Paramedic Electrophysiology. Colbeck

1. How does the heart generate electricity and make
itself contract?
2. How does our body control the rate and strength of
those contractions?
3. How can we, as paramedics, affect this process using
medications?
Paramedic Cardiology
Electrophysiology

Part 0 – Cardiac Electrophysiology - 0 Fundamentals
• In this lecture we'll be going over some basic biology to get you ready for
cardiac electrophysiology.
• https://youtu.be/gCbHyK6y4Ms
Part 1 – Cardiovascular Electrophysiology 1 - Movement through the membrane
• In this lecture we're going to describe how different ions are able to move in
and out of the cell.
• https://youtu.be/IW3J2Y2ty6w
Part 2 – Cardiovascular Electrophysiology 2 - Electrical Flow In The Heart
• In this lecture we're going to talk about how a hunk of meat in your chest can
generate electricity.
• https://youtu.be/5A_lEW1suAM
Electrophysiology

Part 3 - Cardiovascular Electrophysiology 3 - Action Potential of the Myocytes
• In this lecture, we're going to go over the pattern of how ions move in and out of the
cell in a regular, repeating pattern - called the Action Potential.
• https://youtu.be/KV3AaXWrNeY
Part 4 - Cardiovascular Electrophysiology 4 - Action Potential of the Pacemaker Cells
• In this lecture we're going to describe how 'pacemaker' cells can spontaneously
depolarize without anything stimulating them externally.
• https://youtu.be/M39wMZFd22o
Part 5 - Cardiovascular Electrophysiology 5 - Anatomy and Physiology of Myocytes
• In this lecture we describe how cardiac cells physically contract.
• https://youtu.be/qqnL0Fy3e2g
Electrophysiology

Part 6 - Cardiovascular Electrophysiology 6 - Excitation Contraction Coupling
• In this video we're going to go over how depolarisation initiates contraction of
the heart.
• https://youtu.be/UBINkoW6JzM
Part 7 - Cardiovascular Electrophysiology 7 - ANS Influence on the Heart
• In this lecture we cover how our body changes the rate and strength of our
heart, going from external stimuli to the actual ionic changes that take place
in the myocardial cells. If I yell 'boo!', your heart speeds up. Why? How?
• https://youtu.be/JmAaibgOrLw
Part 8 - 8 Paramedic Pharmacology – Antidysrhythmics
• In this final lecture, we review cardiac antidysrhythmics with a fairly
introductory discussion of how they are classified and how they work.
• https://youtu.be/oY0XVEkfKr4
Electrophysiology

Electrophysiology
Part 0
Fundamentals
Marc Colbeck

© Marc Colbeck and Paramedicine.com, used by permission of the author. See:
https://creativecommons.org/licenses/by-nc-sa/4.0/
Maintaining this note in the file is sufficient attribution of authorship as per the author.

Topics
0. Fundamentals
1. Movement Through the Membrane
2. Electrical Flow in the Heart
3. The Action Potential – Myocytes
4. The Action Potential – Pacemaker cells
5. Anatomy and Physiology of Myocytes
6. Excitation-Contraction Coupling
7. ANS Influence on the Heart
8. Paramedic Pharmacology - Antidysrhythmics

Priming Questions
1. What is an ‘atom’
2. What is an ‘element’?
3. What is an ‘ion’?
4. How about anions and cations, what are those?
5. What is a cell?
6. Where did cells come from?
7. What are the walls of a cell made out of?
8. What are the major elements that humans are made out of?
9. Why is phosphorous so important to humans?
10. What are the ions that are important in cardiac electrophysiology?

You Should Already Know
Atoms
• Basic building block
– Protons+ and neutrons in nucleus
– Electrons- in orbit
Element
• Substance made entirely of one
type of atom (e.g. H2)
Ions
• An atom or element with a lack or
surplus of either protons or
electrons
– Anions: negative charge
– Cations: positive charge

The Elements of Life
99% CHON (by weight)
http://bookofresearch.com/images/earth-transparent.png
<1% P, as well as some S, Na, Mg, Cl, K, Ca and Fe
10

http://1.bp.blogspot.com/-mrMWO9w3UvE/TdE67QdLgOI/AAAAAAAAAEY/Bpu6nJpEBgk/s1600/periodic_table_of_elements1.jpg
composition (by weight)
11

The Elements of Life - Phosphorus
• Highly reactive, usually found as ‘red phosphorus’
• Used in explosives (napalm), poisons and nerve agents
• ‘Organophosphates’ are used as fertilizers, but can also (along with the
more potent fluorophosphates) be used as neurotoxins.
• 13th Element discovered (in 1669)
• Distilled from urine (100L ≈ 5mg) (later discovered in bones)
• Now mined from rocks
Essential to life:
• Part of DNA, RNA and ATP (‘phosphorylation) as well as phospholipids
http://0.tqn.com/d/chemistry/1/0/Q/4/1/phosphorus_allotropes.jpg
12

• Phosphorous
– binds to 4 oxygen
– hydrophilic
• Hydrocarbon tails
– hydrophobic
http://bioweb.wku.edu/courses/biol115/wyatt/biochem/lipid/P-lipid.gif
13

Cell Membranes
http://www.freethought-forum.com/images/anatomy2/phospholipid_bilayer.jpg
14

Cell Membranes
Liposomes
• “Inside/Outside”
https://upload.wikimedia.org/wikipedia/commons/0/01/Liposome_scheme-en.svg
15

Cell Contents
What’s inside liposomes?
http://www.fossilmuseum.net/Paleobiology/Paleobiology_images/seawater.jpg
16

Cell Contents
http://1.bp.blogspot.com/-mrMWO9w3UvE/TdE67QdLgOI/AAAAAAAAAEY/Bpu6nJpEBgk/s1600/periodic_table_of_elements1.jpg
What’s in sea water?
17

Cell Contents
What’s inside single celled organisms? Same stuff ...
• Cations
– Na+
– K+
– Mg+2
– Ca+2
• Anions
– Cl-
– HCO3
- (Bicarbonate)
– SO4
-2 (Sulphate)
http://www.salmonellablog.com/uploads/image/bacteria.jpg
18

Cell Contents
Single celled life became multi-cellular life, surrounding
each cell with fluid similar to the sea.
http://www.pnas.org/content/104/suppl.1/8613/F1.large.jpg
19

Cell Contents
Multi-cellular life came on land
http://2.bp.blogspot.com/_2ocgSdkueHs/Rh1viEauffI/AAAAAAAAAVk/viHbhiBj2OY/s400/cartoon-drfunmrevolution.gif
20

Cell Contents
Cytosol
Na+
K +
Ca 2+
Cl -
Extracelluar Fluid
Na+
K +
Ca 2+
Cl -
21

Cell Contents – passing through the membrane
• Small, non charged
particles/molecules can move
through the cell membrane easily,
(e.g. O2 and CO2, lipids, hormones,
anesthetic agents).
• Most ions and large molecules (like
proteins) or glucose (which is
hydrophilic) can’t get through.
P
P
P
P
P
P
P
P
P
P
22

Cations
0.6 nm* 0.8 nm* 1.2 nm*
*aqueous values (bonded with H2O)24

Electrophysiology
Part 1
Movement Through the
Membrane
Marc Colbeck

Priming Questions
1. Describe where Na, K and Ca are normally found in the polarised cell.
2. Describe what a voltage gated channel is and what role it plays in depolarisation
3. Describe what a g-coupled protein receptor is and describe how it effects changes
in the cell.
4. Describe what a ligand gated channel is and give one example of a ligand.
5. What are the two primary active transport pumps and describe the ions they
exchange and what drives the movement of those ions.
6. Referencing the ion exchangers, describe how cellular hypoxia leads to irritable
dysrhythmias.
7. What are the two ion exchangers and describe the ions they exchange and what
drives the movement of those ions.

Movement Through the Membrane
How does stuff
get in and
out??
electrochemical
K+electrochemical
electrochemical
Ca2+
Na+
30

31

Voltage Gated
Channels
(VGCs)
“Gating” is the process of
opening the channel.
A “voltage gated”
channel is a channel that
opens due to electrical
(voltage) stimuli.
Time Dependent
• Open when ‘gated’
• Stay open ≈ ‘fast/slow’
• Must close to reset
(which is also voltage
dependent)
I = “intensite de courant”
INa
K
Na
Ca
32

Receptor Gated Channels
VGCs
hormone or
neurotransmitter
(“ligand”)
receptor
RGC
K
Na
Ca
33
Examples:
• Insulin
• Hormones
• Steroids
• Prostaglandins

RGCs
VGCs
G proteins signal
the inside of the cell
to do other stuff
(secondary
messenger systems)
“G coupled
protein receptor”
GCPR
RGC
K
Na
Ca
34
Examples:
• Neurotransmitters
• Adrenaline
• Narcotics
• 1/3 of drugs!

VGCs
Primary Active
Transport
Pumps
3 Na+ out
2 K+ in
ATP
ADP
Na/K
• 1/3 of all ATP use in the body
• 1000 pumps per square micrometre
GCPR
RGCs
RGC
K
Na
Ca
35

VGCs
Primary Active
Transport
Pumps
3 Na+ out
2 K+ in
ATP
ADP
Na/K
Ca2+ out
ATP
ADP
Ca/ATPase
GCPR
RGCs
RGC
K
Na
Ca
36

VGCs
Ion Exchangers
Rely on the
concentration gradient
created by the Na/K
pump
Na/Ca*
3 Na+ in
1 Ca2+ out
1 Na+ in
1 H+ out
Na/Proton
GCPR
RGCs
RGC
K
Na
Ca
*The Na/Ca exchanger is inhibited by acidosis, causing an intracellular hypercalcemia,
increasing irritability in the cell. This is how hypoxia leads to irritable dysrhythmias.
37

Really Important Concept to Understand!
RGCs
VGCs
Na/Ca
Na/Proton
3 Na+ out
2 K+ in
ATP
ADP
Na/K
Ca2+ out
ATP
ADP
Ca/ATPase
3 Na+ in
1 Ca2+ out
1 Na+ in
1 H+ out
GCPR
RGC
K
Na
Ca

Electrophysiology
Part 2
Electrical Flow
in the Heart
Marc Colbeck

Topics
0. Fundamentals
1. Movement Through the Membrane
2. Electrical Flow in the Heart
3. The Action Potential – Myocytes
4. The Action Potential – Pacemaker cells
5. Anatomy and Physiology of Myocytes
6. Excitation-Contraction Coupling
7. ANS Influence on the Heart (!)
8. Paramedic Pharmacology - Antidysrhythmics

Priming Questions
1. What is electricity?
2. How does the heart create an electrical current?
3. Specifically what are the roles of ions and gap junctions.

cell
Sodium
(Na+)
Potassium
(K+)
+ -
There’s more sodium (+) outside,
and more potassium (-) inside
Electrical Flow in the Heart
44
There are also
negatively charged
proteins trapped inside
the cell.

To make electricity …
cell
+
-
Na+
K+
Electricity
“The collection of physical
effects related to the force
and motion of electrically
charged particles, typically
electrons, through or across
matter and space.”
http://www.thefreedictionary.com/electricity
45

The exchange takes place in a wave across the cell
46

Gap Junctions allow Na to flow between cells
47

depolarization
conduction
→
at overshoot
conduction
→
at overshoot
conduction
→
at overshoot
depolarization
48

Electrical flow
- - - - - - - - -+ -+++++++++
49

Heart cells
- - -
----------- --
--
---
-
--------
----------
-
------------
----------
----------
--
--------
-
-
---------- ---------
++
++
+
+
+++
++
+++++
+++++
++
+
++++++++
+
++++++
+
+
+
+
+++++++
+
+
++
++++++
+++
+
+++++
+++
+
+
+++++
+
+
++
+
++++
+
++
++++
+
+
+
++
+
+++

Electrophysiology
Part 3
The Action Potential:
Myocytes
Marc Colbeck

Priming Questions
1. What is meant by ‘resting membrane potential’?
2. Label this diagram appropriately, using the given terms.
1. Polarised
2. Hyperpolarised
3. Depolarisation
4. Repolarisation
3. Also label the phases using the numbers 0-4.
4. Describe in details the movement of ions in phase 0-4 of
the depolarisation.
5. What is a ‘potassium rectifier channel’?

The Action Potential - Myocytes
56
0
RMP: Resting Membrane Potential
The charge of the inside of the cell compared to the outside.
Voltage(mV)
- 90
+ 20
Polarised
Equal internal and external charges
Hyperpolarised

VGCs
K
Na
Ca
57
Neuron
Myocyte
- 90
+ 20

Polarised
Depolarisation
Hyperpolarised
Plateau
Voltage(mV)
- 90
+ 20
Polarised
58

59
Voltage(mV)
- 90
+ 20

Voltage(mV)
- 90
+ 20
PHASE 0
• rapid influx of Na through some Na channels
• Once an area of the cell wall reaches about 10-20mV
less negative than the resting membrane potential
(RMP) all the local voltage-gated Na channels open.
• Sodium ions rapidly diffuse inward through the Na
channels, and depolarisation occurs.
• Sodium channels open at about -70 mV, close at
about +20 mV
• They won’t open again until the RMP falls under
about -65 mV again (they have to ‘reset’)
Extracellular
Intracellular
Phase 0
Na+
membrane

Voltage(mV)
- 90
+ 20
PHASE 1
• Voltage-gated Na channels close
• Na influx stops
• “Fast” K channels open
• A very brief K efflux begins (causing a
brief decrease in the RMP)
Phase 0 Phase 1
Na+
K+
Extracellular
Intracellular
membrane

Voltage(mV)
- 90
+ 20 PHASE 2
• Ca influx begins at -60 to
-50 mV through Ca channels
• The efflux of K is slowed
(small arrow) so an
equilibrium is maintained
• There’s no sodium
movement
Phase 0 Phase 1 Phase 2
Na+
K+
Ca++
K+
Extracellular
Intracellular
membrane

Voltage(mV)
- 90
+ 20
PHASE 3
• Ca Channels close
• An efflux of K from K continues
• The Na and Ca channels reset
Phase 0 Phase 1 Phase 3Phase 2
Na+
K+
Ca++
Intracellular
membrane
Extracellular
K+K+

Voltage(mV)
- 90
+ 20
Phase 4
• The cell returns to -80/-90 mV
• The K rectifier channel keeps the transmembrane
potential stable at -90 mV
• The ATP pump restores K into the cell and Na out
of the cell
• Ca/ATP pump restores Ca to outside the cell
• Na/Ca exchanger restores Na and Ca
• Na/H exchanger removes H from cells
Na+
K+
Ca++
Phase 4
Intracellular
membrane
Extracellular
K+K+ K+

Voltage(mV)
- 90
+ 20
Na+
K+ K+
Ca++
K+ K+
Phase 4
Intracellular
membrane
Extracellular

https://www.youtube.com/watch?v=tLt3ZTeVzEY

https://www.khanacademy.org/science/health-and-medicine/circulatory-system

Electrophysiology
Part 4
The Action Potential:
Pacemaker Cells
Marc Colbeck

Priming Questions
1. How can SA and AV node cells depolarize without being externally
stimulated?
2. What are ‘funny channels’?
3. What ions flow through the funny channels?
4. Why does a pacemaker cell only have phase 4, 0, and 3?
5. Compare the action potential of a pacemaker myocyte versus and
ventricular myocyte.

The Action Potential – Pacemaker Cells
Different tissue in the heart
depolarizes in different ways.
The SA and AV nodes are
different than the rest of the
heart.
They are the pacemakers or
‘auto-rhythmic’ cells.
73

RMP
• Spontaneous phase 4 rise
(pacemaker potential)
• Due to “Funny Channels” (IF) and
Ca(T) channels
• IF = nonspecific cation channels
permeable to both Na+ (influx)
and K+ (efflux):
• At –ve membrane potential Na
influx > K efflux → gradual
depolarization
• AP in SA and AV nodal cells is similar,
but pacemaker potential in SA cells
reaches threshold more rapidly
Pacemaker
Potential
Action Potential
Na+
influx
Ca2+ influx
-40
Resting membrane potential
•Spontaneous phase 4 rise (pacemaker
potential)
•Due to “Funny Channels” (IF) and Ca(T)
channels
• IF = nonspecific cation channels
permeable to both Na+ (influx) and
K+ (efflux):
• At –ve membrane potential Na + Ca
influx > K efflux → gradual
depolarization
• AP in SA and AV nodal cells is similar – but
pacemaker potential in SA cells reaches
threshold more rapidly
4
0 3

Na/Ca
Na/Proton
3 Na+ out
2 K+ in
ATP
ADP
Na/K
Ca2+ out
ATP
ADP
Ca/ATPase
If
Funny Channels
(pacemaker cells only)
3 Na+ in
1 Ca2+ out
1 Na+ out
1 H+ in
GCPR
RGC
K
Na
Ca
No fast Na channels in
pacemaker cells!
Na+
K+
75
Na

PHASE 4
• If type channels gradually close as
membrane potential becomes more
+ve
• Membrane potential threshold @ -
40mV, results in spontaneous AP
PHASE 0
• Depolarization phase caused by
opening of L-type Ca2+ channels
(rather than Na+ in contractile cells)
• Ca2+ channels slower than Na+
• No fast Na channels = no Phase 1
• Rapid deactivation of Ca channels =
no Phase 2
4
0 3
4
- 40
(IF)
Ca(T)
http://rezidentiat.3x.ro/eng/tulbritmeng.files/image001.gif

Pacemaker
Potential
Action Potential
K+ effluxCa2+ influx
- 40mV
PHASE 3
• Repolarisation occurs when Ca2+
channels close and slow K+ channels
open leading to K+ efflux
• Return to –ve potential activates
pacemaker mechanism
Polarized State
• Closure of “slow” K+ channels
(opened during repolarisation of
previous AP)
• Cyclic/rhythmic excitation of the cells
= “autorhythmicity”
Cell has to
hyperpolarize in
order for F channels
to open again.
Cellular hypoxia
obstructs this and so
leads to bradycardia.

The Action Potential
‘Normal’ Myocytes Pacemaker Myocytes
Membrane Potential Stable at – 90 mV Unstable pacemaker potential;
usually starts at – 60 mV
Events leading to threshold
potential
Depolarization enters via gap
junctions
Net Na entry through If channels,
reinforced by CaT entry
Rise phase of action potential Na entry Ca entry
Repolarization phase Extended plateau caused by Ca
entry; rapid phase casued by K efflux
Rapid; caused by K efflux
Hyperpolarization None; resting potential is – 90 mV,
the equilibrium potential for K
Normally none; when repolarization
hits -60 mV the If channels open
again.
Duration of action potential Extended: 200+ msec Variable: generally 150+ msec
Refractory period Long because resetting of Na
channel gates delayed until end of
action potential
None
78

Putting it All Together
Comparison of Action Potential’s across the heart
Top
Bottom
Marieb Fig 18-14

Electrophysiology
Part 5
Anatomy & Physiology
of Myocytes
Marc Colbeck

Priming Questions
1. What percent of myocytes are contractile and what percent are
pacemaker cells?
2. What are the two structures of the intercalated disks? Describe
their function?
3. What is meant by the term ‘functional syncytium’?
4. What are the two main filaments involved in muscular contraction
(which are attached to the M and Z structures)
5. What is tropomyosin? What is its role in contraction? Describe this
by explaining the roles of three elements of the troponin complex,
Ca and ATP.

Myocytes
• ≈99% of cardiomyocytes are contractile
• ≈1% specialised autorhythmic (pacemaker) cells

Myocytes
Z disks: Z stands for “zwischen” which means “between” in German
M line: M stands for “Mittle” which means “middle” in German
A bands: A stand for “anisotropic”
I bands: I stands for “isotropic”,
both A & I have to do with how the structures interact with polarized light
H zone: H stands for “helle” which means “bright” in German

Myocytes
Troponin C
• has a strong affinity for Calcium, when bound it moves the tropomyosin
strand off the actin so that the actin can interact with the myosin
Troponin I
• Inactivates the actin/myosing binding
• Defibrillation and (brief) CPR don’t elevate TnI levels
• TnI is more specific to cardiac muscle, so is theoretically better to test for
Tropinin T
• Ties the TnC and TnI together
• TnT is analyzed in the ER to determine the presence of A.M.I.
• Current research into ‘high sensitivity TnT’ lab tests are being conducted

Myocytes
Free Ca ions binding to
the actin TnC sites (thus
revealing the tropomyosin)
plus ATP to myosin S1 heads
produces the power stroke.

Myocytes
No ATP→ cell unable to
dissociate actin and
myosin filaments
Relaxation of the power
stroke (by decoupling the
actin and myosin) also
requires ATP-supplied
energy.
This is relevant
to APO – any
idea how?

Myocytes
An animated movie (very short) of the power stroke
http://www.sci.sdsu.edu/movies/actin_myosin.html

Electrophysiology
Part 6
Excitation-Contraction
Coupling
Marc Colbeck

Priming Questions
1. What are the ten stages of excitation contraction
coupling?
2. Which ion is the ‘driver’ of contraction?
3. Label the diagram on the following slide

Excitation-Contraction Coupling
How do we go from depoloarizing conductive tissue
(for example, purkinje fibres)
to getting the actin and myosin
in a myocyte to contract ???
This process is called “excitation-contraction coupling”.

The 3 ways a myocyte is usually depolarized
1. Stimulation by a
pacemaker cell (in a node).
2. From an adjacent myocyte,
injecting sodium through
the gap junction.
3. From an adjacent Purkinje
fibre injecting sodium
through the gap junction.

How does getting the membrane of a myocyte to
depolarize cause the actin and the myosin on the inside
to contract?

1. An action potential
enters from adjacent
cell, depolarizing the
plasma membrane.
This wave of
depolarization
continues deep into
the myocyte via the T-
tubules.

2. Voltage gated L-
type Ca channels
open, and Ca enters
the myocyte through
the plasma membrane
Verapamil (isoptin) partially blocks this entry -
acting as a negative inotrope.

3. Ca binds to a
receptor in the
sarcoplasmic
reticulum. This induces
Ca release from the
cisternae of the SR.
This is called Calcium
Induced Calcium
Release (CICR).
“Nice-to-know” (not tested):
These receptors are called “Ryanodine receptors”
because we found (experimentally) that the drug
Ryanodine will bind to them.
“Nice-to-know” (not tested):
These receptors are called “Dihydropiridine
receptors” because we found (experimentally) that
the drug Dihydropiridine will bind to them.

4. The local release of
Ca causes Ca ‘sparks’
(short lived, highly
local releases of Ca
throughout the cell)

5. Summated Ca
sparks create a Ca
signal which travels to
the actin and myosin.

6. Ca binds to
Troponin C (TnC) to
move the tropomyosin
sheath off the actin,
with power from ATP,
the myosin heads
initiate the ‘power
stroke’ and contraction
occurs.

7. Relaxation of the
actin/myosin complex
occurs when Troponin
I (TnI) initiates Ca
release from the TnC,
and the myosin heads
reset to their starting
position.

8. Ca is pumped back
into the SR for
storage.

9. Calcium in the
cytosol is moved out of
the cell by the Na/Ca
exchanger.

10. The Na brought
into the cell by the
Na/CA exchanger is
removed by Na/K-
ATPase pump.

Ca2+ entry in the
cell is the driver
of contraction

Electrophysiology
Part 7
ANS Influence
on The Heart
Marc Colbeck

Priming Questions
1. Sketch the layout of the nervous system using the following terms:
1. Central and peripheral
2. Afferent and Efferent
3. Somatic and Autonomic
4. Sympathetic and Parasympathetic
2. Define the following terms. State the role of the SNS and the PSNS on each.
1. Inotropy
2. Chronotropy
3. Dromotropy
4. Irritability
3. Differentiate between the autonomic innervation of the atria and the ventricles.
4. List 5 important categories of factors that determine the autonomic tone in the body.
5. Sketch and label the transmission of signals from the brain to the heart through the nervous
system. Include the receptors found on the myocytes for both SNS and PSNS signals.
6. Section Review – label the following diagram

ANS Influence
Peripheral Nervous System
Central Nervous
System
Afferent
Nervous System
Efferent
Nervous System
Autonomic Nervous System
Somatic
Nervous
System
Sympathetic Nervous
System
Parasympathetic
Nervous System
The SNS and PSNS balance each other
S ensory is …
A fferent
M otor is …
E fferent
(SAME)

ANS Influence
Most involuntary organs and glands have both sympathetic
and parasympathetic innervation. The SNS and PSNS act
antagonistically to maintain or quickly restore homeostasis.
The sympathetic nervous system excites the receptors (‘fight
or flight’ response).
The parasympathetic nervous system relaxes the receptors
(‘rest and digest’ response).

ANS Influence
If you’re a bit vague on the ANS there’s a lecture on it here:
https://www.youtube.com/watch?v=7lVt0ABcnM4

ANS Influence
Sympathetic Stimulation
(thoraco-lumbar)
SNS innervates both atria and ventricles
↑ heart rate (↑ chronotropy)
↑ conduction velocity (↑ dromotropy)
↑ strength of contraction (↑ inotropy)
↑ irritability

ANS Influence
Parasympathetic Stimulation
(cranio-saccral)
PSNS innervates only the atria
↓ heart rate (↓ chronotropy)
↓ conduction velocity (↓ dromotropy)
↓ strength of contraction (↓ inotropy)
↓ irritability

The sympathetic branch influences both the atria
(i.e. SA Node, the Intraatraial and internodal
pathways, and the AV junction) and the
ventricles.
The parasympathetic branch influences only the
atria.
parasympathetic
sympathetic
ANS Influence

TheAutonomicNervousSystem
This is important!
The SNS can speed up the whole heart, but the PSNS can only slow
down the atria.
If the ventricles are going too fast, it’s no use trying to activate the
PSNS to try and slow them down. The PSNS has no effect on the
ventricles.

ANS Influence
Contractile cells of the:
1. atrial myocardium
2. ventricular myocardium
AV Node cells:
3. velocity of conduction
4. length of refractoriness
Automaticity cells of the:
5. SA node
6. AV node
7. atria
8. ventricular conduction
system (not velocity, just
automaticity)
SNS
Stimulates
PSNS
Inhibits

ANS Influence
What controls the autonomic balance?
1. Nervous Regulation
• cortex and hypothalamus
2. Circulatory Regulation
• venous and arterial
3. Respiratory Regulation
• inspiration and expiration
4. Other Somatic Regulation
• muscles, pain, temp., etc.
5. Chemical Regulation
• O2, CO2 , H+
• Adrenaline, Noradrenaline, Thyroxin & Histamine
• Poisons and Drugs

ANS Influence
What controls the autonomic balance?
Thoughts
Feelings
Hypothalamus
Blood pressure
Respiration
Movement
Pain
Temperature
pH
Hormones
Chemicals
Brain
MedullaOblongata
Cardiac
Acceleratory
Centre
Cardiac
Inhibitory
Centre

ANS Influence
How does the brain send messages to the heart?
MedullaOblongata
CIC&CAC
Preganglionic neuron
R. & L. Vagus Nerve
Sympathetic
Chain Ganglia
Cardiac
Plexus
Postganglionic nerve
HEART

ANS Influence
SNS Ganglia Chain
Cardiac Plexus

ANS Influence
How does the ANS affect the heart?
http://www.thecolor.com/images/Magician.gif
“...and then the
rabbit makes the
heart speed up ...”

ANS Influence
Let’s connect this ...
With this ...
HOW IT
DOES IT
WHAT IT
DOES

ANS InfluenceMedullaOblongata
CIC&CAC
Preganglionic neuron
R. & L. Vagus Nerve
Sympathetic
Chain Ganglia
Cardiac
Ganglia
NAd
Ach
M2
Ach
β1NAd
M2Ach

Na/K
ATP
ADP
Ca2+
ATP
ADP
Ca/Na
Na/H
GCPR
RGC
K
Ca
Clinical Effects of SNS Activation:
1. ↑ Chronotropy: The pumps and
exchangers work more quickly, allowing
the heart to ‘reset’ more quickly,
allowing an increased HR, and an
increased resistance to acidosis.
2. ↑ Dromotropy: Ion channels work
more quickly, increasing the speed of
depolorization.
3. ↑ Inotropy: The increased amount of
calcium entering the cell causes an
increased release of calcium from the
sarcoplasmic reticulum, causing more
actin and myosin to bridge, increasing
the strength of contraction.
β1NAd
Na
ANS Influence
①
②
③

ATP
ADP
ATP
ADP
GCPR
RGC
K
Ca
K+
IKAch
M2Ach
Na/K
Ca2+
Ca/Na
Na/H
2-5x more M2 in the atria than in the ventricles
Clinical Effects of PSNS activation:
1. ↓ Chronotropy: The pumps and
exchangers work more slowly, causing
the heart to ‘reset’ more slowly, causing
a decreased HR, and an decreased
resistance to acidosis.
2. ↓ Dromotropy: Ion channels work more
slowly, decreasing the speed of
depolorization.
3. ↓ Inotropy: The decreased amount of
calcium entering the cell causes a
decreased release of calcium from the
sarcoplasmic reticulum, causing less actin
and myosin to bridge, decreasing the
strength of contraction.
Na
ANS Influence
①
②
③

Under ischemia or cardiac stress
ATP (Adenosine Triphosphate)
is degraded down to just
Adenosine (Ado)
by losing all 3 of its Pi.
Adenosine
(Ado)
P P P
Adenosine
(Ado)
ANS Influence

Ado inhibits NAd release from the SNS
postganglionic nerve terminal.
Ado inhibits the β1 secondary messenger
systems and so acts as a sympatholytic.
Ado ↑K efflux and ↓Ca influx,
hyperpolarizing (mostly) the AVN,
slowing and/or temporarily inactivating it
(up to 30s!).
It’s kind of like an internal,
cardioprotective “emergency brake”. In
effect, it works like the PSNS without
having to invoke the PSNS.
Possibly the nociceptive (pain) pathway
for angina.
ATP
ADP
ATP
ADP
GCPR
RGC
K
If
Na+
K+
K+
IKAch
Na/K
Ca2+
Ca/Na
Na/H
Na
β1
Ca
NAd
ANS Influence

Quick Review
• The SNS speeds things up by affecting various
structures in the plasma membrane.
• The PSNS slows things down by affecting various
structures in the plasma membrane.
• Adenosine kind of does a lot of what the PSNS does,
without having to stimulate the PSNS.
ANS Influence

ATP
ADP
ATP
ADP
GCPR
RGC
K
Na/K
Ca2+
Ca/Na
Na/H
Na
β1
Ca
NAd
Ach M2
MedullaOblongata
CIC&CAC
Preganglionic
neuron
R. & L.
Vagus Nerve
Sympathetic
Chain Ganglia
Cardiac
Plexus
Postganglionic
nerve
Postganglionic
nerve
ANS Influence - Overview
M2

ATP
ADP
ATP
ADP
GCPR
RGC
K
If
Na+
K+
Na/K
Ca2+
Ca/Na
Na/H
Na
β1
Ca
NAd
Ach M2
MedullaOblongata
CIC&CAC
Preganglionic
neuron
R. & L.
Vagus Nerve
Sympathetic
Chain Ganglia
Cardiac
Plexus
Postganglionic
nerve
Postganglionic
nerve
ANS Influence - Overview
M2
Summary of the ANS Influence in One Diagram

Electrophysiology
Part 8
Antidysrhythmic
Pharmacology
Marc Colbeck

Priming Questions
1. Explain the Singh/Vaughan classifications of drugs acting on the heart and indicate where on the graph they act.
a. Class 1:
b. Class 2:
c. Class 3:
d. Class 4
e. Class 5:
2. Explain the actions of the following antidysrhythmic medications
• Adenosine
• Amiodarone
• Beta Blockers
• Calcium Channel Blockers
• Digoxin
• Magnesium Sulphate
• Xylocaine/Lidocaine
3. Why might ‘The Sicilian Gambit’ be a better method to describe ventricular antidysrhythmics?

Antidysrhythmics
• Singh / Vaughan Williams classification
• “Sicilian Gambit” classification

Antidysrhythmics
Singh / Vaughan Williams classification
Introduced in 1970 by doctoral candidate at Oxford
University, Dr. Bramah Singh (a cardiologist)
(his supervisor was EM Vaughan Williams)

Antidysrhythmics – Singh/Vaughan Williams
Na/K pump
Na/Ca exchanger
Na influx through
gap junctions
Fast K
channel
efflux
T and L channel Ca influx
Voltage(mV)
- 90
+ 10
Ca influx stops
K efflux through “slow K” channels
Class II
Beta Blockers
(↓ SNS tone)
Class I (a,b,c)
Fast Na channel
blockers
Class III
Block K efflux
Class IV
Block Ca
Channels
Class V
Does other
stuff

Class I agents: Sodium Channel Blockers
are divided into three groups based upon their effect on the
length of the action potential.
• Ia lengthens the action potential (right shift) Procainamide
• Ib shortens the action potential (left shift) Xylocaine
• Ic does not significantly affect the action potential (no shift) Propafenone
Antidysrhythmics – Class I
http://en.wikipedia.org/wiki/Antiarrhythmic_agent

Antidysrhythmics – Class I
Class Ia Disopyramide, Quinidine, Procainamide Double Quarter Pounder
Class Ib Lidocaine, Mexiletine, Tocainide Lettuce, Mayo*, Tomato
Class Ic Moricizine, Flecainide, Propafenone More* Fries Please.
*note there are two "M"s in the mnemonic, but morcizine and more can clarify
which is which)
How to remember the Class 1 drugs.

Class II agents are conventional beta blockers. They act
by blocking the effects of catecholamines at the β1-
adrenergic receptors, thereby decreasing sympathetic
activity on the heart. They decrease conduction through
the AV node.
Antidysrhythmics – Class II
Cardioselective
Acebutolol
Atenolol
Esmolol
Metoprolol
Non -Cardioselective
Aprenolol
Labetalol
Propranolol
Sotalol

Class III agents predominantly block the potassium
channels, thereby prolonging repolarization. Since these
agents do not affect the sodium channel, conduction
velocity is not decreased.
Antidysrhythmics – Class III
Amiodarone

Class IV agents are slow calcium channel blockers.
They decrease conduction through the AV node, and
shorten phase two (the plateau) of the cardiac action
potential. They thus reduce the contractility of the heart.
However, in contrast to beta blockers, they allow the
body to retain adrenergic control of heart rate and
contractility.
Antidysrhythmics – Class IV
Diltiazem
Verapamil

Class V agents
Since the development of the original Vaughan-Williams
classification system, additional agents have been used that don't fit
cleanly into categories I through IV. Some sources use the term
"Class V". However, they are more frequently identified by their
precise mechanism.
Agents include:
• Digoxin, which decreases conduction of electrical impulses
through the AV node (by inhibiting the Na/K pump) and
increases vagal activity via its central action on the central
nervous system.
• Adenosine, which helps block signals through the AV node
• Magnesium sulfate, which helps block ventricular
dysrhythmias
Antidysrhythmics – Class V

Antidysrhythmics – The Sicilian Gambit
Classification by site of action
https://academic.oup.com/eurheartj/article-abstract/12/10/1112/440813

Antidysrhythmics – The Sicilian Gambit
Classification by site of action
Drugs are classified by the…
• voltage gated channels,
• receptor gated channels,
• pumps
• or exchangers
… that they affect, and how they affect them.

Adenosine - V
Amiodarone - III
Diltiazem - IV
Labetalol - II
Magnesium Sulphate - V
Metoprolol - II
Nifedipine - IV
(Oxygen)
(Phenytoin - I)
Verapamil - IV
Australasian Paramedic Antidysrhythmics

Paramedic Electrophysiology. Colbeck

Paramedic Electrophysiology. Colbeck

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