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Cardiovascular 2018 > Drugs Modifying Cardiac Rate and Force > Flashcards

Drugs Modifying Cardiac Rate and Force Flashcards

1
Q

What is most negative value a nodal cell will reach?

A

-60mV

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2
Q

What does pacemaker potential arise from?

A

A net movement of positive charges into the cell

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3
Q

What is the lb current?

A

A background sodium current (inward)

directly contributes to depolarisation

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4
Q

What is the lCaT current?

A

Transient calcium current (inward) which opens very briefly, allows influx of calcium just around about threshold- final kick in pacemaker potential

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5
Q

What is the lk current?

A

Delayed rectifier potassium current (outward)

open during the repolarisation (phase 3)

open during pacemaker potential its contribution dwindles and is closed at threshold

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6
Q

What is the lf current?

A

mediated by hyperpolarisation-activated and cyclic nucleotide gated (HCN) channels that conduct Na and K (inward)

turned on by -ve membrane potentials and allows sodium ions to move into the cell, it becomes activated at the end of the action potential

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7
Q

What is the resting membrane potential of ventricular myocytes and why?

A

-90mV because of the K efflux which holds the membrane potential steady

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8
Q

What happens when the impulse reaches the ventricles?

A

Activated voltage activated Na channels causing a rapid rise in action potential (phase 0)

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9
Q

What causes the brief period of depolarisation of ventricular myocytes in phase 1?

A

Caused by lTo due to a briefly opening K channel

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10
Q

What is the membrane potential in phase two like and what does this mean for other action potentials? (ventricular myocytes)

A

Near to zero so they cannot be fired

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11
Q

What is phase two mediated by in ventricular myocytes?

A

lCaL channels which are open for a long period of time which generated Ca influx, at the same time potassium channels are open, allowing the efflux of potassium

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12
Q

What happens in phase three of ventricular myocytes?

A

two k outward conductances which bring the membrane potential back to -90mV

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13
Q

What are the post-ganglionic sympathetic neurotransmitters?

A

Noradrenaline and adrenaline

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14
Q

Upon which adrenoreceptors and in which cells do noradrenaline and adrenaline act?

A

B1 adrenoreceptors

Nodal cells and myocardial cells

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15
Q

What effect does sympathetic stimulation have on ventricular function curve?

A

Shifted upwards due to increased stroke volume

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16
Q

How does B1 function?

A

It couples to Gs (Stimulatory) protein which activates adenylyl cycllase to increase cAMP

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17
Q

What does increased sympathetic stimulation cause?

A

increased HR

reduction in threshold for AP initiation

increased contractility

increased conduction velocity in AV node

increased automaticity

decreased duration of systole

increased activity of the Na+/K+ ATPase pump

increased mass of cardiac muscle

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18
Q

What is increased heart rate as a result of sympathetic stimulation caused by?

A

increased in slope of phase 4 caused by enhanced lf and lCa

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19
Q

what is increased contractility as a result of increased sympathetic stimulation caused by?

A

decrease in phase 2 of action potential in heart cells by enhanced Ca influx and increased sensitisation of contractile proteins to Ca

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20
Q

what is increased conduction velocity in AV node (positive dromotropic effect) as a result of increased sympathetic stimulation caused by?

A

enhancement of lf and lCa as in the SA node

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21
Q

What is increased automaticity?

A

tendency for other non-nodal regions to acquire spontaneous activity

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22
Q

what is decreased duration of systole (positive lusitropic action) due to increased sympathetic stimulation caused by?

A

due to increased uptake of Ca2+ into the SR

allows the heart to actually empty

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23
Q

what is increased activity of the Na+/K+-ATPase (Na+-pump) important for?

A

important for restoration of function following general myocardial depolarisation

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24
Q

How does the M2 receptor work?

A

coupling to Gi protein which decreases activity of adenylate cyclase and reduces cAMP and opens potassium channels (GIRK) to cause hyperpolarisation of SA node (mediated by Gi By sy units)

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25
Q

what causes decreased HR mediated by the SA node in parasympathetic system?

A

decreased slope of the pacemaker potential caused by reduced lf and lCa

hyperpolarisation due to opening of GIRK channels

increase in threshold for AP initiation caused by reduced lCa

further to go to get to threshold and it takes longer to get there, causing a reduction in action potential in SA and AV nodes

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26
Q

what causes decreased contractility of the atria after parasympathetic stimulation?

A

ventricles are only slightly innervated by parasympathetic system.

decrease in phase 2 cardiac action potential and decreased Ca2+ entry

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27
Q

what causes reduced conduction in the AV node. (negative dromotropic effect) after parasympathetic response?

A

decreased activity of voltage dependant Ca channels and hyperpolarisation via opening of K channels

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28
Q

why can parasympathetic cause arrythmias ?

A

reduction in AP duration which reduces the refractory period causing re-entrant arrhythmias

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29
Q

What do vagal maoeuvres do?

A

Increase parasympathetic output and may be employed in atrial tachycardia, atrial flutter, or atrial fibrillation to suppress impulse conduction through the AV node

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30
Q

What does the valsalva manoevre do?

A

activates aortic baroreceptors

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31
Q

what does massage of the bifurcation of the carotid artery do?

A

stimulates baroreceptors in the carotid sinus – not recommended

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32
Q
A
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33
Q

The pacemaker potential is modulated by a ———— ——- the ‘funny current’ (If) mediated by channels that are activated by (i) —————– and (ii) cyclic —

A

The pacemaker potential is modulated by a depolarizing current the ‘funny current’ (If) mediated by channels that are activated by (i) hyperpolarization and (ii) cyclic AMP

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34
Q

Hyperpolarization following the action potential activates cation selective HCN channels in the SA node facilitating a slow, —– -, depolarization (— ——— ———)

A

phase 4

the pacemaker potential

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35
Q
A
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36
Q

Blocking of HCN channels decreases the slope of the pacemaker potential and will do what to heart rate?

A

Reduce heart rate

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37
Q

What kind of channels does Ivabradine block?

A

HCN Channels

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38
Q

What is Ivabradine prescribed for?

A

Used to slow HR in angina (slower HR will reduce O2 consumption)

39
Q

What brings about CICR in cardiac muscle?

A

Calcium binds to ryanodine receptor in sarcoplasmic reticulum allowing CICR

40
Q

What happens to the Ca release from the sarcoplasmic reticulum in in relaxation?

A

It ceases

41
Q

What dominates in the relaxation phase in terms of Ca flow?

A

Ca efflux occurs by the Na/Ca exchanger 1 (NCX1) and active sequestration via Ca2+-ATPase (SERCA) of Ca from the cytoplasm now dominates

42
Q

What happens to the force of contraction when the voltage activated Ca channel is phosphorylated and why?

A

Calcium influx is increased which will increase the force of contraction

43
Q

What is the role of PKA in terms of calcium sensitivity?

A

PKA also phosphorylated other components of the contractile machinery making it more sensitive to calcium

44
Q

What does PKA do to phosphalamabam?

A

PKA phosphorylated phospholamabam which increases the activity of CA-ATPase which increased pumping of Ca from the cytoplasm into the SR, causing quicker relaxation

45
Q

What converts the active cAMP to the inactive 5’AMP?

A

Phosphodiesterase Enzyme (PDE)

46
Q

What does inhibition of PDE result in?

A

A positive inotropic effect (this can be achieved by milrinone)

47
Q

Name three B-adrenoreceptor ligands

A

Dobutamine, adrenaline and noradrenaline (catecholamines)

48
Q

What is the pharmacodymic effects of B-adrenoreceptor ligand agonists?

A

increased force, rate, cardiac output and O2 consumption

decreased cardiac efficiency (increased O2 consumption)

49
Q

What causes the decreased cardiac efficacy in the use of B-adrenoreceptor ligand agonists?

A

Oxygen utilisation goes up, not contraction or force etc. purely the relationship between work and O2 consumption

50
Q

What can be a possible side effect of B-adrenoreceptor ligand agonists?

A

Can cause arrhythmias

51
Q

What is the clinical use of adrenaline?

A

Cardiac arrest (IV)

Anaphylactic shock (IM)

52
Q

What are the different ways adrenaline can be administered?

A

IM, SC, IV, or IV infusion

53
Q

What is the result of adrenaline acting on β1 receptors?

A

Positive inotropic and chronotropic actions

54
Q

What is the effect of adrenaline acting on α1 receptors?

A

Redistribution of blood flow to the heart (constricts blood vessels in the skin, mucosa and abdomen)

55
Q

What is the effect of adrenaline acting on β2 receptors?

A

dilation of coronary arteries

56
Q

What receptors does dobutamine act upon?

A

Selective for b-adrenoreceptors

57
Q

How is dobutamine administered?

A

Given as IV infusion

58
Q

What is dobutamine prescribed for?

A

Acute, but potentially reversible, heart failure following cardiac surgery, cardiogenic or septic shock

59
Q

What effect does dobutamine have?

A

Positive inotropic effect

(produces less tachycardia than other β1 agonists)

60
Q

Which receptors dominate in Cardiac muscle and respiratory smooth muscle?

A

B1

B2

61
Q

What does the effect of b-adrenoreceptor antagonists depend upon?

A

Degree of sympathetic activity (low levels=little effect)

62
Q

What receptors does propanolol act upon?

A

b1 and b2

63
Q

What receptors do atenolol, bisprolol, metoprolol act upon?

A

B1 (cardioselective)

64
Q

What receptors does alprenolol act upon?

A

B1 or B2

65
Q

What is significant about alprenolol?

A

Weak partial agonist

mild stimulatory effect on the heart

can block effect of full agonists so is therefore an antagonist

66
Q

What are the pharmacodynamic effects of non-selective B-adrenoreceptor antagonists on the heart?

A

at rest little effect on rate, force, CO or MABP (alprenolol will have a slight increase in rate at rest but reduce it in exercise)

during exercise or stress; rate, force, CO are significantly depressed- reduction in maximal exercise tolerance

Coronary vessel (SMOOTH MUSCLE NOT CARDIAC- EXPRESSES b2) diameter is marginally reduced; but myocardial O2 requirement falls. thus better oxygenation of myocardium

67
Q

What is the clinical use of B-adrenoreceptor antagonists?

A

Treatment of cardiac arrhythmias (decrease sympathetic drive and help to restor normal sinus rythmn)

AF and SVT (delay conduction through the AV node and restore sinus rythmn)

angina (reduce O2 consumption)

heart failure

hypertension (only if angina is present)

68
Q

Why do B blockers not make heart failure worse?

A

the sympathetic system is greatly activated to try and increase the CO, but if the heart is subjected to this over a long period of time this pre-disposes to arrhythmia. SO, in compensated HF the addition of a low dose b-blocker is beneficial as it decreases excessive sympathetic drive

69
Q

What is significant about carvediol?

A

additional a1 adrenoreceptor antagonist activity- will cause vasodilatation and reduce work heart has to do to maintain a given cardiac output

70
Q

What are the adverse effects of B-blockers (non-selective) ?

A
  1. bronchospasm *
  2. aggravation of cardiac failure
  3. Bradycardia
  4. Hypoglyaemia*
  5. Fatigue
  6. Cold extremeties

*Less risk associated with b1-selective agents (e.g. atenolol, bisoprolol, metoprolol

71
Q

How do B blockers cause bronchospasm?

A

block of airway smooth muscle b2-adrenoceptors

circulating adrenaline acts to dilate bronchial smooth muscle- which can be blocked by b blockers

72
Q

How can B blockers aggravate cardiac failure?

A

patients with heart disease may rely on sympathetic drive to maintain an adequate CO

but low dose b-blockers are used in compensated heart failure

73
Q

How can B blockers cause bradycardia?

A

heart block – in patients with coronary disease; b-adrenoceptors facilitate nodal conduction, if an individual already has a nodal sickness the addition of b-blockers can cause heart block

74
Q

How do B blockers cause hypoglycaemia

A

in patients with poorly controlled diabetes – the release of glucose from the liver is controlled by b2-adrenoceptors in response to sympathetic stimulation

75
Q

How do B blockers cause fatigue?

A

CO (β1) and skeletal muscle perfusion (β2) in exercise are regulated by adrenoceptors. Adrenalines stimulate β2 adrenoreceptors on the vessels of VSM, causing dilatation, in the presence of a non-selective blocker, dilatation does not occur and hence fatigue sets in quicker

76
Q

How do B blockers cause cold extremities?

A

loss of β2-adrenoceptor mediated vasodilatation in cutaneous vessels, blockage of them reduces blood supply and skin will feel cold

77
Q

Name a muscarinic ACh receptor antagonist (M2)?

A

Atropine

78
Q

What receptors does atropine act upon?

A

M1 to M5 with equal affinity

79
Q

What are the pharmacodynamic effects of atropine?

A

increase in HR in normal individuals above a certain threshold, more-so in athletes due to the HR being lower normally due the increased mass of cardiac muscle

no effect on arterial BP

no effect on response to exercise

80
Q

What is the clinical usage of atropine?

A

Severe and symptomatic bradycardia

(often post MI when vagal tone is elevated)

anticholinesterase poisoning- insecticide agents- reduced HR due to increase acetylcholine

81
Q

What is sinificant about atropine dosage?

A

can cause complete cessation of heart beat. Since the depression is due to depressed parasympathetic drive it is sensible to give atropine – IV incrementally with HR monitoring. sometimes glycopyrronium is used

at low doses it decreases HR- this would be disastrous post MI

First bolus injection must be at least 300-600 micrograms

82
Q

What kind of drug is Digoxin?

A

Cardiac Glycoside

83
Q

What is the clinical use of digoxin?

A

used to treat HF along with other drugs to provide adequate tissue perfusion

84
Q

What does digoxin and dobutamine do to cardiac contractility?

A

inotropic drugs (digoxin, dobutamine) enhance contractility

cause upwards and leftward shift in the curve

so SV increases at any given EDP

85
Q

How does digoxin increase cardiac contractility?

A

blocking the sarcolemma ATPase

86
Q

Explain how blocking the Na+/K+-ATPase will increase contractility?

A

increase in intracellular concentration of Na

slight loss in resting membrane potential

reduced driving force for sodium to come into the cell

less calcium pumped out of the cell in the presence of digoxin so intracellular calcium conc increases, it will be actively pumped by Ca2+ ATPase into the sarcoplasmic reticulum and increase the storage inside the cell.

this will activate the ryanodine receptors, calcium will flood out and activate the contractile machinery; due to digoxin the CICR is increased, increasing the force of contraction

87
Q

What are the indirect effects of digoxin?

A

slows SA node discharge

slows AV node conduction which increases refractory period

88
Q

What is the direct effect of digoxin?

A

Shortens the action potential and refractory period in atrial and ventricular myocytes (which is pro-arrhythmic); toxic concentration cause membrane depolarization and oscillatory afterpotentials- likely due to Ca2+ overload. if this action potential was large enough to hit threshold it could be very dangerous and produce a series of self propagating action potentials- ventricular arrhytmia

89
Q

What is the clinical use of digoxin?

A

IV in acute heart failure, or orally in chronic heart failure, in patients remaining symptomatic despite optimal use of other drugs (e.g. ACE inhibitors, diuretics)

Particularly indicated in heart failure with atrial fibrillation (AF)

increase in AV node refractory period is beneficial, helps to prevent spreading of the arrhythmia to the ventricles)

90
Q

What are the unwanted effects of digoxin?

A

excessive depression of AV node conduction (heart block)

propensity to cause arrhythmias

91
Q

What are the extracardiac effects of digoxin?

A

nausea

vomiting

diarrhoea

disturbances of colour vision

92
Q

How does levosimedan work?

A
  1. Binds to troponin C in cardiac muscle sensitizing it to the action of Ca2+
  2. Additionally opens KATP channels in vascular smooth muscle causing vasodilation (reduces afterload and cardiac work)

Relatively new agent, used in treatment of acute decompensated heart failure (IV)

93
Q

How do inodilators work?

amirinone and milrinone

A

Inhibit phosphodiesterase (PDE) in cardiac and smooth muscle cells and hence increase [cAMP]i

Increase myocardial contractility, decrease peripheral resistance (haemodynamic indices are improved), but worsen survival – perhaps due to increased incidence of arrhythmias

Use limited to IV administration in acute heart failure

Cardiovascular 2018 (39 decks)

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