STRUCTURE AND FUNCTION OF THE HEART

STRUCTURE AND FUNCTION OF THE HEART
Cardiac function
metabolism.
The overall function of the cardiovascular system is to deliver oxygen and metabolic substrates to the to the tissues and to remove the products of
Cardiac Muscle is a unique type of involuntary striated muscle which resembles skeletal muscle in
many of its features. Cardiac muscle has several structural and functional differences as compared to
skeletal muscle.
Mitochondria
Structurally it is smaller, usually mononuclear, arranged more in series as opposed to parrallel,
Actin
it has a greater number of mitochondria (cardiac muscle is almost entirely aerobic), and has intercalcated discs separated by gap junctions (which bind the muscle cells together and permit electrical
Myosin
coupling).
M Line
Functionally all myocytes display five basic characteristics: rhythmicity (chronotropy),
conductivity (dromotropy), excitiability (bathmotropy), contractility (inotropy) and relaxation
Tropomysin
(lusitropy). Cardiac muscle has automaticity which is the property of the heart to initiate its own heart
Troponin complex
beat. This occurs in specialised pacemaker cells of the SA and AV nodes as well as some ventricular
cells. The resting membrane is not stable in phase 4 and the resting potential decreases towards to the
Intercalcated Disc
threshold potential. This is intrinsic (not requiring external input) although catecholamines may
Gap junctions
increase pacemaker rates. Following depolarisation, the membrane repolarises and then the sequence
Z Line
of spontaneous depolarisation occurs again. This involves a period of absolute refractory period
(where the muscle cannot contract again) and relative refractory period (where with a large enough
stimulus the muscle may contract -although a reduced force). The predictable regularity of this sequence of events gives the heart a regular rhythm. This is known as the
property of rhythmicity. The cardiac muscle enables improved conductivity due to specialised tracts known as the conducting system of the heart. It propogates through
low resistance pathways alongside the intercalcated discs and easily crosses the gap junctions. The benefit of this system is improved coordination of each contraction and
the heart has been described as a functional synctium due to this level of coordination. Cardiac muscle has increased excitability, that is it can respond to smaller stimulus
than skeletal muscles. The steeper the slope of phase 0 the more excitable the myocyte. Contractility is an intrinsic property of cardiac muscle and refers to the ability of
muscle to develop force at a given length. Finally cardiac myocytes demonstrate lusitropy which is an active phase of relaxation in the isovolaemic relaxation phase.
Sarcoplasmic Reticulum
Cardiac Anatomy The left and right coronary arteries arise from the aortic root behind the cusps of the aortic valve.
The right coronary artery perfuses the right ventricle and atrium. The left coronary artery divides into the anterior
descending and circumflex branches and perfuses the left ventricle and atrium. There is considerable overlap between the
Circumflex
SA Node
left and right ateries and the right is more commonly predominant. Most venous blood drains into the right atrium via the
Left Anterior
coronary sinus although the thebsian circulation drains into the left side of the circulation and constitutes a physiological
Descending
Right Coronary
shunt.
AV Node
The heart has dual and opposing nerve supplies. Parasympathetic (acteylcholine - slows
Marginal
Diagonals
heart rate) and is supplied by the vagal nerve and sympathetic (catecholamine transmitter,
Posterior
Anterior
increases heart rate and force of contraction). Sympathetic nerves originate from the
Interventricular
Interventricular
NO
intermediolateral columns of the upper thoracic spinal cord and synapse in the middle of
CONDUCTION
SA Node
stellate ganglia then form a complex plexus (incl. parasympathetic fibres) to innervate the heart. Embryologically the SA develops on the right
Bachman
side (hence right sided nerve supply) and the AV from the left with corresponding supply.
FAST
Wenkebach
Thorel
AV Node
Bundle of His
SLOW
FASTEST
Purkinje Fibres
Pressure (mmHg)
120
There are three bundles of atrial fibres that contain the Purkinje-type fibres and connect the SA to AV. Anteriorly it is the Bachmann tract,
Wenkebach is in the middle and Thorel is posterior. Whilst the SA and AV have slow conduction speeds of 5cm/second, the atrial pathway, bundle
of HIS and ventricular muscle conduct at 100cm/second and the purkinje system at the very fast rate of 400cm/second. Because the AV node is a
gateway its reduced speed means that there is a AV nodal delay of 0.1 second.
Isovolumetric
Contraction
Isovolumetric
Relaxation
100
AV Shuts
80
Aorta
AV Opens
60
Systole
40
20
A
Wave
MV
Shuts
C
Wave
V
Wave
S2
S1
LA pressure
Left Ventricle
Heart Sounds
MV
Opens
Left Ventricle Pressure / Time Curve This curve is used in the context of discussing the
cardiac cycle. The ECG and the heart sounds are used as the timing reference points. The QRS
complex represents the electrical depolarisation of the ventricle. At this point the mitral valve is
forced shut by the increase in LV pressure. There is then a period of isovolumetric contraction
where pressure in the ventricle increases dramatically until it exceeds aortic pressure and the aortic
valve is forced open. The pressure continues to exceed aortic pressure and blood is forced out of
the ventricle. As the blood exits the LV the pressure drops and when it is less than the aortic
pressure the aortic valve snaps shut. There is then a period of active relaxation (lusitropy) with both
valves shut, called isovolumetric relaxation. When the pressure drops below CVP the mitral valve
reopens and diastole occurs allowing the ventricle to refill (CVP>LVP).
ECG
0.25
0.5
Time (seconds)
Volume (ml)
Atrial Kick
LV EDV
120
80
LV ESV
40
0.25
Time (seconds)
Christopher Andersen 2012
0.5
Left Ventricular Volume / Time Curve This trace shows the volume of the left ventricle
throughout the cycle. The important point is the atrial kick. Loss of this kick in atrial fibrillation and
other conditions can adversely affect cardiac function through impaired LV filling. The maximal
volume occurs at the end of diastolic filling and is labelled the left ventricular end-diastolic volume
(LVEDV). In the same way, the minimum volume is the left ventricular end-systolic volume (LVESV).
The difference between these two values must, therefore, be the stroke volume (SV), which is usually
70 ml as demonstrated above. The ejection fraction (EF) is the SV as a percentage of the LVEDV and is
around 60% in the diagram adjacent.
PERIPHERAL VASCULAR ANATOMY

The main indications for central venous cannulation are;
Measurement
Central venous pressure
Pulmonary artery catheterization and monitoring
Frequent blood testing
Non Drug Interventions
Transvenous cardiac pacing
Temporary hemodialysis
Aspiration of air emboli
Drug Administration
Concentrated vasoactive drugs,
Hyperalimentation,
Drugs irritating to peripheral veins,
Prolonged IVABs (endocarditis)
Rapid infusion of fluids (through large cannulas)
Inadequate peripheral access
The main complications are

Mechanical
Vascular injury (arterial or venous)
Cardiac tamponade
Respiratory compromise
Airway compression from hematoma
Pneumothorax
Nerve injury
Arrhythmias
Thromboembolic
Venous thrombosis
Pulmonary embolism
Catheter or guidewire embolism
Infectious
Insertion site infection
Catheter infection
Bloodstream infection
Endocarditis
Misinterpretation of data
Misuse of equipment
JUGULAR FORAMEN
STERNOCLEIDOMASTOID
CAROTID SHEATH
CAROTID ARTERY
VAGUS NERVE
INTERNAL JUGULAR VEIN
ANTERIOR
SCALENE
EXTERNAL JUGULAR
VEIN
CLAVICLE
AXILLARY VEIN &

ARTERY
SUBCLAVIAN VEIN &

ARTERY
1st RIB
LUNG APEX
BRACHIOCEPHALIC VEIN
(INNOMINATE)
SUPERIOR
VENA CAVA
The internal jugular vein
Origin
Terminates
Course
Anterior
Posterior
Medial
Lateral
From the jugular foramen

Behind the sternoclavicular joint in the Subclavian Vein
Relatively straight course in the neck, it lies with the carotid artery and the vagus nerve within the carotid sheath. superficial in the upper part of the
neck before it descends deep to the sterno-cleidomastoid muscle
Superficial fascia superiorly and SCM inferiorly
Vertebral muscles, sympathetic chain and thoracic duct (L only)
The carotid arteries, and CNX as well as CN IX, XI and XII.
SCM and CN XI inferiorly
The external jugular vein

The external jugular vein begins near the angle of the mandible (just inferior to the auricle of the external ear) by the union of the posterior division of the
retromandibular vein with the posterior auricular vein. The EJV crosses the SCM obliquely, deep to the platysma, and then pierces the investing
layer of deep cervical fascia, which forms the roof of this region, at the posterior border of the SCM. The EJV descends to the inferior part of the lateral cervical
region and terminates in the subclavian vein.
The subclavian vein

Origin
Terminates
Course
Anterior
Posterior
Medial
Laterally
Inferior
From the axillary vein

Behind the sternoclavicular joint in the internal jugular vein to become the brachiocephalic vein (innominate)
Commencing from the axillary vein medially it receives flow from the external jugular vein, progressing anterior to the anterior scalene muscle which
separtates the SCV and artery. It crosses travels over the superior surface of the first rib forming a slight groove. It then arches up medially then down
to join the IJV and form the brachiocephalic.
Posterior surface of the Clavicle
Anterior scalene muscles, subclavian artery
Thoracic duct, brachiocephalic trunk
Lower trunk brachial plexus
First Rib, first intercostal space and apex of the lung
Arterial cannulation with continuous pressure transduction and waveform display remains the accepted reference standard for blood pressure monitoring despite the
fact that it is more costly than non invasive and has the potential for more complications.
Indications;
Continuous, real-time blood pressure monitoring
Planned pharmacologic or mechanical cardiovascular manipulation
Repeated blood sampling
Failure of indirect arterial blood pressure measurement
Supplementary diagnostic information from the arterial waveform
Complications;
Distal ischemia, pseudoaneurysm, arteriovenous fistula
Hemorrhage
Arterial embolization
Infection
Peripheral neuropathy
Misinterpretation of data
Misuse of equipment
The most common site utlised for arterial cannulation is the radial artery. Peripheral arteries are preferable due to their lower risk of serious complications such as cerebral
embolisation. Alternatives include the ulnar artery, brachial artery and dorsalis pedis and posterior tibial. The later two mainly in the paediatric population due to increasing
likelhood of PVD in an adult population. The axillary artery and femoral artery are also used occasionally.
The axillary artery provides a site for long term pressure monitoring, the left side being preferred because the tip will lie distal to
the aortic arch and great vessels. It begins at the lateral border of the first rib as the continuation of the subclavian artery and ends at
the inferior border of the teres major. It passes posterior to the pectoralis minor into the arm and becomes the brachial artery when it
passes distal to the inferior border of the teres major. For descriptive purposes, the axillary artery is divided into three parts relative to
the pectoralis minor (the part number also indicates the number of its branches): The first part of the axillary artery is located
between the lateral border of the first rib and the medial border of the pectoralis minor; it is enclosed in the axillary sheath and has
one branch. The second part of the axillary artery lies posterior to the pectoralis minor and has two branches. The third part of the
axillary artery extends from the lateral border of the pectoralis minor to the inferior border of the teres major and has three branches.
BRACHIAL ARTERY
The brachial artery. Despite the absence of anatomic collateral flow at the elbow, brachial artery catheterization for
perioperative blood pressure monitoring is a safe alternative to radial or femoral arterial catheterization. The brachial artery
provides the main arterial supply to the arm and is the continuation of the axillary artery. It begins at the inferior border of the
teres major and ends in the cubital fossa opposite the neck of the radius under cover of the bicipital aponeurosis, where it
divides into the radial and ulnar arteries. The brachial artery, relatively superficial and palpable throughout its course, lies
anterior to the triceps and brachialis. At first, it lies medial to the humerus, where its pulsations are palpable in the medial
bicipital groove. It then passes anterior to the medial supraepicondylar ridge and trochlea of the humerus. As it passes
inferolaterally, the brachial artery accompanies the median nerve, which crosses anterior to the artery. There are three main
branches of the brachial artery that arise from its medial aspect are the profunda brachii artery (deep artery of arm) and the
superior and inferior ulnar collateral arteries.
1ST
2ND
3RD
PECTORALIS MINOR
BICEPETIAL
GROOVE
INFERIOR BORDER
TERES MAJOR
MEDIAN NERVE
BICEPETIAL
APONEUROSIS
ULNAR ARTERY
The radial artery Is the most commonly used artery for placement of cannulas. The Allens test is often recom-
mended although its predictive power has been questioned by large studies. The radial artery is the smaller terminal
branch of brachial artery. It runs inferolaterally under cover of brachioradialis; lies lateral to flexor carpi radialis tendon
in distal forearm; winds around lateral aspect of radius and crosses floor of anatomical snuff box to pierce 1st dorsal
interosseous muscle.
AXILLARY ARTERY
RADIAL ARTERY
INGUINAL LIGAMENT
FEMORAL
NERVE
EXTERNAL ILLIAC
ARTERY & VEIN
FEMORAL SHEATH
/CANAL
ILLIOPSOAS
FEMORAL ARTERY
& VEIN
ADDUCTOR
LONGUS
PECTINEUS
PROFUNDA
FEMORIS VEIN
& ARTERY
GREAT SAPHENOUS
VEIN
SARTORIUS
ADDUCTOR
CANAL
ADDUCTOR HIATUS
POPLITEAL ARTERY
& VEIN
The femoral triangle The boundaries of the femoral triangle are: the inguinal ligament above, sartorius laterally
and adductor longus medially.
The floor consists of: iliopsoas laterally and pectineus medially.
The roof consists of: fascia lata.
The contents include (from lateral to medial) the: femoral nerve, artery, vein and their branches and tributaries. The
femoral canal is situated medial to the femoral vein. Transversalis fascia and psoas fascia fuse and evaginate to form
the femoral sheath below the inguinal ligament. The sheath encloses the femoral artery, vein and canal but the
femoral nerve lies outside on its lateral aspect. The triangle also contains deep inguinal lymph nodes and lymphatic
vessels.
The femoral artery is the chief artery to the lower limb, is the continuation of the external iliac artery, originating
distal to the inguinal ligament. It enters the femoral triangle deep to the midpoint of the inguinal ligament (midway
between the ASIS and the pubic tubercle), lateral to the femoral vein. Lies deep to the fascia lata and descends on the
adjacent borders of the iliopsoas and pectineus. Bisects the femoral triangle and exits at its apex to enter the adductor
canal, deep to the sartorius. Exits the adductor canal by passing through the adductor hiatus and becoming the
popliteal artery. The profunda femoris artery (deep artery of the thigh) is the largest branch of the femoral artery and
the chief artery to the thigh. It arises from the femoral artery in the femoral triangle.
The femoral vein is the continuation of the popliteal vein proximal to the adductor hiatus. As it ascends through the
adductor canal, the femoral vein lies posterolateral and then posterior to the femoral artery. The femoral vein then
enters the femoral triangle, and subsequently the femoral sheath medial to the femoral canal. It ends posterior to the
inguinal ligament, where it becomes the external iliac vein. In the inferior part of the femoral triangle, the femoral vein
receives the profunda femoris vein, the great saphenous vein, and other tributaries. The profunda femoris vein (deep
vein of thigh), formed by the union of three or four perforating veins, enters the femoral vein inferior to the inguinal
ligament and inferior to the termination of the great saphenous vein.
ELECTRICAL PROPERTIES OF THE HEART

Membrane potential (mV)
Ionic basis of the slow-response cardiac action potential
The sino atrial node and the AV node have the same
ionic basis although the AV node is slower. The adjacent diagram represents the SA node. In the slow response cardiac
action potential there is no resting state; rather there is a pacemaker potential which generates cardiac autorhythmicity.
Phases 1 and 2 (of the fast response action potential) are absent in the SA/AV node as there is no depolarisation plateau.
20
0
0
3
Sympathetic
stimulation
-40
PHASE 0
4
Parasympathetic
stimulation
-80
100
200
300
Time (ms)
PHASE 4
400
Ionic basis of the fast-response cardiac action potential Atrial and ventricular muscle and purkinje fibre action
potentials differ from those in nerves as they are much longer in duration, with a distinct plateau phase when
depolarisation is maintained.
30
PHASE 0
Absolute
Refractory
Period
PHASE 1/2
PHASE 3
Relative
Refractory
Period
PHASE 1
PHASE 2
4
-90
-100
PHASE 3
0
100
Depolarisation is produced by the opening of voltage-gated calcium channels (L-Type) and inward movement
of positive ions.
are absent
Repolarisation occurs as Ca2+ channels close and and K+ channels open. Efflux of K+ from within the cell
repolarises the cell fairly rapidly.
The pacemaker potential is produced by a fall in membrane potassium permiability and an increase in a slow
inward current. The slow inward current consists of a voltage gated increase in calcium permiability (via T-Type
channels) and activity of the electrogenic sodium-calium exchange system, driven by inward movement of
calcium ions. This pacemaker activity brings the cell to threshold potential.
200
300
Time (ms)
400
500
The cell is rapidly depolarised from the resting membrane potential by a rise in sodium permiability via fast
sodium channels. The slope is almost vertical. The the membrane is less negative then many sodium channels
will be closed, thus the response will not be as quick.
Repolarisation begins to occur as sodium channels close and potassium channels open.
A plateau occurs owing to the opening of L-type Ca2+ channels which offset the action of K channels and
maintains depolarisation. During this time no further depolarisation is posible, this represents the absolute
refractory period.
The L-type Ca2+ channels close and K efflux now causes repolarisation as seen before this accelerates through
positive feedback. It is now possible to cause another depolarisation although the force of the contraction
will be diminished. This the relative refractory period.
Cardiac excitation - contraction coupling Contraction of cardiac fibres is by the interaction of actin and myosin filaments in the presence of calcium.
Tropomyosin lies in the groove and prevents interaction of the two, this action is modulated by the troponin complex which is activated by calcium (see previous figure).
Similar to skeletal muscle contraction in cardiac muscle results from the temporary release of calcium from the sarcoplasmic reticulum. Unlike skeletal muscle the the SR
Ca2+ release is triggered by the inward flow of Ca2+ across the cell membrane and the T-Tubules during the action potential. Cardiac muscle does not contract in the
absence of calcium in the ECF. This form of excitation contraction coupling may be described as calcium triggered calcium release and is an amplification process
whereby the movement of a small amount of calcium into the cell causes a temporary release of a much larger amount of calcium from the SR. Increases in intracellular
Ca increase the force of contraction. When the cardiac myocyte relaxes the sarcoplasmic reticulum actively takes up the calcium and sequesters it (lusitropy), the calcium
which acted as a trigger is transported out of the cell by active and counter transport methods.
The ECG Electrodes are the sites at which an electrical potential is measured, while ECG leads record the difference in potentials between
two electrodes. Standard surface electrodes (right and left arm, right and left leg, and the six precordial electrodes) measure the electrical
potential at a site. Leads may unipolar or bipolar. Bipolar leads, which include I, II and III measure the difference between two surface
electrodes, and drawn together they form Einthovens triangle. The central terminal of Wilson, is calculated from the average voltage of the
limb leads. This idealized site is meant to represent a reference at the center of Einthoven's triangle where total current is zero. From this
reference point the unipolar leads; aVR, aVL and aVF plus the chest leads are calculated.
Intervals
Normal Durations
Average Range
Events in the Heart during Interval
PR Interval
QRS duration
QT interval
ST interval (QT minus QRS)
0.18
0.08
0.40
0.32
Atrial depolarisation and conduction through the AV node

Ventricular depolarisation and atrial repolarisation
Ventricular depolarisation and subsequent repolarisation
Ventricular repolarisation (during T wave)
0.12-0.20
up to 0.10
up to 0.44
....
PR is actually from the start of the PR segment to the start of the QRS. The PR shortens as the heart rate increases.
Factors which influence cardiac electrical activity

Sodium a fall in plasma Na+ may be associated with low voltage ECG complexes.
Potassium in the setting of hyperkalaemia the most common finding is tall T waves which is a manifestation of abnormal repolarisation. At higer levels
paralysis of the atria and prolongation of the QRS complexes can occur. Ventricular arrhythmias may develop. The resting membrane potential of muscle fibres decreases
as the extracellular K+ concentration increases. The fibres eventually become unexcitable and the heart stops in diastole. In the setting of hypokalaemia causes
prolongation of the PR interval, prominent U waves, and occasionally late T-Wave inversion in precardial leads.
Calcium hypercalcaemia enhances myocardial contractility. There is shortening of the QT interval due to a shorter ST segment. In experiments large doses of
calcium prevents the heart from relaxing and the heart stops in systole (calcium rigor) however calcium levels are rarely significant in the clinical setting. Hypocalcaemia
causes prolongation of the ST segment and consequently the QT interval.
Magnesium Hypomagnesiumaemia results in several ECG changes and may be a result of concurrent hypokalaemia or its actions on several cardiac
membrane channels including those responsible for calcium and poassium. Changes seen include Widening of the QRS complex and peaking of T waves have been
described with modest magnesium loss, while more severe magnesium depletion can lead to prolongation of the PR interval, progressive widening of the QRS complex,
and diminution of the T wave.
Adenosine Adenosine receptors exist in both atrial and nodal tissues and activate the K+ current which transiently hyperpolarises the cell. This has little
effect on in atrial tissue (already at -90mV) but drives the SA and AV nodal tissue further from their threshold and therefore slows its rate. It also antagonises adenylyl
cyclase reduces intracellular Ca2+ and also slows conduction. The result is transient AV node block which is used in supraventricular tachycardias to restore sinus rhythm.
Sympathetic Stimulation acts via noradrenaline at the 1 receptors. It increases heart rate by increasing the rate of phase 4 depolarisation (see figure top
left). This is through increased Na+ influx during phase four. It also increases inward Ca2+ influx which increases conduction through the AV node, decreasing the PR
interval. This is known as the positive dromotropic effect.
Parasympathetic Stimulation is based on acetylcholine acting on muscarinic receptors which results in the opposite effects of sympathetic stimulation,
decreasing HR by reducing Na+ influx and therefore extending phase four duration in the slow response myocytes and decreasing Ca2+ influx which slows conduction
through the AV node.
DETERMINANTS AND CONTROL OF CARDIAC OUTPUT

Assessing myocardial performance The overall function of the cardiovascular system is to deliver oxygen and metabolic substrates to the to the tissues and to
remove the products of metabolism. It performs these functions by pumping blood, therefore most assessments of myocardial performance are based on how well the
heart can pump blood. Measuring pump effectiveness is usually by the volume of blood pumped per unit time. This is done by measuring the cardiac output (CO)
measured in litres per minute. To enable comparison it is sometimes divided by body surface area, this is the cardiac index (CI).
Cardiac Output is the product of Stroke Volume (SV) and Heart Rate (HR).
Stroke volume is determined by three factors: preload, afterload and contractility.
Preload is the initial fibre length. Preload is the load on myocardial fibres just prior to contraction. It can be used to refine our
understanding of myocardial performance beyond just CO or CI. If a heart can pump 5 litres from a low preload then it is
usually considered to be performing better than a heart requiring more preload. As stated above preload is the inital fibre
length of a sarcomere, this however is not possible to measure in an intact heart. Therefore volume and pressure are used as
surrogate markers of preload. The most commonly used is the volume of blood in the left ventricle at the end of diastole
(LVEDV) which is represented on the pressure volume loop at the bottom right. Volumes are often difficult to estimate minute
to minute without monitoring such as an ECHO. Pressure is also used but it is problematic because of compliance as a
confounder. Left atrial pressure will equal ventricular pressure at the end of diastole (LVEDP) (when sarcomeres are stretched
prior to contraction). Left atrial pressure can be estimated using a swan ganz catheter and measuring pulmonary artery
occulsion pressure (PAOP) on the right side of the circulation because it is a low resistance circuit, the artery is occluded and
they are at the same horizontal level. If there is mitral stenosis however then this will be inaccurate. Finally the CVP and right
atrial pressure may be used as indices of the right ventricle preload. This may sometimes also correlate to left sided filing
pressures although this is not always the case.
CONTRACTION
RESTING
PRELOAD
PRELOAD
AFTERLOAD
1. RESTING is at the end of isovolaemic relaxation before

any filling. 2.PRELOAD is at the end of ventricular filling
note the muscle is now stretched. 3. AFTERLOAD is the
extra tension which does not stretch the heart but must
be overcome to inorder to eject. 4. CONTRACTION is at
the conclusion of systole. Note that contractility can be
measured in two muscles if preload, afterload and rate
are kept the same.
Pressure (mmHg)
Afterload is the tension which needs to be generated in cardiac muscle before shortening will occur. Again this is unable to
be measured in the intact heart and the nearest estimation is instantaeous wall tension. There are several surrogate markers. In its simplest terms afterload is thought of as
the impedence to flow from the ventricle during systole. As such mean arterial pressure may be used as an estimate. More accurate still it to consider the relationship
between mean pressure and mean flow represented by systemic vascular resistance (or PVR on the right). Again however this is inaccurate because the flow generated by
the heart is not continuous but intermittant and pulsitile. Using a pressure-volume loop afterload is represented by the end systolic
Isovolumetric
Contraction
pressure connected to the LVEDV point.
120
100
80
60
dP/dT is the
max steepness of
this curve
40
20
Left Ventricle
0
0.25
Myocardial Contractility is defined as the intrinsic ability of the myocardial fibre to shorten independent of preload and
afterload. Brandis defines this as the factor that is responsible for changes in myocardial performance that is not due to changes in
heart rate, preload and afterload. The intracellular mechanism that is responsible for all factors which increase contractility is
increased intracellular calcium. Measurement of contractility is difficult. dp/dtmax refers the the maximum rate of change in pressure
in the left ventricle during isovolumetric contraction. A more forceful contraction would be associated with a greater rise in pressure
and for this reason this is often used as a marker of contractility.
0.5
Stroke Volume or Cardiac Output
Time (seconds)
Frank-Starling mechanism states that the strength of cardiac contraction is dependent on the initial fibre length. Increased fibre
length alters cardiac performance mainly by changing the Ca2+ sensitivity of the myofilaments and, in part by changing the number of
myofilament crossbridges that can interact. Beyond an optimal fibre length, contraction is actually impaired. From a practical
perspective this is important because increases in end-diastolic volume cause an increase in ventricular fibre length, which produces
an increase in developed tension. This is very important because it matches cardiac output to venous return this ensures a precise
matching of the outputs of the right and left ventricles. Positive iontropy increases Ca2+ sensitivity and therefore results in an increase
in CO for any level of right atrial pressure or LVEDV. Negative iontropy does the opposite. The Frank-Starling mechanism is best
represented by a family of so called ventricular function curves which map the CO (or ignore the HR and just use the SV) on the
ordinate (y-axis) and the end diastolic atrial pressure or LVEDV. From left shift implies improved inotropy, right shift negative inotropy.
Control
Negative Inotropic
Effect
Right Atrial Pressure or LVEDV
Myocardial oxygen consumption The heart is an aerobic organ and cannot tolerate (except for brief periods) oxygen debt.
100
80
60
Tension Time
Index
40
20
Left Ventricle
0
0.25
0.5
Time (seconds)
At rest
MVO2 is about 7-9 mls/100g/min (which equates to about 21 to 27mls O2 /min for a 300g heart). An understanding of myocardial oxygen
consumption (MVO2) has both physiological and clinical relevance (especially in the setting of ischaemia). Clinical studies have shown that
the three major determinants of MVO2 are Myocardial Wall Tension, Contractility and Heart Rate. Minor determinants include electrical
depolarisation, direct metabolic effect of catecholamines, basal metabolic activity and external work. This explains why patients with mitral
regurg rarely develop ischaemia (decreased wall tension) why beta blockade is very effective in angina (decreased heart rate) and why
angina is rare in dilated cardiomyopathy (decreased contractility). Further studies have shown a close relationship between the area under
the systolic portion of the LV Pressure-Time curve with MVO2 and this is known as the tension time index.
Vascular Function Curves If the entire circulation was brought to a standstill (eg asystole) then there would be a residual pressure in the
vascular system due to a degree of overfilling. This is the mean systemic pressure (which is measured in the right atria) when cardiac output is
zero and is said to be 8 mmHg this is also known as the mean systemic filling pressure MSFP. The mean systemic pressure may be altered by
either increased volume or resistance. Peter Kam identifies the normal point to by RAP of 0mmHg and CO of 5l/min. The vascular function
curve intersects the y-axis at the point where decreasing the RAP no longer increases vascular return due to starling resistor forces in the
extracardiac vessels. Increasing resistance alters the steepness of the curve but not the MSFP. Increasing the load shifts the curve but not the
steepness.
CO or Venous Return (l/min)
120
Pressure (mmHg)
Positive Iontropic
Effect
15
10
Normal
MSFP
-4
0
4
8
Right Atrial Pressure (mmHg)
Equilibrium
Vascular Function
-4
0
4
8
10
Cardiac Function
Hypervolaemia
5
Hypovolaemia
-4
0
4
8
15
Cardiac Function
10
Increased Resistance
5
Decreased Resistance
-4
0
4
8
10
15
Cardiac Function
15
Cardiac and Vascular Function curves integrated it is possible to overlay the normal Frank-Starling curve shown above and the vascular function curve using RAP
as a surrogate for preload. This is important because it gives the equilibrium point which matches venous return to cardiac output. It will also allow you top predict the
changes that occur with increased contractility, increased fluid volume and changes in peripheral resistance.
Increased Inotropy
15
Cardiac Function
10
Decreased Inotropy
5
Vascular Function
-4
0
4
8
of the left ventricle may be used to derive many values. This is frequently a question in
120
Cardiac Cycle Events
Valve Openings and Closings (A = MV opening, B = MV closes, C = Aortic Valve opens, D = Aortic Valve closes
Isovolaemic Contraction and Relaxation, systolic blood ejection and diastolic ventricle filling
Measurable Values
The Diastolic and Systolic pressures,
80
The Stoke Volume (SV)
Left Ventricular End Diastolic Volume (LVEDV)
Derived values
The area of the loop represents External Work
40
Ejection Fraction = SV/LVEDV
Surrogate Markers (see below)
The LVEDV point on the abscissa (x-axis) represents a surrogate marker of Preload
The Afterload is the angle formed between the Preload and the End Systolic Point when AV closes (D)
The Contractility is the angle formed by the End Systolic Pressure Volume Relationship ESPVR.
The Elastance relates to the End Diastolic Pressure Volume Relationship EDPVR, compliance may be inferred (1/elastance)
ISOVOLAEMIC RELAXATION
Pressure (mmHg)
SYSTOLIC
PRESSURE
D
AREA=WORK
SV
LVEDV
B
A
50
120
Volume (mls)
ESPVR
ESPVR
80
EDPVR
40
50
120
EDPVR
40
120
Volume (mls)
Volume (mls)
Increased Preload is demon-
Increased Afterload note the
strated by a shifting along the

EDPVR curve resulting in an
increased LVEDV. The afterload and
and contractility is unchanged.
80
50
increase in the angle of the afterload

line. The contractility is the same
(ESP on same line) the preload is the
same because the LVEDV point is
the same.
EDPVR
Pressure (mmHg)
40
Increased Contractility note

that the ESP is not on the same line.
The preload is the same (LVEDV is
the same) and the afterload is also
constant (the afterload lines are
parallel).
120
Volume (mls)
Increased Elastance by
definition the elastance is the

P/V ie the slope of the EDPVR.
Often this is erroneously referred to
as compliance in several textbooks.
The End Diastolic Pressure Volume
Relationship is steepened, but
other values held constant.
80
40
50
120
120
Volume (mls)
Volume (mls)
Systolic Heart Failure the
primary pathological process is a

loss of inotropy (contractility). The
heart compensates by increasing
preload. The result is lower systolic
and diastolic pressures and a
decreased EF. Compliance is not
necessarily changed nor is
afterload.
Pressure (mmHg)
LVH causes a decreased compliance

(represented by increased
elastance) and decreased LV filling.
The result is a new EDPVR curve
and reduced preload. Afterload and
contractility may be unchanged
and ejection fraction is often
maintained.
80
40
120
Volume (mls)
Aortic regurgitation there is a
loss of isovolaemic relaxation as the

blood regurgitates. This leads to an
increased LVEDV (and therefore
preload). In accordance with the
Frank Starling mechanism this leads
to increased pressures hence the
raised systolic pressure.
Pressure (mmHg)
Diastolic Heart Failure due to
Pressure (mmHg)
50
120
80
40
50
120
Volume (mls)
Mitral regurgitation there
main pathological proces is a loss

of isovolaemic contraction as the
blood regurgitates. As some of the
blood backflows, there is increased
filling in distole therefore increased
LVEDV. Unlike AR however the
systolic pressure is reduced due to
only part of the blood ejecting from
the aorta.
Pressure (mmHg)
Pressure (mmHg)
80
50
EDPVR
40
120
ESPVR
50
80
Volume (mls)
Disease States
120
Pressure (mmHg)
EDPVR
40
120
120
Pressure (mmHg)
Pressure (mmHg)
80
Pressure (mmHg)
120
120
50
DIASTOLIC
PRESSURE
C
ISOVOLAEMIC
CONTRACTION
Pressure - Volume Loop
exams and vivas.
80
40
50
80
40
50
Volume (mls)
Aortic stenosis the main
pathological problem is increased

LV resistance to ejection and
subsequent increase in afterload.
The result is a wide pulse pressure
with a high systolic pressure. The
heart may compensate, but if the
AS is severe the result will be a
decrease in SV.
Volume (mls)
Mitral Stenosis the main

pathological process is an
impairment of LV filling. This leads
to decreased Preload and by the F-S
Mechanism reduced CO and aortic
pressure (the accompaining
decrease in afterload partially
compensates).
BLOOD PRESSURE and CIRCULATION CONTROL

Distribution of blood volume The total blood volume is 5L in a 70kg male. (usually 70ml/kg). The typical distribution in the erect position is 65% veins, 13% arteries,
2% arterioles, 5 % capillaries and 15% central blood volume. The last term includes the blood in the heart during diastole (roughly 350ml) and the blood in the lungs
(roughly 450ml).
Cardiac Output
(SVxHR)
IN
Venous
Return
Total
Circulating
Volume
OUT
Vascular
Beds
Peripheral Runoff
(PRESSURE/TPR)
The systemic blood pressure is determined by the amount of blood in the arterial system at any one time. The amount of
blood in the arterial system is determined by volume entered (cardiac output) and the volume removed (peripheral run off ).
Cardiac output is determined by the product of stroke volume and heart rate. Peripheral run off is determined by the mean arterial
pressure difference divided by total peripheral resistance (TPR). (derived from flow = pressure/resistance).
It is possible to measure the CO and the MAP. It is also assumed in a steady state that CO = Peripheral run off. Therefore using normal
values of CO=5000ml/min and MAP=100mmHg, and assuming CVP is close to 0 it is possible to calculate total peripheral resistance
as
CO
= PRESSURE/TPR
Alternatively this may be calculated in dynes
CO
= (MAP-CVP)/TPR
MAP-CVP/CO x 80 (correction factor) = TPR
5000mL/min = 100mmHg/TPR
(100/5 litres)80 = TPR (usually called SVR in this setting)
TPR
= 20mmHg/mL/min
SVR = 1600 dynes/cm2
(divided by Body Surface Area = SVRI)
Therefore the main determinants of mean arterial pressure are cardiac output and total peripheral run off. Anything that increases
CO (increased preload, decreased afterload, increased contractility or HR) or decreases peripheral run off (increased arteriole
resistance) or total circulating volume (without any compensation) will increase MAP.
Regulation of systemic blood pressure the most important mechanisms for regulating arterial pressure are a fast, neurally mediated baroreceptor mechanism and a
slower, hormonally regulated renin-angiotensin-aldestrone system. Other mechanisms play a significant but lesser role.
Barorecpetor reflex is a fast neural negative feedback system which provides minute to minute regulation of arterial blood pressure. Baroreceptors are stretch
receptors that are located on the walls of the aorta and the bifurcation of the carotid arches. They send information back to the vasomotor centre which is located in
NTS of the medulla via CNX and CNIX respectively. The vasomotor centre has a set point of around 100mmHg MAP and will modify parasympathetic (via the CVLM)
and sympathetic responses (via RVLM) to achieve this set point. This results in measures to increase CO by venous constriction (which increases venous return and
preload), increases in heart rate, and increases in contractility. There is also vasoconstriction of the arterioloes which increase TPR. Baroreptors do not have a role in the
long term regulation of blood pressure and will reset the target blood pressure when pressures are elevated for extended periods of time (eg essential hypertension).
Renin-angiotensin-aldesterone system is a slow hormonal system. It is used in long term blood pressure regulation by the adjustment of blood volume. Decreases in
renal perfusion lead to the excretion of renin which catalyses angiotensinogen to angiotensin I. This is further catalysed by ACE to angiotensin II which causes
vasoconstriction of the arterioles which increases TPR and stimulates the secretion of aldosterone which causes the retention of Na2+ and therefore fluid retention
which increases the overall blood volume.
Other mechanisms include; chemoreceptors in the carotid bifucation and aortic arch are very sensitive to decreases in PO2 and will increase arteriole constriction and
therefore TPR when activated. Vasopressin release is related the the control of BP in haemorrhage but not the minute to minute regulation of BP. It acts on V1 receptors
in the arterioles to increase TPR and increases water reabsorption in the renal distal tubule and collecting ducts via V2 receptors. Atrial naturetic peptide is released
from the atrial in response to increases in atrial pressures. The result is arteriole relaxation, increased Na2+ and water excretion and inhibition of renin secretion.
Response of body to 1000mL blood loss this is a common question in exams. It is important to state that this is a significant loss of blood (20% in a 70kg
male) and will result in decreased cardiac output and decreased arterial blood pressure.
Blood pressure is maintained by
Baroreceptor response and sympathetic activation resulting in increased CO (preload, contractility and HR) and reduced run-off (increased TPR)
Renin-angiotensin-aldesterone system activation
Chemoreceptors
Vasopressin
Adrenergic release by the adrenal medulla augments sympathetic responses
Increased thirst
Blood redistribution is also an important temporiser;
Decreased renal perfusion (which in combination with the RAAS system and Vasopressin release also decreases urine output)
Decreased muscle perfusion
Maintained cerebral perfusion
A net reabsorption of interstitual fluid due to starling forces
Delayed responses should be mentioned and they include
Hepatitic synthesis of plasma protiens
Increased erythropoietin and subsequent erythropoesis will lead to a reticulocyte count peak at day ten
CVS response to central neural blockade Spinal (subarachnoid) and epidural anaesthesia produce central neural blockade. The cardiovascular responses are
more pronounced and quicker in onset in spinal compared to epidural anaesthesia. Generally sympathetic blockade results in vasodilation below the level of the block
which reduces the TPR and the venoconstriction, both of these contribute to a reduction in blood pressure. Reflex vasocontriction will often occur above the level of the
block, so too some of the compensatory mechanisms noted above including the RAAS activation and ADH release. Effects are greatly dependent on the level of the block.
A sacral block will have minimal cardiovascular effects because it primarily affects the parasympathetic pathways. A block to the mid thoracic region may result in
decreased blood flow to the kidneys and augmentation of the RAAS response. High thoracic blocks T1-T4 may impair the hearts ability to improve contractility and HR due
to sympathetic stimulation (exacerbating the hypotension). A brainstem block will inhibit the vasomotor centre in the medulla and can produce profound hypotension
and is considered life threatening.
CVS response to posture change. Thie initial response is for reduced venous return less preload stroke volume CO and therefore BP. This is sensed rapidly by
the arterial baroreceptors which activate a sympathetic response via the medullary vasomotor centre and cause increased CO (venous constriction, increase HR and
contractility) and increased TPR (arteriolar constriction). This response is less effective in the elderly and may result in lightheadedness due to momentarily reduced
cerebral perfusion (cerebral autoregulation is also reduced).
CVS response to rapid infusion of fluid This causes to opposing effects. The first a a baroreceptor response which in this setting reduces heart rate in order to
maintain a stable blood pressure. There are other atrial receptors which also feedback using the vagus nerve but cause an increase in heart rate by the Bainbridge reflex
(nb that the other aspects of sympathetic stimulation are not actioned - there is no increase in venous and arteriole constriction nor contractility). In high volume states
the bainbridge reflex will predominate, in low volumes states the baroreceptors will predominate. Specific responses to boluses depend on the fluid type. With blood and
albumin remaining largely within the intravascular space and dextrose and saline distributing to all fluid compartments according to their contribution to total body water.
REGIONAL VASCULAR SYSTEM

Regional circulations The resting cardiac output is 5-6 litres per minute and this may be divided up between the various organs in the systemic circulation. Flow is
determined by the pressure change divided by the resistance. From this we know can derive that the percentage of each organ blood flow is dependent on the organ
vascular resistance (as the pressure change from the arterial to venous side is constant across all organs). Most of the resistance in the systemic system results from the
arterioles, therefore it is the state of contraction and relaxation in the smooth muscle cells of the arterioles which determines the distribution of blood to organs.
Organ Blood Flow ml/min
Extrinsic control of blood flow was covered in a previous summary. It is determined by the general formula flow = pressure/resistance. As such the factors which
are important are the total peripheral resistance and cardiac output, coupled with the total circulating volume. The main extrinsic control of blood flow is therefore by
sympathetic control (controlling vascular tone, HR and contractility), parapsympathetic control (controlling heart rate and vasodilation) and extrinsic hormonal control
(such as RAAS, ANP and ADH).
Autoregulation flow is locally controlled in certain vascular beds by a process known as autoregulation. This is defined as the ability of
an organ to maintain relatively constant blood flow in the face of variations in perfusion pressure. Since flow = pressure/resistance, as the
pressure changes the resistance also changes (usually via vessel relaxtion or constriction) to maintain flow. The result is a characteristic
autoregulatory curve seen adjacent. Outside the limits of autoregulation, flow is dependent on driving pressure. Autoregulation is seen in
the kidneys, brain and heart. The skin and the lungs demonstrate minimal autoregulation.
Autoregulation
Blood Flow in Left

Coronary Artery
Intrinsic control of blood flow Autoregulation of local blood flows is dependent on two
mechanisms. Pressure Autoregulation refers to the myogenic stretch response that occurs in response
to increases and decreases in pressure with vasoconstriction (in the setting of increased pressures to
Mean Arterial Pressure mmHg
increase resistance and thus maintain stable flow) and vasodilation in low pressure settings.
Metabolic or Vasoactive Autoregulation refers to the direct action of locally derived metabolites and vasoactive substances which
cause local variations in flow according to requirements. This is not completely understood. Examples include vasodilation in the
setting of increased buildup of CO2, H+ and temperature during exercise and the release of the potent vasoconstrictor thromboxane
A2 by platelets to cause vasocontriction in the setting of vessel damage.
Most flow in
Diastole for LCA
Blood Flow in Right

Coronary Artery
Good flow throughout

for RCA
Systole
Diastole
Cardiac Cycle
Pressure Autoregulation
myogenic stretch response
ARTERIOLE
Metabolic Autoregulation
local release of vasoactives
and metabolites
Coronary blood flow At rest the heart receives approximately 200-250ml per minute of blood flow which equates roughly
to 5% of the total CO. Myocardial O2 consumption is very high in the order of 8 mL O2 /min/100g of tissue which is almost 20
times that of skeletal muscle. The main determinants of myocardial oxygen demand are wall tension (30-40%), HR (15-25%),
contractility (10-15%), basal metabolism (25%) and external work (10-15%). In order to achieve its high oxygen requirements
the heart has two adaptations. Firstly it has a very high denisty of capillaries which enable extensive exchange opportunities.
Secondly, myocardium extracts up to 75% of O2 compared to a whole body extraction of 25%. A result of this high extraction is
that blood returned via the coronary sinus and thebsian circulation has a markedly decreased PO2. The coronary circulation has
both parasympathetic and sympathetic innervation and does demonstrate local myogenic stretch control, however it is the
local metabolic control of flow that predominates especially in exercise states. This is not well understood but postulated
metabolites include NO, adenosine, H+, CO2 and reduced O2 tension. Mechanical aspects of the coronary blood flow are also of
particular importance. Unlike most organs where driving pressure is the arterial pressure - venous pressure, in the heart the
external pressure on the arteries is also considered. In this setting therefore, three pressures become important, during diastole
it is the pressure at the aortic root (arterial) minus the pressure in the right artria (venous). In systole however the ventricle
pressure becomes significant in a starling resistor model. It is now the pressure in the aortic root (arterial) minus the pressure in
the ventricle wall (external pressure on the vessel). As a result flow will often cease in early systole in the LCA. The RCA
maintains good flow due to the significantly lower ventricle wall pressures. See adjacent diagram.
Cerebral blood flow At rest the brain receives around 750ml of flow which equates to approximately 15% of total CO. It has a high myocardial consumption of 3-3.5
ml O2 /min/100g which when calculated using the weight of the brain (1400g) results in around 50 ml of oxygen which is 20% total consumption (remembering that
total oxygen consumption is around 250ml/min). As always flow = pressure/resistance. In this setting it is the cerebral blood flow (CBF) = cerebral perfusion pressure
(CPP) / cerebrovascular resistance (CVR). The CPP is normally MAP - CVP, however in pathological states where there is raised ICP a starling resistor model is set up. In this
setting ICP>CVP and therefore the CPP = MAP -ICP. Extrinsic nerve and hormonal control have little influence on CBF. The cerebral circulation demonstrates a very well
controlled autoregulation normally within the range of 50-150mmHg. It should be noted that in chronic hypertension this may be reset. The mechanism of autoregulation has not been fully elucidated, however it is believed to by primarily due to myogenic stretch factors. Local metabolic factors are significant also, but primarily from
a regional cerebral flow perspective and may include adenosine, NO, H+. The exceptions to this are arterial PCO2 which demonstrates an almost linear relationship with
CBF from 20mmHg-80mmHg, and to a lesser extent O2 which when to oxygen content drops significantly (associated with a PaO2 of less than 50mmHg which is on the
steep part of the dissociation curve) there is an increase in CBF. Above this point oxygen saturations have little influence.
Renal blood flow. At rest the kidneys receive approximately 1100 ml/min of blood flow which equates to around 20-25% of blood
flow. The main resistors in the kidneys which modify the flow according to different pressures are the efferent and afferent arterioles.
Extrinsically there is both neural and hormonal regulation. The kidneys have extensive sympathetic innervation and resistance is
increased in response to carotid and aortic body stimulation via the medulla to increase resistance in the afferent and efferent arterioles
and reduce flow. The renin angiontensin aldosterone system is also activated in low volume states to retain sodium and water which
influences overall flow along with ADH release. Intrisically the kidney demonstrates autoregulation, maintaining a renal blood flow
within a systemic pressure range of 75-170 mmHg. The intrinsic control of blood flow is mediated by myogenic stretch mechanisms and
tubuloglomerular feedback via afferent ateriole constriction. Tubuloglomerular feedback involves the macula densa which releases
adenosine if the renal perfusion pressure rises, and reduces production if the pressure falls. It may also release NO in response to a
decreased perfusion pressure.
EXTRINSIC
sympathetic
EFFERENT
AFFERENT
INSTRINSIC
myogenic stretch
tubuloglomerular
Splanchnic (including hepatic) blood flow the splanchnic system recieves approximately 1250ml of the CO which equates to approximately 25%. Anatomically
the blood is derived from the coeliac, superior and inferior mesenteric arteries. It is unique in that it is partially in parallel (incl gastric, spleen, pancreas, small intestine
and colonic) and partially in series. The liver is the reason for this, as it recieves 25% of its flow from the hepatic artery and the remainer from the portal system. The
heaptic system has the capacity to increase flow arterial or portal flow if the reciprocal is decreased. The liver maintains a tightly controlled oxygen utilisation due to very
effective variable extraction, and uses approximately 50ml O2 per minute (20%). The splanchnic system is also an important reservoir with pooling occuring in the
capacitance vessels of the mesentary, spleen and liver. Control of flow extrinsically is almost exclusively through sympathetic activity. Sympathetic activation results in
increased venous constriction which increases the circulating blood volume, and increased resistance of the arterioles which diverts blood away from the digestive
system to prioritised organs. Intrinsic blood flow control demonstrates significantly less autoregulation than other organs such as the kidney, brain and heart. It is
present however in the hepatic artery in response to modulate the differences in pressures in the compared to the portal vein (100mmHg compared to 10mmHg) and to
vary flow if portal return to decreased. Metabolic control is important however in regional control of blood flow, particularly in settings such as food ingestion and
consumption with local release of hormones such as gastrin and cholecystokinin increasing flow to the digestive tract.
APPLIED CARDIOVASCULAR PHYSIOLOGY

The cardiovascular reflexes Cardiac reflexes are fast-acting reflex loops between the heart and central nervous system (CNS) that contribute to regulation of cardiac
function and maintenance of physiologic homeostasis. As with most rhomeostasis questions it is useful to structure your response into
RECEPTOR
CENTRAL PROCESSING UNIT
EFFECTORS
Cardiac receptors are linked to the CNS by myelinated or unmyelinated afferent fibers that travel along the vagus nerve. Cardiac receptors can be found in the atria, ventricles,
pericardium, and coronary arteries. Extracardiac receptors are located in the great vessels and carotid artery. Sympathetic and parasympathetic nerve input is processed in
the CNS. After central processing, efferent fibers to the heart or the systemic circulation will provoke a particular reaction. The baroreceptor reflex is the most important
cardiac reflex and maintains second to second control of BP via a negative feed back loop. Long term it acts via a set point which may be elevated in settings such as essential
hypertension. Changes in blood pressure are monitored by circumferential and longitudinal stretch receptors located in the carotid sinus and aortic arch. The CPU is the NTS
in the cardiovascular centre of the medulla. The effectors are the autonomic nervous system. Chemoreceptor Reflex -Chemosensitive cells are located in the carotid bodies
and the aortic body. These cells respond to changes in pH status and blood oxygen tension. The Bainbridge reflex is elicited by stretch receptors located in the right atrial wall
and the cavoatrial junction. An increase in rightsided filling pressure sends vagal afferent signals to the cardiovascular center in the medulla. These afferent signals inhibit
parasympathetic activity, thereby increasing the heart rate. The purpose of this reflex is to ensure the extra blood arriving at the heart is pumped out. The Bezold-Jarisch reflex
responds to noxious ventricular stimuli sensed by chemoreceptors and mechanoreceptors within the LV wall by inducing the triad of hypotension, bradycardia, and coronary
artery dilatation. The Cushing reflex is a result of cerebral ischemia caused by increased intracranial pressure. Cerebral ischemia at the medullary vasomotor center induces
initial activation of the sympathetic nervous system. Such activation will lead to an increase in heart rate, blood pressure, and myocardial contractility in an effort to improve
cerebral perfusion. As a result of the high vascular tone, reflex bradycardia mediated by baroreceptors will ensue. The oculocardiac reflex is provoked by pressure applied to
the globe of the eye or traction on the surrounding structures. Stretch receptors are located in the extraocular muscles and their activation results in increased parasympathetic tone. - See Miller 7th edition for further details
Shock is defined as inadequate tissue perfusion resulting in tissue damage. It is usually further classified according to the physiological cause into four categories. Hypovol-
aemic shock is due to a decrease in the circulating blood volume, most commonly due to haemorrhage, but gastrointestinal or non sensible losses may also cause this state.
Low resistance shock is a result of the a dramatic decrease in total peripheral resistance, this may be seen in spinal cord injuries, anaphylaxis and most commonly excessive
inflammatory response in sepsis. Cardiogenic shock is due to decreased cardiac output from an intrinsically cardiac cause, normally due to a large MI, myocarditis, or valvular
disease. Obstuctive shock is due to a decrease in cardiac output due to obstruction from an cause extrinsic to the heart, such as cardiac tamponade, tension pneumothorax or
PE.
Cardiovascular response to shock is similar for all types of shock, however the underlying pathology will determine the degree of success to the physiological
response. Note this information has already been covered in responses to 1000ml of blood loss. Blood pressure is maintained by baroreceptor response and sympathetic
activation resulting in increased CO (preload, contractility and HR) and reduced run-off (increased TPR), Renin-angiotensin-aldesterone system activation, Chemoreceptors,
Vasopressin, Adrenergic release by the adrenal medulla augments sympathetic response and finally there is increased thirst. Blood redistribution is also an important
temporiser; decreased renal perfusion (which in combination with the RAAS system and Vasopressin release also decreases urine output), decreased muscle perfusion,
maintained cerebral perfusion and a net reabsorption of interstitual fluid due to starling forces. Delayed responses in the setting of shock due to blood loss include hepatitic
synthesis of plasma protiens, increased erythropoietin and subsequent erythropoesis will lead to a reticulocyte count peak at day ten.
Normal aging
Myocardial changes include: A decrease in the resting and maximum cardiac index, the maximum heart rate, diastolic compliance, sensitivity to
catecholamines and the number of functioning myocytes. There is an accumulation of pigment within the myocytes and increase in contraction and relaxation time
(cardiac cycle) of the heart. Peripheral vascular changes include: An increase in total peripheral resistance as well as decreases in arterial and venous compliance (less
windkessel effect), and capillary density in some tissue beds. A blunted baroreceptor response mechanism due to decreased stretch in the carotid and aortic bodies and
impaired response due to impaired sympathetic responses (less noradrenaline and adrenaline sensitivity). Haemodynamic consequences of the above include: increased
pulse pressure (windkessel) and mean arterial pressure, increased afterload due to raised blood pressure.
Cardiovascular effects of IPPV and PEEP.
(from respiratory section) IPPV and PEEP cause a reduction in cardiac output by reducing venous return to the right
atrium because of increased intrathoracic pressure. With normal inspiration there is negative intrathoracic pressure which acts as a pump to draw blood into the chest from
the major veins and this is abolished with postive intrathoracic pressure. The reduction in RV filing leads to less LV filling and therefore preload, which is exacerbated in
hypovolaemic states. Furthermore the increased airway pressures lead to increased pulmonary vascular pressures and this increases RV strain. It is noted that whilst PEEP
may improve PaO2 the decrease in CO may actually lead to decreased O2 delivery to the tissues (remember that DO = CO(sats x Hb + dissolved O2)). There is some increase
in peripheral vascular resistance to counter the decreased CO but this is often inadequate. Interestingly, in heart failure patients the reduced RV filling may actually
improve function by moving an overloaded RV to a more favourable position on the starling curve.
Cardiovascular changes during pregnancy include;
Blood Pressure
mmHg
II
III
IV
40
Blood Pressure
mmHg
refers to the cardiovascular responses to forced expiration against a closed glottis for a duration of ten seconds or
more. There are four main phases described in the diagram below.
Phase I
Increased intrathoracic pressure causes a brief increase in preload as the pulmonary vasculature
empties to the LA/LV. This causes an increase in CO and therefore blood pressure and a fast barorecep
tor driven decrease in heart rate.
Phase II The increased intrathoracic pressure causes reduced venous return which leads to decreased preload
and CO. As blood pressure now falls the baroreceptor response is an increase in HR and TPR. The
increase in TPR means that the diastolic pressure will be increased more than the systolic and as a
result the pulse pressure narrows.
Phase III The intrathoracic pressure now drops, transiently decreasing preload and CO as blood pools in the
pulmonary vasculature. There is a transient decrease in blood pressure.
Phase IV As CO returns to normal, the residual increase in TPR (and probable venous constriction) means that
there is an overshoot and blood pressure spikes (with associated fast baroreceptor decrease in HR)
before stabilising.
200
160
120
80
40
Heart Rate BPM
Valsalva Manoeuver was first described by the Italian Anatomist Antonio Valsalva in the early 18th century. It
Airway Pressure
mmHg
Upward and leftward cardiac displacement, aortocaval compression after 20/40 with associated maternal
hypotension and decreased uteroplacental flow (hence left lateral positioning), Placental blood flow of 625 mLmin-1, 30-50% increase in circulating volume (mediated by
aldosterone, oestrogen and progesterone) ~12% increase in HR, 25% increase in stroke volume, 30-40% increase in cardiac output, 20-40% decrease in TPR due to the
placental circulation (low resistance running in parallel with other systemic organs), 5-10 mmHg decrease in diastolic pressure at 12-20/40, increase in renal plasma flow
and GFR (75% and 50% respectively), During labor: 300-500 mL autotransfusion with uterine contractions and ~ 25% increase in cardiac output.
100
80
60
Time (seconds)
I
II
III
160
IV
In heart failure most mechanisms are blunted and the pressure on the aorta leads to an increase in blood
pressure and a characteristic square wave pattern of blood pressure changes.
120
80
Blood Pressure
mmHg
40
160
120
In autonomic dysfuction the TPR is not increased which impairs the response of phase II and removes the
cause of the overshoot in Phase IV.
80
40
Time (seconds)
CARDIOVASCULAR PHYSICS AND MEASUREMENT

Starling forces determine to net movement of fluid across the capillary wall. The capillary wall is
semi permiable to water and solutes but not to large molecules such as albumin. A plasma ultrafiltrate, free of these large molecules (mostly protiens) is filtered through the capillary wall by the action BLOOD
of opposing hydrostatic and oncotic pressures. Starling forces refer to the opposing oncotic and
hydrostatic pressures. The sum of these values determine whether there is a net movement into, or
out of the capilliary.
CAPILLARY
Capilliary
hydrostatic
pressure (Pc)
Plasma
oncotic
pressure (p)
Net Filtration Pressure = (Force inward) - (Force outward)

= (Pif + p) - (Pc + if)
If the value is positive, then there is a net inward movement, if the value is negative then there is
outward movement. This may be used to explain oedema due to increased pressure (eg right heart
failure) or decreased oncotic pressure (hypoalbuminaemia). Some texts also discuss a gradient along
the capillary from higher pressure on the arterial side (NFP positive) to lower pressures on the venous
side (NFP negative). Most filtrate is returned to the circulating volume via lymphatics (3 litres / day).
Interstitual fluid
hydrostatic
pressure (Pif)
Interstitual fluid
oncotic
pressure (if)
The physics of blood flow
Flow is defined as the quantity of fluid passing a point per unit time. Flow may be either laminar or turbulent. Laminar is similar to
a fast running stream without rapids, the water in the middle moves the fastest and that on the edges barely moves at all. Turbulent flow is chaotic and all water in
the river is moving forward in a front. Reynolds number predicts whether flow will be turbulent or laminar it is calculated using velocity.diameter.density/viscosity
and a number greater than 2000 suggests turbulent flow. Therefore increased viscosity, or decreased velocity, density or diameter is more likely to be laminar.
Poiseuille measured laminar flow of homogenous (Newtonian) fluid and described the mathematical relationship between flow, pressure, vessel length, vessel
radius and viscosity. From this he derived resistance to be equal to 8nL/r4. Where n = viscosity, = 3.14, r = radius and L = length
Remember that
flow = pressure change/resistance.
Therefore Poiseuilles equation is
flow = (pressure change) r4

8nL
This is an experimental result and is useful for describing flow in the cardiovascular system, however it is very difficult to use this formula empirically because of
several reasons. Firstly blood vessels are not rigid tubes but have features of distensibility and contractility which alters the relationship between pressure and
flow. Furthermore myogenic stretch mechanisms involved in autoregulation mean the radius may vary counterintuitively with increased pressure. Secondly,
Poiseuille measured constant flow, the CVS however is characterised by pulsatile flow. Thirdly blood is not a Newtonian fluid and is often heterogenous, with
viscosity varying according to both its contents and the ambient temperature. Finally blood flow is often not laminar but turbulent.
Non invasive blood pressure measurement is performed most simply with an inflatable cuff (20% greater than diameter of the arm) and a manometer to
measure pressure. Using a stethoscope over the brachial artery pressure is increased to a point inexcess of systolic pressure where there is no sounds. It is then reduced by
2-3mmHg until the onset of a pulsitile bruit, this is turbulent flow commencing and indicates systole. This point is the first Korotkoff sound. This is followed by a brief
muffling (K2) then an increase in noise (K3) then a reduction in sound (K4). Finally sound is completely lost (Korotkoff 5) which indicates diastolic pressure whereby the
flow is no longer turbulent enough to produce sound. Non invasive measurement is also possible using a single cuff automated oscillometric technique, which is set up
similar to the manual technique however a signal transducer measures both the pressure and onset of oscillations (systole), the maximal oscillation (mean pressure) and
estimates the diastolic pressure. Other methods include; Von Recklinghausen technique which uses two cuffs (one for pressure and one for oscillations), doppler
ultrasound and the Penaz technique (volumetric clamp method). Non invasive methods are effective if the correct cuff size is utilised, but their utility is decreased if there
is an arrythmia or the pressure is very low.
Invasive blood pressure measurement
the indications for invasive blood pressure management have been covered previously and include; Continuous,
real-time blood pressure monitoring, planned pharmacologic or mechanical cardiovascular manipulation, repeated blood sampling, failure of indirect arterial blood
pressure measurement, supplementary diagnostic information from the arterial waveform. Complications include distal ischemia, pseudoaneurysm, arteriovenous fistula,
hemorrhage, arterial embolization, infection, peripheral neuropathy, misinterpretation of data, misuse of equipment. The standard set up for invasive arterial measurement is a plastic cannula in a peripheral artery (preferably the radial) where there is good collateral flow. The tubing is pressurised with a heparised saline mixture at
300mmHg. A column of saline is continuos with a diaphram which fluctuates as pressures change. The diaphram is connected to transducer with either a pizoelectric
crystal or a strain gauge which converts the movement of the diaphram into an electrical voltage or a change in resistance respectively. The signal is then reproduced
following Fourier decomposition (which reduces the signal into sine or cosine waves, with the fundamental frequency measured in Hz being heart rate/60), and amplified.
Measurement of Cardiac Output
Cardiac output is the amount of blood ejected from the left ventricle per minute. It is calculated by the formula stroke volume x
heart rate. Because stroke volume is difficult to directly measure there is a number of methods employed to achieve accurate measurements of CO. Methods may be
classified according to the underlying principles used in their calcuation. Ficks principle is an application of the conservation of mass and is the underlying principle used
for the thermo and dye dilution techniques, PiCCO (Pulse induced contour cardiac output) and oxygen consumption methods. Doppler ultrasound assessment of stroke
volume using TOE or TTE is another method employed. Electrical impedence is another principle used to assess stroke volume and thus CO.
concentration
Ficks Principle is an expression of the conservation of mass, A+B=C. Dye dilution methods applies this
B
method but inserting a known amount dye into B. The amount at A is 0 and therefore
amount = flow(concentration). Measuring the concentration at C (using a denistometer) enables the
equation to be solved for flow. As this is over a time period the concentration is the area under the curve. It
A
C
A+B=C
should be noted that following one complete circulation there will be a second peak
which represents A no longer being 0. Thermodilation uses similar principles with
more complex calculations. An injectate of normal saline of known temp and volume
recirculation is introduced to the RA and a thermistor (metal device which converts temp changes to an electrical signal) measures the temperature change in the
peak
pulmonary artery. PiCCO uses the same principles but the measurements are made at a peripheral artery and the cool saline is injected via a central
line which removes the requirement for a pulmonary catheter. The same principles are used in Oxygen uptake assessments of CO. In this setting
AUC
A=(mixed venous O2 concentration)flow, B= oxygen uptake (usually 250ml/min) and C=arterial O2 concentration)flow. CO2 elimination is another
time
application, but in this setting becuase it is elimination A = B + C.
Measurement of regional blood flows The same principles underlie the assessment of regional blood flows to those that measure CO. The clearance of PAH is used
to determine renal blood flow, also using an application of the Fick principle. PAH is not utilised or excreted by any other organ apart from the kidney, and once filtered by
the kidney it is not reabsorbed. It has an excretetion ration close to 1.0 therefore the amount excreted is a direct fraction of the plasma filtered which if the haematocrit is
known it can be used to assess renal blood flow. The Kety-Schmidt method is an experimental method applying Ficks principle to cerebral blood flow usually using N2O, it
measures the amount taken up by the brain divided by the arterial-venous concentration difference. PET scanning may be used to assess uptake by a radioactive
substance or tagged glucose in another method in assessing different regional circulations.
INOTROPES AND VASOPRESSORS

Inotrope An alters the force of contraction of cardiac muscle without changing preload or afterload. Positive inotropes increase cardiac contractility whilst negative
inotrops decrease cardiac contractility. Vasopressors are drugs that have a predominantly vasoconstrictive action on the peripheral vasculature, both arterial and venous.
These drugs are used primarily to increase mean arterial pressure. Many of the commonly used agents such as the catecholamines have both inotropic and variable effects
on the peripheral vasculature that include venoconstriction, arteriolar vasodilatation and constriction. Vasoregulatory agents may modulate the responsiveness of the
peripheral vasculature to vasoactive drugs in pathological states such as sepsis. These agents include vasopressin and corticosteroids. Given the overlap of pharmacodynamic effects of these drugs, the term vasoactive therapy is a more appropriate description. The ideal inotrope; Is pharmaceutically suitable; Non-toxic, cost effective,
stable preparation, compatable with other drugs, peripherally deliverable, Has beneficial pharmacodynamic properties: Increases contractility, Increases mean arterial
pressure, Maintenance of diastolic blood pressure, Increases cardiac output, Improves regional perfusion, without pharmocodynamic costs No increase in myocardial
oxygen consumption, Avoidance of tachycardia, Non-arrhythmogenic, suitable in pregnancy and paediatric populations has an excellent pharmocokinetic profile Does not
develop tolerance, Titratable, Rapid onset, Rapid termination of action, metabolised independent of liver and kidney function, doesnt require concentration monitoring.
Classification of Inotropes and Vasopressors
The common ultimate cellular mechanism of action of these agents involves an influence on the release,
utilisation or sequestration of intracellular calcium. These agents are divided into two main groups based on whether or not their actions depend upon increases in
intracellular cyclic adenosine 3,5-monophosphate (cAMP).
cAMP Dependent Inotropes
cAMP Independent Inotropes
Selective Vasopressors
Catecholamines (Beta Adrenegric Agonists)

Natural
Adrenaline
Noradrenaline
Dopamine
Synthetic
Dobutamine
Isoprenaline
Phosphodiesterase inhibitors
Milrinone
Levosimendan
Calcium Sensitisers
Levosemindan
Glucagon
Catecholamines (Alpha1 Adrengeric Agonists

at higher doses)
Adrenaline
Noradrenaline
Dopamine
Other
Digoxin
Calcium
Thyroid hormone
Vasopressin
Metaraminol
GREATER ALPHA
AFFINITY
HO
HO
HO
HO
HO
GREATER BETA
AFFINITY
Catecholamines consist of an aromatic ring attached to a terminal amine by a carbon chain. The configuration of each drug is important for determining affinity to respective receptors. Dopamine is hydroxylated to form
noradrenaline, which is the predominant peripheral sympathetic chemotransmitter in humans, acting at all
adrenergic receptors. The release of noradrenaline from sympathetic terminals is controlled by reuptake
mechanisms mediated via alpha2-receptors and augmented by adrenaline released from the adrenal gland at
times of stress. Noradrenaline is converted to form adrenaline that is subsequently metabolised in liver and lung.
All catecholamines have very short biological half-lives (12 minutes) and a steady state plasma concentration is
achieved within 510 minutes after the start of a constant infusion. This allows rapid titration of drug to a clinical
end-point such as mean arterial pressure. Adrenaline and noradrenaline infusions produce blood concentrations
similar to those produced endogenously in shock states, whereas dopamine infusions produce much higher
concentrations than those naturally encountered. Dopamine may exert much of its effect by being converted to
noradrenaline, thus bypassing the rate limiting (tyrosine hydroxylase) step in catecholamine synthesis. The
synthetic catecholamines are derivatives of dopamine. These agents are characterised by increased length of the
carbon chain, which confers affinity for beta-receptors. Dobutamine is a synthetic derivative of isoprenaline.
These agents have relatively little affinity for alpha receptors due to the configuration of the terminal amine,
which differs from the endogenous catecholamines. As a general rule, the longer the terminal amine, the more
beta adrenergic effects predominate, the shorter the chain, alpha effects predominate (relatively). From a drug
specific perpective at low doses with the natural catecholamines it is the beta effects that are more significant,
alpha effects kicking in at higher doses.
[The catecholamines have

variable vasopressor activity and
are not usually considered here]
HO
HO
HO
NORADRENALINE
CH2 CH2 NH2
OH
ADRENALINE
CH2 CH2 N
OH
CH3
H
CH2 CH2 N
OH
CH(CH3)2
H
CH2 CH2 N
OH
ISOPRENALINE
DOBUTAMINE
CH(CH3)2CH2CH2
OH
Phosphodiesterase inhibitors and Calcium Sensitisers are compounds that cause non-receptor mediated competitive inhibition of phosphodiesterase
isoenzymes (PDE), resulting in increased levels of cAMP. Importantly, cAMP also affects diastolic heart function through the regulation of phospholamban, the regulatory
subunit of the calcium pump of the sarcoplasmic reticulum. This enhances the rate of calcium re-sequestration and thereby diastolic relaxation. For cardiovascular tissue,
inhibition of isoenzyme PDE III is responsible for the therapeutic effects. Cardiac effects are characterised by positive inotropy and improved diastolic relaxation. The latter is
termed lusitropy and may be beneficial in patients with reduced ventricular compliance or predominant diastolic failure. These agents also cause potent vasodilatation with
reductions in preload, venous return and afterload as well as a reduction in pulmonary vascular resistance. The term inodilation has been used to describe this dual
haemodynamic effect. Tolerance is not a feature. Titration pharmacokinetics of phosphodiesterase inhibitors are markedly different from catecholamines. Drug half-lives
may be prolonged and excretion is predominantly renal. Hypotension may result from vasodilatation, and combined use with catecholamines (e.g. noradrenaline or
adrenaline) may be necessary and complementary to maintain mean arterial pressure. Milrinone is currently used in clinical practice, exhibiting more inotropic effects than
vasodilatation. Levosimendan is a dose-dependent selective phosphodiesterase inhibitor with a unique action on myocardial calcium metabolism. By increasing myofilament calcium sensitivity throughout the cardiac cycle by binding to cardiac troponin C, associated conformational changes induce improved inotropic and lusitropic
function. Vasodilatation is also induced through ATP-sensitive potassium channels. Calcium-sensitive actions predominate at low doses, whilst PDE-inhibition effects
predominate at higher doses. The half-life of levosimendan is shorter than older PDE III inhibitors (approximately 1 hour) and it may be given by infusion. Glucagon is a
naturally occurring polypeptide that directly stimulates adenyl cyclase via specific receptors to increase cAMP concentration in myocardial cells resulting in positive inotropy
without producing myocardial excitability. Large doses are required to achieve this effect which is associated with a high incidence of metabolic side-effects.
cAMP independent inotropes The direct effect of digoxin is via Inhibition of Na+/K+ ATPase is considered to be the primary biochemical mechanism of action. Then
higher intracellular Na reduces action of the Na-Ca pump leading to decreased calcium extrusion and therefore increased intracellular Ca therefore increased inotropy.
Thyroid hormone is required for synthesis of contractile proteins and normal myocardial contraction. It is also a regulator of the synthesis of adrenergic receptors. Preliminary
studies suggest that treatment with thyroid hormone in these patients may reduce the need for vasoactive therapy to achieve satisfactory haemodynamics. When injected
intravenously, calcium produces an intense positive inotropic effect lasting 10 to 20 minutes and manifesting as increases in stroke volume and decreases in left-ventricular
end-diastolic pressure. Heart rate and systemic vascular resistance decrease. Calcium chloride, at 5 to 10 mg/kg IV to adults, may be administered to improve myocardial
contractility and stroke volume at the conclusion of cardiopulmonary bypass.
Selective Vasopressors Metaraminol is a direct-acting a2-agonists that are selective vasoconstrictors, both venous and arterial, with minimal b-activity. They have
similar pharmacokinetics to catecholamines and may be given by infusion. In patients with normal sympathetic tone, these drugs may cause reflex bradycardia, particularly
following bolus administration. Vasopressin Specific vasopressinergic receptors (V1, V2) have been identified in association with sympathetic terminals. Vasopressin is a
naturally occurring peptide secreted by the posterior pituitary gland. Reduced serum levels of vasopressin have been demonstrated in septic shock and following cardiopulmonary bypass, suggesting an inflammatory mediated mechanism. Levels are maintained during cardiogenic shock. A proportion of patients with severe septic shock
requiring high levels of catecholamines to support the circulation may respond to low doses of infused vasopressin (0.04 U/hour) significantly reducing doses of infused
catecholamine. This phenomenon appears to be independent of any directly attributable vasopressor effect; rather it is a supplemental catecholamine sparing strategy,
particularly in patients with mild to moderate shock states. The impact in severe shock or on mortality has not been substantiated in a large clinical trial (VASST Study)
AUTONOMIC NERVOUS SYSTEM AND SYMPATHETIC DIVISION PHARMACOLOGY

Sympathetic
Iris circular
muscles
Brainstem
Cerebral Cortex
Hypothalamus
Amygdala
III
VII
Lacrimal glands
Salivary glands
both the sympathetic and parasympathetic nervous systems (shown in blue on the adjacent diagram). The
parasympathetic postganglionic fibres secrete acetlycholine onto their target organs, while noradrenaline is
principally secreted by the postganglionic sympathetic fibres (red). The two exceptions to this are the adrenal
medulla which acts as a postganglonic fibre itself and secretes 80% adrenaline and 20% noradrenaline into the
systemic circulation, and sweat glands whose sympathetic postganglionic fibres secrete ACh. See also AI on
neurotransmitters, and iontropes.
Iris radial muscles

Salivary glands
Blood vessels
IX
Cervical
Neurotransmitters of the ANS Acetylcholine is the principle transmitter released by preganglionic fibres of
Parasympathetic
VAGUS
(75% PNS)
Heart
Lungs
Gut
Heart
Lungs
Blood vessels
Thoracic
Autonomic Nervous System is a division of the nervous system separate from the somatic system which
maintains body homeostasis by integrating signals from afferent somatic and visceral sensors to modulate organ
perfusion and function. These signals are integrated in medulla and modulated by the central autonomic network
which consists (in addition to the medulla) of the cerebral cortex, hypothalamus and amygdalla. Information is
then sent from the medulla to the effector organs by the efferent components of the ANS which are the
parasympathetic and sympathetic nervous systems. Their tonic activity maintains cardiac activity and visceral and
vascular smooth muscle in a state of immediate function from which rapid increases or decreases in autonomic
outflow can adjust blood flow and organ activity in response to the environment.
Gut
Kidneys
Sweat glands
Receptors of the ANS
Like the muscarinic receptors, adrenergic receptors are also seven transmembrane domain protiens coupled to G
Protiens however there are multiple subtypes and actions. There are four major subtypes 121 and 2. Adrenoceptors respond to catecholamines in an order of potency; for alpha adrenoceptors this is noradrenaline
adrenaline isoproterenol, for beta adrenoceptors it is the reverse isoproterenol adrenaline noradrenaline.
(this makes sense when you remember that we give adrenaline for bronchoconstriction not norad). There is also
desensitisation in minutes from continued exposure to catecholamines and downregulation in hours.
Lumbar
Descending colon
Kidneys
Ureter
Bladder
Genitals
Adrenal medulla
Descending colon
Bladder
Genitals
Blood vessels
S2,3,4
Muscarinic
receptors
Nicotinic
receptors
Sacral
Nicotinic receptors are ligand gated ion channels which are located in skeletal muscle,
on postganglionic neurons in both the SNS and PNS, on adrenal chromaffin cells and within the CNS. Muscarinic
receptors are seven transmembrane domain proteins coupled to a family of G Proteins that inhibit adenylyl
cyclase activity. They are located on the heart where they are inhibitory, and in the smooth muscle and the glands
where there are excitatory.
Nicotinic
receptors
Acetylcholine
Adrenergic
receptors
(1212 )
Noradrenaline
Sympathetic nervous system pharmacology (see neuropharmacology 2 for pharmacology related to the parasympathetic division of the ANS)
The alpha adrenoceptors exist at both presynaptic and postsynaptic neuroeffector junction sites throughout the human body and are involved in cardiovascular regulation, metabolism, consciousness and nociception. Whilst there are at least six subtypes it is the alpha 1&2 subtypes which are the most important physiologically. It is
possible to classify the differences in the two primary alpha receptors as shown below.
Alpha 1 Adrenoceptors
Alpha 2 Adrenoceptors
Stimulated by
Phenylephrine, Methoxamine
Clonidine, Dexmedetomidine
Blocked by
Prazosin
Yohimbine
Order of Potency
noradadrenalineisoproterenol
norad has greater potency vrs 2
activates Gq stimulates phospholipase C hydrolysis
and increases intracellular Ca2+ levels
noradadrenalineisoproterenol
norad has lesser potency vrs 1
activates Gi and results in decreased adenylyl cyclase
activation of cAMP
Vasoconstriction, relaxation of GIT smooth muscle,

contraction of genitourinary smooth muscles
Inhibition of noradrenaline release from nerve endings,

platelet aggregation, vascular smooth muscle contraction
G Protien Subtypes
Physiological Effects
The beta adrenoceptors b Receptors regulate numerous functional responses, including heart rate and contractility, smooth muscle relaxation, and multiple metabolic
events. All three of the b receptor subtypes (b1, b2, and b3) couple to Gs and activate adenylyl cyclase. Thus, stimulation of b adrenergic receptors leads to the accumulation
of cyclic AMP, activation of PKA, and altered function of numerous cellular proteins as a result of their phosphorylation. In addition, Gs can enhance directly the activation of
voltage-sensitive Ca2+ channels in the plasma membrane of skeletal and cardiac muscle.
Beta 1 Adrenoceptors
Beta 2 Adrenoceptors
Stimulated by
No selective agonist
Salbutamol
Blocked by
Esmolol, Metoprolol, Bisoprolol
No selective antagonist but several non selective inc propanolol
Order of Potency
isoproterenoladrenalinenorad
isoproterenoladrenalinenorad
G Protien Subtypes
activates Gs increases cAMP through adenylyl

cyclase activation
activates Gs increases cAMP through adenylyl

cyclase activation
Physiological Effects
Located at the SA and AV nodes and ventricular

tissue, it increases inotropy and chronotropy
Widespread distribution, located in bronchial and vascular smooth

muscle, where they mediate vasodilation and bronchial relaxation
Christopher R Andersen 2012
ANTIHYPERTENSIVE MEDICATIONS 1
Antihypertensive Classification The main determinants of mean arterial pressure are cardiac output and total peripheral run off. Anything that increases CO
(increased preload, decreased afterload, increased contractility or HR) or decreases peripheral run off (increased arteriole resistance) or total circulating volume (without
any compensation) will increase MAP. There are a range of different drug agents used to decrease MAP. The following is one scheme to classify anti-hypertensive mediciations. Following this explanation there will be a detailed explanation of each of the classes. Some of the material overlaps with other sections such as diuretics, adrenergic
blockers and anti arrythmics. Also see associated drug description cards.
Renin Angiotensin Aldosterone System
Angiotensin Converting Enzyme (ACE) Inhibitors

Angiotensin Receptor Blockers
Aldosterone Antagonists
Sympathetic Nervous System
Peripheral adrenergic blockers (Alpha blockers, Beta Blockers)

Central adrenergic agonists (Alpha agonists)
Vasodilators
Calcium channel antagonists

Potassium channel activators
Nitrogen related agents
Direct vasodilators
Diuretics
Thiazides
Loop diuretics
Potassium sparing
Aldosterone antagonists
Osmotic
Carbonic anhydrase inhibitors
Renin Angiotensin Aldosterone System is a critical part of the neuroendocrine response to regulate Na+ and K+ homeostasis and blood pressure and is
subsequently a target for blood pressure control. Renin is the rate limiting step in the RAAS. Renin is released from the granular cells of the juxtaglomerular apparatus in
response to three main triggers. Firstly, activation of the sympathetic nervous system via the medulla as a result of carotid and aortic baroreceptor sensing of a decrease in
blood pressure. Secondly, in response to decreased renal perfusion pressures noted by intrarenal baroreceptors and finally in response to reduced delivery of NaCl by the
macula densa. Renin is a catalyst for he proteolysis of hepatic protein angiotensinogen into angiotensin I. This is further converted into angiotensin II by angiotensin
converting enzyme (ACE) mostly in the lungs. Angiotensin II has many functions, directly causing vasoconstriction and acting on tubules to increase Na+ reabsorption. Long
term it effects cardiovascular remodelling. It also acts on the posterior pituitary to secrete antidiuretic hormone (vasopressin). ADH increases the water permiability of the
collecting duct luminal membrane which increases water reabsorption. Angiotensin II the adrenal cortex to secrete aldosterone. Aldosterone is the main determinant of
tubular sodium reabsortion and stimulates potassium secretion.
ACE Inhibitors The essential effect of these agents on the reninangiotensin
system is to inhibit the conversion of Angiotensin I to the active Angiotensin II,
Thus, ACE inhibitors attenuate or abolish responses to AngI but not to AngII.
They do not interact directly with other components of the reninangiotensin
Angiotensinogen
GLOMERULUS
system, and their principal pharmacological and clinical effects all apparently
Cardiovascular
arise from suppression of AngII synthesis. Nevertheless, ACE is an enzyme with
remodelling
Renin
many substrates, and inhibition of ACE may induce effects unrelated to
MACULA DENSA
reducing the levels of AngII. Since ACE inhibitors increase bradykinin levels
Angiotensin I
and bradykinin stimulates prostaglandin biosynthesis, bradykinin and/or
prostaglandins may contribute to the pharmacological effects of ACE
inhibitors. In a healthy, Na+ replete person, a single oral dose of an ACE
inhibitor
has little effect on blood pressure, but repeated doses over several
Angiotensin
converting
enzyme
Angiotensin
I
days cause a small reduction in blood pressure. By contrast, even a single dose
of these inhibitors lowers blood pressure substantially in normal subjects
when they have been depleted of Na+. In general, ACE inhibitors differ with
POSTERIOR
regard to three properties: (1) potency (ramipril >lisinopril>captopril), (2)
Angiotensin II
PITUITARY
whether ACE inhibition is primarily a direct effect of the drug itself or the effect
of an active metabolite (captopril has active metabolites, ramipril is a prodrug
ADRENAL CORTEX
and lisinopril itself is active), and (3) pharmacokinetics (i.e., extent of absorption, effect of food on absorption, plasma t1/2, tissue distribution, and
Decreased Na+ excretion and
Antidiuretic
hormone
Aldosterone
mechanisms of elimination) Captopril has a much shorter half life and duration
therefore water retention
(Vasopressin)
of action compared to ramipril and lisinopril.
Angiotensin receptor blockers Angiotensin II receptor blockers (ARBs) interfere with the renin-angiotensin system by impairing the binding of angiotensin II to the AT1
receptor on the cell membrane, thereby inhibiting the action of angiotensin II. Blockade of the action of angiotensin II leads to elevations in plasma levels of renin, angiotensin I, and angiotensin II. However, this build-up of precursors does not overwhelm the receptor blockade, as evidenced by a persistent fall in both blood pressure and plasma
aldosterone levels with treatment. In comparison to the ACE Inhibitors, the bradykinin levels are not elevated, this may prevent the cough associated with ACE but removes
the vasodilatatory benefit provided by bradykinin. ACE inibitors also block both AT1 and AT2, however ARBs only block AT1, it has been postulated that AT2 stimulation is
renal protective. Angiotensin I may also be converted by enzymes other than ACE therefore ARBs may block more completely.
Aldosterone antagonists These agents are also placed in the diuretic category. Spironolactone is a nonselective aldosterone antagonist that may be used alone or in
combination with a thiazide diuretic. It may be a particularly effective agent in patients with low-renin essential hypertension, resistant hypertension, and primary
aldosteronism. In patients with CHF, low-dose spironolactone reduces mortality and hospitalizations for heart failure when given in addition to conventional therapy with
ACE inhibitors, digoxin, and loop diuretics. Because spironolactone binds to progesterone and androgen receptors, side effects may include gynecomastia, impotence, and
menstrual abnormalities. These side effects are circumvented by a newer agent, eplerenone, which is a selective aldosterone antagonist.
Sympathetic Nervous System antihypertensives included in this classification system are the peripheral acting adrenergic blockers and the central acting alpha 2
agonists. Other agents which are not commonly used but would be considered to fall within this classification are the ganglion blockers such as trimetaphan, the noradrenaline depleters such as reserpine and guanethidine and false neurotransmitters such as methyldopa.
Peripheral adrenergic blockers including the beta blockers, the selective alpha blocker prazosin and the non selective alpha blocker phenoxybenzamine. This were covered in
the previous page.
Central Alpha2 Agonists which include clonidine and dexmetomidine. Central pathways in the hypothalamus, the nucleus tractus solitarius, locus ceruleus and the cardioaccelerator and vasomotor centres in the medulla are under the modulatory control of alpha2-adrenoceptors, increased agonism of these pathways by clonidine and dexmetomidine results in a negative feedback and decreased activity. This leads to the main effects seen by the centrally acting agents such as sympatholysis (a drop in peripheral
noradrenaline) causing decreased TPR and MAP, decreased HR and CO, analgesia, and sedation. The sedation specifically is caused by depression of the locus ceruleus due to
alpha2 stimulation and is opposed by alpha1 stimulation, this explains why clonidine does not achieve full anesthesia. Drawbacks include somnolence, dry mouth, and
rebound hypertension on withdrawal.
ANTIHYPERTENSIVE MEDICATIONS 2
Vasodilator medications This category includes those drugs who cause vasodilation. Ca2+ Channel blockers are considered separately in some classification
schemes.
Ca2+ Channel Blockers Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the entry of extracellular Ca2+ into smooth muscle and cardiac myocytes and
sinoatrial (SA) and atrioventricular (AV) nodal cells in response to electrical depolarization. In both smooth muscle and cardiac myocytes, Ca2+ is a trigger
for contraction. All Ca2+ channel blockers relax arterial smooth muscle; they have little effect on most venous beds and hence do not affect cardiac preload
significantly. In cardiac muscle, Ca2+ channel blockers can produce a negative inotropic effect. All bind to the alpha1 subunit of the L-type Ca2+ channels and reduce Ca2+
flux through the channel; however, there are fundamental differences amongst verapamil, diltiazem, and the dihydropyridines (including nifedipine), especially with
respect to pharmacokinetic characteristics and pharmacodynamic aspects such as electrical conduction through the hearts conducting pathways and the vasodilatatory effects.
Blood Pressure
Heart Rate
AV Conduction Time
Myocardial Contractility
Peripheral and Coronay vasodliation
Verapamil
Nifedipine
Diltazem
or
or
or
Vascular endothelium
ENDOTHELIAL
CELL
Acetylcholine
ATP
Bradykinin
Serotonin
Substance P
Histamine
Shear Forces
Arachidonic acid
Endothelin
Vasoconstriction
Prostacyclin
Inhibits vasoconstriction
Platelet aggregation
Stimulates NO
Production
L-arginine
Nitric oxide (EDRF)
The whole of the cardiovascular system (heart and blood

vessels) is lined with a single layer of endothelial cells forming the surface contact with
blood. In addition to their capillary functions of nutrient and waste product diffusion
and fluid filtration, endothelial cells produce vasoactive substances throughout the
cardiovascular system. Prostacyclin is produced by the endothelium from arachidonic
acid, and inhibits platelet aggregation and vessel constriction. Endothelial cells
generate the vasodilator nitric oxide (also called endothelium derived relaxing factor)
from L-arginine. NO increases smooth muscle cGMP, which decreases the intracellular
Ca2+ producing muscle relaxation and vasodilation. Endothelial NO production is
stimulated by acetylcholine, ATP, bradykinin, serotonin, substance P and histamine. NO
production may also be enhanced by the shear forces caused by increased blood flow.
Endothelial cells also make the potent peptide vasoconstictor endothelin which
increases the peripheral vascular resistance and therefore the blood pressure. Vascular
endothelial cells will form new cappillary networks under the influence of angiogenic
factors.
Vasodilation
Potassium Channel Activators act by opening the normally closed potassium channels causing leakage of potassium from myocardial cells and arterioles and
subsequent hyperpolarisation. This hyperpolarisation results in smooth muscle relaxation. The most commonly used drug in this class in nicorandil which as the name
suggests also has a nitrate moiety which augments its vasodilatory actions.
Direct acting vasodilators the mechanism of these drugs are not well understood. However they include minoxidil and hydralazine. Hydralazine is a potent vasodilator
of arterioles. It has little or no effect on venous smooth muscle and its precise mode of action is unclear. It is endothelium dependent suggesting a role for nitric oxide. It
also interferes with the mobilisation of calcium in the vascular smooth muscle. Its use in associated with a baro-reflex mediated sympathetic increase in heart rate and
an increase in renin production and fluid retention; all of these effects counteract the antihypertensive effect of hydralazine. Minoxidil mechanism of action and
principle effects are believed to be similar to hydralazine, although it should be noted that in Goodman it is described as a Potassium Channel Activator.
POTASSIUM CHANNEL ACTIVATOR

SMOOTH
MUSCLE CELL
K+ATP
CHANNEL
Ca2+ CHANNEL ANTAGONIST

L-Type
Ca2+ CHANNEL
NITRIC OXIDE
CLOSES
OPENS
Guanylyl Cyclase
Potassium Outflow
Hyperpolarisation
Intracellular Calcium
cGMP
Smooth Muscle Relaxation

Nitrogen related antihypertensives The nitrogen related hypertensives primarily dilate venous capacitance vessels to reduce BP. Their effects are caused by the
spontaneous or tissue mediated release of nitric oxide from the drugs. Nitric oxide stimulates guanylyl cyclase in vascular smooth muscle to increase cGMP levels, which
in turn decreases intracellular calcium and cause arterial and venous dilation.
Sodium nitroprusside is used primarily to treat hypertensive emergencies but can also be used in many situations when short-term reduction of cardiac preload and/or
afterload is desired. Nitroprusside dilates both arterioles and venules equally; the hemodynamic response results from a combination of venous pooling and reduced
arterial impedance. In subjects with normal left ventricular function, venous pooling affects cardiac output more than does the reduction of afterload; cardiac output
thus tends to fall. In patients with severely impaired left ventricular function and diastolic ventricular distention, the reduction of arterial impedance leads to a rise in
cardiac output. Tolerance does not develop to nitroprusside but it has a very short duration of action, thus requiring constant infusion. The short term side effects are
related to excessive vasodilation. Long term toxicity is a result of the production of cyanomethemoglogin which may interfere with oxidative phosphorylation and cause
tissue hypoxia.
Glyceryl trinitrate is used in the treatment of stable and unstable angina, as well as acute pulmonary oedema. The dilation in venous system is more pronounced than in
the arterial system unlike SNP (where there is equal dilitation. The ability of nitrates to dilate epicardial coronary arteries is modest; the bulk of evidence favors a
reduction in myocardial work and thus in myocardial oxygen demand as their primary effect in chronic stable angina. Unlike SNP repeated use of GTN leads to tolerance
and decreased efficacy, regular interuptions in treatment are required. Side effects are related to the cardiovascular affects with headache being a common complaint.
They should never be used in conjuction with PDE inhibitors such as sildenafil as this may lead to a profound peripheral dilation and associated hypotension.
ANTI-ARRHYTHMIC DRUGS 1
Potassium Efflux
Classification Schemes The most common classification scheme used is the
Vaughan Williams Classification. This

describes the various antiarrythmic medications in terms of their mechanism of action with regard to the cardiac action
potential. This is useful when conceptualising in terms of the slow and fast cardiac action potential, but several of the
antiarrythmics are not easily categorised such as amiodarone which may be included in several categories and some are
ignored and lumped into the other category including digoxin, adenosine, and magnesium. It also is of little clinical benefit it
terms of treatment modalities for various arrythmias. It also makes no allowance for the fact that some medications work
differently in diseased and non diseased hearts.
Calcium Influx
30
0
Fast
Sodium
Influx
-90
-100
100
200
300
Time (ms)
400
500
Vaughan Williams Classification

Class
Action
Blocks Sodium Channels
Effect
Drugs
Therapeutic Indications
Prolongs refractory period of action potential
Procainamide
Atrial and ventricular arrhythmias especially post MI
Ib
Shortens refractory period of action potential
Lignocaine, Phenytoin
Ventricular arrhythmias post MI, digoxin induced arrhythmias
Ic
No effect on period of action potential
Flecainide
Refractory arrhythmias
Ia
II
Beta Adrenergic Blockers
Reduced SA firing
Propanolol / Sotalol
Rate control in AF, AT, Flutter and VT
III
Potassium Channel Blockers
Prolong refractory period of the action potential
Amiodarone#, ilbutalide
AF / Flutter termination
IV
Calcium Channel Blockers
AV conduction, PR prolonged, decreased contractility
Verapamil, Diltiazem
SVT and AF or Flutter
OTHER
Blocks Na /K
Increased contractility and AV conduction
Digoxin
AF rate control and heart failure
Hyperpolarises myocardium , AV conduct, SA firing
Adenosine
Terminate SVT or reveal underlying rhythm in tachycardias
Stimulates Na /K
Membrane stabilisation
Magnesium
VF / Torsades de Pointes
ATPASE,
ATPASE
2+
Class IC
Flecainide is the prototype drug with group 1C actions. These drugs have no effect on ventricular AP duration or
the QT interval. They are powerful depressants of sodium current, however, and can markedly slow conduction velocity in
atrial and ventricular cells. They increase the QRS duration of the ECG.
Beta adrenergic blockers Propranolol and esmolol are prototypic antiarrhythmic
blockers. The antidysrhythmic effects of

beta-adrenergic antagonists most likely reflect a blockade of the responses to beta-receptors in the heart to sympathetic nervous system
stimulation (decreasing G-protien S responses and reducing intracellular cAMP), as well as the effects of circulating catecholamines. As a
result, the rate of spontaneous phase 4 depolarization is decreased and the rate of sinoatrial node discharge is decreased. The AV node is
particularly sensitive to blockers and the PR interval is usually prolonged by group 2 drugs. Sotalol and amiodarone, generally classified
as group 3 drugs, also have group 2 -blocking effects.
Potassium Channel Blockers The hallmark of group 3 drugs is prolongation of the AP duration. This AP prolongation is caused by
blockade of IK potassium channels that are responsible for the repolarization of the AP. AP prolongation results in an increase in effective
refractory period and reduces the ability of the heart to respond to rapid tachycardias. Sotalol, ibutilide, dofetilide, and amiodarone (and
group 1A drugs; see above) produce this effect on most cardiac cells; the action of these drugs is, therefore, apparent in the ECG as an
increase in QT interval. Antiarrhythmic agents that prolong the duration of the action potential may be of value in the management
of patients with supraventricular tachyarrhythmias, or in arrhythmias associated with anomalous conduction pathways. Nevertheless, all
drugs that prolong the ventricular action potential may induce torsade de pointes (prolongation of the Q-T interval followed by
episodes of polymorphic tachycardia).
Calcium Channel Blockers Verapamil is the prototype. Diltiazem is also an effective antiarrhythmic drug. Nifedipine and the other
dihydropyridines are not useful as antiarrhythmics, probably because they decrease arterial pressure enough to evoke a compensatory
sympathetic discharge to the heart. Pacemaker cells in the SA and the AV node are almost entirely dependent on inward Ca2+ currents for
depolarization. Verapamil and Diltiazem cause a state- and use-dependent selective depression of calcium current in tissues that require
the participation of L-type calcium channels. AV conduction velocity is decreased and effective refractory period increased by these drugs.
PR interval is consistently increased. Drugs that block Ca2+ channels are particularly effective in preventing reentrant arrhythmias in the AV
node and including nodal tachycardia.
Action
Potential
Lengthened
-90
-100
100
200
300
Time (ms)
400
500
1B
30
Action
Potential
Shortened
-90
-100
Class IB
Lignocaine is the prototype 1B drug and is used exclusively by the IV or IM routes. Lignocaine selectively affects
ischemic or depolarized Purkinje and ventricular tissue and has little effect on atrial tissue; the drug reduces AP duration in
some cells, but because it slows recovery of sodium channels from inactivation it does not shorten (and may even prolong)
the effective refractory period. Because these agents have little effect on normal cardiac cells, they have little effect on the
ECG. Phenytoin , an anticonvulsant and not a true local anesthetic, is sometimes classified with the group 1B antiarrhythmic
agents because it can be used to reverse digitalis-induced arrhythmias. It resembles lignocaine in lacking significant effects
on the normal ECG.
100
200
300
Time (ms)
400
500
1C
30
Action
Potential
Unchanged
-90
-100
Procainamide is a Class 1A prototype. Other drugs with group 1A actions include quinidine and disopyramide. Amiodarone ,
often classified in group 3, also has typical group 1A actions. These drugs affect both atrial and ventricular arrhythmias. They
block INa, and therefore slow conduction velocity in the atria, Purkinje fibers, and ventricular cells. At high doses they also slow
AV conduction. The reduction in ventricular conduction results in increased QRS duration in the ECG. In addition, the 1A
drugs block IK and slow repolarization. Therefore, they increase AP duration and the effective refractory period (ERP) in
addition to slowing conduction velocity and ectopic pacemakers. The increase in AP duration generates an increase in QT
interval. Amiodarone has similar effects on sodium current (INa block) and has the greatest AP-prolonging effect (IK block).
1A
30
100
200
300
Time (ms)
400
500
II
20
0
0
-40
Rate
Decreased
4
-80
0
Sodium Channel Blockers
* Propanolol also has sodium channel blocking activity

^ Sotalol has two isomers, and is presented as a racemic mixture. One is an effective beta blocker and both have class III action potential prolongation activity
# Amiodarone is a special case. It blocks sodium, calcium, and potassium channels and exhibits beta blockade, although is usually categorised into Class III
100
200
300
Time (ms)
Beta
Blocker
Effect
400
III
30
Action
Potential
Lengthened
-90
-100
Notes
Opens K+ channels via adenosine receptors
leads to Ca , K , Ach
100
200
300
Time (ms)
400
500
IV
20
0
0
-40
Conduction
Velocity
Decreased
-80
0
100
200
300
Time (ms)
400
ANTI-ARRHYTHMICS DRUGS 2
Amiodarone is considered here as a special case, although it is usually categorised with the class III action potential
prolonging antiarrhythmics in the Vaughan-Williams Classification. Amiodarone is useful in most types of arrhythmias
and is considered the most efficacious of all antiarrhythmic drugs, prolonging the effective refractory period of all cardiac
tissues, including the sinoatrial node, atrium, atrioventricular node, His-Purkinje system, and ventricle. This may be
because it has a broad spectrum: It blocks sodium, calcium, and potassium channels and adrenoceptors. It is a benzofluorene derivative, is 37% iodine by weight and structurally resembles thyroxine. Amiodarone has a prolonged elimination
half-time (29 days) and large volume of distribution (Vd). This drug is minimally dependent on renal excretion. The
principal metabolite, desethylamiodarone, is pharmacologically active and has a longer elimination half-time than the parent drug, resulting in an accumulation of this
metabolite following chronic therapy. Amiodarone causes microcrystalline deposits in the cornea and skin, thyroid dysfunction (hyper- or hypothyroidism), paresthesias,
tremor, and pulmonary fibrosis. Amiodarone rarely causes new arrhythmias, perhaps because it blocks calcium channels and receptors as well as sodium and potassium
channels. Because of its toxicities, amiodarone is approved for use mainly in arrhythmias that are resistant to other drugs. Nevertheless, it is used very extensively, off label,
in a wide variety of arrhythmias because of its superior efficacy.
Digoxin All cardiac glycosides include a steroid nucleus and a lactone ring; most also have one or more sugar residues. The cardiac glycosides are
often called "digitalis" because several come from the digitalis (foxglove) plant. Digoxin is the prototype agent. Inhibition of Na+/K+ ATPase of the cell
membrane by digitalis is well documented and is considered to be the primary biochemical mechanism of action. Inhibition of Na+/K+ ATPase results
in a small increase in intracellular sodium. The increased sodium alters the driving force for sodium-calcium exchange by the exchanger, NCX, so that
less calcium is removed from the cell. The increased intracellular calcium is stored in the sarcoplasmic reticulum and upon release increases contractile force. Other mechanisms of action for digitalis have been proposed, but they are probably not as important as the inhibition of ATPase. The
increase in contractility evoked by digitalis results in increased ventricular ejection, decreased end-systolic and end-diastolic size, increased cardiac
output, and increased renal perfusion. These beneficial effects permit a decrease in the compensatory sympathetic and renal responses previously
described. The decrease in sympathetic tone is especially beneficial: reduced heart rate, preload, and afterload permit the heart to function more
efficiently. Increased PR interval, caused by the decrease in atrioventricular (AV) conduction velocity, and flattening of the T wave are common
electrocardiogram (ECG) effects. The effects on the atria and AV node are largely parasympathetic (mediated by the vagus nerve) and can be partially
blocked by atropine. The increase in the AV nodal refractory period is particularly important when atrial flutter or fibrillation is present because the
refractoriness of the AV node determines the ventricular rate in these arrhythmias. The effect of digitalis is to slow ventricular rate. Shortened QT,
inversion of the T, and ST depression may occur later.
Adenosine is a natural purine nucleoside. It acts on the A1 adenosine receptors found in the SA and AV. When it is given in high doses (6-12 mg) as
an intravenous bolus, the drug markedly slows or completely blocks conduction in the atrioventricular node, probably by hyperpolarizing this tissue
(through increased IK1) and by reducing calcium current. Adenosine is extremely effective in abolishing AV nodal arrhythmias, and because of its very
low toxicity it has become the drug of choice for this arrhythmia. Adenosine has an extremely short duration of action (about 15 s). Sude effects
includes flushing and hypotension, but because of their short duration these effects do not limit the use of the drug. Transient chest pain and dyspnea
(probably due to bronchoconstriction) may also occur.
Magnesium is the fourth most common cation in the body (after Na+, K+ and Ca2+), and approximately 3540% is present in cardiac and skeletal muscle. It has an
established or putative role in many physiological systems, including the inhibition of acetylcholine and noradrenaline release, and antagonism of NMDA receptors in
the CNS. Magnesium ions are bound to cellular ATP, and act as a cofactor for Na+/K+ ATPase, so that intracellular concentrations of Mg2+ may affect Na+ and K+ transfer.
Decreased Mg2+ concentrations may be associated with a variety of cardiac arrhythmias, and the effects observed are similar to hypokalaemia. Magnesium deficiency
may facilitate Ca2+ influx, which has a central role in cellular death during myocardial ischaemia. Magnesium salts have been used in the treatment of supraventricular
arrhythmias for at least 75 years. Magnesium sulphate [20 mmol (2.5 g), given as 5 mL 50% over 2030 min] is commonly used in ventricular tachycardia and torsade de
pointes induced by antiarrhythmic agents, or to reverse arrhythmias associated with digitalis toxicity. In shock and refractory ventricular fibrillation, magnesium sulphate
(816 mmol, i.e. 12 g) is sometimes given via a peripheral vein. After myocardial infarction, a bolus dose followed by an infusion of 6572 mmol in 24 hours has been
recommended. Mortality appears to be reduced, and there may be a prophylactic effect on the development of arrhythmias. However, an improvement in coronary
blood flow (due to the vasodilating properties of magnesium) and a reduction in platelet aggregation may be contributory factors.
Antiarrhythmic induced ECG changes note that class IB causes no change in the ECG
QRS Widened
1.0
QT Prolongation
0.5
Flecanide (IC)
Propanolol (II)
Amiodarone (III)
Sotalol (II/III)
Verapamil (IV)
Adenosine (other)
Digoxin (other)
0.5
Procainamide (IA)
Flecanide (IC)
Amiodarone (III)
0.5
Procainamide (IA)
Amiodarone (III)
Sotalol (II/III)
Ibutilide (III)
-0.5
PR
INTERVAL
0
0.2
0.4
0.6
Time (s)
-0.5
0.2
0.4
-0.5
QRS DURATION
0
mV
1.0
mV
PR Prolongation
mV
1.0
0.6
Time (s)
QT INTERVAL
0
0.2
0.4
0.6
Time (s)
Prodysrrhythmic effects Most of the antiarrhythmic drugs discussed here have a narrow therapeutic window and must be used judiciously. One of the more
concerning side effects in the generation of new arrhythymias. Calcium channel blockers, beta blockers and digoxin all decrease automaticity and therefore may cause
sinus bradycardia. Any drug that prolongs the QT interval (usually by modifying potassium outflow) may precipitate torsades de pointes and this includes the class IA and
the class III antiarrhythmics (although it is rare for amiodarone to cause this). Some drugs effectively slow conduction enough to permit a recurrent rentry circuit to occur
causing and incessant ventricular tachycardia (Class IA and IC). Wide complex tachycardias may be precipitated by class IC drugs in the setting of structural heart disease.
Summary of management The management approach may be summarised as follows
1.
Initial
Ensure patient is haemodynamically stable, if not proceed to ALS guidelines

Perform an ECG and correctly identify the arrhythmia
2.
Assessment
Identify any precipitating factors; proarrhythmogenic drugs, electrolyte abnormalities, acid/base disturbance, hypoxia, ANS disturbance,
hypothermia, structural heart disease and or recent ischaemia
3.
Management
Correct or remove precipitating factors

Establish goals of management (this may include no treatment if there is limited indication)
Consider non pharmacological treatment including external defibrillation, implanted pacemaker/defib, radiofrequency ablation
Pharmacological therapy as indicated
4.
Longer term
Monitoring is required during drug initiation

Reduce long term risks; stroke prevention in AF, avoidance of QT prolonging medications, management of structural heart disease

STRUCTURE AND FUNCTION OF THE HEART

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STRUCTURE AND FUNCTION OF THE HEART

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STRUCTURE AND FUNCTION OF THE HEART

PERIPHERAL VASCULAR ANATOMY

The main complications are

AXILLARY VEIN &

SUBCLAVIAN VEIN &

From the jugular foramen

The external jugular vein

The subclavian vein

From the axillary vein

Christopher Andersen 2012

Christopher Andersen 2012

ELECTRICAL PROPERTIES OF THE HEART

Ionic basis of the slow-response cardiac action potential

Membrane potential (mV)

Events in the Heart during Interval

Atrial depolarisation and conduction through the AV node

Factors which influence cardiac electrical activity

DETERMINANTS AND CONTROL OF CARDIAC OUTPUT

1. RESTING is at the end of isovolaemic relaxation before

Stroke Volume or Cardiac Output

Right Atrial Pressure or LVEDV

CO or Venous Return (l/min)

Christopher Andersen 2012

CO or Venous Return (l/min)

CO or Venous Return (l/min)

CO or Venous Return (l/min)

CO or Venous Return (l/min)

Increased Preload is demon-

Increased Afterload note the

strated by a shifting along the

increase in the angle of the afterload

Increased Contractility note

definition the elastance is the

Systolic Heart Failure the

primary pathological process is a

LVH causes a decreased compliance

Aortic regurgitation there is a

loss of isovolaemic relaxation as the

Christopher Andersen 2012

Diastolic Heart Failure due to

Mitral regurgitation there

main pathological proces is a loss

Pressure - Volume Loop

exams and vivas.

Aortic stenosis the main

pathological problem is increased

Mitral Stenosis the main

BLOOD PRESSURE and CIRCULATION CONTROL

Christopher Andersen 2012

REGIONAL VASCULAR SYSTEM

Organ Blood Flow ml/min

Blood Flow in Left

Blood Flow in Right

Good flow throughout

Christopher Andersen 2012

APPLIED CARDIOVASCULAR PHYSIOLOGY

CENTRAL PROCESSING UNIT

Cardiovascular effects of IPPV and PEEP.

Cardiovascular changes during pregnancy include;

Heart Rate BPM

Christopher Andersen 2012

CARDIOVASCULAR PHYSICS AND MEASUREMENT