11 - Drugs and the Heart Flashcards
What cells constitute the primary pacemaker site within the heart and how are they characterised?
Cells of the Sinoatrial Node (SAN)
- characterised as having no true resting potential
- instead they generate regular, spontaneous action potentials
How is the depolarising current carried into SAN cells?
Unlike non-pacemaker action potentials in the heart, and most other cells that elicit action potentials (e.g., nerve cells, muscle cells), the depolarizing current is carried Into the SAN cells primarily by relatively slow Ca2+ currents instead of by fast Na+ currents.
There are no fast Na+ channels and currents operating in SAN cells
DEPOLARISATION IS NOT DRIVEN BY SODIUM AS IT NORMALLY IS IN THE BODY, BUT BY CALCIUM
What parts of the heart control heart rate?
Sinoatrial Node (SAN)
Atrioventricular Node (AVN)
Explain the mechanism behind depolarisation in the SAN
- Several channels are important in regulating the sinoatrial action potential
- if = funny channel
- Full Name: Hyperpolarisation-activated cyclic nucleotide-gated channel (HCN channels)
- This channel is responsible for allowing the action potential to propagate
- It is a sodium channel
- If opens at the most negative potential
- You initially sodium influx then a certain amount of depolarisation and then the calcium channels open
- The calcium channels come in TWO forms:
- T type = transient
- L type = long lasting
- The opening of the calcium channels increases the depolarisation
- Potassium channels opening is responsible for repolarisation
- Beta adrenoceptors are coupled with adenylate cyclase and cause an increase in cAMP
- This is important in opening the if channel
- So the sympathetic nervous system is responsible for causing this increase in cAMP and it also has a positive effect on calcium entry
- The sympathetic nervous system increases heart rate via its positive effect on the if channel
- The parasympathetic nervous system is negatively coupled with adenylate cyclase and promotes the opening of potassium channels and prolongs repolarisation
Where is the major store of calcium within the myocytes?
Sarcoplasmic Reticulum
What are the two signalling pathways used by the heart to elevate levels of intracellular second messengers?
The heart has two signalling pathways that are involved in elevating the levels of intracellular second messengers:
- cAMP
- Ca2+
What happens in the heart in response to depolarisation?
- Calcium enters the cells thrrough calcium channels in the plasma [dihydropyridine receptors (DHPR)]
- This calcium then goes to bind to calcium release channel [ryanodine receptors (RyR)] to stimulates calcium release from the sarcoplasmic reticulum
- After stimulating contraction by binding to troponin in the thin filament, the calcium is the removed from the myoplasm by the Plasma Membrane Calcium ATPase (PMCA) or Na+-Ca2+ exchangers, noth of which are found in the plasma membrane
- The calcium can also be taken back up into the sarcoplasmic reticulum by sarco-enodplasmic reticulum calcium ATPase (SERCA2a)
What is SERCA2a responsible for?
The removal of >70% of myoplasmic Ca2+ in humans
As a result, SERCA2a determines both:
- the rate of Ca2+ removal (and consequently the rate of cardiac muscle relaxation)
- the size of Ca2+ store (which affects cardiac contracility in the subsequent beat)
What regulates the activity of SERCA2a?
Its activity is regulated by its interaction with phospholamban (PLN) which is a target for phosphorylation by protein kinase A via the second signalling pathway (adrenergic receptor pathway)
- In its dephosphorylated form, PLN is an inhibitor of SERCA2a
- When phosphorylated by PKA, PLN dissociates from SERCA2a activating the Ca2+ pump
As a result, the rate of cardiac relaxation is increased and, on subsequent beats, contractility is increased in proportion to the elevation in the size of the SR Ca2+ store and the resulting increase in Ca2+ release from the SR
How is PLN dephosphorylated?
PLN is dephosphorylated by a protein phosphatase (PP1) which terminates the stimulation phase
How much of the calcium needed for contraction comes from influx?
20-30%
Why is it relatively easy for myocardial oxygen demand to exceed supply?
The heart isn’t particularly well perfused compared to the brain
What vessels deliver oxygen and nutrients to the heart muscle?
Coronary vessels
What does oxygen delivery to the heart depend on?
- Heart Rate
- Preload
- Afterload
- Contractility
What are preload and afterload linked to?
PRELOAD
- Linked to venous return
- Increased venous return = increased cardiac contractility
AFTERLOAD
- Increased afterload = increased TPR
- Heart has to work harder against increased TPR
These are all associated with increased myocardial work and myocardial oxygen demand
What can increase force of contraction?
Myocyte contraction = primary determinant of myocardial oxygen demand
↑ H.R. = more contractions;
↑ afterload or contractility = greater force of contraction
↑ preload = small ↑ in force of contraction
( 100% ↑ ventricular volume would only ↑ F.O.C. by 25%)
What is preload?
Preload is the end diastolic volume that stretches the right or left ventricle of the heart to its greatest dimensions under variable physiologic demand.
What is afterload?
Afterload is the pressure against which the heart must work to eject blood during systole.
How can certain drugs influence myocardial oxygen/supply demand?
ORGANIC NITRATES
- Substrates for NO production
- Enter they endothelial cells and promote NO production
- NO diffuses into vascular smooth muscle
- Causes smooth muscle relaxation
POTASSIUM CHANNEL OPENERS
- Promote potassium efflux
- So they hyperpolarise the smooth muscle
- Reduces its ability to contract
- Smooth muscle relaxation ensues
THEREFORE, BOTH TYPES OF DRUGS PROMOTE SMOOTH MUSCLE RELAXATION AND HENCE, VASODILATION
- Vasodilation reduces TPR
- Hence reduces afterload
- This means that the heart has to work less against the resistance
- The drugs also cause venodilation which reduces venous return to the heart
- Hence reduces preload and contractility
- This reduction is afterload and preload causes a decrease in myocardial oxygen demand
- Improves balance between supply and demand, meaning they are potentially good treatments for angina
What is the Vaughan Williams Classification system?
A classification system for anti-arrhythmic drugs
Vaughan Williams classification is of limited clinical significance
CLASS I
- Sodium channel blockade
CLASS II
- Beta adrenergic blockade
CLASS III
- Prolongation of repolarisation (‘membrane stabilisation’, mainly due to potassium channel blockade)
CLASS IV
- Calcium channel blockade
What is adenosine used for in the context arrythmia?
It is a selected anti-arrythmic
Used intravenously to terminate supraventricular tachyarrhythmias(SVT)
Its actions are short-lived (20-30s) and it is consequently safer than verapamil.
The action of adenosine in cardiac tissue is:
- Adenosine binds to type 1 (A1) adenosine receptors in the cardiac muscle and vascular smooth muscle
- These receptors are coupled to Gi proteins
- Activativtion of the Gi protein decreases cAMP
- This means that there is less cAMP within the nodal tissue and so it impacts on the depolarisation within the AV node
- Less cAMP inhibits L-type calcium channels and therefore calcium entry into the cell. (Adenosine receptors are negatively coupled with adenylate cyclase)
- Activation of this pathway opens potassium channels, which hyperpolarizes the cell.
- So if you have tachyarrhythmia, you can slow the heart down and restore normal rhythm so there is more efficiency in the movement of blood from the atria to the ventricles
- In cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits the pacemaker current (If), which decreases the slope of phase 4 of the pacemaker action potentialthereby decreasing its spontaneous firing rate (negative chronotropy).
What is Verapamil used for in the context of arrythmia?
Used for reduction of ventricular responsiveness to atrial arrythmias
It depresses SA automaticity and subsequent AV node conduction
- This mainly targets the L-type calcium channels
- This slows down the ability of the nodal tissue to depolarise
- If you have rapid excessive depolarisations, as in tachyarrhythmias, you want to reduce that effect
- CCBs block the membrane calcium channels so there is less calcium entry so the speed with which tissue can depolarise is reduced
This restores some normal contraction
What is Amiodarone used for in the context of arrythmia?
Used for supraventricular and ventricular tachyarrhythmias (often due to reentry)
Work via complex action probably involving multiple ion channel blocking
- This prolongs repolarisation
- It has a complex mechanism of action that involved multiple ion channel blockade but its main action seems to be through potassium channel blockade
- By prolonging repolarisation, you’re prolonging the time during which the heart can NOT depolarise, thus restoring normal rhythm
- By prolonging repolarisation, you’re trying to reduce re-entry
- With cardiac tissue, as the action potential is propagated through the tissue you can have damaged bits of tissue where the action potential struggles to pass through
- IMPORTANT POINT: THIS IS USUALLY UNIDIRECTIONAL
- The action potential will struggle to go one way but then it is fine to go back in the opposite direction
- In the bottom left diagram, the action potential (red) passes around the bottom left corner and because the damaged tissue (shaded blue) has not been depolarised by the action potential on the way down from the top, the action potential can pass back up the tissue and you get cyclical depolarisation
- This is the basis of arrhythmias
- By prolonging repolarisation you can reduce the likelihood of re-entry happening
How can rentry precipitate ventricular and atrial tachyarrhythmias?
In normal tissue (top panel of figure), if a single Purkinje fiber forms two branches (1 & 2), the action potential will travel down each branch.
An electrode (*) in a side branch off of branch 1 would record single, normal action potentials as they are conducted down branch 1 and into the side branch.
If branches 1 & 2 are connected together by a common, connecting pathway (branch 3), the action potentials that travel into branch 3 will cancel each other out
Reentry (bottom panel) can occur if branch 2, for example, has a unidirectional block.
- In such a block, impulses can travel retrograde (from branch 3 into branch 2) but not orthograde.
- When this condition exists, an action potential will travel down the branch 1, into the common distal path (branch 3), and then travel retrograde through the unidirectional block in branch 2 (blue line).
- Within the block (gray area), the conduction velocity is reduced because of depolarization.
- When the action potential exits the block, if it finds the tissue excitable, then the action potential will continue by traveling down (i.e., reenter) the branch 1.
- If the action potential exits the block in branch 2 and finds the tissue unexcitable (i.e., within its effective refractory period), then the action potential will die.
Therefore, timing is critical in that the action potential exiting the block must find excitable tissue in order for that action potential to continue to propagate.
- If it can re-excite the tissue, a circular (counterclockwisein this case) pathway of high frequency impulses (i.e., a tachyarrhythmia) will become the source of action potentials that spread throughout a region of the heart (e.g., ventricle) or the entire heart.
Local sites of reentrymay involve only a small region within the ventricle or atrium and can precipitate ventricular or atrial tachyarrhythmias, respectively.
Because both timing and refractory state of the tissue are important for reentry to occur, alterations in timing (related to conduction velocity) and refractoriness (related to effective refractory period) can either precipitate reentryor abolish reentry.
For this reason, changes in autonomic nerve function can significantly affect reentrymechanisms, either precipitating or terminating reentry. Many antiarrhythmic drugsalter effective refractory period or conduction velocity, and thereby affect reentrymechanisms (hopefully abolish).
What are the adverse effects of digoxin (cardiac glycoside)?
- dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
- Note: Hypokalaemia (usually a consequence of diuretic use) lowers the threshold for digoxin toxicity because potassium and digoxin compete for the same binding site
- When it binds, it prevents sodium potaasium exchnage
- At low blood potassium, digoxin has easier access to block the receptor so has a much more powerful effect
