Drugs Modifying Cardiac Rate and Force Flashcards
3 Major ions to consider in Drugs?
Na+
K+
Ca++
How many types of AP in the heart? What are they called?
2 types
Fast and Slow response
Where is the fast AP response present?
Atrial and ventricular muscle; purkinje fibers
Where is the slow AP response present?
SA node (normal pacemaker) AV node (normal route of AP conduction between atria and ventricles)
Phases of fast response?
Phase 4 = -90mV Phase 0 = Rise to +30 mV Phase 1 = Small decrease from +30mV Phase 2 = Plateau Phase 3 = Larger decrease back to -90mV
Phases of the slow response?
Phase 4 = Small incline from -65mV
Phase 0 = Rise up to +10mV
(No distinct phase 1 or 2)
Phase 3 = Decrease back to -65mV
What is the fast response dependent on?
Sodium dependent
What is the slow response dependent on?
Calcium dependent
What can cause significant changes to the duration and phases of an AP?
- Normal, physiological, influences such as autonomic transmitters and some hormones
- Cardiac disease (ischaemia)
- pH of the blood and electrolyte abnormalities
- Drugs, either intentionally, or unintentionally (adverse effects)
Membrane potential in ventricular cardiac muscle cells in phase 4?
-90mV (resting potential)
What is dominant in phase 4 of a fast response?
Outwards flux of K+
What Vm?
Membrane potential
What is significant about resting Vm in phase 4 of FR?
Close to the equilibrium potential for K+ (-94mV) due to K+ conductance via specific voltage-regulated K+ channels conducting an outwards hyperpolarizing current called iK1
However Ek and Vm are not completely the same due to to small inwards depolarizing leak conductance to Na+
How are ion concentration gradients across the membrane maintained? And what drug can affect this?
Na+/K+ ATPase
This can be inhibited by digoxin - which then causes the cell to depolarizes slightly
What is dominant in phase 0 of a FR?
Inward flux of Na+
What is the appearance of phase 0?
Upstroke to +30mV
What triggers ventricular and atrial impulses?
SA node
What does triggering V & A impulse involve?
Rapid activation of voltage-activated Na+ channels at threshold potential (-65mV) generating a Na+ conductance and an inward depolarizing Na+ current that drives Vm towards the Na+ equilibrium potential (-74mV)
This is very brief as the Na+ channels rapidly inactivate during depolarization to non conducting state and they only recover from this at partial repolarization
What is dominant in phase 1 of FR?
Outwards flux of K+
How would you describe phase 1 of FR? Depolarization or repolarization?
Early repolarization
Describe phase 1 of FR?
Brief
Most evident in cardiac cells that have predominant phase 2 (plateau) (eg purkinje fibers)
What causes phase 1?
Rapid inactivation of I.Na
-Activation of transient K+ current
called I.to mediated by a specific class if voltage activated potassium channel distinct from the inwards rectifier K+ channels
What is dominant in phase 2?
Inward flux of Ca++ is roughly balanced by outward flux of K+
How would you describe phase 2?
Plateau
What is phase 2 caused by?
A balance of conductances - inwards depolarizing flow of Ca++ and an outwards repolarizing flow of Na++
Inwards flow of Ca++= via voltage activated Ca++ channels (L-type) (activate relatively slowly in upstroke of the AP [-30mV], inactivate even more slowly = produces long lasting Ca++ current crucial to C. muscle contraction
What effect does any drug which increases the Calcium movement have?
Decrease the force of contraction of the heart
What is the effect of any drug which decreases potassium?
Augment the force of contraction of the heart
What changes occur in potassium conductance in phase 2?
- I (K1) decreases, facilitating the depolarizing effect of I(Ca,L)
- Ito= continues to exert a repolarizing effect initially but reduces with time
- Voltage activated delayed rectifier potassium channels slowly open generating the repolarizing current Ik
How long does the plateau persist for?
For as long as the charge carried by the inward flux of Ca++ is balanced by that carried by the outward flux of K+
What do calcium blockers do to the plateau phase?
Reduce I.Ca,L thus reduce the duration of plateau and force of cardiac contraction
What do drugs that block potassium channels do to the plateau phase? Give examples?
Delayed rectifiers
Increase the duration of ventricular AP, producing an acquired long QT syndrome (major concern)
How would you describe phase 3?
Final repolarization
What is dominant in phase 3?
Outwards flux of K+
What causes phase 3?
When outwards K+ currents exceed inward I,Ca,L- during plateau IcaL slowly decreases due to inactivation of L type Ca++ channels, whereas I .Kr and I.Ks slowly activate in succession
Which 3 K+ currents contribute to rapid depolarization in FR?
I.Kr
I.Ks
I.K1- minimal during plateau - contributes substantially to late repolarization - resumes dominance in Phase 4
1 notable difference between the ionic conductances mediating the AP in ventricular and atrial muscle cells?
An additional ultra rapid delayed rectifier outward K+ current (I.Kur) is absent from ventricular cells which has effect of initiating final repolarization more rapidly (phase 2 is less evident)
Why is phase 2 less evident in atrial muscle cells AP?
Additional ultrarapid delayed rectifier outward K+ current is present
How the slow reponse differs from the fast response?
-Vm between AP (phase 4) is much less steady- gradually shifting with a slope in the direction of depolarization (pacemaker potential)
-Upstroke(depolarization) is much less steep due to the opening of L- type Ca++ channels that mediate I.CaL NOT voltage activated Na+ channels
- No distinct steady plateau phase (2)
-Instead more of a gradual repolarization (3)
caused by the opening of delayed rectifier k+ channels mediating I.K
What does slope steepness in the SA node set?
AP interval
and thus
Heart Rate
What is pacemaker potential determined by?
3 time dependent and voltage regulated conductances that interact with eachother in phase 4:
- Repolarizing outward current I.K that mediates phase 3 gradually decreasing facilitating depolarization
- Inward current I.CaL that mediates a depolarizing effect gradually increases. At threshold I.CaL rapidly increases= upstroke
- At the end of phase 3 a cation conductance mediated by HCN channels develops in response to hyperpolarization triggering the funny current (HCN channels conduct Na+ ions inwardly causing depolarization)
What activates B1 adrenoceptors and where?
Noradrenaline and adrenaline
Nodal cells and myocardial cells
Which beta is used on the heart Beta 1 or Beta 2?
Beta 1
1 heart = Beta 1
2 Lungs = Beta 2
What does B1 adrenoceptor activation cause?
- Increased SA node AP frequency and HR (positive chronotropic effect)
- Increased Contractility
- Increased conduction velocity in AV node
- Increased automaticity
- Decreased duration of systole
- Increased activity of K+/Na+ - ATPase(Na+ pump)
- Increase mass of cardiac muscle
What is increased SA node AP frequency and increased HR due to when B1 adrenoceptor is used?
- Increase in slope of phase 4 depolarization (Pacemaker potential) by enhance I.f and I.Ca.L
- Reduction in threshold for AP initiation by enhanced I.Ca.L
What is increased contractility due to when B1 adrenoceptors are taken?
Positive inotropic response
- Increase in phase 2 of the cardiac AP in atrial and ventricular myocytes and enhanced Ca++ influx
- Sensitisation of contractile proteins to Ca++
What is increased conduction velocity in AV node when B1 adrenoceptors are taken due to?
Positive dromotropic effect
Enhancement of I.f and I.Ca
What is decreased duration of systole due to when taking B1 adrenoceptors?
Positive lusitropic effect
- Increased uptake of Ca++ into the sarcoplasmic reticulum
What sympatehtic system are B1 adrenoceptors activated in?
Sympathetic
What does acetylcholine activate?
M2 muscarinic cholinoceptors - largely in nodal cells
What does activation of M2 muscarinic receptors cause?
- Decreased SA node AP frequency and HR (negative chronotropic effect)
- Decreased contractility
- Decreased conduction in AV node
What is an increased chronotropic effect due to when M2 receptors are activated?
Decrease in the slope of phase 4 depolarization (PMP) by decreased I.f and I.Ca.L
Increase in the threshold for AP initiation caused by reduced I.Ca.L
Hyperpolarization in phase 4 via GIRKs
What is decreased conduction in AV node in the activation of M2 receptors caused by?
Negative dromotropic affect
Decreased activity of voltage dependent Ca++ channels and hyperpolarization via opening of GIRKs K+ channels
Whta is decreased contractility in the activation of M2 receptors due to?
Negative inotropic affect
ATRIA ONLY
Due to increase in phase of cardiac AP and decreased Ca++ entry
What might parasympathetic stimulation in the heart cause?
Arrhythmias in the atria
What are vagal maneuvers for?
Arrhythmias in atria
atrial tachcardia, atrial fibrillation, atrial flutter- parasympathetic output is increased to suppress impulse conduction through the AV node
2 maneuvers= to activate baroreceptors
2 vagal maneuvors?
Valsava maneuvre- activates aortic baroreceptors
Massage of the bifurcation of the carotid artery - stimulates baroreceptors in carotid sinus (not recommended in old people)
What is the pacemaker modulated by?
Funny current (I.f) (depolarizing)channels mediated by channels that are activated by: -hyperpolarization -Cyclic AMP HCN channels
What does HCN channels stand for?
Hyperpolarization activated nucleotide gated channels
What facilitates the slow phase 4 depolarization? (PMP)
Hyperpolarization following AP activates cation selective HCN channels in the SA node
What decreases the slope of PMP and reduced HR?
Block of HCN channels
What does ivabradine do?
Selective blocker of HCN channels that is used to slow heart rate in angina - slower heart rate reduces O2 consumption
What do dobutamine, noradrenaline and adrenaline do to the heart pharmacodynamically?
Increase force rate and cardiac output and O2 consumption
Decrease cardiac efficiency - can cause disturbances in cardiac ryhthm
Clinical uses of adrenaline?
Given IM, IV, SC, or as IV infusion
Treats cardiac arrest - positive ino and chronotropic affects
dilation of coronary arteries
redistribution of blood flow to the heart
Anaphylactic shock (IM)
Clinical uses of dobutamine?
Given as IV infusion
Acute but potentially reversible heart failure
Pro of dobutamine? and cons
Causes less tachycardia than other beta 1 agonists
Extended use- shortens life expectancy
Examples of beta 1 agonists?
Adrenaline
Noradrenaline
Dobutamine
Pharmacodynamic effects of non-selective beta blockers?
At rest little effect on CO, rate, force or MABP
During exercise rate, force and CO are significantly depressed
Clinical uses of beta adrenorecpetors antagonists?
Treatment of disturbances of cardiac rhythm
Angina treatment (alternative to calcium entry blockers)
Treatment of compensated heart failure - stat low go slow
Treatment of hypertension however no longer first line unless co-morbidities are present (angina)
What can beta blockers do in treating disturbances of heart rhythm?
Decreases XS sympathetic drive and help restore normal sinus rhythm
Beta blockers delay conduction through AV node and help restore sinus rhythm in AF and supraventricular tachycarda
Why shouldn’t asthmatics have beta blockers?
They cause bronhcospasm
Adverse effects of beta blockers?
Bronchospasm
Aggravation of cardiac failure
Bradychardia (can cause different degrees of Heart block)
Hypoglycaemia - not good for poorly controlled diabetes
Fatigue
Cold extremeties
THERE is LESS risk associated with B1 selective agents
Example of a non-selective Muscarinic AcH receptor antagonist?
Atropine
Pharmacodynamics of atropine?
Increased HR especially in athletes
No affect upon arterial BP
No effect upon response to exercise
Clinical uses for atropine?
First line management of sever bradycardia particularly after MIs
In anticholinesterase poisoning
What happens in heart failure?
There is a CO insufficient to provide adequate tissue perfusion
Which types of drugs increase contractility for heart failure?
Inotropic
- Digoxin
- Dobutamine
How does digoxin increase contractility?
Inhibiting sarcolemma ATPase Na+/K+ is inhibited Increased I.Na an reduced Vm Decreased Na+ and Ca++ exchange Increased storage of Ca++ in SR Increased CICR , increased contractility
Pharmacodynamics of digoxin?
Binds to the alpha sub-unit of K+/Na+ ATPase
Indirect actions of digoxin on electrical activity?
Increased vagal activity
Slows SA node discharge
Slow AV node conduction
Increases refractory period
Direct actions of digoxin on electrical activity?
Shortens the AP and refractory period in atrial and ventricular myocytes
Clinical uses of digoxin?
IV in acute heart failure
Orally in chronic HF
Particularly indicated in HF with atrial fibrillation
Adverse affects of digoxin (many)?
Excessive depression of AV node conduction (heart block) Causes arrhythmias *These are the 2 SERIOUS ones* Other non cardiac affects Nausea Vomiting Diarrhoea Disturbance of colour vision
Other inotropic drugs? + examples
Calcium sensitizers -Levosimendan Inodilators -Amrinone -Milrinone
What does levosimendan do?
Binds to troponin C in cardiac muscle sensitizing it to the action of Ca++
Additionally opens K ATP channels in vascular smooth muscle causing vasodilation
Reduces amount of work that the heart has to do
When is levosimendan used?
Acute decompensated Heart failure (IV)
What do inodilators do?
Inhibit phosphodiesterase in smooth and cardiac muscle cells and hence increase cAMP 1
Increase myocardial contractility, decrease peripheral resistance but worsens survival
When to use inodilators?
Restricted to treating acute heart failure until transplant with IV
