Manipulation of the Cardiac Action Potential

Question 1

Why treat a dysrhythmia?

Answer 1

Degeneration to a fatal rhythm

Impact on cardiac output

Affect ability of heart to fill and empty – affecting cardiac ability lowering blood pressure leading to death

Question 2

Describe the cardiac action potential in terms of its ion channels

Answer 2

Cardiac muscle has a stable resting membrane potential determined primarily by potassium concentrations.

Depolarisation is mediated increase in Na+ permeability, which is then followed by a slow opening and closing of voltage gated Ca2+ channels leading to a prolonged period of being depolarised

Results in a long refractory period.

Potassium permeability is low during this period also maintaining depolarisation.

Potassium channels open and the cell repolarises.

Cardiac action potentials mostly mediated by voltage gated calcium channels, rather than sodium channels. These calcium channels open and close more gradually which means the action potentials develop over a longer time and last longer as opposed to the rapid firing

Question 3

List the pacemaker cells in the heart

Answer 3

SA node (main/ default)

AV node is another pacemaker – backup node

Myocardiocytes each have a level of pacemaker function so if each nodes fails then the ventricles can kick in, but this can lead to complications in cardiac function

Question 4

How do pacemaker cells create an action potential?

Answer 4

Spontaneous depolarisation involving particular ion channels:

At -65mV sodium and calcium channels open (slow sodium channels rather than fast) and potassium channels reduce in permeability resulting in a gradual march towards depolarisation and the threshold value.

Then an action potential occurs mediated by calcium channels followed by potassium channels and the system resets, starting again.

Action potential + pacemaker potential = Absolute refractory period.

Question 5

Outline the propagation of the cardiac action potential

Answer 5

SA node has the shortest refractory period

AV next

Autorhythmic cells of the bundle of his and purkinje fibres

Question 6

Describe the effect noradrenaline has on the cardiac cycle and outline how it achieves this effect

Answer 6

Adrenaline increases cytosolic calcium concentration which then leads to increasing contraction force:
Binds to beta1 receptors, activating adenylyl cyclase and augment the formation of cAMP.
cAMP phosphorylates calcium channels prolonging opening times and allowing more calcium to enter the cell – which leads to increased contraction force:

Calcium is removed from the cells via calcium pumps in the ECF and phospholamban proteins into the sarcoplasmic reticulum. cAMP phosphorylates phospholamban, therefore adrenaline also reduces contraction time – i.e. reset occurs quicker.

Adrenaline increases heart rate and contraction force.

Influx of calcium during the action potential is only small, but the calcium causes further release of calcium from the sarcoplasmic reticulum (calcium induced calcium release). An increased number of actin and myosin cross bridges form leading to stronger muscle contraction.

Conditions causing increased intracellular or extracellular calcium can lead to more forceful contractions as a result, and vice versa.

Question 7

List some of the main causes of dysrhythmias

Answer 7

Structural cardiac disease

Drugs by manipulating P/S systems / ion channels

Toxins by manipulating P/S systems / ion channels

Metabolic diseases/electrolyte imbalance –such as potassium or calcium e.g. renal disease

Systemic disease – sepsis, neoplasia

Sympathetic and Parasympathetic tone – increased epinephrine release – e.g. pain, fear

Question 8

List the methods of treatment for dysrhythmias

Answer 8

Treat the underlying problem.
If the underlying problem is untreatable or the arrythmia is severe then look at manipulation of the heart

Agonists/antagonists

Those acting directly at ion channels – not via a receptor

Question 9

List the target types of agonist / antagonists used to treat dysrhythmias

Answer 9

Sympathetically mediated arrythmia –
Parasympathetically mediated arrythmia
Adenosine mediated arrythmia

Question 10

List the target types for acting directly at sodium ion channels

Answer 10

Sodium Channel Blocker
Potassium Channel Blocker
Calcium Channel Blockers

Question 11

Explain how sympathetic control of the heard can be utilised to mediate arrythmias

Answer 11

Sympathetic control increases HR which utilises adrenoreceptors

Beta (b)-Blockers (antagonists) can be used to prevent the binding of adrenaline onto Beta receptors to prevent increasing HR and reduce contraction force
(Propranolol / Esmolol )

Question 12

Explain how parasympathetic control of the heard can be utilised to mediate arrythmias

Answer 12

Parasympathetic control reduces contraction by slowing conduction at the AV node and used ACH to do this

ACH blocks adenylyl cyclase formation, reduces cAMP production
Reduces calcium effects as reduction of cAMP reduces Ca2+ channel activation
Binds to M2 receptor which activates K+ channels which allows potassium efflux – Hyperpolarisation in phase 3

To counter this:
Atropine
Muscarinic antagonist
- Reduces parasympathetic (vagal) tone (e.g. severe pain)
- Increases heart rate by reducing suppression (‘heart block’)

Question 13

How can parasympathetic control be enhanced naturally?

Answer 13

Muscarinic agonist - Toxins

Muscarine found in mushrooms

Pilocarpine - treatment for glaucoma

Question 14

Explain how Adenosine can reduce heart rate

Answer 14

A1 receptor blocks adenylyl cyclase and increase potassium efflux

Prolongs AV conduction by an activation of potassium channels /an inhibition of the slow Ca2+ inward current (AV node).

Cardiac bradyarrhythmia’s in hypoxia attributed to increased formation and release of adenosine.

Able to terminate supraventricular tachycardias involving AV node

Since it has a very short duration of action it might prove safe and hence advantageous to conventional therapy in the treatment of supraventricular tachycardias.

Question 15

Explain how sodium channel blockers function

Answer 15

Reduces Phase 0 rate of depolarisation

Lidocaine (lignocaine) – Sodium Channel Blocker
Raises depolarisation threshold
Slow Na Channels
Slows AP generation

Treatment for Ventricular tachycardia

NB: Lidocaine is used as a anesthetic drug as by block channels it prevents AP being transported in all Nerves. Too much can have detrimental effects

Sodium channel blockers are also extensively used as toxins in wildlife

Question 16

Explain how potassium channel blockers function

Answer 16

Slow phase 3 increasing refractory period & duration of AP as repolarization takes longer to occur

Amiodarone, Sotalol

Treatment for Ventricular Tachycardia

At higher heart rates they don’t work as well, so typically better at preventing arrythmias than converting. Because of this, efficacy is higher in low tissue use – so potentially toxic effects are exacerbated in bradycardia.

Question 17

Explain how calcium channel blockers function

Answer 17

Block voltage-dependent L-type Ca2+ channels in cardiac muscle and vascular smooth muscle.

Slow conduction, reduce contraction force and cause coronary vasodilation – reduces myocardial ischaemia in humans

Verapamil and Diltiazem

SVT
Feline HCM - Diltiazem

Diastolic dysfunction – allows ventricular relaxation

Question 18

Outline the calcium channel blocker drug exception

Answer 18

Digoxin
cardiac glycoside

Doesn’t affect a receptor or ion channel.

Affects movements of ions by inhibiting Na+/K+ ATPase, this increases intracellular Na+ by reducing Na+ & Ca2+ exchange

Having Ca2+ retained in the cell prevents repolarisation increasing refractory period – as a by product you have increase of calcium within the cell which increases force of contraction whilst slowing the rate

Management of supraventricular arrythmias

Question 19

Outline the classification of antidysrhythmic drugs

Answer 19

Vaughan William’s System

Class I sodium channel blockers
Class II b-adrenoceptor antagonists
Class III prolong action potential
Class IV block voltage sensitive calcium channels