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Medicines Group: Drugs for the Circulatory Tract Summary
- Vak
- (WBFA03305)
- Instelling
- Rijksuniversiteit Groningen (RuG)
Medicines Group: Drugs for the Circulatory Tract Summary
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CIRCULATORY TRACT, lOMoAR cPSD| 5583220
Contents
Introduction .................................................................................................................................. 4
Introduction to cardiovascular system.................................................................................... 4
Anatomy of the heart.............................................................................................................. 4
Heart rhythm – mechanical events ......................................................................................... 4
Electrical conduction in the heart – pacemaker cells ............................................................. 5
Electrical conduction in the heart – conducting system ......................................................... 5
Muscle tissues......................................................................................................................... 6
Action potential – skeletal muscle .......................................................................................... 7
Action potentials – cardiac muscle ......................................................................................... 7
Autonomic nervous system .................................................................................................... 9
Hypertension .............................................................................................................................10
History...................................................................................................................................10
Mean arterial blood pressure MAP.......................................................................................10
Control of mean arterial pressure.........................................................................................10
Comparison arteries and veins .............................................................................................11
Poiseuille’s law ......................................................................................................................11
π ∙ r4 ...........................................................................................................................................11
Velocity of flow .....................................................................................................................12
Autonomic regulation of blood pressure ..............................................................................12
Humoral regulation of blood pressure ..................................................................................13
Pathophysiology of the cardiovascular system .....................................................................13
Atherosclerosis .....................................................................................................................13
Hypertension ........................................................................................................................14
Antihypertensive drugs .........................................................................................................14
RAAS system .........................................................................................................................15
ACE inhibitors........................................................................................................................15
Angiotensin receptor antagonists ARBs ................................................................................16
Calcium antagonists ..............................................................................................................16
β-receptor antagonists .........................................................................................................18
Situation Medicinal drug of preference ...........................................................................19
Arrythmias..................................................................................................................................21
Action potential ....................................................................................................................21
Pacemakers...........................................................................................................................22
Electrocardiogram ................................................................................................................22
Arrythmias ............................................................................................................................23
Antiarrhythmics ....................................................................................................................23
Class Mechanism Drug...................................................................................................23
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Disturbance of the heart rhythm ..........................................................................................24
Mechanism of cardiac arrhythmias ......................................................................................24
Heterotopic automaticity .....................................................................................................24
Class I antiarrhythmics ..........................................................................................................25
Class Ia ..................................................................................................................................26
Class Ib ..................................................................................................................................26
Class Ic ..................................................................................................................................26
Class II antiarrhythmics .........................................................................................................26
Class III antiarrhythmics ........................................................................................................27
Class IV antiarrhythmics........................................................................................................28
Adenosine .............................................................................................................................28
Bradyarrhythmias .................................................................................................................28
Heart failure ................................................................................................................................30
Dysfunction of systole versus diastole ..................................................................................30
Regulation of contraction .....................................................................................................30
Background of heart failure ..................................................................................................31
Heart failure classification ....................................................................................................31
Circulus vitosus .....................................................................................................................31
Therapeutical approach ........................................................................................................32
Positive inotropic drugs: cardiac glycosides ..........................................................................32
Beta sympathomimetic drugs ...............................................................................................34
PDE inhibitors .......................................................................................................................34
Calcium sensitizers and agonists ...........................................................................................35
Angina Pectoris ..........................................................................................................................36
Beta-receptor antagonists ....................................................................................................36
Calcium antagonists ..............................................................................................................36
Nitric oxide production .........................................................................................................36
Nitrates .................................................................................................................................37
Lipid metabolism .......................................................................................................................39
Transport through the body..................................................................................................39
Structure of lipoproteins.......................................................................................................39
Cholesterol levels ..................................................................................................................39
Lipid metabolism ..................................................................................................................40
Regulation of cellular cholesterol levels ...............................................................................40
Atherosclerosis .....................................................................................................................41
Hyperlipoproteinemia ..........................................................................................................41
Statins ...................................................................................................................................42
Resins ....................................................................................................................................42
Fibrates .................................................................................................................................43
Cholesterol absorption inhibitor: Ezetimibe .........................................................................43
PCSK9 antibodies ..................................................................................................................43
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Omega-3 fatty acids: fish oil..................................................................................................43
Diuretics ......................................................................................................................................44
Kidney function .....................................................................................................................44
Formation of urine ................................................................................................................44
Proximal tubule.....................................................................................................................45
Loop of Henle........................................................................................................................45
Distal tubule ..........................................................................................................................46
Collecting duct ......................................................................................................................46
Diuretics ................................................................................................................................46
Osmotic diuretics ..................................................................................................................47
Carbonic anhydrase inhibitors ..............................................................................................47
Loop diuretics .......................................................................................................................47
Thiazide diuretics ..................................................................................................................48
Thiazide analogues ...............................................................................................................48
K-sparing diuretics ................................................................................................................49
Aldosterone antagonists .......................................................................................................49
Vasopressin / ADH ................................................................................................................49
Hemostasis and thrombosis ...................................................................................................50
Blood coagulation .................................................................................................................50
Pathology ..............................................................................................................................50
Intrinsic, extrinsic and common pathway .............................................................................51
Risk factors improper blood clotting .....................................................................................51
Anticoagulants ......................................................................................................................51
Coagulation monitoring ........................................................................................................52
Heparin .................................................................................................................................52
Coumarin derivatives (VKAs) ................................................................................................53
Direct oral anticoagulants (DOAC) ........................................................................................54
Fibrinolytic agents.................................................................................................................54
Thrombocyte aggregation inhibitors ....................................................................................55
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Medicine group: Circulatory Tract
Introduction
Introduction to cardiovascular system
The heart is a pump that delivers blood to the organs via blood vessels. The heart uses blood as a transport medium
which contains oxygen, nutrients, waste, and other substances. The blood is composed of water, oxygen, CO2,
nutrients, hormones, ions and (immune) cells.
Veins contain the deoxygenated blood, with low levels of O2 (towards
the heart). The arteries contain oxygen rich blood (from the heart).
Important difference between arteries and veins: the veins contain
valves. Valves prevents returning of the blood flow. In the middle of all
this, we have the heart. The blood from the veins go into the heart,
first into the right atrium and then into the right ventricle. The right
ventricle pump the blood to the pulmonary artery (artery although
contains deoxygenated blood!!!). The pulmonary vein brings the
oxygenated blood to the left atrium, left ventricle and via the aorta to
various organs. Importantly is that the heart has his own blood supply.
There is a branching from the aorta to the coronary arteries. In the
organs we have capillaries, very small blood vessels that are
permeable for nutrients, O2 and CO2.
The strength of heartbeat, heart rate and blood flow are all linked.
Anatomy of the heart
The inferior and superior vena cava transports the blood form the organs to
the heart, into the right atrium. From the right atrium the blood goes to the
right ventricle. The heart contains valves which prevents the blood from
flowing back into the atrium. When the right ventricle contracts, the blood
goes via the pulmonary artery to the lungs. The oxygenated blood streams
back to the heart via the pulmonary veins into the left atrium. The left
ventricle pumps the oxygen rich blood into the aorta and via different
branches towards the organs.
The left ventricle has a much thicker muscle layer, because it needs more
force to pump the blood to all parts of the body. The right ventricle pumps
the blood only to the lungs, which needs less effort so the muscle layer is
thinner.
Heart → aorta → large artery → small artery → arteriole → capillaries → venule → vein → Vena Cava → heart
Heart rhythm – mechanical events
the diastole is the phase during which the heart relaxes and fills with
blood. The systole is the phase during which the heart’s
atria/ventricle contract.
At the start of the heart rhythm, there is the late diastole: both sets
of chambers are relaxing and ventricles fill passively. Then there is
the atrial systole, where atrial contraction forces a small amount of
blood into the ventricles. The next phase is the isovolumic ventricular
contraction: contraction pushes AV valves closed but does not create
enough pressure to open semilunar valves. The ventricles do not
change in volume, only pushing against AV valves. This is followed by
the ventricular ejection. As the ventricular pressure rises and exceeds
pressure in the arteries, the semilunar valves open and blood is ejected. Last, there is the isovolumic ventricular
relaxation: as ventricles relax, pressure in the ventricles falls, blood flows back into cups of semilunar valves and
snaps then closed.
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Figure is an overview of the left ventricular pressure and the amount of blood. →
At A, there is diastole. The ventricle fills with blood and the pressure increases
slightly up to point B. At point B, the heart is filled: End-Diastolic Volume EDV. The
atria start to contract, they pump a little bit more blood into the ventricles. The
pressure in the ventricles increases. At point C, there is the isovolumetric
contraction. The valves close, which increases the pressure. When the pressure is
high enough, the valves open and the blood is pushed into the vessels, decreasing
the blood volume. This ends in point D, the End Systolic Volume ESV.
Electrical conduction in the heart – pacemaker cells
The pacemaker cells (also autorhythmic cells) are responsible for the
heartbeat. They are located in the SA node (sinal atrial node). Pacemaker
cells have an unstable membrane potential which rises to an electrical
current. The current is spread over the heart. The cardiomyocytes can
propagate the current to the next cells because they have intercalated
disks with gap junctions.
When there is damage to the SA node due to e.g. hypoxia, there are also
other pacemaker cells in the heart: the AV node, the bundle of His and
the Purkinje fibers. They can take over the SA node function but they
have a lower frequency. The membrane potential of autorhythmic cells
are small peaks. They are characterized by unstable potential, due to Na influx. The sharp rise towards the peak is the
action potential, which is caused by Ca influx. The repolarization is due to K. The membrane potential of
cardiomyocytes is very different. After the peak/action potential, caused by Na, there is a plateau before total
repolarization.
Electrical conduction in the heart – conducting system
The electrical current originates in the SA node. The SA node depolarizes and the current goes via internodal
pathways to the AV node. There is a small delay in the electrical conductance. The delay prevents the ventricles from
contracting when the atria are still full of blood. The electrical signal goes via the bundle of His to the apex of the
heart. In the apex, the Purkinje fibers are located, which causes a depolarization wave that spreads from the apex
upwards over the ventricles.
After an action potential initiates, the cardiac cell is unable to initiate another action potential for some duration of
time. This period of time is referred to as the refractory period, which is approx. 250ms in duration and helps to
protect the heart. There is no accumulation of muscle tension and therefore tetanus is prevented.
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Muscle tissues
There are several muscle tissues: smooth, cardiac, and skeletal muscle. They differ in action potential mechanism and
in contraction mechanism. These mechanism are important to understand because of target sites for medication!!
Skeletal muscle
The tendon is where the skeletal muscle is attached to bones. The skeletal
muscle is composed of several muscle bundles. Between the bundles, nerves
and blood vessels are located. The muscle bundles consist of muscle fibers.
Muscle fibers are very long and multi-nucleated.
In the muscle fibers there are myofibrils, which are the contractile bundles. A
myofibrils are composed of sarcomeres. Sarcomeres are the interaction
between myosin and actin. The thick filaments, the myosin, consist of a
myosin tail and a myosin head that are connected by the Hinge region. The
thin filaments, actin, consists of troponin and tropomyosin. Tropomyosin
prevents the myosin head to interact with the actin. Calcium binds to the
tropomyosin, so actin becomes available for the myosin head to attach.
In the resting state, the myosin head is blocked. It contains ADP and
inorganic phosphate. Tropomyosin blocks the interaction between actin
and myosin head. The myosin head can only weakly bind to the actin
filament. When cytosolic Ca increase, there is initiation of contraction. Ca
binds to troponin. The troponin-calcium complex pulls away the
tropomyosin, allowing the myosin head to interact with the actin
filaments. Then there is detachment of inorganic phosphate (Pi) and the
head of the myosin can move at causes a power stroke and the actin
filaments are moving.
ADP + Pi -> Pi
release
You need a certain degree of overlap between the actin and
myosin filaments to reach optimal tension. Complete overlap of
the filaments, there cannot be gained any force anymore. The
optimal overlap it the point where maximal tension can be
generated. When there is little or no overlap at all, it is very
difficult for the muscle to contract because the interaction
between the filaments is very little.
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Smooth muscle cells
in smooth muscles, the myosin and actin is less well organized compared to in skeletal
muscles. The smooth muscle does not have troponin and do also not have sarcomeres.
Smoot muscle contraction is way slower than skeletal muscle contraction.
Increased cytosolic calcium derived from extracellular fluid or sarcoplasmic reticulum
induces the contraction of smooth muscles. Ca binds to calmodulin (CaM). The Ca-
CaM complex activates Myosin-Light Chain Kinase MLCK, which can phosphorylate the
myosin light chain and also increases the ATPase activity. ATP is needed in the myosin
head to cause contraction.
Cardiac muscles
Cardiac muscles are striated. There is only one nucleus per cell and
there are sarcomeres present. Contraction is induced by calcium.
Desmosomes are structures that provide cell-cell contact.
The action potential goes over the membrane and opens the voltage-
gated Ca channels, the L-type calcium channels. There is a small influx
of calcium, which induces calcium release from the SR via the RyR-
channels. This is calcium-induced calcium release. This causes so-called
calcium sparks. Calcium binds to troponin, giving the same contraction
mechanism as in skeletal muscles.
Calcium unbinds from the troponin, relaxing the sarcomeres. Calcium
is transported back into the SR via pumps and also pumped out of the
cell itself via ion balance.
Action potential – skeletal muscle
A skeletal muscle is dependent on the somatic motor neurons. You can activate
these motor neurons voluntary. Somatic motor neurons release ACh at the
neuromuscular junctions. ACh works on the nicotinic receptors on the motor end
plate. The net entry of Na through ACh receptor-channel initiates a muscle action
potential. The action potential travels over the membrane into the T-tubule. The
action potential can open the DHP Ca channels, which are coupled to the RyR-
channels on the sarcoplasmic reticulum (SR). This induces the release of Ca from the
SR. Ca binds to troponin, which then can displace the myosin heads.
Action potentials – cardiac muscle
Pacemaker cells
Pacemaker cells are autorhythmic and do not have a true
resting potential. The voltage starts about -60 mV and
spontaneously moves up to the threshold of -40 mV. This is
due to so-called FUNNY channels that open when the
potential is lower than -40 mV and allows slow influx of Na.
The resulting depolarization is called the pacemaker
potential. At threshold, Ca channels open, allowing calcium
ions to flow in the cell for further depolarization of the
potential: the rising phase. At the peak of polarization, Ca
channels close and K-channels open. K ions leave the cell
and returns the potential to -60 mV, the falling phase or repolarization.
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Cardiomyocytes
Cardiomyocytes have a different set of ion channels, besides, their sarcoplasmic
reticulum stores a large amount of Ca. Cardiomyocytes have a stable resting
potential of -90 mV, and only repolarize when stimulated, usually by neighboring
myocytes. This is possible because when a cell is depolarized, there is more Na and
Ca inside the cell, which leak through the gap junctions to the adjacent cells and
brings the membrane potential of this cell to the threshold potential of -70 mV. At
threshold, fast Na-channels open, creating a rapid Na influx and a sharp rise in
voltage: depolarization. L-type/slow Ca channels open at -40 mV. As the action
potential nears its peak, Na channels close quickly and K-channels open. The K-
channels cause a small decrease in membrane potential, known as early
repolarization. However, the Ca channels remain open and the K efflux eventually balances the Ca influx, giving a
plateau.
The Ca influx of the extracellular fluid is not enough to induce contraction. Instead, it triggers Ca release from the SR
in the process called Ca-induced Ca release. Ca then sets up muscle contraction. The contraction starts about half-
way the plateau phase and lasts until the end of the phase. As Ca channels slowly close, K-efflux predominates,
resulting in repolarization to the resting potential.
What is the main difference between the action potential of a pacemaker cell and a cardiomyocyte?
- No plateau phase with pacemaker cells
Which ion channels are responsible for the “pacemaker potential” phase of the pacemaker cell action potential?
- Potential phase (-60 mV to -40 mV): funny Na channels/If channels
Which ion channels are responsible for the rising phase of the pacemaker action potential?
- Influx of Ca -> Ca-channel
What are differences between pacemaker and cardiomyocyte?
- Cardiomyocyte has sarcolemma, large intracellular calcium store, different ion channels and AP initiates at
-90 mV instead of -60 mV.
How occurs conduction of action potential from one cardiomyocyte to the other?
- Conduction occurs via ion flow through gap junctions -> threshold action potential of -70 mV is reached, rapid
Na channels open
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Autonomic nervous system
The heart is an autonomic organ because of the autorhythmic cells. The sympathetic and parasympathetic NS are
important for the control of the contraction frequency, contraction strength, and the velocity of conductance of the
electrical stimulus over the heart. But the PNS and SNS are not able to generate an action potential!!
Sympathetic nervous system SNS
Sympathetic stimulation and epinephrine depolarize the autorhythmic cell and
speed up the depolarization rate, increasing the heart rate together with the
contractile force. They also lower the threshold. The heart has both β1 and β2
adrenoceptors, although the predominant receptor type in number and function
is β1.
Norepinephrine binds to the β1-adrenoreceptor, which is Gs coupled. Activation
of Gs protein, activated adenylyl cyclase, which increases the production and
thus level of cAMP. cAMP activates PKA, that has several functions like:
- Phosphorylation of sites on SR, which enhances the release of calcium
through the RyR-channel.
- Phosphorylation of myosin light chains, which may also contribute to
positive inotropic effect of beta adrenoceptor stimulation
Gs proteins also increase heart rate by opening ion channels responsible for pacemaker currents in the SA node.
The SNS is both positive inotropic and positive chronotropic. A possible adverse effect is that the heart’s O2
consumption increases.
Parasympathetic nervous system PNS
Parasympathetic stimulation hyperpolarizes the
membrane potential of the autorhythmic cell and slows
depolarization, decreasing the heart rate. There is
increased K permeability and reduced Ca permeability.
The PNS works via muscarinic receptors. The M2
receptor is mainly present on the atria and pacemaker
cells. M2 receptors are Gi coupled. Gi proteins increase the permeability of the potassium channels. Besides, it
decreases adenylyl cyclase activity, which reduces the cAMP levels. Decreased cAMP levels inhibits the funny
channels, so the influx of Na is reduced.
The PNS causes reduces automaticity of the pacemaker cells and reduced AV node conduction.
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