per cent of the blood emptying occurring during the first third of the period of ejection and
the remaining 30 per cent emptying during the next two thirds. Therefore, the first third is
called the period of rapid ejection, and the last two thirds, the period of slow ejection.
2. Protodiastole (0.04 sec) – ejection has finished & pressure starts to fall until aortic valve
closes
Phases of diastole:
1. Isovolumetric relaxation (0.03-0.06): lasts from closure of the aortic valve until the mitral
valve opens
2. Rapid filling phase: blood flows rapidly into the ventricles. The period of rapid filling lasts for
about the first third of diastole.
3. Distasis (reduced filling): During the middle third of diastole, only a small amount of blood
normally flows into the ventricles; this is blood that continues to empty into the atria from the
veins and passes through the atria directly into the ventricles.
4. Atrial systole: During the last third of diastole, the atria contract and give an additional thrust
to the inflow of blood into the ventricles; this accounts for about 20 per cent of the filling of the
ventricles during each heart cycle.
Pressure Changes in the Atria:
The a wave: caused by atrial contraction. Ordinarily, the right atrial pressure increases 4 to 6 mm Hg during atrial
contraction, and the left atrial pressure increases about 7 to 8 mm Hg.
The c wave: occurs when the ventricles begin to contract; it is caused partly by slight backflow of blood into the
atria at the onset of ventricular contraction but mainly by bulging of the A-V valves backward toward the atria
because of increasing pressure in the ventricles. Pressure drop after c wave is x descent.
The v wave: results from slow flow of blood into the atria from the veins while the A-V valves are closed during
ventricular contraction. Then, when ventricular contraction is over, the A-V valves open, allowing this stored atrial
blood to flow rapidly into the ventricles and causing the v wave to disappear. Pressure drop after c wave is y
descent.
Pressure Changes in the Aorta:
Opening of semilunar valves allows blood to immediately flow out of the ventricle hence the pressure
in the ventricle rises much less rapidly. The entry of blood into the arteries causes the walls of these
arteries to stretch and the pressure to increase to about 120 mm Hg. Next, at the end of systole, after
the left ventricle stops ejecting blood and the aortic valve closes, the elastic walls of the arteries
maintain a high pressure in the arteries, even during diastole. A so-called incisura occurs in the aortic
pressure curve when the aortic valve closes. This is caused by a short period of backward flow of
blood immediately before closure of the valve, followed by sudden cessation of the backflow. After the
aortic valve has closed, the pressure in the aorta decreases slowly throughout diastole because the
blood stored in the distended elastic arteries flows continually through the peripheral vessels back to
the veins. Before the ventricle contracts again, the aortic pressure usually has fallen to about 80 mm
Hg (diastolic pressure). The pressure curves in the right ventricle and pulmonary artery are similar to
those in the aorta, except that the pressures are only about one sixth as great.
Relationship of the Electrocardiogram to the Cardiac Cycle
The P wave is caused by spread of depolarization through the atria, and this is followed by
atrial contraction, which causes a slight rise in the atrial pressure curve immediately after the
electrocardiographic P wave.
About 0.16 second after the onset of the P wave, the QRS waves appear as a result of
electrical depolarization of the ventricles, which initiates contraction of the ventricles and
causes the ventricular pressure to begin rising, as also shown in the figure. Therefore, the
QRS complex begins slightly before the onset of ventricular systole.
ventricular T wave: This represents the stage of repolarization of the ventricles when the
ventricular muscle fibers begin to relax. Therefore, the T wave occurs slightly before the end
of ventricular contraction.
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Explain the ionic basis of spontaneous electrical activity of cardiac muscle cells (automaticity)
Cardiac action potential (normal duration 250 ms): Figure shows the cardiac action potential
with 4 phases & ionic currents:
PHASE 0: Resting membrane has potential is close to -90mv. Depolarization to threshold
voltage results in opening of the activation gates of the sodium channels. These are now
active. Na diffuses in rapidly across electrochemical gradient and membrane rapidly reaches
the sodium equilibrium potential Ena (about +70 MV). The sodium current is brief as the
opening of activation gate is followed by the closure of the inactivation gate. Inactivation gate
(h) have voltage dependent function. They begin to close between -70 to - 55 mv and begin to
recover from -55 to -70 mv.
PHASE 1 & 2: The action potential plateau (phases 1 and 2) reflects the turning off of most of
the sodium current, the waxing and waning of calcium current, and the slow development of a
repolarizing potassium current. Most calcium channels become activated and inactivated in
what appears to be the same way as sodium channels, but in the case of the most common
type of cardiac calcium channel (the "L" type), the transitions occur more slowly and at more
positive potentials.
PHASE 3: (repolarization phase) results from completion of sodium and calcium channel
inactivation and the growth of potassium permeability, so that the membrane potential once
again approaches the potassium equilibrium potential close to -90mv. The major potassium
currents involved in phase 3 repolarization include a rapidly activating potassium current (IKr)
and a slowly activating potassium current (IKs). These two potassium currents are sometimes
discussed together as "IK.”
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PHASE 4: is the resting membrane potential. This is the period that the cell remains in until it is
stimulated by an external electrical stimulus (typically an adjacent cell). This phase of the action
potential is associated with diastole of the chamber of the heart. In addition to stimulus from
adjacent cells, certain cells of the heart have the ability to undergo spontaneous depolarization,
in which an action potential is generated without any influence from nearby cells
There are two types of action potential seen in heart: (Also see comparison table in Kerry pg 88)
Fast response fibres ( cardiac muscle & HIS Slow response fibres (SA & AV nodes)
purkinje system)
SA node and AV node have resting membrane potential in the range of – 50 to -70 mv hence all
na channels are inactivated. Such depolarized cells exhibit “slow responses” – slow upstroke
velocity and slow conduction – which depends on calcium inward current. Other relatively
depolarized cells exhibiting slow depolarization & conduction include cells exposed to
hyperkalemia, sodium pump blockade, or ischemic cells.
Pacemaker Potentials: Rhythmically discharging cells (eg SA & AV nodes)have a membrane
potential that, after each impulse, declines to the firing level. Thus, this prepotential or
pacemaker potential triggers the next impulse. At the peak of each impulse, IK begins and brings
about repolarization. IK then declines, and as K+ efflux decreases, the membrane begins to
depolarize, forming the first part of the prepotential. Ca2+ channels then open. These are of two
types in the heart, the T (for transient) channels and the L (for long-lasting) channels. The
calcium current (ICa) due to opening of T channels completes the prepotential, and ICa due to
opening of L channels produces the impulse.
Describe the normal and abnormal processes of cardiac excitation
Normal process of cardiac excitation:
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SA node is the normal pacemaker of heart. It has the steepest phase 4 pacemaker current &
hence depolarizes first. Depolarization initiated in the SA node spreads radially through the
atria, then converges on the AV node. Atrial depolarization is complete in about 0.1 s. Because
conduction in the AV node is slow, there is a delay of about 0.1 s (AV nodal delay) before
excitation spreads to the ventricles. This delay is shortened by stimulation of the sympathetic
nerves to the heart and lengthened by stimulation of the vagi. From the top of the septum, the
wave of depolarization spreads in the rapidly conducting Purkinje fibers to all parts of the
ventricles in the 0.08-0.1 s. In humans, depolarization of the ventricular muscle starts at the left
side of the interventricular septum and moves first to the right across the midportion of the
septum. The wave of depolarization then spreads down the septum to the apex of the heart. It
returns along the ventricular walls to the AV groove, proceeding from the endocardial to the
epicardial surface. The last parts of the heart to be depolarized are the posterobasal portion of
the left ventricle, the pulmonary conus, and the uppermost portion of the septum. The velocity
of conduction of the excitatory action potential signal along both atrial and ventricular muscle
fibers is about 0.3 to 0.5 m/sec. The velocity of conduction in the Purkinje fibers—is as great as 4
m/sec. The conduction velocity across SA & AV node is 0.05m/sec. The normal refractory period
of the ventricle is 0.25 to 0.30 second, which is about the duration of the prolonged plateau
action potential. There is an additional relative refractory period of about 0.05 second during
which the muscle is more difficult than normal to excite but nevertheless can be excited by a
very strong excitatory signal.
Abnormal process of cardiac excitation: (Arrythmias)
Abnormal automaticity:
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Non-pacemaker cells begin to spontaneously and abnormally initiate an impulse, believed to
be the result of reduced (more positive) RMP bringing it closer to the threshold potential. Eg.
Ischemia and electrolyte imbalances
Acceleration of pacemaker discharge, brought about by increased phase 4 depolarization
slope. Eg. hypokalemia, β stimulation, positive chronotropic drugs, fibre stretch, acidosis and
partial depolarization by currents of injury.
After depolarization (or triggered activity): Spontaneous depolarizations requiring a preceding
impulse (a triggering beat)
• Early after depolarizations (EAD): After depolarizations originating during phase 2 or 3 of
the AP. Seen with prolonged action potential eg. Prolongation of QT interval (repolarization)
by inhibition of delayed rectifier potassium current (sotalol, quinidine, dofetilide and
procainamide). Torsade de pointe (TdP), a potentially lethal polymorphic ventricular
arrhythmia, is an example of EAD, precipitated by K+channel blockers
• Delayed afterdepolarization (DAD): After depolarizations originating during phase 4 of AP.
Ventricular arrhythmias secondary to digoxin toxicity is an example of delayed
afterdepolarization. Digoxin mediated increased intracellular Ca++ is believed to be the
mechanism of this type of arrhythmia.
Disorders of impulse conduction: Most common mechanism of arrhythmias.
conduction block: 1st , 2nd & 3rd degree heart block
reentry:
o Impulse recirculates in the heart and cause repititive activation
o Pre-requisites:
Propagating impulse encounters electrophysiologically inhomogeneous
tissue with unidirectional block allowing retrograde conduction
retrograde conducting impulse encounters excitable tissue
o Examples of reentrant arrhythmias: AV nodal reentrant tachycardia (AVNRT),
Atrioventricular reentrant tachycardia (AVRT), Atrial flutter, Atrial fibrillation,
Ventricular tachycardia.
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To explain the physiological basis of the electrocardiograph in normal and common
pathological states
Normal electrocardiograph:
Feature Description Duration
During normal atrial depolarization, the main electrical vector is directed from the SA
P wave node towards the AV node, and spreads from the right atrium to the left atrium. This 80ms
turns into the P wave on the ECG.
PR 150 to
The PR segment connects the P wave and the QRS complex.
segment 200ms
QRS The QRS complex is a recording of a single heartbeat on the ECG that corresponds to 70 to
complex the depolarization of the right and left ventricles. 110ms
ST The ST segment connects the QRS complex and the T wave. Is iso-electric. Represents 80 to
segment period when ventricles are depolarized. 120ms
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The T wave represents the repolarization (or recovery) of the ventricles. The interval
from the beginning of the QRS complex to the apex of the T wave is referred to as
T wave 160ms
the absolute refractory period. The last half of the T wave is referred to as the relative
refractory period (or vulnerable period).
PR The PR interval is measured from the beginning of the P wave to the beginning of the 120 to
interval QRS complex. Represents AV nodal conduction delay. 200ms
ST
The ST interval is measured from the J point to the end of the T wave. 320ms
interval
QT The QT interval is measured from the beginning of the QRS complex to the end of the T 300 to
interval wave. Represents the entire period of depolarization & repolarization of the ventricles. 440ms
The U wave is not always seen. It is typically small, and, by definition, follows the T
U wave
wave.
ECG in common pathological states
Pathological state ECG finding Mechanism
Abnormal potential
Pericardial effusion Low voltage complexes Fluid decreases conduction
Tamponade
Old infarcts Less myocardial mass
Emphysema Parenchymal Air decreases
conduction
Axis Deviation
Left ventricle hypertrophy Left axis deviation 1. Larger myocardium
LBBB increased action
Right ventricle hypertrophy Right axis deviation potential
RBBB 2. Greater time to
depolarize
Abnormal P wave
Left atrial hypertrophy P mitrale (biphasic p wave) Mechanisms similar to
ventricular hypertrophy
Right atrial hypertrophy P pulmonale (tall p wave)
Abnormal PR interval
Abnormal QRS complex
Hypertrophic/dilated heart Broad QRS Increased mass/increased
Purkinje block syndromes path of depolarization
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Ventricular ectopics Broad, bizarre QRS Normal pattern of
depolarization lost
Abnormal QT
Abnormal T wave
Chronic progressive ischemia Inverted t waves Slow conduction, abnormal
Hyperkalemia repolarization
Digitalis overdose Earliest sign: biphasic t
waves
Current of injury
Mechanical trauma ST changes Damaged myocardium
Infectious process remains partially or totally
Ischemia depolarized, resulting in flow
of current (current of injury)
to adjacent myocardium
when it begins repolarizing.
NSTEMI ST depression
STEMI ST elevation
Anterior wall MI V1-V4 ST changes
Lateral wall MI I, aVL, V5, V6 ST changes
Inferior wall MI II, III, aVF ST changes
Electrolyte disorder ECG changes
Hyperkalemia Tall peaked T waves
Flattening p-waves. In extreme hyperkalemia p-waves
may disappear altogether.
Prolonged depolarization leading to QRS widening
(nonspecific intraventricular conduction defect)
sometimes > 0.20 seconds
At concentrations > 7.5 mmol/L atrial and ventricular
fibrillation can occur
Hypokalemia ST depression and flattening of the T wave
Negative T waves
A U-wave may be visible
Hypercalcemia mild: broad based tall peaking T waves
severe: extremely wide QRS, low R wave, disappearance
of p waves, tall peaking T waves.
Hypocalcemia narrowing of the QRS complex
reduced PR interval
T wave flattening and inversion
prolongation of the QT-interval
prominent U-wave
prolonged ST and ST-depression
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drugs ecg
Quinidine, Low voltage T waves (or T wave inversion)
phenothiazines and ST segment depression
tricyclic Prolonged Q-T interval
antidepressants Increased height of U wave
Widening and notching of P waves
Toxic doses of quinidine may cause widened QRS complexes, heart
block, VT and VF.
Lidocaine No effects at therapeutic doses. Toxic doses may cause sinus
tachycardia, sinus arrest and AV block.
Diphenylhydantoin No noticeable changes occur at normal doses. Occasionally, an
(Phenytoin) increase in PR interval may be seen. With pre-existing severe
myocardial disease, the drug has been associated with bradycardia,
A-V block, asystole or VF.
Amiodarone Prolongation of the Q-T interval and increase in the height of the U
waves occurs. This correlates with its effect of prolongation of the
action potential.
Verapamil slowing of the sinus rate and AV conduction (hence, a prolonged PR
interval). The effects of verapamil on the SA and AV nodes are
additive with beta-blocking drugs. The use of these two together
can give rise to catastrophic bradycardias.
Digoxin Digoxin can induce direct and indirect changes on the heart. The
direct changes are due to inhibition of the normal active process of
sodium ion transport (and also potassium ion transport) across the
membranes of myocardial and pacemaker cells. Digoxin induces
indirect changes by increasing the vagal tone.
Therapeutic doses produce ECG changes in a patient taking digitalis.
These changes are referred to as the "digoxin effect". These
changes are:
1) Decreased T wave amplitude
2) ST segment depression
3) Increase in U wave amplitude
4) Shortening of the Q-T interval
One of the earliest and commonest changes is reduction in T wave
voltage. Occasionally, biphasic or inverted T waves may be seen.
ST segment changes are seen as a downward sloping ST segment
depression, which is often associated with T wave flattening. This is
called the "reversed tick" phenomenon (resembles the tick made by
a left-handed person).
Digoxin toxicity:
16
The following arrhythmias are seen commonly:
1) Ventricular premature beats (including coupled and multifocal
VPCs)
2) Junctional tachycardia
3) Sinus bradycardia
4) Atrial tachycardia with A-V block
5) Heart blocks (1st degree, 2nd degree Mobitz Type I and 3rd
degree)
6) Multifocal atrial premature beats
7) Atrial fibrillation and flutter
8) SA block and sinus arrest
9) VF and VT
Drugs causing prolonged QT:
Antibiotics Anaesthetics Antipsychotics
azithromycin halothane risperidone
clarithromycin fluphenazine
erythromycin Antiarrhythmics haloperidol
roxithromycin disopyramide clozapine
metronidazole procainamide thioridiazine
(with alcohol) quinidine ziprasidone
Some fluroquinolone amiodarone pimozide
sotalol droperidol
Antifungals
fluconazole Antidepressants Antihistamines
(in cirrhosis) amitriptyline terfenadine*
ketoconazole clomipramine astemizole*
imipramine
Antivirals dothiepin Other
nelfinavir doxepin probucol
cisapride
Antimalarials
chloroquine
mefloquine
Describe the factors that may influence cardiac electrical activity
Factors affecting electrical activity:
1. Nervous system
2. Electrolytes
3. Drugs
4. Temperature
5. Anatomical alterations:
17
a. Myocardial ischemia/infarction
b. Aberrant pathway
c. Bundle branch blocks
Nervous system:
(Also read the nerve supply under anatomy question)
Nodal tissue especially SA node is heavily innervated by both PANS (acetylcholine) & SANS
(norepinephrine) fibres activating M2 & b1 receptors respectively
Phase 4 slope is increased by an increase in cAMP resulting from b1 receptor activation and
slowed by a decrease in cAMP resulting from M2 receptor activation
Increase in cAMP will:
- Increase upstroke velocity in pacemaker by increase of iCa
- Shorten AP duration by increase of IK
- Increase HR by increase of Ina, thus increasing slope of phase 4
Decrease in cAMP will:
- Does the opposite plus produces a K+ current (IKIACh), which produces
hyperpolarization and slows the rate of diastolic depolarization and thus decreases
HR by both SA & AV nodal depression. Strong vagal stimulation can cause complete
heart block with ventricular escape.
- Beta blockers prevent cAMP formation, with primary effects on SA & AV nodal
tissues.
Electrolyte disorder Effect on cardiac electrical activity
Hyperkalemia The faster repolarization of the cardiac action potential causes
the tenting of the T waves, and the inactivation of sodium
channels causes a sluggish conduction of the electrical wave
around the heart, which leads to smaller P waves and widening
of the QRS complex. Bradycardia can occur.
Hypokalemia In the heart, it causes myocytes to become hyperexcitable.
Lower membrane potentials in the atrium may cause
arrhythmias because of more complete recovery from sodium-
channel inactivation, making the triggering of an action potential
more likely. In addition, the reduced extracellular potassium
(paradoxically) inhibits the activity of the IKr potassium current
and delays ventricular repolarization. This delayed repolarization
may promote reentrant arrythmias.
Hypocalcemia prolongs phase 2 of the action potential. See ecg changes in
previous question
Hypercalcemia See ecg changes in previous question
Drugs Effect on action potential Effect on ECG
Class I A (Quinidine, Slow phase 0 depolarization, Supress AV conduction, prolong
procainamide, prolong APD PR, QRS, QT
disopyramide)
18
Class I B (lidocaine, Shorten phase 3 Usually no ECG changes
tocainide, mexiletine) repolarization & decrease
APD
Class IC (Flecainide, Markedly slow phase 0 Markedly delays conduction,
propafenone) depolarization. variable prolong PR, broaden QRS
effect on APD
B blockers Slow phase 4 depolarization Prolong PR, decreased HR
Class III (sotalol, Prolong phase 3 Prolonged QT
amiodarone) repolarization
CCB – verapamil & Slow phase 4 spontaneous Prolonged PR
diltiazem depolarization
Effect of temperature:
Increased body temperature, causes a greatly increased heart rate, sometimes to as fast as
double normal. Decreased temperature causes a greatly decreased heart rate. These effects
presumably result from the fact that heat increases the permeability of the cardiac muscle
membrane to ions that control heart rate, resulting in acceleration of the self-excitation
process.
Anatomical alterations:
a. Myocardial ischemia/infarction: results in current of injury. Reperfusion
injury produces increased automaticity and ectopics. Re-entry arrhythmias.
Scarred myocardium can delay in conduction or can lead to re-entry circuits.
b. Aberrant pathway: eg VPW syndrome can cause AV reentrant tachycardias
c. Bundle branch blocks: primarily result in delayed conduction.
Explain the Frank-Starling mechanism and its relationship to excitation-contraction coupling
Frank-Starling law: "energy of contraction is proportional to the initial length of the cardiac
muscle fiber."
For the heart, the length of the muscle fibers (ie, the extent of the preload) is proportionate
to the end- diastolic volume.
Increased venous return increases the end-diastolic volume and therefore preload, which is
the initial stretching of the cardiac myocytes prior to contraction. Myocyte stretching
increases the sarcomere length, which causes an increase in force generation. Increasing the
sarcomere length increases troponin C calcium sensitivity, which increases the rate of cross-
bridge attachment and detachment, and the amount of tension developed by the muscle
fiber. The effect of increased sarcomere length on the contractile proteins is termed length-
dependent activation.
This ability of the heart to change its force of contraction and therefore stroke volume in
response to changes in venous return is called the Frank-Starling mechanism. The
mechanism is very important for:
1. Rapidly responding to acute changes in venous return
19
2. Keeping the right and left ventricle outputs exactly equal
The relation between ventricular stroke volume and end-diastolic volume is called the
Frank-Starling curve.
Positive inotropic effect
Negative inotropic effect
Frank-Starling curves however, does not show how changes in venous return affect end-
diastolic and end-systolic volume. In order to do this, it is necessary to describe ventricular
function in terms of pressure-volume diagrams. The increased stroke volume is manifested
by an increase in the width of the pressure-volume loop.
Steps in excitation contraction coupling:
1. Action potential spreads from the cell membrane into the T tubules
2. Inward calcium current: During the plateau of action potential, Ca2+ conductance is
increased and calcium enters the cell from the extracellular fluid
3. Ca2+ induced Ca2+ release: the Ca2+ entry triggers release of even more Ca2+ from
the sarcoplasmic reticulum. The amount of calcium released from SR depends upon
the amount of calcium stored and on the size of inward current during the plateau
phase
20
4. Net intracellular calcium increases
5. Ca2+ binds to troponin C: & tropomyosin is moved out of the way, removing the
inhibition of actin and myosin binding.
6. Actin and myosin bind: Thick and thin filament slide past each other and myocardial
cell contracts. The magnitude of tension is proportional to intracellular calcium
7. Relaxation occurs when Ca2+ is re-accumulated by the SR by an active Ca2+ - ATPase
pump
Define preload, afterload and myocardial contractility
Preload: is the load on myocardial cell just before the onset of contraction. The pre-load is
said to be initial fiber length.
After load: is the impedance to the ejection of blood from the heart into the arterial
circulation.
Myocardial contractility: is the intrinsic ability of the cardiac muscle to develop force at a given
muscle length independent of changes in HR or After-load.
Describe the factors that determine preload, afterload and myocardial contractility
Factors determining preload:
Factors that normally increase or decrease the length of ventricular cardiac muscle fibers.
Increase Preload (increased venous return)
Stronger atrial contractions : Atrial contractions aid ventricular filling
Increased total blood volume : An increase in total blood volume increases venous
return.
Increased venous tone : Constriction of the veins reduces the size of the venous
reservoirs, decreasing venous pooling and thus increasing venous return
Increased pumping action of skeletal muscle : muscular activity increases it as a
result of the pumping action of skeletal muscle.
Increased negative intrathoracic pressure : An increase in the normal negative
intrathoracic pressure increases the pressure gradient along which blood flows to
the heart, whereas a decrease impedes venous return
Decrease Preload (decreased venous return)
Standing : Standing decreases venous return
Increased intrapericardial pressure
Decreased ventricular compliance : An increase in ventricular stiffness produced
by myocardial infarction, infiltrative disease, and other abnormalities
Factors determining Afterload:
Afterload is related to ventricular wall stress (σ), where
21
(P, ventricular pressure; r, ventricular radius; h, wall thickness).
This relationship is similar to the Law of LaPlace, which states that wall tension (T) is proportionate to the pressure (P) times
radius (r) for thin-walled spheres or cylinders. Therefore, wall stress is wall tension divided by wall thickness.
Determinants of after load:
Systemic vascular resistance
Aortic root impedance
Transmural pressure across ventricular wall: Myocardium has to contract against a
negative intrathoracic pressure which constantly produces outward pull on
myocardium.
Ventricular wall thickness: A hypertrophied ventricle (thickened wall) reduces wall
stress and afterload. The thicker the wall, the less tension experienced by each
sarcomere unit.
Ventricular radius: At a given pressure, wall stress and therefore afterload are
increased by an increase in ventricular inside radius (ventricular dilation).
Factors determining myocardial contractility:
Factors that increase contractility:
1. Increased heart rate: Increased HR increased frequency of action potential more
Ca2+ enters cellmore Ca2+ released from SR and greater tension is produced.
Examples:
a. Positive staircase or bowditch staircase. Increased HR increases the force of
contraction in a stepwise fashion as the intracellular Ca2+ increases
cumulatively over several beats
b. Post extrasystolic potentiation: beat after extrasystole has increased force of
contraction because extra Ca2+ enters during extrasystole.
2. Sympathetic stimulation via b1 receptors increases contractility by two mechanisms:
a. Increases inward Ca2+ current during the plateau of each action potential
b. Increases the activity of Ca2+ pump of SR by phosphorylation of
phasopholamban resulting in more accumulation and subsequent release of
Ca2+
3. Cardiac glycosides: inhibits Na K ATPaseintracellular Na+ increasesdiminished
Na+ gradientinhibits Na-Ca exchange that extrudes Ca2+ out of cell and depends
on Na gradient.
4. Xanthines such as caffeine and theophylline that inhibit the breakdown of cAMP are
positively inotropic. Glucagon, which increases the formation of cAMP, is positively
inotropic.
Factors that decrease contractility:
22
1. Parasympathetic stimulation: via M2 receptor decreases the force of contraction in
the atria by decreasing the inward Ca2+ current during the plateau phase of the
action potential.
2. Hypercapnia, hypoxia, acidosis
3. Drugs such as quinidine, procainamide, and barbiturates
4. The contractility of the myocardium is also reduced in heart failure (intrinsic
depression). The cause of this depression is not known.
Describe myocardial oxygen demand and supply, and the conditions that may alter each
MYOCARDIAL OXYGEN DEMAND
The basal myocardial O2 consumption in asystole: 2 mL/100 g/min.
O2 consumption by the beating heart is about 9 mL/100 g/min at rest.
Cardiac venous O2 tension is low i.e PO2 of 20mmhg , and little additional O2 can be
extracted from the blood in the coronaries, so increases in O2 consumption require
increases in coronary blood flow.
Tension time index: Area under the systolic part of LV pressure time curve.
Correlates well with the myocardial oxygen consumption
Determinants of myocardial oxygen consumption:
o Major determinants:
Myocardial wall tension: law of Laplace states that the tension
developed in the wall of a hollow viscus is proportionate to the radius
of the viscus, and the radius of a dilated heart is increased. Hence
increased pre-load also leads to increased O2 consumption.
23
Contractility
Heart rate- O2 consumption per unit time increases when the heart
rate is increased by sympathetic stimulation because of the increased
number of beats and the increased velocity and strength of each
contraction.
o Minor determinants:
Basal energy metabolism (25% of total O2 consumption)
External work performed: Work is measured as a product of pressure
and volume. The oxygen cost of myocardial work depends on the way
the work is performed eg ‘pressure work’ like AS requires higher
myocardial oxygen consumption that ‘volume work’ like AR for the
same cardiac output.
Energy for electrical activation (1% of total O2 consumption)
MYOCARDIAL OXYGEN SUPPLY
Oxygen delivery = coronary blood flow * oxygen content
= Coronary blood flow * 1.34*Hb*SO2
Coronary blood flow:
Coronary blood flow is 200-250mls/min. This is 5% of CO
Coronary perfusion pressure: is the driving force for the coronary blood flow and is
calculated as the aortic diastolic pressure – the larger of either LV diastolic pressure
or the RA pressure (representing the coronary sinus pressure). Usually the perfusion
pressure in circulations is just the difference between the arterial and venous
pressure, however the circulations like heart, lung and brain are examples of starling
resistors where another pressure needs to be considered eg LV pressure when
calculating the perfusion pressure.
Coronary blood flow variation with the cardiac cycle:
o LV: flow predominantly during diastole. Subendocardial flow ceases during
systole.
o RV: flow during both systole and diastole, as RV pressures are low during
both systole and diastole.
Significant flow only
in diastole
Blood flow in left coronary
0
Significant flow both
in systole & diastole
Blood flow in right coronary
0
Systole Diastole
24
Most important factors regulating coronary blood flow is vasodilatation produced by
the local metabolic factors: hypoxia and adenosine. Sympathetic nerves play a minor
role.
Describe and explain cardiac output curves, vascular function curves and their correlation
Cardiac and vascular curves are simultaneous plots of cardiac output and venous return as a
function of the right atrial pressure or end diastolic volume
1. The cardiac output or the cardiac function curve
a. Depicts the frank starling relationship for the ventricle
b. Shows that cardiac output increases as a function of end diastolic
volume(primary mechanism)
2. The venous return or vascular function curve
a. Depicts the relationship between blood flow through the vascular system and
right atrial pressure
b. Mean systemic pressure:
i. Point at which vascular function curve intersects the X axis
ii. Equals the right atrial pressure when there is no flow in the
cardiovascular system
iii. Increased by increase in blood volume or by decrease in venous
compliance and is reflected by a shift of the vascular function curve to
the right
iv. Decreased by decrease in blood volume or by increase in the venous
compliance and is reflected by a shift of the vascular function curve to
the left
c. Slope of the venous return curve: determined by the resistance of the
arterioles
i. Clockwise rotation of venous return curve indicates a decrease in total
peripheral resistance (TPR). Decrease in TPR increases the venous
return
ii. Anticlockwise rotation of venous return curve indicates a increase in
TPR. Increase in TPR decreases the venous return.
3. Combining cardiac output & venous return curves
a. The point at which the two curves intersect is the equilibrium or the steady
state point Here the cardiac output equals venous return
b. Cardiac output can be changed by altering the cardiac output curve, the
venous return curve or both the curves simultaneously. The superimposed
curves can be used to predict the direction or magnitude of changes in
cardiac output. Eg of such changes are as follows:
i. Inotropic agents change the cardiac output curve
25
1. Positive inotropic agents produce increased cardiac output.
The equilibrium point shifts to a higher CO and a
correspondingly lower RA pressure. RA pressure decreases
because more blood is ejected from the heart on each beat
2. Negative inotropic agents produce decreased contractility and
decreased CO
ii. Changes in blood volume or venous compliance
1. Increases in blood volume or decreases in venous compliance
increases mean systemic pressure, shifting the venous return
curve to the right in parallel fashion. A new equilibrium point
is established at which both cardiac output and RAP are
increased
2. Decreases in blood volume or increases in venous compliance
decrease mean systemic pressure and shift the venous return
curve to left in parallel fashion. A new equilibrium point is
established at which both cardiac output and RAP are
decreased.
iii. Changes in TPR change both the cardiac output & venous return curve
1. Increases in TPR causes a decrease in both cardiac output and
venous return. There is counterclock wise rotation of venous
return curve and there is a downward shift of the cardiac
output curve. A new equilibrium point is reached at which
both CO & venous return are decreased but right atrial
pressure is unchanged.
2. Decreasing TPR causes an increase in both CO and venous
return. There is clockwise rotation of venous return curve and
upward shift of the cardiac output curve. A new equilibrium
point is established at which both cardiac output and venous
return are increased.
26
Describe the pressure-volume relationships of the ventricles and their clinical applications
12
12- effective arterial elastance
In the above figure ‘10’ also represents end systolic elastance
Best index of preload LVEDV
Best index of afterload slope of the line joining the LVEDV on x axis to the end systolic
point. (line no. 12 in the above figure) also known as effective arterial elastance line(Ea)
27
The pressure volume graph can be used to predict the changes in pressurve volume
relationship of heart produced by changes in preload, afterload or contractility
Increased Preload
Referes to increase in end diastolic volume and is the result of increased venous
return
Causes an increase in the stoke volume based on frank starling mechanism and is
reflected by the increased width of the loop.
In the figure showing increased preload the afterload lines of the 2 loops are parallel
so they have same afterload. Both end systolic points are on the same contractility
line so they have same contractility
Increased afterload
Refers to increased aortic pressure
Results in the decreased stroke volume – reflected by decreased width of the
pressurve volume loop
Decrease in the stroke volume results in increased end systolic volume
In the figure the preload is same in two loops because the EDV is same and
contractility is also same as the end systolic point of the two loops are on the same
contractility line
Increased contractility
The ventricle develop greater than uisual tension during systole causing an increase
in the stroke volume represented by the increased width of the PV loop
The increase in the stroke vol. decrease the end systolic volume
In the figure the slope of the end systolic pressure volume line is increased in for the
loop 2 representing the increased contractility. The end systolic point of the two
loops are on the same afterload line hence after load is same for the loops. Preload
i.e. EDV is same for the two loops
28
Increased Preload
Increased afterload
29
Increased contractility
Describe the factors that determine cardiac output
After load Contractility Pre load
Myocardial fiber shortening Left ventricular size
Heart rate Stroke volume
Cardiac output Peripheral resistance
Arterial pressure
Interactions between the components that regulate cardiac output and arterial pressure. Solid lines
indicate increases, and the dashed line indicates a decrease.
Effect of various conditions on cardiac output.
Condition or Factor1
No change Sleep
Moderate changes in environmental temperature
30
Increase Anxiety and excitement (50-100%)
Eating (30%)
Exercise (up to 700%)
High environmental temperature
Pregnancy
Epinephrine
Decrease Sitting or standing from lying position (20-30%)
Rapid arrhythmias
Heart disease
1
Approximate percent changes are shown in parentheses.
Variations in cardiac output can be produced by changes in cardiac rate or stroke volume.
The cardiac rate is controlled primarily by the cardiac innervation, sympathetic stimulation
increasing the rate and parasympathetic stimulation decreasing it. The stroke volume is also
determined in part by neural input, sympathetic stimuli making the myocardial muscle fibers
contract with greater strength at any given length and parasympathetic stimuli having the
opposite effect.
The force of contraction of cardiac muscle is dependent upon its preloading and its
afterloading.
Preload: is the load on myocardial cell just before the onset of contraction. The pre-load is
said to be initial fiber length.
After load: is the impedance to the ejection of blood from the heart into the arterial
circulation.
Relation of Tension to Length in Cardiac Muscle
Frank starling law: "energy of contraction is proportional to the initial length of the cardiac
muscle fiber." For the heart, the length of the muscle fibers (ie, the extent of the preload) is
proportionate to the end- diastolic volume.
Regulation of cardiac output as a result of changes in cardiac muscle fiber length is
sometimes called heterometric regulation, whereas regulation due to changes in
contractility independent of length is sometimes called homometric regulation.
Increase Preload (increased venous return)
Stronger atrial contractions : Atrial contractions aid ventricular filling
Increased total blood volume : An increase in total blood volume increases venous
return.
Increased venous tone : Constriction of the veins reduces the size of the venous
reservoirs, decreasing venous pooling and thus increasing venous return
Increased pumping action of skeletal muscle : muscular activity increases it as a
result of the pumping action of skeletal muscle.
Increased negative intrathoracic pressure : An increase in the normal negative
31
intrathoracic pressure increases the pressure gradient along which blood flows to
the heart, whereas a decrease impedes venous return
Decrease Preload (decreased venous return)
Standing : Standing decreases venous return
Increased intrapericardial pressure
Decreased ventricular compliance : An increase in ventricular stiffness produced
by myocardial infarction, infiltrative disease, and other abnormalities
Factors determining Afterload:
Afterload is related to ventricular wall stress (σ), where
(P, ventricular pressure; r, ventricular radius; h, wall thickness).
This relationship is similar to the Law of LaPlace, which states that wall tension (T) is proportionate to the pressure (P) times
radius (r) for thin-walled spheres or cylinders. Therefore, wall stress is wall tension divided by wall thickness.
Determinants of after load:
Systemic vascular resistance
Aortic root impedance
Transmural pressure across ventricular wall: Myocardium has to contract against a
negative intrathoracic pressure which constantly produces outward pull on
myocardium.
Ventricular wall thickness: A hypertrophied ventricle (thickened wall) reduces wall
stress and afterload. The thicker the wall, the less tension experienced by each
sarcomere unit.
Ventricular radius: At a given pressure, wall stress and therefore afterload are
increased by an increase in ventricular inside radius (ventricular dilation).
Myocardial Contractility
The contractility of the myocardium exerts a major influence on stroke volume.
Factors that increase contractility:
5. Increased heart rate: Increased HR increased frequency of action potential more
Ca2+ enters cellmore Ca2+ released from SR and greater tension is produced.
Examples:
a. Positive staircase or bowditch staircase. Increased HR increases the force of
contraction in a stepwise fashion as the intracellular Ca2+ increases
cumulatively over several beats
b. Post extrasystolic potentiation: beat after extrasystole has increased force of
contraction because extra Ca2+ enters during extrasystole.
32
6. Sympathetic stimulation via b1 receptors increases contractility by two mechanisms:
a. Increases inward Ca2+ current during the plateau of each action potential
b. Increases the activity of Ca2+ pump of SR by phosphorylation of
phasopholamban resulting in more accumulation and subsequent release of
Ca2+
7. Cardiac glycosides: inhibits Na K ATPaseintracellular Na+ increasesdiminished
Na+ gradientinhibits Na-Ca exchange that extrudes Ca2+ out of cell and depends
on Na gradient.
8. Xanthines such as caffeine and theophylline that inhibit the breakdown of cAMP are
positively inotropic. Glucagon, which increases the formation of cAMP, is positively
inotropic.
Factors that decrease contractility:
5. Parasympathetic stimulation: via M2 receptor decreases the force of contraction in
the atria by decreasing the inward Ca2+ current during the plateau phase of the
action potential.
6. Hypercapnia, hypoxia, acidosis
7. Drugs such as quinidine, procainamide, and barbiturates
8. The contractility of the myocardium is also reduced in heart failure (intrinsic
depression). The cause of this depression is not known.
Describe the distribution of blood volume and flow in the various regional circulations and to
explain the factors that may result in redistribution of blood
33
Circulation Local Vasoactive Sympathetic control Mechanical
(% of resting metabolic metabolites effects
CO) control
Coronary (5%) Most Hypoxia Least important Mechanical
important Adenosine mechanism compression
mechanism during systole
Cerebral (15%) Most CO2 Least important Increases in
important H+ mechanism intracranial
mechanism pressure
decrease
cerebral blood
flow
Muscle (20%) Most Lactate Most important Muscular
important K+ mechanism at rest activity causes
mechanism Adenosine (αvasoconstriction, temporary
during exercise β vasodilatation) decrease in
blood flow
Skin (5%) Least Most important
important mechanism is
mechanism temperature
regulation
Pulmonary Most Hypoxia Least important Lung inflation
(100%) important vasoconstricts mechanism
mechanism
Renal (25%)
Mechanisms of Blood Flow Control
Local blood flow control can be divided into two phases:
(1) acute control : achieved by rapid changes in local vasodilation or vasoconstriction of
the arterioles, metarterioles, and precapillary sphincters,
(2) long-term control : increase or decrease in the physical sizes and numbers of actual
blood vessels supplying the tissues.
Acute Blood Flow Regulation
34
Local (intrinsic) control of blood flow:
1. Autoregulation:
a. Blood flow to the organ remains constant over wide range of perfusion
pressure
b. Organs with auto regulation: heart, brain, kidney
2. Active hyperemia:
a. Blood flow to the organ is proportional to its metabolic demand
3. Reactive hyperemia:
a. Increase in blood flow to an organ that occurs after a period of occlusion of
flow
b. The longer the period of occlusion the greater the increase in blood flow
above preocclusion levels
Mechanisms that explain local control of blood flow
1. Myogenic hypothesis:
a. explains autoregulation but not active or reactive hyperemia
b. based on observation that vascular smooth muscle contracts when it is
stretched
c. increased perfusion pressure causes stretch of the vascular smooth muscle
which contracts & produces vasoconstriction to maintain constant flow.
2. Metabolic hypothesis
a. Based on observation that tissue supply of oxygen is matched to tissue
oxygen demand
b. Vasodilator metabolites are produced as a result of metabolic activity in
tissue. These vasodilators are CO2, H+, K+, lactate and adenosine.
3. Tissue pressure theory
a. Applicabale in encapsulated organs (evidence lacking)
b. As the perfusion pressure increasesincreased extravasation of
fluidsincreased tissue hydrostataic pressuresmall vessels compressed
4. Mechanism for dilating upstream arteries when microvascular blood flow
increases— the endothelium-derived relaxing factor (nitric oxide): increase in blood
flow increase endothelial stressrelease of EDRF (i.e. NO t1/2 of 6 sec)
dilatation of arterioles decrease flow
Humoral (extrinsic) control of blood flow:
1. Sympathetic innervations of vascular smooth muscle
a. Increased sympathetic tone causes vasoconstriction
b. Decreased sympathetic tone causes vasodilatation
c. Density of innervations varies: skin has the greatest innervations, while
coronary, pulmonary, and cerebral vessels have little innervations
2. Local vasoactive hormones
a. Histamine
i. Causes arteriolar dilatation and venous constrictionincreased
capillary hydrostatic pressureedema
ii. Released in reponse to trauma
b. Bradykinin:
i. Causes arteriolar dilatation and venous constrictionincreased
capillary hydrostatic pressureedema
35
c. Serotonin
i. Arteriolar constriction
ii. Released in reponse to blood vessel trauma
iii. Implicated in vascular spasms of migrane
d. Prostaglandins:
i. Prostacyclin: vasodilator in several vascular beds
ii. E series prostaglandins: vasodilators
iii. F series prostaglandins: vasoconstrictors
iv. Thromboxane A2: vasoconstrictor
e. Endothelin:
i. A Powerful Vasoconstrictor in Damaged Blood Vessels as large as 5
millimeters.
ii. Present in the endothelial cells of all or most blood vessels, released
by damage to the endothelium
3. Systemic vasoactive hormones
a. Angiotensin II
i. powerful potent vasoconstrictor of the small arterioles.
ii. Normally acts on many of the arterioles of the body at the same time
to increase the total peripheral resistance, thereby increasing the
arterial pressure.
b. Vasopressin
i. Most potent vasoconstrictor
ii. Formed in hypothalamus transported to the posterior pituitary gland,
where it is finally secreted into the blood.
iii. Concentration of circulating blood vasopressin after severe
hemorrhage can rise high enough to increase the arterial pressure as
much as 60 mm Hg.
Long-Term Blood Flow Regulation:
Over a period of hours, days, and weeks, a long-term type of local blood flow regulation
develops
in addition to the acute regulation and gives far more complete regulation.
Mechanism of long-term local blood flow regulation is principally to change the
amount of vascularity of the tissues. If metabolic demand increases vascularization
increase and vice-versa.
Rapidity & extent of change decreases with age
Vascularity Is Determined by Maximum Blood Flow Need
Factors promoting vascularization:
o O2: Oxygen is important not only for acute control of local blood flow but
also for long-term control. Classic eg retrolental fibroplasia of neonate
developing after removal of exposure to high O2
o Angiogenic factors: Important ones vascular endothelial growth factor
(VEGF), fibroblast growth factor, and angiogenin released by the lack of O2
Explain the factors that determine systemic blood pressure and its regulation
36
Blood pressure = CO * total peripheral resistance
The most important mechanisms for regulating arterial pressure are the fast, neutrally
mediated baroreceptor mechanism and the slower hormonally regulated renin agiotensin
aldosterone mechanism.
Major mechanisms:
1. Baroreceptor reflex (Acute control)
2. Renin-angiotensin-aldosterone system (long term control)
3. Other mechanisms:
a. Cerebral ischemia
b. Chemoreceptor in carotid and aortic bodies
c. Vasopressin
d. ANP
Baroreceptor reflex
1. Includes fast neural mechanisms
2. Responsible for minute to minute regulation of arterial blood pressure
3. Produces vbasoconstrictor activity tonically which accounts for vasomotor tone
4. Baroreceptors are stretch receptors located within the wall of carotid sinus near the
bifurcation of common carotid arteries
5. STEPS:
a. Decrease in the arterial pressure decreases the stretch on the wall of carotid
sinus. Baroreceptors are more sensitive to the ‘change’ in pressure rather
than the actual pressure. Additional baro-receptors in the aortic arch respond
to increases but not to decreases in pressure
b. Decreased stretch decreases the firing of the Hering’s nerve (cranial nerve IX)
which carries signal to vasomotor centre in medulla.
c. The set point for the mean arterial pressure in the vasomotor centre is about
100mmHg. Therefore if mean arterial pressure is less than 100mmHg a series
of autonomic responses is co-ordinated by the vasomotor centre to correct
the pressure
d. The vasomotor centre responds to low pressure by decreasing
parasympathetic outflow to the heart and increasing the sympathetic outflow
to the heart and blood vessel. The results are as follows:
i. ↑ HR
ii. ↑ contractility: resulting from the increased sympathetic tone to the
heart. Increased contractility + increased HR increased
COincreased pressure
iii. ↑ TPR due to vasoconstriction secondary to ↑ sympathetic outflow
iv. ↑ venoconstriction secondary to ↑ sympathetic activity shifts
vascular function to right ↑ venous return ↑SV↑CO
37
e. Baroreceptor mechanism is a negative feedback system. As the blood
pressure picks up there will be increased stretch on the carotid sinus
baroreceptors which will decrease the signals to vasomotor centre
6. Example of baroreceptor reflex mechanism: response to acute blood loss
Renin-Angiotensin-aldosterone system
1. Slow hormonal mechanism used in long term pressure regulation by adjusting the
blood volume
2. Steps:
a. Decrease in the renal perfusion pressure causes the juxtaglomerular cells of
the afferent arteriole to secrete rennin.
b. Renin catalyzes the conversion of angiotensinogen to angiotensin I in plasma
c. ACE converts angiotensin I to physiologically active angiotensin II in lungs
d. Angiotensin II has two effects:
i. Stimulates the synthesis and secretion of aldosterone from adrenal
cortex. Aldosterone increases NaCl reabsorption by the renal distal
tubule thereby increasing blood volume and arterial pressure
ii. Causes the vasoconstriction of the arterioles thereby increasing TPR
and mean arterial pressure
Other mechanisms of arterial pressure regulation:
Cerebral ischemia
1. When the brain is ischemic the conc. Of CO2 and hydrogen ion in the brain tissue
increases
2. Chemoreceptors in the vasomotor centre respond by increasing both sympathetic
and parasympathetic outflow:
a. Ventricular contractility and TPR are increased but HR is decreased because
of overriding parasympathetic influence
b. Peripheral vasoconstriction reduces blood flow to other organs to preserve
blood flow to brain
3. Cushing’s reflex is an example of the response to cerebral ischemia. ↑ICP
compresses blood vessels and ↓ blood flow & cerebral ischemia
Chemoreceptors in carotid and aortic bodies:
1. Located near the bifurcation of common carotid arteries and along the aortic arch
2. Have very high rates of O2 consumption and therefore are very sensitive to hypoxia.
3. A decrease in arterial pressure decreases O2 delivery to the chemoreceptors. In turn,
information is sent vasomotor centre to increase BP
Vasopressin
1. Involved in regulation of blood pressure in response to hemorrhage but not in
minute to minute regulation of normal blood pressure
2. Atrial receptors respond to decreased blood pressure and cause the release of
vasopressin from posterior pituitary
38
3. Vasopressin has two affects:
a. Potent vasoconstrictor that increases TPR by V1 receptors in the arterioles
b. Increases water reabsorption by the renal distal tubules and collecting ducts
via V2 receptors
ANP
1. Released from atria in response to increase atrial pressure
2. Causes relaxation of vascular smooth muscle cells, dilatation of arterioles and
decreased TPR
3. Causes increased excretion of salt and water by the kidney, which reduces blood
volume and attempts to bring arterial pressure down to normal
4. Inhibits renin secretion
Describe total peripheral vascular resistance and factors that affect it
Vascular resistance is a term used to define the resistance to flow that must be overcome to
push blood through the circulatory system. The resistance offered by the peripheral
circulation is known as the systemic vascular resistance (SVR) or total peripheral resistance.
Units for measuring vascular resistance are dyn·s·cm-5 or pascal seconds per cubic metre
(Pa·s/m³). Pediatric cardiologists use hybrid reference units (HRU), also known as Wood
units
Measurement Reference Range
Systemic vascular resistance 900–1200 dyn·s/cm5
Pulmonary vascular resistance 100–200 dyn·s/cm5
Factors affecting peripheral resistance:
As per Ohm’s law:
Resistance = ΔP/Flow……………………………(1)
As per poiseuille’s law:
Flow = ΔPπr4/8ηL ………………………….(2)
Combining equation (1) and (2)
Resistance = 8 ηL/ πr4
Hence Resistance ηL/r4
Where,
η represents viscosity
L represents length of vessel
39
r represents radius
In other words, resistance is directly proportional to both the fluid viscosity and the
structure’s length, and inversely proportional to the fourth power of the structure’s radius.
Blood viscosity is not fixed but increases as hematocrit increases, and changes in
hematocrit, therefore, can have significant effects on the resistance to flow in certain
situations. Under most physiological conditions, however, the hematocrit and, hence,
viscosity of blood is relatively constant and does not play a role in the control of resistance.
Similarly, since the lengths of the blood vessels remain constant in the body, length is also
not a factor in the control of resistance along these vessels. In contrast, the radii of the
blood vessels do not remain constant, and so vessel radius is the most important
determinant of changes in resistance along the blood vessels. Decreasing the radius of a
tube twofold increases its resistance sixteenfold. Sympathetic nervous system would cause
generalized vasoconstriction and hence would increase TPR.
There is a parallel arrangement of organs and their circulation. This is beneficial as parallel
arrangement decreases total vascular resistance. This is because in parallel circuit,
R=1 / [(1/R1) + (1/R2) + (1/R3)]
Small arteries and arterioles are primary site of resistance.
Describe the essential features of the micro-circulation including fluid exchange (Starling
forces) and control mechanisms present in the pre- and post-capillary sphincters
Microcirculation is the term used to refer to the smallest blood vessels and include :
smallest arterioles, metarterioles, the pre-capillary sphincters, the capillaries and the
small venules.
Structural aspects:
Metarterioles branch into capillary beds. At the junction of the arterioles and
capillaries is a smooth muscle band called the pre-capillary sphincter
True capillaries do not have smooth muscle and consist only of a single layer of
endothelial cell surrounded by basement membrane
Systemic capillaries contain only about 5% of blood volume
Clefts (pores) between the endothelial cells allow passage of water solube
substances. Cleft represents very small fraction fraction of surface area ( 20%, the compensatory mechanisms become inadequate and the CO and BP
start to decrease. When the blood pressure decreases below 50mmHg CNS ischemic response is
elicited causing a powerful sympathetic stimulation. Irreversible hypotension can occur with a blood
loss greater than 30% of blood volume. Inadequate tissue perfusion leads to increased anaerobic
glycolysis with the production of large amounts of lactic acid lactic acidosis depresses the
myocardium and reduces catecholamine responsiveness in peripheral vessels.
Loss of blood volume causes the venous return curve to be shifted to the left because of fall in
systemic filling pressure, but this is partially restored by the increased sympathetic activity which
also shifts the CO curve upwards and consequently a new equilibrium point is established.
65
Hormonal response:
decreased venous return decreased right atrium stretch decreased ANF release and stimulation
of ADH.
Renal vasoconstriction renin release renin-angiotensin system Increased aldosterone from
adrenal cortex.
ADH and aldosterone mediate Na and water reabsorption
Angiotensin and vasopressin system take between 1min to 1 hr to respond completely
Increased sympathetic activity causes release of cortisol and catecholamines from adrenal gland
Long-Term Compensatory Reactions
After a moderate hemorrhage, the circulating plasma volume is restored in 12-72 hours. There is
also a rapid entry of preformed albumin from extravascular stores, but most of the tissue fluids that
66
are mobilized are protein-free. They dilute the plasma proteins and cells, but when whole blood is
lost, the hematocrit may not fall for several hours after the onset of bleeding. After the initial influx
of preformed albumin, the rest of the plasma protein losses are replaced, presumably by hepatic
synthesis, over a period of 3-4 days. Erythropoietin appears in the circulation, and the reticulocyte
count increases, reaching a peak in 10 days. The red cell mass is restored to normal in 4-8 weeks.
However, a low hematocrit is remarkably well tolerated because of various compensatory
mechanisms. One of these is an increase in the concentration of 2,3-DPG in the red blood cells,
which causes hemoglobin to give more O2 to the tissues. In long-standing anemia in otherwise
healthy individuals, exertional dyspnea is not observed until the hemoglobin concentration is about
7.5 g/dL. Weakness becomes appreciable at about 6 g/dL; dyspnea at rest appears at about 3 g/dL;
and the heart fails when the hemoglobin level falls to 2 g/dL.
Explain the cardiovascular effects and responses in different forms of shock
Shock is multifactorial syndrome resulting in inadequate tissue perfusion and cellular oxygenation.
In 1972 Hinshaw and Cox suggested the following classification: hypovolemic, cardiogenic,
distributive and obstructive shock. (CHOD)
Type of shock Pathophysiology
Hypovolemic Absolute loss of circulating volumedecreased venous return
decreased venous filling pressure decreased CO decreased BP
decreased perfusion
Most common
Eg hemorrhagic
Cardiogenic Decreased stroke volume due to systolic or diastolic failuredecreased
CO decreased BP decreased perfusion
Eg. Myocardial infarction, cardiomyopathy, arrhythmias, contusio cordis,
or cardiac valve problems
Distributive "relative" hypovolaemia due to dilation of blood vessels which diminishes
systemic vascular resistance decreased venous return decreased
venous filling pressure decreased CO decreased BP decreased
perfusion
Septic shock: Caused by an overwhelming systemic infection resulting in
vasodilation
Anaphylactic shock: Caused by a severe anaphylactic reaction to an
allergen, antigen, drug or foreign protein causing the release of histamine
which causes widespread vasodilation, leading to hypotension and
increased capillary permeability.
Neurogenic shock: trauma to the spinal cord resulting in the sudden loss
of autonomic and motor reflexes below the injury level decrease in
peripheral vascular resistance, leading to vasodilation and hypotension.
Obstructive Mechanical obstruction to blood flow resulting in either failure of
ventricular filling or emptying decreased stroke volume decreased
CO decreased BP decreased perfusion.
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Eg. Cardiac tamponade, Constrictive pericarditis, Tension pneumothorax,
Massive pulmonary embolism, Aortic stenosis.
PCWP CVP CO SVR
Hypovolemic Low Low Low High
Cardiogenic High High Low High
Inflammatory Low / N Low/N High Low
Neurogenic Low Low Low Low
Obstructive Low/high high low high
To explain the cardiovascular responses accompanying pregnancy, birth, ageing, cardiac
failure, and during intermittent positive pressure ventilation, positive end-expiratory
pressure, and the Valsalva manoeuvre.
Valsalava manoeuvre
Forced expiration against a closed airway is termed valsalva manoeuvre. This results in a rise
in the intrathoracic, intra-abdominal and CSF pressure. The CVP rises by about 7mmhg for a
10mmHg rise in mouth pressure.
Clinically this can be performed by a person blowing into mercury column to produce a
pressure of 40mmhg and holding it for 10-15sec.
Normal cardiovascular changes associated with the valsalva manoeuvre may be divided into
4 phases:
o Phase I: at the onset of manoeuvre there is a transient small rise in blood pressure
with a brief fall in HR. this Is due to the transmission of increased intra-thoracic
pressure onto the aorta
o Phase II: raised intra-thoracic pressure causes a decrease in venous return to the
right heart that reduces CO and causes a fall in BP stimulates baroreceptors and
compensatory mechanisms. Sympathetic stimulation increases HR and causes
vasoconstriction. These changes restore BP
68
o Phase III: immediately after release of positive airway pressure, there is transient fall
in blood pressure with a further rise in the HR. this is brought about by the loss of
the transmitted raised intra-thoracic pressure on the aorta
o Phase IV: with the intrathoracic pressure returning to baseline, venous return is
restored and a normal cardiac output results. The delivery of normal CO into
constricted peripheral vascular bed causes overshoot of blood pressure. This rise in
BP is sensed by the baro-receptors resulting in reflex bradycardia by vagal action.
Abnormal responses:
o Patients with diminished baro-receptor reflexes eg. Quadriplegia and diabetic
autonomic neuropathy excessive fall in BP in phase II and an absence of overshoot
and bradycardia in phase IV
o In CHF: square wave response: BP elevated throughout phase II and there is no
overshoot in phase IV and little change in HR.
Valsalva maneuver may be used to assess ANS (using valsalva ratio – ratio of minimum HR
and maximum HR in phase 4) and also to slow SVT.
69
describe the factors that affect mixed venous oxygen saturation
Sampling of mixed venous blood: True mixed venous blood must be obtained via slow
aspiration from a pulmonary artery catheter where blood from SVC, IVC and coronary
sinus have fully mixed. Thus, mixed venous pO2 and pCO2 reflect O2 extraction and CO2
addition from the entire body. In the presence of central (ASD,VSD etc) or peripheral (AV
fistula) shunt, it may not be possible to obtain a sample of true mixed venous blood.
Typical values for a mixed venous blood gas on a person breathing room air are:
o PvO2 of 40mmHg
o PvC02 of 45mmHg
o Sa02 of 75%
o Venous 02 content of 15mls/dL for normal ranges of Hb in the blood.
Oxygen content = 1.34*Hb*SO2 + 0.003*PO2
Relationship between PO2 and O2 content in mixed venous blood:
o P02 relationship with O2 content dependent on shape of Hb02 dissociation curve.
o Right shifted Hb02 decreases Hb’s affinity for 02 and increases the amount
dissolved i.e. P02 – factors which right shift are decrease in pH, increase in C02,
and increase in temperature and increase in 2,3 DPG levels.
Factors affecting mixed venous oxygen saturation
o Modification of the FICK equation: VO2 = (CaO2 - CvO2)*Q gives
o Cv02 = Ca02 – V02/Q
o This equation demonstrates the inverse relationship between oxygen extraction
by tissues and the cardiac output. If cardiac output decreases, oxygen extraction
by the tissues increases, causing mixed venous 02 concentration to fall. This fall in
concentration causes a decrease in mixed venous Pv02.
o Cv02 is directly proportional to Ca02. However, clinically, this factor is not as
important as the level of cardiac output. This is because relatively large increases
in partial pressure of oxygen (eg hyperbaric) are required to substantially increase
the 02 content of arterial blood above 20ml/dl as Hb is near fully saturated at a
70
Pa02 of 100mmHg and any additional increase in partial pressure contributes a
relatively miniscule 0.003mls of 02/mmHg/ml of blood.
Outline the physics of blood flow
Poiseuille’s equation:
Developed by poiseuille based on study of laminar flow of Newtonian (homogenous)
fluid in glass capillary tubes. Conceptually can be applied to blood flow. The equation
states that
Flow=π(Pi-Po)r4/8ηL
Where Pi-Po is the hydrostatic pressure gradient acting along the length of the vessel,
η is the blood viscosity, L is the vessel length, and r is the vessel radius
Viscosity
Blood is a non-newtonian fluid and the measured viscosity varies with the flow.
Higher the viscosity slower the flow and vice versa.
Blood has a relative viscosity of 4-5 when measured at moderate or high shear rates
Hydraulic resistance
Hydraulic resistance = pressure drop/flow
Substituting poisseuille equation
Resistance = 8ηL/ πr4
Where η is blood viscosity, L is the length of vessel and r is the vessel radius
The radius is very important as resistance is inversely proportional to the fourth
power of radius
Resistance of vessels in series and parallel
Arteries, capillaries and veins lie in series but many individual organ circulations lie in
parallel
In series R = R1+R2+R3+……..+Rn
In parallel resistances 1/R = 1/R1+1/R2+1/R3+……..+1/Rn
71
In other words when vessels lie in parallel the combined total hydraulic resistance is
less than any one of the individual vessel resistance
Capillaries are of smaller diameter than arterioles yet the main site of resistance is
the arterioles because the no. of capillaries in parallel is so huge that the combined
hydraulic resistance is much lower than arterioles.
Physiological deviations from poiseuille’s equation
Blood vessels are not rigid tubes. The pressure flow relationships of different blood
vessels vary considerably but may be considered as being of three types as shown in
figure
Pulsatile blood flow: one function of the large elastic arteries is to convert the
intermittent ventricular output to more continuous pulsatile flow. Because of this
flow in the capillaries is relatively steady.
Anomalous viscosity of blood: blood viscosity changes with temperature, hematocrit,
vessel diameter and flow rate. Blood viscosity is also lower when measured in-vivo
than in-vitro, because of laminar flow patterns in small vessels which decreases
viscosity. The viscosity of blood falls progressively when the vessel diameter is
reduced below 300 µm.
Turbulent flow: turbulence tends to develop in large diameter vessels with high flow
velocity, low fluid viscosity and high fluid density. The Reynolds number can be used
to predict the presence of turbulent flow in a long straight tube: Reynolds number
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(Re)=ρDv/η where ρ is fluid density, D is the vessel diameter, v is the mean velocity
and η is the fluid viscosity. Flow is usually turbulent is Re > 2000 and laminar if
Re1.0).
the required resonant frequency is always one quarter of the pulse rate. So in more general
terms, the required system is D = 0.64 (always) and Resonant frequency = (Pulse rate /4) Hz.
These levels of dynamic accuracy is required only for accurate measurement of systolic and
diastolic pressures. Physiologically, for nearly all the tissues in the body it is the mean
arterial pressure which is most important for determining perfusion pressure. The mean
pressure can be measured very accurately by invasive means as accuracy depends only on
the static calibration and is independent of the dynamic calibration of the system.
79
explain the various methods of measuring cardiac output as well as their limitations
Cardiac output (CO) is the volume of blood being pumped by the heart per minute and is
equal to the heart rate multiplied by the stroke volume. The normal value at rest for a 70 kg
male is around 5 L/min. Invasive and non invasive measures.
Invasive
The Fick principle
Fick described the following relationship in the 19th century:
Q = M / (V - A)
Q volume of blood flowing through an organ in a minute
M number of moles of a substance added to the blood by an organ in one minute
V are the venous concentrations of that substance
A are the arterial concentrations of that substance
This principle can be used to measure the blood flow through any organ that adds
substances to, or removes substances from, the blood. The heart does not do either of
these but the CO equals the pulmonary blood flow, and the lungs add oxygen to the blood
and remove carbon dioxide from it.
The concentration of the oxygen in the blood in the pulmonary veins is 200 ml/L and in the
pulmonary artery is 150 ml/L, so each litre of blood going through the lungs takes up 50 ml.
At rest, the blood takes up 250 ml/min of oxygen from the lungs and this 250 ml must be
carried away in 50 ml portions; therefore, the CO must be 250/50 or 5 L/min.
Limitations
Original method described by Fick difficult to carry out.
Accurate collection of the gas is difficult unless the patient has an endotracheal tube
80
Analysis of the gas is straightforward if the inspired gas is air, but if it is oxygen-
enriched air there are two problems, (a) the addition of oxygen may fluctuate and
produce an error and (b) it is difficult to measure small changes in oxygen
concentration at the top end of the scale.
The denominator of the equation requires the mixed venous (i.e. pulmonary arterial)
oxygen content to be measured and therefore a pulmonary artery catheter is
needed to obtain the sample. Complications may arise from these catheters.
Not practicable in routine clinical practice. Several variants of the basic method have
been devised, but usually their accuracy is less good.
Dilution techniques:
Thermodilution
Dye dilution (eg. Indocyanin green, lithium)
Principle: If a known quantity of an indicator substance is introduced to an unknown flow,
assuming no indicator is lost and mixing is thorough the flow will be equal to the amount of
indicator injected divided by the average downstream concentration of the indicator.
In practice this is done by measuring the downstream concentration of the indicator over
time, and then integrating the area under the measured concentration-time curve to obtain
the average indicator concentration.
This is expressed by the Stewart-Hamilton equation:
where q is the quantity of indicator injected
c is indicator concentration
dt is change in time.
Thermodilution
In order to measure the Cardiac output by this method, a PA floatation catheter is required.
Indicator: Mass of cold
Sensor: Thermistor
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Method: PA catheter inserted through a central vein. It is 50cm long, has a thermistor 4cm
from tip. Tripple lumen- air filled lumen for inflation of a small balloon at tip, proximal
lumen 20cm from tip which sits in RA, distal lumen which opens at the tip distal to the
balloon. A mass of indicator is added via the proximal lumen 20cm from the tip (in the RA).
This is mixed with a volume of blood flowing past this point and is diluted with it. The
thermistor measures the change in temperature over time. There is a thermistor at the
injection port also to measure temp of injectate.
Mass injected is mass of cold (derived from vol/ density/ temperature and specific heat
capacity of injectate). Dependent also on catheter size and rate of injection.
In practice a computer determines the CO by plotting the log of the indicator concentration
against time. The initial decline in concentration, linear on a semilog plot, is extrapolated to
the axis , giving the time for the first passage of the indicator through the circulation. There
is often a recirculation hump (less prominent in thermodilution).
Accuracy: 3-13% variability compared with direct electromagnetic flow measurement
Larger injectate volume , greater reproducibility.
smooth & rapid injection
Reject uneven curves.
Best of three consecutive measurements Injection ideally less that 4 secs
5% Dex better than saline
Clinical situations where result may be invalid TR /IPPV/ R-L shunt/ Rapid infusion into
SVC/ RA port lies within sheath
Calculation of CO is achieved using the Stewart-Hamilton equation. Application of this
equation assumes three major conditions; complete mixing of blood and indicator, no loss
of indicator between place of injection and place of detection and constant blood flow. The
errors made are primarily related to the violation of these conditions.
The amount of indicator (n) is related to its mean concentration (c), cardiac output (Q) and
the time for which it is detected (t2 - t1).
Advantages :
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Indicator is non toxic
Does not re-circulate. Repeat measurements are only limited by volume constraints
and the time to regain temperature stability between injections
The method shows good agreement with the fick and indocyanin green methods.
However there is considerable variability. A clinically significant change in CO cannot
be diagnosed with certainty unless there is a difference of approximately 15%
between the mean of three CO determinations and the previous mean.
Dye dilution: A known amount of dye is injected into the pulmonary artery, and its
concentration is measured peripherally.
Indocyanine green: Indocyanine green is suitable due to its low toxicity and short
half-life. A curve is achieved, which is replotted semi-logarithmically to correct for
recirculation of the dye. CO is calculated from the injected dose, the area under the
curve (AUC) and its duration. (Short duration indicates high CO).
Lithium: has also been used as an alternative to indocyanine green. It is injected via a
central venous catheter and measured by a lithium-sensitive electrode incorporated
into the radial arterial cannula. Limitations include:
o It cant be used in patients recieiving lithium therapy
o Electrode drift can occur in the presence of high peak doses of muscle
relaxants
o Abnormal shunts can result in erroneous cardiac output measurements
o Ex vivo analysis requires disposal of sampled blood
Ultrasound-Based Methods for Cardiac Output Monitoring
Uses the Doppler principle When ultrasound waves strike moving objects, these waves are
reflected back to their source at a different frequency, termed the Doppler shift frequency,
that is directly related to the velocity of the moving objects and the angle at which the
ultrasound beam strikes these objects. The Doppler equation:
Where
Fd = frequency shift
Ft = transmitted frequency
V = velocity of flow
cosθ = cosine of the angle of transmitted frequency to flow (normally
assumed to be 1)
C = velocity of sound through medium (normally assumed to be approx 1560
meters/s)
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To measure blood flow velocity, this equation is rearranged to solve for velocity
v=f.c/2.f0.cosθ
Where f = Doppler shift frequency
v = velocity of red blood cell targets
f0 = transmitted ultrasound beam frequency
Theta = angle between the ultrasound beam and the vector of red blood cell flow
c = velocity of ultrasound in blood (approximately 1570 m/sec)
In general, measurement of blood flow velocity requires just a single measurement, the
Doppler shift frequency, because the velocity of ultrasound in blood and the transmitted
ultrasound frequency are known, and cosine theta is assumed to equal 1 as long as the angle
of insonation is small. Hence it is important that the ultrasound beam be oriented as much as
possible in a direction that is parallel to blood flow. Once the Doppler shift frequency is
measured and blood flow velocity is calculated, stroke volume can be determined from the
following Equation.
SV = v · ET · CSA
where SV = stroke volume (mL)
v = spatial average velocity of blood flow (cm/sec)
ET = systolic ejection time (sec)
CSA = cross-sectional area of the vessel (cm2)
Continious and pulsed wave Doppler are used to measure flow. Pulse wave Doppler allows
the site of sampling to be specified, the target sample is usually the central laminar flow.
With continious wave Doppler, a piezoelectrical crystal transmits the ultrasound beam while
nother measures the frequency of refelected wave. The velocity of all the red cells moving
along the path of the ultrasound beam are recorerded.
Oesophageal Doppler monitoring
Measures the blood flow in the descending aorta with a Doppler probe usually 4 MHz
continuous wave or 5 MHz pulsed wave depending upon device, incorporated in the tip of
flexible probe. The probe is positioned in the oesophagus 30-40 cmm from the teeth. At this
84
point the aorta lies parallel to the oesophagus and cross sectional area varies least. Aortic
cross sectional area is either measured usuing M mode or calculated based upon
nomograms.
Advantages:
1. only short period of training is required
2. probe (6mm) are minimally invasive
3. contraindications are few – severe agitation, pharyngo oesophageal pathology,
aortic balloon counter-pulsation, aotic dissection or severe aortic coarctation
Disadvantages:
Based on the assumption that descending aortic flow is the 70% of the total CO and
nomograms accurately determine cross section area and cross sectional area is constant
Flow in the aorta is not always laminar eg in valvular disease or severe anaemia
Finding and maintaining optimal probe positioning
Probe may be poorly tolerated in the poorly sedated patients
Transthoracic impedance
Can be measured across externally applied electrodes. Impedance changes with the cardiac
cycle (changes in blood volume). The rate of change of impedance is a reflection of cardiac
output. It is thought to be useful in estimating changes but not for absolute measurements.
Limitations
Contraction of the heart produces a cyclical change in transthoracic impedance of about
0.5%, unfortunately giving a rather low signal to noise ratio. Although the method has been
reported to give accurate results in normal subjects, several studies have some inaccuracy in
critically ill patients,
Explain mechanisms and physiological consequences of alpha 1, alpha 2, beta 1 and beta 2
receptor blockade
85
Alpha receptor Beta receptor
Rank order of potency of Adr ≥ NA > Iso Iso > Adr > Na
agonists
Antagonist Phenoxybenzamine Propanolol
Effector pathway IP3/DAG↑, cAMP ↓, K+ cAMP ↑, Ca 2+ channel ↑
channel ↑
Beta 1 Beta 2 Beta 3
Location Heart, Jg cells in Bronchi, blood Adipose tissue
kidney vessels, uterus, GIT,
urinary tract, eye
Alpha 1 Alpha2
Location Postjunctional on effector Prejunctional on nerve
organs endings (α2A), also post
junctional in brain,
pancreatic β cells, platelets
and extrajunctional in certain
blood vessels
Function subserved Smooth muscle – contraction Inhibition of transmitter
release
Vasoconstriction
Vasoconstriction
Gland-secretion
Decreased central
Gut relaxation
sympathetic flow
Heart arrythmia
Decreased insulin release
Platelet aggregation
Effector pathway IP3 /DAG ↑, phospholipase cAMP ↓
A2 ↑
K channel ↑
Ca2+ channel ↑ or ↓
86
IP3/DAG ↑
1 Receptor Antagonism 2 Adrenergic Receptor
Antagonism
Inhibit vasoconstriction induced by endogenous Activation of presynaptic 2
catecholamines receptors inhibits the release
Vasodilation may occur of norepinephrine and other
Fall in blood pressure due to decreased peripheral cotransmitters from
resistance peripheral sympathetic nerve
The magnitude of such effects is less in supine than in endings and leads to a fall in
upright subjects and is particularly marked if there is blood pressure;
hypovolemia. Blockade of 2 receptors can
The fall in blood pressure is opposed by baroreceptor increase sympathetic outflow
reflexes that cause increases in HR & CO, as well as and potentiate the release of
fluid retention. These reflexes are exaggerated if the norepinephrine from nerve
antagonist also blocks 2 receptors on peripheral endings, leading to activation
sympathetic nerve endings, leading to enhanced of 1 and 1 receptors in the
release of norepinephrine and increased stimulation heart and peripheral
of postsynaptic 1 receptors in the heart and on vasculature with a consequent
juxtaglomerular cells. rise in blood pressure.
Blockade of 1 receptors also inhibits vasoconstriction The physiological role of
and the increase in blood pressure produced by the vascular 2 receptors in the
administration of a sympathomimetic amine. They regulation of blood flow
block pressor action of Adr which then produces only within various vascular beds is
fall in BP due to beta 2 mediated vasodilatation - uncertain.
vasomotor reversal of dale. the effect of blockade of
Tone of smooth muscle in the bladder trigone, platelet 2 receptors in vivo is
sphincter and prostate is reduced by the blockade of not clear.
alpha 1 receptors (mostly of the alpha 1A subtype) - Blockade of pancreatic 2
urine flow in pts with BHP increases receptors may facilitate
Alpha blockers can inhibit ejaculation; this may insulin release. Alpha receptor
manifest as impotence antagonists reduce smooth
Nasal stuffiness and miosis result from blockade of muscle tone in the prostate
alpha receptors in the nasal blood vessels and radial and neck of the bladder,
muscles of iris respectively thereby decreasing resistance
intestinal motility is increased due to partial inhibition to urine outflow in benign
of relaxant sympathetic influences prostatic hypertrophy (see
occur below).
Beta 1 antagonism Beta 2 antagonism
receptor antagonists slow the heart rate During sympathetic activity peripheral
and decrease myocardial contractility, resistance increases as a result of blockade
especially during exercise or stress. However of vascular 2 receptors and activation of
87
stroke volume is often preserved. vascular receptors.
long-term administration of these drugs to
hypertensive patients ultimately leads to a
fall in peripheral vascular resistance Blockade of 2 receptors tends to blunt the
increase in blood flow to active skeletal
muscle during submaximal exercise
With long-term use of receptor
antagonists, total peripheral resistance
returns to initial values or decreases in Increased incidence of bronchospasm in
patients with hypertension obstructive airway disease
Receptor antagonists reduce Sinus rate, glycogenolysis in the human liver is at least
slow conduction in atria and AV node and partially inhibited after β2-receptor blockade
decrease automaticity.
improved relationship between cardiac
oxygen supply and demand; exercise
tolerance generally is improved in patients
with angina, whose capacity to exercise is
limited by the development of chest pain
The release of renin from the
juxtaglomerular apparatus is stimulated by
the sympathetic nervous system via 1
receptors, and this effect is blocked by
receptor antagonists
Effects of non-selective betablockade:
Metabolic Effects.
Nonselective blockers may delay recovery from hypoglycemia in IDDM but infrequently in
NIDDM. Block glycogenolysis.
During hypoglycemia by blunt the perception of symptoms such as tremor, tachycardia, and
nervousness.
88
Attenuate the release of free fatty acids from adipose tissue (important source of energy for
exercising muscle)
Nonselective receptor antagonists consistently reduce HDL cholesterol, increase LDL
cholesterol, and increase triglycerides. In contrast, 1-selective antagonists, including
celiprolol, carteolol, nebivolol, carvedilol, and bevantolol, reportedly improve the serum lipid
profile of dyslipidemic patients.
In contrast to classical blockers, which decrease insulin sensitivity, the vasodilating
receptor antagonists (e.g., celiprolol, nipradilol, carteolol, carvedilol, and dilevalol) increase
insulin sensitivity in patients with insulin resistance.
Eye: Decreased aqueous secretion from the ciliary epithelium
Classify alpha and beta receptor blocking agents according to their pharmacokinetic and
pharmacodynamic properties
Classification of alpha blockers:
NON-COMPETITIVE ANTAGONISTS
β-Haloalkylamines: Phenoxybenzamine
COMPETITIVE ANTAGONISTS
Nonselective α1 selective α2 selective
antagonists antagonists antagonists
Ergot alkaloids – Prazocin Yohimbine
Ergotamine, Terazocin
ergotoxin Doxazosin
Tamsulosin
Hydrogenated ergot
alkaloids –
dihydroergotamine,
dihydroergotoxin
Imidazolines –
89
Tolazoline,
Phentolamine
Miscellaneous –
chlorpromazine,
ketanserine
Comparative Information About α Adrenergic Receptor Antagonists
HALOALKYLAMINES IMIDAZOLINES QUINAZOLINES
Prototype Phenoxybenzamine Phentolamine Prazosin
Antagonism Irreversible Competitive Competitive
Selectivity α1 with some α2 Nonselective Selective for α1; does not
between α1 and distinguish among α1
α2 subtypes
Hemodynamic Decreased PVR and blood Similar to PBZ Decreased PVR and blood
effects pressure pressure
Venodilation is prominent Veins less susceptible than
arteries; thus, postural
hypotension less of a
problem
Cardiac stimulation Cardiac stimulation is less
(cardiovascular reflexes and (NE release is not enhanced
enhanced NE release due to due to α1 selectivity)
α2 antagonism)
Actions other Some antagonism of ACh, Cholinomimetic; At high doses some direct
than α 5-HT, and histamine adrenomimetic; vasodilator action, probably
blockade histamine-like due to PDE inhibition
actions
Blockade of neuronal and Antagonism of 5-
extraneuronal uptake HT
Routes of Intravenous and oral; oral Similar to PZB Oral
administration absorption incomplete and
erratic
90
Adverse Postural hypotension, Same as PBZ, Some postural hypotension,
reactions tachycardia, miosis, nasal plus GI especially with the first
stuffiness, failure of disturbances due dose; less of a problem
ejaculation to overall than with PBZ or
cholinomimetic phentolamine
and histamine-
like actions
Therapeutic Conditions of Same as PBZ Primary hypertension
uses catecholamine excess (e.g.,
pheochromocytoma)
Peripheral vascular disease Benign prostatic
hypertrophy
Classification of beta blockers:
91
Pharmacological/Pharmacokinetic classification/properties of β Receptor Blocking Agents
DRUG MEMBRANE INTRINSIC LIPID EXTENT OF ORAL t 1/2 PROTEIN
STABILIZING AGONIST SOLUBILITY ABSORPTION BIOAVAILA (hours) BINDING
ACTIVITY ACTIVITY (%) BILITY (%) (%)
Classical non-selective β blockers: First generation
Nadolol 0 0 Low 30 30-50 20-24 30
Propranolol ++ 0 High 95 ~100 3-4 40
β1-Selective β blockers: Second generation
Acebutolol + + Low 90 20-60 3-4 26
Atenolol 0 0 Low 90 50-60 6-7 6-16
Bisoprolol 0 0 Low ≤90 80 9-12 ~30
Esmolol 0 0 Low NA NA 0.15 55
*
Metoprolol + 0 Moderate ~100 40-50 3-7 12
Non-selective β blockers with additional actions (α blocker): Third generation
Carteolol 0 ++ Low 85 85 6 23-30
Carvedilol ++ 0 Moderate >90 ~30 7-10 98
Labetalol + + Low >90 ~33 3-4 ~50
β1-selective β blockers with additional actions (β 2 agonistic): Third generation
Betaxolol + 0 Moderate >90 ~80 15 50
Celiprolol 0 + Low ~74 30-70 5 4-5
Beta 2 selective blocker
Butoxamine
describe the pharmacology of alpha receptor blocking agents and apply this to their clinical
use
Phenoxybenzamine
Physicochemical
Structure Haloalkylamine
Presentation 10mg cap. And 50mg/ml inj.
Pharmacodynamics
MOA blocks 1 and 2 receptors irreversibly
Inhibits reuptake of released norepinephrine by presynaptic adrenergic
nerve terminals.
Blocks histamine (H1), acetylcholine, and serotonin receptors at high
doses
Use Treatment of pheochromocytoma almost always used to
92
treat the patient in preparation for surgery.
Was used for BPH; not used any more due to side effects.
Has been used to control the manifestations of autonomic
hyperreflexia in patients with spinal cord transection.
Dose A conservative approach is to initiate treatment with
phenoxybenzamine (at a dosage of 10 mg twice daily) 1 to 3 weeks
before the operation. The usual daily dose of phenoxybenzamine in
patients with pheochromocytoma is 40 to 120 mg given in two or
three divided portions.
CVS progressive decrease in peripheral resistance and reflex increase in
CO
Marked postural hypotension
CNS fatigue, sedation, and nausea
Respiratory Nasal stuffiness due to vasodilatation
Other Smooth muscle relaxation in bladder and vas deference
Side effects/ Postural hypotension with reflex tachycardia and other
adverse arrhythmias
effects Exaggerated hypotension in volume depleted subjects
Reversible inhibition of ejaculation
Nasal stuffiness
Mutagenic in ames test
Interactions
Pharmacokinetics
Absorption absorbed after oral administration, although bioavailability is low.
Administered orally.
Distribution Chronic administration leads to accumulation in adipose tissue
Metabolism Cyclizes spontaneously into highly active intermediate. half-life of
phenoxybenzamine probably is less than 24 hours. However, the
duration of its effect is dependent not only on the presence of the
drug, but also on the rate of synthesis of receptors. irreversible
blockade of long duration (14–48 hours or longer).
Excretion Most of the administered dose is excreted in urine in 24 hrs.
Prazocin
Physicochemical
Structure contain a piperazinyl quinazoline nucleus. Structurally similar to
terazocin
Presentation 0.5, 1 and 2 mg tabs
Pharmacodynamics
MOA The major effects result from its potent and selective blockade of 1
receptors in arterioles and veins. 1:2 1000:1. Also inhibits
93
phosphodiesterase.
Use Hypertension
BHP
LVF refractory to diuretics and digitalis
Raynauds disease
Dose HT: The initial dose should be 1 mg at bed time to reduce the risk of
syncopal reactions (The first dose effect). the dose is titrated upward
depending on the blood pressure. A maximal effect generally is
observed with a total daily dose of 20 mg in patients with
hypertension in 2 to 3 divided doses.
BPH: 1 to 5 mg twice daily typically are used.
CVS ↓ TPR & venous return ↓CO. usually does not increase heart rate
as it has little or no 2 receptor-blocking effect and does not promote
the release of norepinephrine from sympathetic nerve endings.
depresses baroreflex function in hypertensive patients.
CNS suppress sympathetic outflow
Respiratory
Other favorable effects on serum lipids, ↓ LDL and triglycerides and ↑ HDL
Side effects/ 1st dose effect: postural syncope
adverse Nasal stuffiness
effects Relaxes bladder smooth muscle
Interactions
Pharmacokinetics
Absorption Good oral absorption. bioavailability ~ 60%.
Distribution Peak conc. reached in ~ 2 hrs after oral dose.
Tightly bound to plasma proteins (primarily 1-acid glycoprotein) and
only 5% of the drug is free
Metabolism Extensively metabolized in the liver.
T1/2 ~ 2.5 hrs ( 6 to 8 hours in congestive heart failure).
The duration of action: 7 to 10 hours in the treatment of hypertension.
Excretion Excreted mainly in bile & little unchanged drug is excreted by the
kidneys
Phentolamine (Regitine)
Physicochemical
Structure Imidazoline
Presentation 10mg/ml Inj.
Pharmacodynamics
MOA competitive receptor antagonist that has similar affinities for 1 and
2 receptors
Inhibits reuptake of released norepinephrine by presynaptic adrenergic
94
nerve terminals.
Phentolamine also can block receptors for 5-HT, and it causes
release of histamine from mast cells; phentolamine also blocks K+
channels
Use short-term control of hypertension in patients with
pheochromocytoma
relieve pseudo-obstruction of the bowel in patients with
pheochromocytoma
used locally to prevent dermal necrosis after the inadvertent
extravasation of an receptor agonist
Treatment of hypertensive crises that follow the abrupt
withdrawal of clonidine or that may result from the ingestion of
tyramine-containing foods during the use of nonselective MAO
inhibitors.
Direct intracavernous injection of phentolamine (in combination
with papaverine) has been proposed as a treatment for male
sexual dysfunction.
Buccally or orally administered phentolamine may have
efficacy in some men with sexual dysfunction
Dose 5mg IV repeated as required
CVS progressive decrease in peripheral resistance and reflex increase in
CO
Marked postural hypotension
CNS fatigue, sedation, and nausea
Respiratory Nasal stuffiness due to vasodilatation
Other
Side effects/ severe tachycardia, arrhythmias, and myocardial ischemia, especially
adverse after intravenous administration. With oral administration, adverse effects
effects include tachycardia, nasal congestion, and headache.
Interactions
Pharmacokinetics
Absorption limited absorption after oral administration.
Distribution Its pharmacokinetic properties are not well known;
Metabolism it may reach peak concentrations within an hour after oral administration
and has a half-life of 5–7 hours
Excretion
Tamsulosin
Physicochemical
95
Structure Benzenesulfonamide
Presentation 0.4 mg capsules
Pharmacodynamics
MOA a1 receptor antagonist with some selectivity for a1A (and a1D) subtypes
compared to a1B subtype. This selectivity may favor blockade of a1A
receptors in prostate
Use Treatment of BPH with little effect on BP
Dose Tamsulosin may be administered at a 0.4-mg starting dose; a dose of
0.8 mg ultimately will be more efficacious in some patients
CVS Little effect on BP as compared to other alpha antagonists
CNS
Respiratory
Other
Side effects/ Dizziness & retrogade ejaculation
adverse
effects
Interactions
Pharmacokinetics
Absorption well absorbed orally
Distribution
Metabolism It is extensively metabolized by CYPs in liver. T1/2 ~ 5 to 10 hours.
Excretion Biliary excretion
describe the pharmacology of beta blockers with particular reference to propanolol, atenolol,
metoprolol, esmolol, carvedilol, sotalol and labetalol
Propanolol
Physicochemical
Structure
Presentation 10, 40, 80 mg tab, 1mg/ml Inj
Pharmacodynamics
MOA Propranolol interacts with 1 and 2 receptors with equal affinity, lacks
intrinsic sympathomimetic activity, and does not block receptors.
Use HT
Angina
Arrythmias: supraventricular arrhythmias/tachycardias,
ventricular arrhythmias/tachycardias, premature ventricular
contractions, digitalis-induced tachyarrhythmias
96
myocardial infarction
pheochromocytoma
prophylaxis of migraine
variceal bleeding in portal hypertension
generalized anxiety disorder
Dose For HT and angina initially 40 – 80 mg/day titrated upwards.
CVS Heart-decreases HR, force of contraction and CO. Cardiac work and O2
consumption reduced. Decreases automaticity. AV conduction is
delayed.
Blood vessels: Initially TPR increases and CO decreases, little change in
BP. With prolonged administration BP decreases due to decrease in
TPR. This is due to (i) reduced NA release from sympathetic terminus (ii)
Decreased rennin release from kidney (beta 1) (iii) decreased central
sympathetic outflow
CNS Forgetfulness, increased dreaming and nightmares, suppresses
anxiety
Respiratory Inreases bronchial resisatnce by blocking beta 2 receptors
Other Metabolic: blocks adrenergically induced lipolysis reduced free fatty
acids. Plasma TGL and LDL/HDL ratio is increased. Inhibits
glycogenolysis. Carbohydrate intolerance during prolonged
administration.
Potent local anaesthetic
Inhibits adrenergically induced tremors
Reduce exercise capacity
Reduced secretion of aqueous
Relaxation of uterus is blocked
Side effects/ Accentuates myocardial insufficiency- can ppt CHF and edema
adverse Bradycardia
effects Risk of life threatening attack of asthma
Exacerbates variant angina
Carbohydrate intolerance
Altered lipid profile
Reduced exercise capacity- inability to increase blood flow
Worsening of PVD-cold hands and feet
Interactions The bioavailability of propranolol may be increased by the
concomitant ingestion of food and during long-term administration of
the drug.
Additive depression of Sinus node and AV conduction with digitalis
and verapamil
Delays recovery from hypoglycaemia
Indomethacin and other NSAIDs attenuate anti-hypertensive action
Propanolol decreases lignocaine metabolism by decreasing HBF
Pharmacokinetics
Absorption highly lipophilic and is almost completely absorbed after oral
administration.
Distribution large volume of distribution (4 liters/kg), 90% protein bound.
97
Metabolism Extensive hepatic metabolism – systemic bioavailability ~ 25%. great
interindividual variation in the clearance of propranolol by the liver;
this contributes to enormous variability in plasma concentrations
(approximately twentyfold). Metabolism depends upon hepatic blood
flow. Prolonged administration decreases HBF and decreases
metabolism
Excretion Metabolites excreted in urine
The features of cardioselective beta blockers (metoprolol, atenolol, acebutolol)
lower propensity to cause bronchoconstriction
less interference with carbohydrate metabolism
less chance of ppt raynaud’s phenomenon
less deleterious effect on lipid profile
ineffective in blocking essential tremor
less liable to impair exercise tolerance
Atenolol
Physicochemical
Structure
Presentation 25, 50 mg tab
Pharmacodynamics
MOA 1-selective antagonist that is devoid of intrinsic sympathomimetic and
membrane stabilizing activity
Use HT
Angina
Dose The initial dose of atenolol for the treatment of hypertension usually is
50 mg per day, given once daily may be increased to 100 mg; higher
doses are unlikely to provide any greater antihypertensive effect. The
drug accumulates in patients with renal failure, and dosage should be
adjusted for patients whose creatinine clearance is less than 35
ml/minute.
CVS
CNS
Respiratory
Other
Side effects/
adverse
98
effects
Interactions
Pharmacokinetics
Absorption Atenolol is incompletely absorbed (about 50%), but most of the
absorbed dose reaches the systemic circulation.
Distribution
Metabolism There is relatively little interindividual variation in the plasma
concentrations of atenolol; peak concentrations in different patients
vary over only a fourfold range., and the elimination half-life is about 5
to 8 hours.
Excretion The drug is excreted largely unchanged in the urine
Metoprolol
Physicochemical
Structure
Presentation 25, 50, 100mg tab/ 5mg/ml Inj
Pharmacodynamics
MOA 1-selective receptor antagonist that is devoid of intrinsic
sympathomimetic activity and membrane-stabilizing activity.
Use chronic heart failure.
HT
MI
Tachyarrythmias
Dose Usual initial dose is 100 mg per day. Metoprolol generally is used in
two divided doses for the treatment of stable angina
CVS
CNS
Respiratory
Other
Side effects/
adverse
effects
Interactions
Pharmacokinetics
Absorption Completely absorbed after oral administration, but bioavailability is
relatively low (about 40%) because of first-pass metabolism.
99
Distribution
Metabolism Metoprolol is extensively metabolized in the liver, with CYP2D6 the
major enzyme involved. Plasma concentrations of the drug vary
widely (up to seventeenfold), perhaps because of genetically
determined differences in the rate of metabolism. The half-life of
metoprolol is 3 to 4 hours, but can increase to 7 to 8 hours in
CYP2D6 poor metabolizers.
Excretion 90 % biliary excretion and 10% unchanged urinary excretion
Esmolol
Physicochemical
Structure
Presentation 100mg/ml Inj
Pharmacodynamics
MOA 1-selective antagonist with a very short duration of action. It has little
if any intrinsic sympathomimetic activity, and it lacks membrane-
stabilizing actions
Use SVT
AF
MI
Hypertension
Dose Loading dose 0.5mg/kg followed by 0.05 – 0.2mg/kg/min
CVS
CNS
Respiratory
Other
Side effects/
adverse
effects
Interactions
Pharmacokinetics
Absorption Administered IV
Distribution apparent volume of distribution of approximately 2 liters/kg.
Metabolism Inactivated by blood esterases. T1/2 24 to 48 hrs especially if renal
function is impaired
o Symptoms - anorexia, nausea, fatigue, disorientation, and toxic
psychosis
o Plasma conc. of thiocyanate should be monitored and should not
be allowed to exceed 0.1 mg/ml
o Rarely, excessive concentrations of thiocyanate may cause
hypothyroidism by inhibiting iodine uptake by the thyroid gland. In
patients with renal failure, thiocyanate can be removed readily by
hemodialysis.
MetHb:
o Unlikely to accumulate to levels which are toxic, even in Pts
with congenital MetHb reductase deficiency
o To develop 10% metHb → need 10mg/kg SNP (really high dose)
o Treatment: methylene blue (1-2mg/kg) BUT not advised as
metHb needed for CN- clearance
Worsening of arterial hypoxemia in patients with COPD because the drug
interferes with hypoxic pulmonary vasoconstriction ventilation
perfusion mismatch.
↑ICP and ↓CPP
117
↓ Platelet aggregation
Interactions
Pharmacokinetics
Unstable molecule - decomposes under alkaline conditions or when exposed to light
Onset of action is within 30 seconds; the peak hypotensive effect occurs within 2 minutes,
and when the infusion of the drug is stopped, the effect disappears within 3 minutes.
Nitroprusside undergoes reduction in red cells to form MetHb and release NO and 5 cyanide
molecules. MetHb binds one cyanide molecule to form non-toxic compound.
Cyanide is further metabolized by liver mitochondrial enzyme rhodanase to thiocyanate,
which is eliminated almost entirely in the urine. The mean elimination half-time for
thiocyanate is 3 days in patients with normal renal function, and it can be much longer in
patients with renal insufficiency.
GTN
Physicochemical
Structure
Presentation S/L spray 400mcg/dose
S/L tablets 300-600mcg
Buccal tabs 1-5mg
Oral tablets 2.6-10mg
Patch 5-15mg/24hrs
Injection 1-5mg/ml → diluted to 100mcg/ml (0.01%)
Pharmacodynamics
MOA Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite ion is
released, which is then converted to nitric oxide. A different unknown
enzymatic reaction releases nitric oxide directly from the parent drug
molecule. NO activates guanylyl cylase → ↑cGMP → ↓Ca2+ influx into
vascular smooth mm / ↑Ca2+ uptake into smooth ER Overall ↓Ca2+ in
cytoplasm → relaxation smooth mm → vasodilatation
Use Angina
CHF & acute LVF
118
MI
Biliary colic
Esophageal spasm
Cyanide poisoning
Dose Drug Dose Duration of
Action
"Short-acting"
Nitroglycerin, sublingual 0.15–1.2 mg 10–30 minutes
NTG infusion 5µg/min - 100µg/min
"Long-acting"
Nitroglycerin, oral 6.5–13 mg per 6–8 hours 6–8 hours
sustained-action
Nitroglycerin, 2% ointment, 1–1.5 inches per 4 hours 3–6 hours
transdermal
Nitroglycerin, slow-release, 1–2 mg per 4 hours 3–6 hours
buccal
Nitroglycerin, slow-release 10–25 mg per 24 hours 8–10 hours
patch, transdermal (one patch per day)
CVS Vessels:
- 1° venodilatation
↓tendency for VR
↓preload RV
- Vasodilation
↓end-diastolic pressure / ↓vent wall tension → ↓afterload
Heart:
- ↓metabolic O2 requirements
2° above factors → ↓myocardial work → ↓O2 demand
- ↑coronary BF
2° ↓vent wall tension (↓afterload), redirecting blood flow to
119
subendocardium
2° coronary vasodilatation → improve O2 supply
- Results in favourable ↑supply:demand ratio
- CO
o ↓VR → ↓CO in normal Pts
HF
�� Pts → ↑CO 2° ↓SVR and improved myocardial performance
Periphery:
- Vasodilatation
o Orthostatic hypotension
o High doses → ↓systemic vascular resistance (SVR)
��↓MAP more pronounced in volume depleted
CNS ↑CBF/↑ICP 2° vasodilatation, headache
Respiratory ↓PVR → ↑capacitance of pulmonary vessels → favour absorption
transudate
Release of hypoxic pulmonary vasoconstriction → ↑shunt
Other - Uterus
↓uterine tone
↑blood flow → ↑risk haemorrhage
Haematological
Rarely precipitates metHb
Platelets → ↑cGMP → ↓Ca2+ in cytoplasm → ↓platelet
aggregation
Side effects/ Methemoglobinemia (rare): Nitrite ion reacts with hemoglobin
adverse (which contains ferrous iron) to produce methemoglobin (which
effects contains ferric iron). Because methemoglobin has a very low affinity
for oxygen, large doses of nitrites can result in pseudocyanosis,
tissue hypoxia, and death.
orthostatic hypotension
tachycardia
Throbbing headache.
TOLERANCE: may be caused in part by a decrease in tissue sulfhydryl
120
groups. Increased generation of oxygen free radicals during nitrate
therapy may be another important mechanism of tolerance
Interactions Sildenafil – dangerous hypotension
Pharmacokinetics
Absorption High first pass metabolism – oral bioavailability 400mg/day) lupus erythematosus-like syndrome -
arthralgia, myalgia, pleuritis, pericarditis, skin rashes, and fever
Uncommon - pyridoxine-responsive polyneuropathy and drug fever
Coronary steal
Interactions
Pharmacokinetics
Absorption Well absorbed but high first pass – oral bioavailability ~25%
Distribution
127
Metabolism Metabolized in part by acetylation in bowel/liver. rapid acetylators have
greater first-pass metabolism, lower bioavailability, and less
antihypertensive benefit. T1/2~ 1.5 to 3 hours, but vascular effects persist
longer. peak hypotensive effect of the drug occur within 30 to 120 minutes
of ingestion.
Excretion Biliary excretion
Nicorandil
Physicochemical
Structure nicotinamide ester ester
Presentation 5, 10mg tab, 2mg/vial inj
Pharmacodynamics
MOA Activates ATP sensitive K channels- hyperpolarizing vascular smooth muscle
vasodilatation
Also donates NO which increase cGMP and cause vasodilatation – both
arterial and venous
Use Angina
HT
MI
CHF
Dose 5-20mg BD
CVS vasodilating properties in normal coronary arteries but more complex
effects in patients with angina.
Reduces both preload and afterload. No significant effects on contractility
or conduction
Provides some myocardial protection via preconditioning by activation of
cardiac KATP channels.
Mitochondrial K+ channel opening exerts myocardial protection by process
of ischaemic preconditioning which reduces myocardial stunning,
arrhythmias and infarct size when coronary artery is suddenly blocked
CNS
Respiratory
Other
Side effects/ Flushing
adverse Palpitation
effects Weakness
Headache
128
Dizziness
Mouth ulcers, nausea and vomiting
Interactions
Pharmacokinetics
Absorption Absolute bioavailability is 75 ± 23%. peak plasma levels occur within 0.30 to
1.0 hours after dosing
Distribution weakly bound to human plasma proteins (free fraction greater than 75%)
Metabolism Main biotransformation pathways are de-nitration and then introduction
into the nicotinamide metabolism.
Excretion
Minoxidil
Physicochemical
Structure
Presentation Oral: 2.5, 10 mg tablets
Topical: 2% lotion
Pharmacodynamics
MOA Metabolized by hepatic sulfotransferase to the active molecule,
minoxidil sulfate. Minoxidil sulfate opens the ATP-modulated K+
channel K+ efflux hyperpolarization relaxation of smooth
muscle
Use Reserved for poorly responding severe hypertension,
especially in male patients with renal insufficiency. Used
concurrently with a diuretic to avoid fluid retention and with a
sympatholytic drug (usually a receptor antagonist) to control
reflex cardiovascular effects.
Alopecia
Dose The initial daily dose of minoxidil may be as little as 1.25 mg, which
can be increased gradually to 40 mg in one or two daily doses.
CVS Produces arteriolar vasodilation. no effect on the capacitance vessels.
Increases blood flow to skin, skeletal muscle, the gastrointestinal tract, and
the heart more than to the CNS. Strong reflex increase in heart rate,
myocardial contractility and in cardiac output.
129
CNS
Respiratory
Other renal artery vasodilator, but systemic hypotension can ↓ RBF. Renal
function usually improves in patients who take minoxidil for the treatment
of hypertension. Very potent stimulator of renin secretion.
Side effects/ Tachycardia, palpitations, angina, and edema
adverse
Headache, sweating, and hirsutism
effects
fluid and salt retention
Interactions
Pharmacokinetics
Absorption Well absorbed. peak conc. occur 1 hour after oral administration, the
maximal hypotensive effect of the drug occurs later
Distribution
Metabolism Metabolized by hepatic sulfotransferase to the active molecule,
minoxidil sulfate. Minoxidil has a half-life in plasma of 3 to 4 hours, but
its duration of action is 24 hours or occasionally even longer.
Excretion 20% of the absorbed drug is excreted unchanged in the urine, and the
main route of elimination is by hepatic metabolism
physiological and pharmacological basis of antiarrhythmic therapy
130
A schematic representation of Na+ channels cycling through different conformational states during
the cardiac action potential. Transitions between resting, activated, and inactivated states are
dependent on membrane potential and time. The activation gate is shown as m and the
inactivation gate as h. Potentials typical for each state are shown under each channel schematic as
a function of time. The dashed line indicates that part of the action potential during which most
Na+ channels are completely or partially inactivated and unavailable for reactivation
131
Inactivation gate (h) have voltage dependent function. They begin to close between -70 to - 55 mv
and begin to recover from -55 to -70 mv
Refractory period
• The time between phase 0 and sufficient recovery of sodium channels in phase 3 to permit
a new propagated response to an external stimulus is the refractory period.
• Less negative resting membrane potential results in prolongation of refractory time. Since
inactivation gates of sodium channels close between -70 to - 55 mv, hence, fewer sodium
channels are available for diffusion of sodium ions when an AP is evoked from a resting
potential of -60mv than when it is evoked from resting potential of – 80 mv
• SA node and AV node have resting membrane potential in the range of – 50 to -70 mv
hence all na channels are inactivated.
• Such depolarized cells exhibit “slow responses” – slow upstroke velocity and slow
conduction – which depends on calcium inward current.
132
• Other relatively depolarized cells exhibiting slow depolarization & conduction include cells
exposed to hyperkalemia, sodium pump blockade, or ischemic cells.
Mechanisms of arrhythmias
Abnormal automaticity
• Non-pacemaker cells begin to spontaneously and abnormally initiate an impulse, believed
to be the result of reduced (more positive) RMP bringing it closer to the threshold
potential. Eg. Ischemia and electrolyte imbalances
• Acceleration of pacemaker discharge, brought about by increased phase 4 depolarization
slope. Eg. hypokalemia, β stimulation, positive chronotropic drugs, fibre stretch, acidosis
and partial depolarization by currents of injury.
After depolarization (or triggered activity)
• Spontaneous depolarizations requiring a preceding impulse (a triggering beat)
133
• Early after depolarizations (EAD): After depolarizations originating during phase 2 or 3 of
the AP
• Delayed afterdepolarization (DAD): After depolarizations originating during phase 4 of AP
Early after depolarization
• Prolonged action potential eg. Prolongation of QT interval (repolarization) by inhibition of
delayed rectifier potassium current (sotalol, quinidine, dofetilide and procainamide)
• Torsade de pointe (TdP), a potentially lethal polymorphic ventricular arrhythmia, is an
example of EAD, precipitated by K+channel blockers
Delayed after depolarization
• Ventricular arrhythmias secondary to digoxin toxicity is an example of delayed
afterdepolarization.
• Digoxin mediated increased intracellular Ca++ is believed to be the mechanism of this type
of arrhythmia
Disorders of impulse conduction
• Most common mechanism of arrhythmias
• Can result in conduction block and reentry
134
Re-entry
• Impulse recirculates in the heart and cause repititive activation
• Pre-requisites:
– Propagating impulse encounters electrophysiologically inhomogeneous tissue with
unidirectional block allowing retrograde conduction
– retrograde conducting impulse encounters excitable tissue
• Lengthening of the refractory period and / or slowing of the velocity of conduction may
help terminate reentry.
• Examples of reentrant arrhythmias:
– AV nodal reentrant tachycardia (AVNRT)
– Atrioventricular reentrant tachycardia (AVRT)
– Atrial flutter
– Atrial fibrillation
– Ventricular tachycardia.
Mechanism of action of anti-arrhythmics
• Aim of therapy:
– Reduce ectopic pacemaker activity
– Modify conduction or refractoriness in reentry circuits to disable circus movement
• Major mechanisms to accomplish these goals:
– 1. Sodium channel blockade
– 2. Blockade of sympathetic autonomic effects in heart
– 3. Prolongation of effective refractory period
– 4. Calcium channel blockade
Abnormal automaticity
• State dependent action of Na+ blockers: binding preference to the activated & inactivated
channels than the resting channels
• Hence arrhythmic cells with rapid activity and depolarization of resting potential will have
more channels in A and I stage and hence will be favorably blocked by the drug.
• In cells with abnormal automaticity most of the drugs reduce phase 4 slope by blocking
either sodium and calcium channel thereby reducing the ratio of sodium to potassium
permeability.
Reentry arrhythmias
• Slow conduction by:
– Steady state reduction in the number of the unblocked channels which reduces the
excitatory current to a level below that required for propagation
– Prolongation of refractory time. (conversion to bi-direction block)
• Excessive slowing promotes reentry by allowing time for unidirectional block to recover.
Hence powerful Na+ channel blockers e.g. Flecainide, Propafenone may actually promote
ventricular tachyarrhythmias
135
Classify antiarrhythmic agents by their electro-physiological activity and mechanisms of action
• The widest employed Vaughan-Williams classification.
• Major drawbacks:
– Over simplification of the effect
– The classification relies on the effect these agents have on normal tissue
– Major effects of an agent from one group overlaps with the effects of agents from
other groups
• A more comprehensive classification of anti arrhythmic agents is available and has been
called the “Sicilian Gambit”.
Vaughan-Williams classification (1969) involves 4 classes. In 1979 harrison divided class I into
subclass A B & C.
136
describe the pharmacology, with particular reference to the antiarrhythmic properties, of
the sodium channel blocking agents (eg. lignocaine and flecainide)
Subclass IA
Intermediate kinetics of binding & dissociation.
Combined Na+ & K+ blockade
137
Supress AV conduction, prolong PR, QRS, QT and APD
138
Subclass IB
Rapid kinetics of binding and dissociation
Do not delay channel recovery or depress AV conduction or prolong APD, ERP & QT
139
Subclass IC
Slow kinetics of binding and dissociation
Most potent Na+ channel blockers with more prominent action on
open state and longest recovery times. Markedly delays conduction,
prolong PR, broaden QRS but have variable effect on APD.
Lignocaine
140
Physicochemical
Structure
Presentation 20mg/ml inj
Pharmacodynamics
MOA • Blocks preferentially inactivated Na+ channels. Hence selective for
partially depolarized cells & those with long AP (eg. PF &
ventricular). Automaticity and after depolarizations in these cells
supressed
• PF and Ventricular muscle: decreases APD duration (no class III
action), and ERP to a lesser extent
• No action on APD or ERP of Atrial fibres.
• SA and AV node not affected
Use • Only in ventricular tachyarrythmias especially in digitalis toxicity
setting where it does not effect AV node
• Used to be given prophylactially by infusion in acute MI – reduces
incidence of VF
• Current status: not used as prophylactic as failed to show survival
and also increase short term mortality, possibly by increasing the
incidence of asystole
Dose • loading dose of 150–200 mg over 15 minutes followed by a
maintenance infusion of 2–4 mg/min. Therapeutic plasma conc. 2-5
microgram/ml. steady-state concentrations may be achieved in 8–10
hours in normal patients .
• In liver disease, the maintenance dose should be decreased, but
usual loading doses can be given.
• In patients with heart failure, lidocaine's volume of distribution and
total body clearance may both be decreased. Thus, both loading and
maintenance doses should be decreased.
• No change in renal disease
CVS
CNS High dose can cause seizures
Respiratory
Other
Side effects/ Cardiac
adverse
141
effects • least cardiotoxic of the currently used sodium channel blockers
• Only in toxic doses:
• Proarrhythmic effects (uncommon) - sinoatrial node arrest,
worsening of impaired conduction, and ventricular
arrhythmias
• May cause hypotension—partly by depressing myocardial
contractility.
Extra-cardiac
• Seizures
• Nystagmus
• Paresthesia
• Blurred vision
• Disorientation
• Drowsiness
• Nausea
• Hypotension at high doses
Interactions • Drugs that decrease liver blood flow (eg, propranolol, cimetidine)
reduce lidocaine clearance and so increase the risk of toxicity unless
infusion rates are decreased.
Pharmacokinetics
Absorption • High hepatic 1st pass metabolism: 3% oral bioavailability
Distribution
Metabolism • Duration of action 10 to 20 min because of rapid redistribution
• Hydrolyzed, deethylated and conjugated. Metabolites excreted in
urine
• T1/2 of early distribution phase is 8 min while late elimination is 2
hours
Excretion
Flecainide
Physicochemical
142
Structure
Presentation Oral: 50, 100, 150 mg tablets
Pharmacodynamics
MOA Flecainide blocks Na+ current and delayed rectifier K+ current (IKr).
very long recovery from Na+ channel block
also blocks Ca2+ currents
APD ↓ in Purkinje cells ↑ in ventricular cells, probably owing to block
of delayed rectifier current
Flecainide does not cause EADs in vitro or torsades de pointes.
In atrial tissue, flecainide disproportionately prolongs action potentials
at fast rates
Flecainide prolongs the duration of PR, QRS, and QT intervals even
at normal heart rates.
Use maintenance of sinus rhythm in patients with supraventricular
arrhythmias, including atrial fibrillation, in whom structural heart
disease is absent, WPW
Dose 100–200 mg twice a day
CVS
CNS
Respiratory
Other
Side effects/ Dose-related blurred vision
adverse can exacerbate CHF in pts with LV dysfunction
effects
Pro-arrythmogenic: acceleration of ventricular rate in patients with atrial flutter,
increased frequency of episodes of re-entrant ventricular tachycardia, and
increased mortality in patients convalescing from MI
Interactions
Pharmacokinetics
Absorption Well absorbed.
Distribution
Metabolism T1/2~20hrs. Elimination occurs by both renal excretion of
unchanged drug and hepatic metabolism by CYP2D6 to inactive
metabolites.
Excretion Both biliary and urinary excretion
143
The beta blockers
These drugs diminish phase 4 depolarization thus depressing automaticity, prolonging AV
conduction, and decreasing HR and contractility
Useful in treating tachyarrhythmias caused by increased sympathetic activity. They are also used
for atrial flutter and fibrillation and for AV nodal reentrant tachycardia
144
All betablockers covered above
Class III agents
Class III: Potassium channel blockers
• Action is manifest by prolongation of the APD
• Most drugs with this action block the rapid component of the delayed rectifier
potassium current, IKr.
• Undesirable property of "reverse use-dependence": action potential prolongation is
least marked at fast rates (where it is desirable) and most marked at slow rates,
where it can contribute to the risk of torsade de pointes.
145
146
Amiodarone
Flecainide
Physicochemical
Structure
Presentation 400mg, 200mg tab
150mg/3ml Inj
Pharmacodynamics
MOA • Markedly prolongs the APD (and the QT interval on the ECG) by
blockade of IKr.
• IKs is blocked during chronic administration.
• Does not have reverse use-dependent action.
• Also significantly blocks inactivated sodium channels & decreases
conduction velocity.
• Weak adrenergic and calcium channel blocking actions.
• Effects: slowing of the HR & AV node conduction.
• The broad spectrum of actions may account for its relatively high
efficacy and low incidence of torsade de pointes despite significant
QT interval prolongation.
• Extracardiac Effects: peripheral vasodilation, following intravenous
administration. May be related to the action of the vehicle.
(Polysorbate 80 and benzyl alcohol)
Use • Low doses (100–200 mg/d) of amiodarone are effective in
maintaining normal sinus rhythm in patients with atrial fibrillation.
• Effective in the prevention of recurrent ventricular tachycardia.
• Its use is not associated with an increase in mortality in patients with
coronary artery disease or heart failure.
• In many centers, the implanted cardioverter-defibrillator (ICD) has
succeeded drug therapy as the primary treatment modality for
ventricular tachycardia, but amiodarone may be used for ventricular
tachycardia as adjuvant therapy to decrease the frequency of
uncomfortable ICD discharges.
• The drug increases the pacing and defibrillation threshold and these
devices require retesting after a maintenance dose has been
achieved.
147
Dose • A total loading dose of 10 g is usually achieved with 0.8–1.2 g daily
doses. The maintenance dose is 200–400 mg daily. Intravenous: 300
mg intravenously, over 10—60 min depending on the circumstances
and haemodynamic stability of the patient, followed by an infusion
of 900 mg over 24 h. Additional infusions of 150 mg can be repeated.
Maximum total daily dose of 2 g. Can cause thrombophlebitis if given
by peripheral vien. Can be given by large bore peripheral line in
emergency.
• Shock resistant VF: 300 mg followed by 150 mg if required.
• Therapeutic plasma range - 0.5 to 2.5 μg/mL. Measured levels do
not correlate well with efficacy or adverse effects
• Pharmacologic effects achieved rapidly by intravenous loading. With
this route QT-prolonging effect is modest whereas bradycardia and
atrioventricular block may be significant.
CVS
CNS
Respiratory
Other
Side effects/ • Cardiac: may produce symptomatic bradycardia & heart block in
adverse patients with preexisting sinus or AV node disease.
effects • Extracardiac: Accumulates in many tissues, including the heart (10–
50 times greater than plasma), lung, liver, and skin, and is
concentrated in tears.
Neuropsychiatric
• The most common are tremor and ataxia (3%-35%, depending on
dose and duration of therapy).
• Peripheral neuropathy is uncommon (0.3% annually) but may be
severe, requiring dose reduction or discontinuation of therapy.
• Insomnia, memory disturbances, and delirium also have been
reported.
Eye
• Asymptomatic corneal microdeposits (>90%), drug discontinuation is
usually not required.
• Optic neuropathy/ neuritis ( reduced automaticity. APD is increased thereby
increasing absolute refractory period and reducing relative refractory
period.
159
• Electrophysiological properties enhanced in the setting of increased
extracellular K, hence, utility appears greatest in setting of ischemia
(loss of intracellular K)
Uses
• Acute rate control of AF
• Preventive post op SVT
• Acute control of MAT
• Ventricular arrythmias associated with triggered activity eg. Torsades
& digoxin toxicity
• Polymorphic VT induced by class I agents
• Very effective at controlling transient ventricular arrythmia in setting
of ischemia eg post infarct and cardiac surgery
Dose
• AF rate and MAT control: 0.15 mmol/kg slow IV push. Subsequent dose
recommendation has varied from 60 mmol to 0.1 mmol/kg/hr for 24
hrs
• SVT prophylaxis following cardiac surgery: 20-25 mmol / day for 4 days
• Transient ventricular arrythmia: 10 mmol slow iv push
• LIMIT-2 post MI dose: 8 mmol bolus over 5 min, followed by 65 mmol
over 24 hrs
• Plasma levels for potent anti-arrythmic action are atleast 1.8mmol/l
Adverse effects
• Rapid bolus hypotension by vasodilatation
• Skeletal muscle weakness
• Excessive action in the setting of hyperkalemia bradycardia and
heart block
Proarrythmic effects of anti-arrythmic drugs
• ‘quinidine syncope’ due to VF and polymorphic VT at therapeutic
concentration (also seen with disopyramide)
• CAST trial which involved flecainide, encainide and morizicine was
terminated early because of adverse outcome in flecainide and
encainide groups (RR of arrythmic death or non-fatal cardiac arrest of
3.6)
• Most pro-arrythmic events occur soon after starting the drug
• Proarrythmia appears to be correlated with the degree of drug induced
QT prolongation or characteristics of sodium channel blockade
• Agents with short time constant of sodium channel blockade where
sodium channel blockade is more pronounced at fast hr are less pro-
160
arrythmic than drugs with long time constants (eg flecanide and
propafenone)
• Class III drugs and quinindine pr-arrythmia correlate with the degree of
QT prolongation
• Reentry is more likely to occur with shorter refractory period and
reduced conduction velocity. Class Ib shorten RP. While class 1A and III
prolong and hence would be beneficial in re-entry
• The scale of potency of pro-arrythmia has been found to be: flecainide >
propafenone > quinidine > disopyramide > procainamide > mexiletine >
lidocaine > sotalol
• Anti-arrythmic drugs are effective at suppressing abnormal automaticity
with the exception of triggered automaticity due to EAD. Class IA and III
can produce proarrythmia due to EAD
• Digoxin can be pro-arrythmic via production of triggered activity due to
DAD
INOTROPES & VASOPRESSORS
161
Adrenaline
Physicochemical
Structure
Presentation First, epinephrine is unstable in alkaline solution; when exposed to air or light, it
turns pink from oxidation to adrenochrome and then brown from formation of
polymers. Epinephrine injection is available in 1 mg/ml (1:1000), 0.1 mg/ml
(1:10,000), and 0.5 mg/ml (1:2,000) solutions.
Pharmacodynamics
MOA potent stimulant of 1, 1 and 2 receptors
Use respiratory distress due to bronchospasm
rapid relief of hypersensitivity reactions, including anaphylaxis
Prolong the action of local anesthetics, presumably by decreasing local
blood flow
cardiac arrest
topical hemostatic agent on bleeding surfaces such as in the mouth or in
bleeding peptic ulcers during endoscopy
inhalation of epinephrine may be useful in the treatment of postintubation
and infectious croup.
Refractory shock especially where both inotropic & vasoconstrictive effects
are desired
Dose Usual S/C dose 0.3 to 0.5 mg.
Dose in cardiac arrest 1mg IV boluses
Anaphylaxis, 1ml boluses of 1:10000 soln
1% (10 mg/ml; 1:100) formulation is available for inhalation.
IV infusions 2-5µg/min for shock.
CVS Blood Pressure.
IV blous of normal dose ↑systolic > ↑diastolic, ↑ pulse pressure. As the
response wanes, the mean pressure may fall below normal before returning to
control levels.
mechanism: (1) positive inotropic action (2) positive chronotropic action and (3)
vasoconstriction in many vascular bedsespecially in the precapillary resistance
vessels of skin, mucosa, and kidneyalong with marked constriction of the veins.
162
↑HR ↑BPvagal discharge ↓HR
IV bolus of low dose (0.1 g/kg) ↓BP. Reason greater sensitivity to 2
receptors than receptors
Slow IV infusion or S/C adrenaline ↓peripheral resistance owing to dominant
action on 2 receptors of vessels in skeletal muscle ↓ diastolic BP & ↑blood
flow. ↑ systolic pressure due to ↑HR, SV, and CO ↑blood flow ↑ venous
return, ↑ RAP. At higher doses of infusion α actions predominate and ↑ TPR.
Vascular Effects.
Marked ↓ cutaneous blood flow. constricting precapillary vessels and small
venules
↓ renal blood flow by as much as 40%
Blood flow to skeletal muscles ↑ by therapeutic doses. 2 effect > α effect. At
higher doses α effect predominates.
Arterial and venous pulmonary pressures ↑due to direct pulmonary
vasoconstriction + redistribution of blood from the systemic to the pulmonary
circulation pulmonary edema can occur
Coronary blood flow ↑ under physiological conditions. Cause: ↑ diastolic time,
↑blood pressure, ↑myocardial O2 demand metabolic vasodilatation mediated
by adenosine.
Cerebral circulation does not constrict in response to arenaline. Autoregulation
limits ↑ in CBF
Cardiac Effects.
predominant 1 stimulation. ↑HR, ↑SV, ↑CO, ↑work & O2 consumption. Cardiac
systole is shorter.
↓ Cardiac efficiency (work done relative to oxygen consumption)
Pro-arrythmic :
Activates latent pacemakers, ↑ automaticity. ↑ slope of phase 4 depolarization,
↑ amplitude and rate of phase 0 depolarization seen in conducting fibres. Not in
atrial and ventricular muscle fibres.
↓ refractory period of AV node by direct effects. However reflex vagal discharge
163
may indirectly tend to prolong it.
CNS Poor penetration. At therapeutic doses restlessness, apprehension, headache, and
tremor due to effects on cardiovascular system
Respiratory Relaxes bronchial muscle (β2 effect).
Inhibition of antigen-induced release of inflammatory mediators from mast cells (β
effect), diminution of bronchial secretions and congestion within the mucosa
(effect.
Other Smooth Muscles.
Gastrointestinal smooth muscle – relaxed. Pyloric and ileocecal sphincters are
contracted, but these effects depend on the preexisting tone of the muscle. If tone
already is high, epinephrine causes relaxation; if low, contraction.
During the last month of pregnancy and at parturition, epinephrine inhibits uterine
tone and contractions (2 effect)
Urinary bladder: relaxes detrusor muscle ( effect) and contracts the trigone and
sphincter muscles ( effect).
Metabolic Effects.
20% to 30% ↑ in oxygen consumption
Hyperglycemia
↑ lactate
↑insulin secretion due to 2 receptors , ↓ insulin secretion due to α receptors.
Predominant effect is inhibition.
↑Glucagon secretion ( receptors on cells of pancreatic islets).
↓ uptake of glucose by peripheral tissues
↑ glycogenolysis ( receptors)
↑ free fatty acid conc. ( receptors in adipocytes)
Renal: ↓RBF. Since the glomerular filtration rate is only slightly and variably
altered, the filtration fraction is consistently increased. Excretion of Na+, K+, and Cl-
is decreased. The secretion of renin is increased as a consequence of a direct
164
action of epinephrine on 1 receptors in the juxtaglomerular apparatus.
Miscellaneous
↑ number of circulating polymorphonuclear leukocytes
accelerates blood coagulation and promotes fibrinolysis.
Stimulates lacrimation and a scanty mucus secretion from salivary glands.
Mydriasis
lowers intraocular pressure
increase physiological tremor, at least in part due to receptor-mediated
enhancement of discharge of muscle spindles.
Epinephrine promotes a fall in plasma K+, largely due to stimulation of K+ uptake
into cells.
Side effects/ restlessness, throbbing headache, tremor, and palpitations.
adverse cerebral hemorrhage and cardiac arrhythmias.
effects
Angina may be induced by epinephrine in patients with coronary artery disease.
Contraindicated in patients who are receiving nonselective receptor blocking
drugs, since its unopposed actions on vascular 1 receptors may lead to severe
hypertension and cerebral hemorrhage.
Interactions
Pharmacokinetics
Absorption Not effective orally. Rapidly conjugated and oxidized in the GI mucosa and liver.
Absorption from subcutaneous tissues occurs relatively slowly, more rapid after
intramuscular injection. In emergencies, it may be necessary to administer
epinephrine intravenously.
Distribution
Metabolism
Rapidly inactivated. The liver is rich in both of the enzymes responsible for
destroying circulating epinephrine (COMT and MAO).
165
Excretion only small amounts appear in the urine
Noradrenaline
Physicochemical
Structure
Presentation 1 mg/mL for injection
Pharmacodynamics
MOA Major chemical mediator liberated by mammalian postganglionic sympathetic
nerves
Sympathomimetic
• Acts on both & 1- receptors but has relatively little effect on 2-receptors
• Like adrenaline: low dose predominantly beta effect; higher dose alpha
• Causes i) vasoconstriction [-receptor]
Clinical effects
ii) Inotrope [1-receptors] offset by increased
iii) Chronotrope [1-receptors] afterload
• Consequently increases systemic BP and coronary artery blood flow
Use In the treatment of low blood pressure, the dose is titrated to the
desired pressor response.
Dose 0.06-0.15µg/kg/min
CVS ↑Systolic, diastolic and pulse pressure
CO - unchanged or decreased
↑ TPR
vagal reflex activity ↓ HR
↓ renal blood flow
Constricts mesenteric vessels and ↓ splanchnic and hepatic blood
flow.
Coronary flow ↑
166
CNS
Respiratory
Other hyperglycemia and other metabolic effects similar to those produced by
epinephrine but these are observed only when large doses are given because
norepinephrine is not as effective a "hormone" as epinephrine.
Side effects/ severe hypertension
adverse
effects necrosis and sloughing can occur at the site of intravenous injection owing to
extravasation of the drug. The infusion should be made high in the limb, preferably
through a long plastic cannula extending centrally. Impaired circulation at injection
sites, with or without extravasation of norepinephrine, may be relieved by
infiltrating the area with phentolamine, an receptor antagonist.
Caution:
• Should not be mixed in saline alone [water O.K.]
• Risk of arrhythmias with volatile anaesthetics
• Give with caution to patients on MAO or tricyclics as will prolong action
Interactions • Should not be mixed in saline alone [water O.K.]
• Risk of arrhythmias with volatile anaesthetics
• Give with caution to patients on MAO or tricyclics as will prolong action
Pharmacokinetics
Absorption ineffective when given orally and is absorbed poorly from sites of
subcutaneous injection
Distribution
Metabolism Rapidly inactivated. The liver is rich in both of the enzymes responsible for
destroying circulating epinephrine (COMT and MAO).
Excretion Small amounts normally are found in the urine
Evidence
some survival benefit in septic shock, compared with high-dosage dopamine and epinephrine
epinephrine norepinephrine
Heart rate + -
Stroke volume ++ ++
167
Cardiac output +++ 0/-
Arrhythmias ++++ ++++
Coronary blood flow ++ ++
Systolic BP +++ +++
MAP + ++
Diastolic BP +/0/- ++
Mean PAP ++ ++
TPR -/+ ++
Cerebral blood flow ++ 0/-
Muscle blood flow +++ 0/-
Skin blood flow -- --
Renal blood flow - -
Splanchnic blood flow - 0/-
Oxygen demand ++ 0/+
Blood glucose +++ 0/+
Blood lactate +++ 0/+
Vasopressin
Physicochemical
Structure nonapeptide with a 6-amino-acid ring and a 3-amino-acid side chain.
Presentation Inj 20 U/ml
Pharmacodynamics
MOA Vasopressin is a peptide hormone released by the posterior pituitary in response
to rising plasma tonicity or falling blood pressure. Vasopressin possesses
antidiuretic and vasopressor properties. Acts via G protein coupled V1 and V2
receptors. It exerts its circulatory effects through V1 (V1a in
vascular smooth muscle, V1b in the pituitary gland) and V2
receptors (renal collecting duct system; Table). V1a stimulation
168
mediates constriction of vascular smooth muscle,
whereas V2 receptors mediate water reabsorption by enhancing
renal collecting duct permeability.
Use Cardiac arrest
Vasopressor sparing/catecholamine hyposensitivity in shock states
Bleeding esophageal varices
0.01 to 0.05 units/min
Dose 40 U boluses in cardiac arrest
CVS Vasopressin causes less direct coronary and cerebral vasoconstriction
than catecholamines and has a neutral or inhibitory
impact on CO, depending on its dose-dependent increase
in SVR and the reflexive increase in vagal tone. A
vasopressin-modulated increase in vascular sensitivity to
norepinephrine further augments its pressor effects. The agent
may also directly influence mechanisms involved in the
pathogenesis of vasodilation, through inhibition of ATP-activated
potassium channels, attenuation of nitric oxide
production, and reversal of adrenergic receptor downregulation.
The pressor effects of vasopressin are relatively
preserved during hypoxic and acidotic conditions, which
commonly develop during shock of any origin.
CNS does not penetrate BBB
Respiratory
Other
Side effects/ Allergic reactions & anaphylaxis
adverse Cardiac arrest, circumoral pallor, arrhythmias, decreased cardiac output,
effects angina, myocardial ischemia, peripheral vasoconstruction and gangrene.
Gastrointestinal: abdominal cramps, nausea, vomiting.
Nervous System: tremor, vertigo, palpitations
Respiratory: bronchial constriction.
Skin and Appendages: sweating, urticaris, cutaneous gangrene
Interactions Drugs which potentiate antidiuretic effect: carbamazepine; chlorpropamide;
clofibrate; urea; fludrocortisone; tricyclic antidepressants.
Drugs which decrease the antidiuretic effect of vasopressin: demeclocyline;
norepinephrine; lithium; heparin, alcohol.
Ganglionic blocking agents may produce a marked increase in sensitivity to
the pressor effects of vasopressin.
Pharmacokinetics
Absorption Orally destroyed by trypsin
Distribution
169
Metabolism T1/2 10 to 20 minutes. Metabolized by enzymatic cleavage in many
organs especially liver and kidney
Excretion
Dobutamine
Physicochemical
Structure
Presentation 12.5mg/ml Injection
Pharmacodynamics
MOA strong +ve inotropy due to beta1 agonist effects and
alpha1 agonism
- mild +ve chronotropy due (+) isomer effect on beta receptors
- weaker alpha receptor blockade and beta2 stimulation,
produced by (+) isomer and alpha1 agonism produced by
(-) isomer
- overall peripheral effect should be an increase in blood flow
to skeletal muscle (beta2 agonism) and some reduction in skin
blood flow (alpha1 agonism balanced by some alpha
blockade). These effects are weak compared to the
myocardial effects
- net effects are an increase in SV and CO. SVR may be
unchanged or moderately decreased and arterial pressure
may thus rise, fall slightly or remain unchanged
- at doses > 15 mcg/kg/min tachycardia and arrhythmias are
more likely
- tolerance may be seen after 48-72 hrs, presumably due to
down-regulation of beta receptors. May necessitate an
increase in dose. Dose required to produce toxic effects
seems to be increased equivalently
Use
Dose
CVS
CNS
Respiratory
Other
Side effects/ tachycardia and tachyarrhythmias less frequent than with
170
adverse dopamine
effects - enhances AV conduction and may precipitate AF in predisposed
patients
Interactions
Pharmacokinetics
Absorption
Distribution
Metabolism Onset of action within 2 min and maximal effect associated
with a given infusion rate occurs approximately 10 min
after starting the infusion. metabolized by COMT to. t1/2
2.3 min
Excretion inactive metabolites which are excreted in the urine
Dopamine
Physicochemical
Structure
Presentation 200mg ampule
Pharmacodynamics
MOA Acts on D1, D2, α and β1 receptors
D1 receptors in renal and mesenteric blood vessels are most sensitive-at
low doses-increased blood flow->↑GFR↑Na excretion
Higher doses stimulate β1 receptors inotropic actions
Large doses have predominant αactions vasoconstriction
Use CHF, particularly in patients with oliguria and low or normal peripheral
vascular resistance.
Cardiogenic and septic shock.
Dose Dopamine hydrochloride is used only intravenously. The drug initially
is administered at a rate of 2 to 5 g/kg per minute; this rate may be
increased gradually up to 20 to 50 g/kg per minute or more as the
clinical situation dictates
CVS At low doses (1 to 3 µg/kg per min) Vascular D1 receptors in in the
renal, mesenteric, and coronary beds activates adenylyl cyclase,
171
↑cAMP vasodilation ↑ GFR, renal blood flow, and Na+ excretion.
Total peripheral resistance usually is unchanged
At higher conc. (3 to 10 µg/kg per min) 1 receptors +ve inotropic
actions, release of norepinephrine from nerve terminals ↑SBP &
pulse pressure, minimal effect on DBP.
At ever higher conc. (10 to 20 µg/kg per min) predominant
activation of vascular 1 receptors generalized vasoconstriction
CNS Poor penetration – no effect
Respiratory
Other
Side effects/ Nausea, vomiting, tachycardia, anginal pain, arrhythmias, headache, hypertension,
adverse and peripheral vasoconstriction
effects Extravasation ischemic necrosis and sloughing.
Rarely, gangrene of the fingers or toes
Interactions MAO inhibitor, TCA
Pharmacokinetics
Absorption ineffective when administered orally
Distribution
Metabolism Dopamine is a substrate for both MAO and COMT
Excretion
evidence
Published data in sepsis suggest that dopamine may impair hepatosplanchnic
No benefit of renal dose dopamine
Isoprenaline
Physicochemical
Structure
Presentation 1000 microgram/5mL
Pharmacodynamics
172
MOA activating β1 and β2 receptors equally
Use To treat shock, cardiac arrest, bradyarrythmias, bronchospasm
Dose 0.05 - 0.5 microgram/kg/minute
CVS positive chronotropic, dromotropic, and inotropic effect ↑SBP. In
skeletal muscle arterioles it produces vasodilatation ↓DBP
CNS
Respiratory relaxation of bronchial smooth muscle
Other
Side effects/ Tachycardia – continuously monitor heart rate.
adverse Cardiac dysrhythmia, hypertension, hypotension, vomiting, tremor.
effects
Interactions
Pharmacokinetics
Absorption
Distribution
Metabolism T1/2 ~2hrs
Excretion
milrinone
Physicochemical
Structure
Class Phosphodiesterase inhibitor
Presentation Injection, solution: 1 mg/mL (10 mL, 20 mL, 50 mL)
Pharmacodynamics
173
MOA phosphodiesterase III inhibitors potentiates the effect of cyclic adenosine
monophosphate (cAMP).
Milrinone also enhances relaxation of the left ventricle by increasing Ca2+-
ATPase activity on the cardiac sarcoplasmic reticulum. This increases
calcium ion uptake.
Use Cardiogenic shock
Pulmonary hypertension eg with PE
Dose Adults: I.V.: Loading dose (optional): 50 mcg/kg administered over 10 minutes followed by a
maintenance dose titrated according to the hemodynamic and clinical response; Maintenance
dose: I.V. infusion: 0.375-0.75 mcg/kg/minute.
If hypotension is a problem, loading doses may be omitted and maintenance infusions
initiated. There is some delay in hemodynamic effects, but it is minimal (1-3 hours).
Monitoring Parameters
Platelet count, CBC, electrolytes (especially potassium and magnesium), liver function and
renal function tests; ECG, CVP, SBP, DBP, heart rate; infusion site
CVS +ve inotropic and vasodilatation
CNS
Respiratory
Other
Side effects/ >10%: Cardiovascular: Ventricular arrhythmia (ectopy 9%, NSVT 3%, sustained ventricular
adverse tachycardia 1%, ventricular fibrillation <1%)
effects
1% to 10%:
Cardiovascular: Supraventricular arrhythmia (4%), hypotension (3%), angina/chest pain (1%)
Central nervous system: Headache (3%)
<1% (Limited to important or life-threatening): Atrial fibrillation, hypokalemia, MI,
thrombocytopenia, tremor, ventricular fibrillation
Postmarketing and/or case reports: Anaphylaxis, bronchospasm, injection site reaction, liver
function abnormalities, rash, torsade de pointes
Interactions no known significant interactions
Pharmacokinetics
Absorption Good Oral absorption
Distribution Onset of action: I.V.: 5-15 minutes
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Distribution: Vdss: 0.32-0.45 L/kg
Protein binding, plasma: ~70%
Metabolism Metabolism: Hepatic (12%)
Half-life elimination: Normal renal function: ~2.5 hours; CVVH: 20.1 hours (Taniguchi, 2000)
Excretion Excretion: Urine (85% as unchanged drug) within 24 hours; active tubular secretion is a
major elimination pathway for milrinone
levosimendan
Physicochemical
Structure
Class Calcium sensitizer
Presentation 2.5 mg
per 5 mL per ampoule and 10mL per ampoule
Pharmacodynamics
MOA does not increase intracellular
concentrations of free calcium. It binds to cardiac
troponin C in a calcium-dependent manner and
stabilises troponin C. This causes actin-myosin
cross-bridges, without increasing myocardial
consumption of adenosine triphosphate (ATP). Also opening of ATP-dependent
potassium (K_) channels causes vasodilatation
Use indicated for inotropic support in acutely-decompensated severe congestive
heart failure
Dose 6 to
12 μg/kg loading dose over 10 minutes followed by
0.05 to 0.2 μg/kg/min as a continuous infusion
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CVS enhance cardiac contractility. No arrythmogenic potential. venous, arterial
and
coronary vasodilation, probably by opening ATPsensitive
potassium channels in smooth muscle.
CNS
Respiratory
Other
Tachycardia, enhanced AV conduction
Side effects/
Hypotension
adverse
effects
Interactions No significant interactions
Pharmacokinetics
Absorption well
absorbed orally
Distribution 98% bound to plasma proteins
Metabolism 5% dose is converted in intestines to highly active metabolite with
t1/2 75-80h. Effects after infusion hence may persist 7-9 days after
stopping infusion. T1/2 of levosimendan otherwise is 1hr.
Excretion
Evidence
Some of the Phase-III studies in the extensive clinical program were the trials LIDO (200
patients), RUSSLAN (500), CASINO (250), REVIVE-I (100), REVIVE-II (600) and finally SURVIVE
(1350),[1] a head-to-head trial between levosimendan and dobutamine in acute
decompensated heart failure. levosimendan did not significantly reduce all-cause mortality
at 180 days
In the randomised Levosimendan Infusion versus Dobutamine (LIDO) trial in 203 patients
with severe, low-output decompensated CHF,[10] significantly more patients in the
levosimendan group achieved the primary efficacy end-point of an increase from baseline in
cardiac index ≥ 30% and a decrease in PCWP ≥ 25% than in the dobutamine group (5 to 10
µg/kg/min for 24 hours) [28 and 15%, respectively].
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