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Cardio > Drugs Modifying Cardiac Rate and Force > Flashcards

Drugs Modifying Cardiac Rate and Force Flashcards

1
Q

3 Major ions to consider in Drugs?

A

Na+
K+
Ca++

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2
Q

How many types of AP in the heart? What are they called?

A

2 types

Fast and Slow response

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3
Q

Where is the fast AP response present?

A

Atrial and ventricular muscle; purkinje fibers

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4
Q

Where is the slow AP response present?

A 
SA node (normal pacemaker)
AV node (normal route of AP conduction between atria and ventricles)
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5
Q

Phases of fast response?

A 
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
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6
Q

Phases of the slow response?

A

Phase 4 = Small incline from -65mV
Phase 0 = Rise up to +10mV
(No distinct phase 1 or 2)
Phase 3 = Decrease back to -65mV

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7
Q

What is the fast response dependent on?

A

Sodium dependent

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8
Q

What is the slow response dependent on?

A

Calcium dependent

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9
Q

What can cause significant changes to the duration and phases of an AP?

A
  • 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)
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10
Q

Membrane potential in ventricular cardiac muscle cells in phase 4?

A

-90mV (resting potential)

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11
Q

What is dominant in phase 4 of a fast response?

A

Outwards flux of K+

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12
Q

What Vm?

A

Membrane potential

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13
Q

What is significant about resting Vm in phase 4 of FR?

A

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+

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14
Q

How are ion concentration gradients across the membrane maintained? And what drug can affect this?

A

Na+/K+ ATPase

This can be inhibited by digoxin - which then causes the cell to depolarizes slightly

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15
Q

What is dominant in phase 0 of a FR?

A

Inward flux of Na+

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16
Q

What is the appearance of phase 0?

A

Upstroke to +30mV

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17
Q

What triggers ventricular and atrial impulses?

A

SA node

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18
Q

What does triggering V & A impulse involve?

A

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

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19
Q

What is dominant in phase 1 of FR?

A

Outwards flux of K+

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20
Q

How would you describe phase 1 of FR? Depolarization or repolarization?

A

Early repolarization

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21
Q

Describe phase 1 of FR?

A

Brief

Most evident in cardiac cells that have predominant phase 2 (plateau) (eg purkinje fibers)

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22
Q

What causes phase 1?

A

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

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23
Q

What is dominant in phase 2?

A

Inward flux of Ca++ is roughly balanced by outward flux of K+

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24
Q

How would you describe phase 2?

A

Plateau

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25
Q

What is phase 2 caused by?

A

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

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26
Q

What effect does any drug which increases the Calcium movement have?

A

Decrease the force of contraction of the heart

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27
Q

What is the effect of any drug which decreases potassium?

A

Augment the force of contraction of the heart

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28
Q

What changes occur in potassium conductance in phase 2?

A
  • 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
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29
Q

How long does the plateau persist for?

A

For as long as the charge carried by the inward flux of Ca++ is balanced by that carried by the outward flux of K+

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30
Q

What do calcium blockers do to the plateau phase?

A

Reduce I.Ca,L thus reduce the duration of plateau and force of cardiac contraction

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31
Q

What do drugs that block potassium channels do to the plateau phase? Give examples?

A

Delayed rectifiers

Increase the duration of ventricular AP, producing an acquired long QT syndrome (major concern)

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32
Q

How would you describe phase 3?

A

Final repolarization

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33
Q

What is dominant in phase 3?

A

Outwards flux of K+

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34
Q

What causes phase 3?

A

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

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35
Q

Which 3 K+ currents contribute to rapid depolarization in FR?

A

I.Kr
I.Ks
I.K1- minimal during plateau - contributes substantially to late repolarization - resumes dominance in Phase 4

36
Q

1 notable difference between the ionic conductances mediating the AP in ventricular and atrial muscle cells?

A

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)

37
Q

Why is phase 2 less evident in atrial muscle cells AP?

A

Additional ultrarapid delayed rectifier outward K+ current is present

38
Q

How the slow reponse differs from the fast response?

A

-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

39
Q

What does slope steepness in the SA node set?

A

AP interval
and thus
Heart Rate

40
Q

What is pacemaker potential determined by?

A

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)
41
Q

What activates B1 adrenoceptors and where?

A

Noradrenaline and adrenaline

Nodal cells and myocardial cells

42
Q

Which beta is used on the heart Beta 1 or Beta 2?

A

Beta 1
1 heart = Beta 1
2 Lungs = Beta 2

43
Q

What does B1 adrenoceptor activation cause?

A
  • 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
44
Q

What is increased SA node AP frequency and increased HR due to when B1 adrenoceptor is used?

A
  • 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
45
Q

What is increased contractility due to when B1 adrenoceptors are taken?

A

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++
46
Q

What is increased conduction velocity in AV node when B1 adrenoceptors are taken due to?

A

Positive dromotropic effect

Enhancement of I.f and I.Ca

47
Q

What is decreased duration of systole due to when taking B1 adrenoceptors?

A

Positive lusitropic effect

- Increased uptake of Ca++ into the sarcoplasmic reticulum

48
Q

What sympatehtic system are B1 adrenoceptors activated in?

A

Sympathetic

49
Q

What does acetylcholine activate?

A

M2 muscarinic cholinoceptors - largely in nodal cells

50
Q

What does activation of M2 muscarinic receptors cause?

A
  • Decreased SA node AP frequency and HR (negative chronotropic effect)
  • Decreased contractility
  • Decreased conduction in AV node
51
Q

What is an increased chronotropic effect due to when M2 receptors are activated?

A

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

52
Q

What is decreased conduction in AV node in the activation of M2 receptors caused by?

A

Negative dromotropic affect

Decreased activity of voltage dependent Ca++ channels and hyperpolarization via opening of GIRKs K+ channels

53
Q

Whta is decreased contractility in the activation of M2 receptors due to?

A

Negative inotropic affect
ATRIA ONLY
Due to increase in phase of cardiac AP and decreased Ca++ entry

54
Q

What might parasympathetic stimulation in the heart cause?

A

Arrhythmias in the atria

55
Q

What are vagal maneuvers for?

A

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

56
Q

2 vagal maneuvors?

A

Valsava maneuvre- activates aortic baroreceptors
Massage of the bifurcation of the carotid artery - stimulates baroreceptors in carotid sinus (not recommended in old people)

57
Q

What is the pacemaker modulated by?

A 
Funny current (I.f)
(depolarizing)channels 
 mediated by channels that are activated by:
-hyperpolarization 
-Cyclic AMP HCN channels
58
Q

What does HCN channels stand for?

A

Hyperpolarization activated nucleotide gated channels

59
Q

What facilitates the slow phase 4 depolarization? (PMP)

A

Hyperpolarization following AP activates cation selective HCN channels in the SA node

60
Q

What decreases the slope of PMP and reduced HR?

A

Block of HCN channels

61
Q

What does ivabradine do?

A

Selective blocker of HCN channels that is used to slow heart rate in angina - slower heart rate reduces O2 consumption

62
Q

What do dobutamine, noradrenaline and adrenaline do to the heart pharmacodynamically?

A

Increase force rate and cardiac output and O2 consumption

Decrease cardiac efficiency - can cause disturbances in cardiac ryhthm

63
Q

Clinical uses of adrenaline?

A

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)

64
Q

Clinical uses of dobutamine?

A

Given as IV infusion

Acute but potentially reversible heart failure

65
Q

Pro of dobutamine? and cons

A

Causes less tachycardia than other beta 1 agonists

Extended use- shortens life expectancy

66
Q

Examples of beta 1 agonists?

A

Adrenaline
Noradrenaline
Dobutamine

67
Q

Pharmacodynamic effects of non-selective beta blockers?

A

At rest little effect on CO, rate, force or MABP

During exercise rate, force and CO are significantly depressed

68
Q

Clinical uses of beta adrenorecpetors antagonists?

A

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)

69
Q

What can beta blockers do in treating disturbances of heart rhythm?

A

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

70
Q

Why shouldn’t asthmatics have beta blockers?

A

They cause bronhcospasm

71
Q

Adverse effects of beta blockers?

A

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

72
Q

Example of a non-selective Muscarinic AcH receptor antagonist?

A

Atropine

73
Q

Pharmacodynamics of atropine?

A

Increased HR especially in athletes
No affect upon arterial BP
No effect upon response to exercise

74
Q

Clinical uses for atropine?

A

First line management of sever bradycardia particularly after MIs

In anticholinesterase poisoning

75
Q

What happens in heart failure?

A

There is a CO insufficient to provide adequate tissue perfusion

76
Q

Which types of drugs increase contractility for heart failure?

A

Inotropic

  • Digoxin
  • Dobutamine
77
Q

How does digoxin increase contractility?

A 
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
78
Q

Pharmacodynamics of digoxin?

A

Binds to the alpha sub-unit of K+/Na+ ATPase

79
Q

Indirect actions of digoxin on electrical activity?

A

Increased vagal activity
Slows SA node discharge
Slow AV node conduction
Increases refractory period

80
Q

Direct actions of digoxin on electrical activity?

A

Shortens the AP and refractory period in atrial and ventricular myocytes

81
Q

Clinical uses of digoxin?

A

IV in acute heart failure
Orally in chronic HF
Particularly indicated in HF with atrial fibrillation

82
Q

Adverse affects of digoxin (many)?

A 
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
83
Q

Other inotropic drugs? + examples

A 
Calcium sensitizers 
-Levosimendan 
Inodilators 
-Amrinone 
-Milrinone
84
Q

What does levosimendan do?

A

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

85
Q

When is levosimendan used?

A

Acute decompensated Heart failure (IV)

86
Q

What do inodilators do?

A

Inhibit phosphodiesterase in smooth and cardiac muscle cells and hence increase cAMP 1

Increase myocardial contractility, decrease peripheral resistance but worsens survival

87
Q

When to use inodilators?

A

Restricted to treating acute heart failure until transplant with IV

Cardio (36 decks)

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