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Cardiovascular: pharmacology > Drugs modifying cardiac rate and force > Flashcards

Drugs modifying cardiac rate and force Flashcards

1
Q

what are the regulatory influences on heart rate?

A
  • balance of autonomic input
  • stretch
  • temperature
  • hypoxia
  • blood pH
  • thyroid hormones
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2
Q

what is overdrive suppression?

A

the SA node sets the rhythm for the heart because it discharges APs at a greater frequency than AV and his system

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3
Q

what four currents are important in the phase 4 (pacemaker potential ) of SA and AV nodes?

A

Ib - background sodium current inward

increased funny current - HCN channels open to conduct Na and K inward

ICaT - transient inward calcium current

and decreased Ik - delayed rectifier potassium current

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4
Q

why is it called the funny current?

A

The inward movement of Na and Sodium is mediated by hyperpolarisation and cyclic nucleotide gated (HCN) channels

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5
Q

what is the sequence of channel opening in

A

immediately after AP the membrane potential reaches its most negative value this is enough to open channles that conduct NA and K

then I cat switches on just before we hit threshold
at this point another class of VA channels opens
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6
Q

what mediates phase 0 of nodal AP?

A

increased Ical - long calcium current

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7
Q

what mediates phase 3 - downstroke of nodal AP ?

A

increased Ik - delayed rectifier potassium current

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8
Q

what current/ s mediated phase 4( diastolic potential) of atrial and ventricular myocyte APs ?

A

Ik1 - inward rectifier potassium current - this steady membrane potential is determined by a constant trickle of K ions OUTWARD

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9
Q

what does the outward trickle of K in phase 4 of atrial and ventricular myocyte APs result in?

A

the activation of VA I na - this is responsible for upstroke.

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10
Q

the majority of Na channels do not remain conducting for long. They go into a _____ _______ state after a millisecond.

A

the majority of Na channels do not remain conducting for long. They go into a nonconducting inactivated state after a millisecond.

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11
Q

what is responsible for the small flux after upstroke in atrial and ventricular myocyte APs ?

A

due to a combination of

  1. Na ceasing
  2. Ito - a transient outwards potassium current
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12
Q

what mediates phase 2 (plateau) in atrial and ventricular myocyte APs?

A
  1. Increased CaL - long calcium current (inward)
    as this happens K channels are slowly activated so the plateau is a fine balance of inward Ca movement by outwards K movement.
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13
Q

what two other mechanisms support phase 2 of atrial and ventricular myocyte APs?

A
  1. not all VA Na inactivate - about 1% remain open and this gives rise to INaL - this is a late (or persistent) sodium current inward.
  2. This is not an ion channel but a transporter. The Na Ca exchanger. This is in several forms in the body but it is NX1 in the heart. At resting potential it allows 3Na in and expells 1 Ca - this Ca has a +2 charge though! If, however, the MP is at depolarising potential this transporter will run backwards.
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14
Q

what mediates phase 3 of atrial and ventricular myocyte APs?

A

Ik - there are two components

  • a fast activating one fast I kr which opens first
  • a slow activating one - Iks
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15
Q

Noradrenaline (postganglionic transmitter) and adrenaline (adrenomedullary hormone) activate _____ in nodal cells and myocardial cells to sympathetic system

A

b1 adrenoceptors

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16
Q

B1 adrenoceptors are __ coupled. The__ protein that they couple to is __. This is a stimulatory_ ____ which activates the membrane enzyme _____ _____ which in turn generates ____ from ATP.

A

B1 adrenoceptors are G coupled. The G protein that they couple to is Gs. This is a stimulatory G protein which activates the membrane enzyme adenylyl cyclase which in turn generates cAMP from ATP.

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17
Q

what happens to the heart rate when sympathetic system is stimulated?

A

increase HR - a positive chronotropic effect

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18
Q

what two things happen to increase AP rate?

A

i) increase in the slope of phase 4 depolarisation

ii) reduction in the threshold for AP initiation

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19
Q

what mediates the increase in the slope of phase 4 depolarisation from sympathetic stimulation?

A

increased If and ICa

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20
Q

what mediates the decrease in threshold of phase 4 depolarisation from sympathetic stimulation?

A

I Ca - Because inward Ca is stimulated this means that the pacemaker potential reaches threshold at a more negative value than usual.

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21
Q

what other things happen to the heart on sympathetic stimulation?

A
  1. increased contractility
  2. increased conduction velocity
  3. increased automacity
  4. decreased duration of systole
  5. decrease in cardiac efficiency
  6. increased activity of the Na/ K ATPase
  7. increased mass of cardiac muscle
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22
Q

what causes the increased contractility from sympathetic stimulation ?

A

i) an increase in phase 2 of the cardiac action potential in atrial and ventricular myocytes and enhanced Ca influx and
(ii) sensitisation of contractile proteins to Ca

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23
Q

what causes increased conduction velocity in AV node in sympathetc stimulation?

A

due to enhancement of If and I ca (as in SA node) This occurs because of the calcium flux in the AV node is increased

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24
Q

what causes increased automacity in sympathetc stimulation? (i.e. tendency for non-nodal regions to acquire spontaneous activity – explored in later

A

If the muscle cells are stimulated hard then even muscle cells can discharge AP at their own rhythm i.e. without SA control
this leads to ventricular fibrillation- very dangerous

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25
Q

what causes a decrease in the duration of sytstole in sympathetic stimulation

A

due to cAMP due to increased uptake of Ca2+ into the sarcoplasmic reticulum

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26
Q

why is there also a decrease in the duration of diastole in sympathetic stimulation?

A

the rate of relaxation must also increase because if it didnt then the ventricles would be partially filled with blood before the next filling.

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27
Q

there is also a decrease in cardiac efficiency in sympathetic stimulation with respect to____ consumption which increases disproportionately with increasing work

A

there is also a decrease in cardiac efficiency in sympathetic stimulation with respect to oxygen consumption which increases disproportionately with increasing work

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28
Q

Parasympathetic fibres are stimulated by the____ nerve.

_____ is the postganglionic transmitter and it activates ________ largely in ___ cells.

A

Parasympathetic fibres are stimulated by the vagus nerve.

Acetylcholine is the postganglionic transmitter and it activates M2 muscarinic cholinoceptors largely in NODAL cells.

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29
Q

It is the ____ and ____ subunits that are important in the cardiac regulation of the parasympathetic system

A

It is the beta gamma subunits that are important in the cardiac regulation

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30
Q

what do the beta and gamma subunits do in parasympathetic stimulation?

A

they switch on special K channels called GIRKs

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31
Q

when do GIRKS do?

A

are found in the AV node and when they are activated they hyperpolarize the node so slow the impulse conduction.

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32
Q

coupling through the G protein in parasympathetic stimulation does 2 things. what are they?

A

i) decreases activity by adenylate cyclase and reduces (cAMP)
ii) opens potassium channels (GIRK) to cause hyperpolarization of SA node (mediated by Gi βγ subunits)

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33
Q

what three things cause the decrease in heart rate from parasympathetic stimulation?

A

(i) decreased slope of the pacemaker potential caused by reduced If and ICa,
(ii) hyperpolarization caused by the opening of GIRK channels,
(iii) increase in threshold for AP initiation caused by reduced ICa

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34
Q

why is there decreased contractility in parasympathetic stimulation?

A

due to decrease in phase 2 of cardiac action potential and decreased Ca2+ entry
- this is only seen at the atria as ventricles dont have parasympathetic innervation

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35
Q

why is there decreased conduction in parasympathetic stimulation?

A

due to decreased activity of voltage-dependent Ca2+ channels and hyperpolarization via opening of K+ channels

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36
Q

what does parasympathetic stimulation have the ability to cause - bad?

A

may cause arrhythmias to occur in the atria (AP duration is reduced and correspondingly the refractory period – predisposes the re-entrant arrhythmias

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37
Q

what is the pacemaker potential modulated by?

A

If

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38
Q

what activates the funny current?

A

(i) hyperpolarization and

(ii) cyclic AMP [called hyperpolarization-activated cyclic nucleotide gated (HCN) channels

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39
Q

how does cAMP increase the activation of HCN ?

A

cAMP increases the activation of the HCN channels by making the channel more sensitive so it is activated more readily.

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40
Q

what does the ivabradine do?

A

it is a selective blocker of HCN 4 channels that is used to slow HR in angina. Slower HR reduces oxygen consumption

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41
Q

what are the 6 steps in Ca contraction coupling in cardiac muscle

A
  1. ventricular AP
  2. opening of voltage - activated Ca channels (mainly L- type) during phase 2 of action potential
  3. Ca influx into the cytoplasm
  4. Ca release from the sarcoplasmic reticulum (CICR)
  5. Ca binds to troponin C and shifts tropomyosin out of the actin cleft
  6. cross bridge formation between actin and myosin resulting in contraction via the sliding filament mechanisms
42
Q

what are the 6 steps in Ca relaxation coupling in cardiac muscle

A
  1. repolarisation in phase 3 to phase 4
  2. VA l-type Ca channels close
  3. Ca influx ceases. Ca efflux occurs by the Na/Ca exchanger NCX1 - a plasma membrane ATPase is less importatnt
  4. Ca release from the sarcoplasmic reticulum ceases. Active sequestration via Ca- ATP ase (SERCA) of Ca from the cytoplasm now dominates
  5. Ca dissociates from troponin C
  6. Cross bridges between actin and myosin break resulting in relaxation
43
Q

what does adenylate cyclase convert ?

A

ATP to cAMP

44
Q

what does cAMP activate?

A

protein kinase A

45
Q

what three things does protein kinase A do?

A
  1. phosphorylates L-type calcium channels leading to Ca influx
  2. increase the sensitivity of the MLC to Ca which leads to increased contractility
  3. phosphorylates phospholamban which increases the pumping of Ca and increases the rate of relaxation
46
Q

what can convert cAMP to inactive 5AMP?

A

a phosphodiesterase enzyme (PDE)

47
Q

what does inhibition of PDE cause ?

A

a positive inotropic effect that can be achieved with drugs such as mirinone that are now seldom used, except in heart failure.

48
Q

what are 3 examples of B adrenoceptor agonists?

A

dobutamine, adrenaline and noradrenaline (cetacholamines)

49
Q

what is the pharmacodynamic effects of beta agonists ? 2 things

A
  • they increase the force, rate and cardiac output (i.e. HR xSV) and O2 consumption
  • they decrease cadiac efficiency (O2 consumptions is increased more than cardiac work)
50
Q

what adverse effect can beta agonists have ?

A

can cause disturbances in cardiac rhythm

51
Q

what is the effect of adrenaline on beta 1 receptors ?

A

has a positive inotropic and chronotropic effect

52
Q

what is the effect of adrenaline on beta 2 receptors ?

A

dilate the coronary arteries

53
Q

what is the effect of adrenaline on alpha 1 receptors ?

A

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

54
Q

what receptor does dobutamine act on?

A

selective for beta adrenoceptors

55
Q

what is dobutamine used for?

A

acute, but potentially reversible, heart failure (e.g. following cardiac surgery, or cardiogenic, or septic, shock). For reasons unknown, causes less tachycardia than other β1 agonists)

56
Q

what is the main effect of dobutamine on the heart?

A

it does not increase the heart rate too much but increases contractions

57
Q

what do the effects of beta antagonists depend on?

A

the degree to which the sympathetic nervous system is activated.

58
Q

give an example of a beta antagonist that blocks non- selectively

A

propranolol

59
Q

give an example of a beta antagonist that blocks selectively

A

atenolol, bisoprolol, metoprolol

60
Q

give an example of a beta antagonist that is non- selective and a partial agonist

A

alprenolol

61
Q

why do beta antagonists reduce maximal exercise tolerance?

A

during exercise, or stress, rate and force and CO are significantly depressed

62
Q

beta antagonists reduce the diameter of coronary vessels, why is there better oxygenation of the myocardium though?

A

the myocardial oxygen requirement falls

63
Q

what are b-adrenoceptor antagonists used for?

A
  1. treatment of disturbances of cardiac rhythm (arrhythmias)
  2. Treatment of Angina
  3. heart failure
  4. hypertension
64
Q

what can excessive sympathetic activity associated with stress, emotion, or disease (e.g. heart failure, myocardial infarction) lead to

A

tachycardia, or spontaneous activation of ‘latent cardiac pacemakers’ outside nodal tissue

65
Q

what do beta antagonists do to prevent arrhythmias?

A

they decrease excessive sympathetic drive and help to restore normal sinus rhythm

66
Q

what do beta blockers do in AF and SVT ?

A

they block conduction through the AV node and help restore sinus rhythm

67
Q

what are the adverse effects of beta blockers?

A
  • non-specific may cause bronchospasm
  • aggrevation of heart failure (patients with heart disease may rely on sympathetic drive to maintain an adequate CO)
  • bradycardia
  • hypoglycaemia
  • fatigue
  • cold extremities
68
Q

what is a complication of using beta blockers which are causing bradycardia?

A

heart block because in patients with coronary disease; β-adrenoceptors facilitate nodal conduction

69
Q

which patients may get hypoglycaemia in response to beta blockers? and why?

A

in patients with poorly controlled diabetes – the release of glucose from the liver is controlled by β2-adrenoceptors

70
Q

why do people experience cold extremities with beta blockers?

A

loss of β2-adrenoceptor mediated vasodilatation in cutaneous vessels

71
Q

why do people experience fatigue with beta blockers?

A

CO (β1) and skeletal muscle perfusion (β2) in exercise are regulated by adrenoceptors

72
Q

what is an example of a Non-Selective Muscarinic ACh Receptor Antagonist?

A

atropine

73
Q

what are the pharmacodynamic effects of atropine ?

A
  • increases HR
  • no effect upon arterial BP
  • no effect upon the response to exercise
74
Q

why do Non-Selective Muscarinic ACh Receptor Antagonists have no effect upon arterial BP?

A

the resistance vessels lack a parasympathetic innervation

75
Q

what are Non-Selective Muscarinic ACh Receptor Antagonists used for clinically ?

A

First line in management of severe, or symptomatic bradycardia, particularly following myocardial infarction (in which vagal tone is elevated)

Some practitioners recommend no less than 600 micrograms as low-dose atropine may paradoxically transiently slow heart rate (see figure)

76
Q

what is digoxin ?

A

Digoxin - A Cardiac Glycoside That Increases Contractility of the Heart

77
Q

what is digoxin used in?

A

heart failure - as CO is insufficinet to produce adequate perfusion

78
Q

what three parts structurally make up digoxin?

A

Digoxin has a sugar, steroid and lactone part. The steroid and lactone make up the pharmacophore

79
Q

Digoxin increases the contractility by blocking the ____ ___ase.

A

Digoxin increases the contractility by blocking the sarcolemma ATPase.

80
Q

what does the Na/K ATP ase do to the membrane potential?

A

Na/K ATPase results in the movement of 1 positive charge out so this has a hyperpolarizing influence on the membrane.

81
Q

This ATP ase generates an ______ gradient for sodium and the ___/__ exchanger uses this energy from the gradient to pump __ back into the cell. note there is ____ net change in Na concentration.

A

This ATP ase generates an electrochemical gradient for sodium and the Na/Ca exchanger uses this energy from the gradient to pump Na back into the cell. note there is no net change in Na concentration.

82
Q

Digoxin blocks the Na/K ATPase which lead to

  1. increased intracellular __ levels
  2. slight _______ of the MP
  3. Because there is an increased __ concentration there is a _______ driving force for ___ to enter the cell
A

Digoxin blocks the Na/K ATPase which lead to

  1. increased intracellular Ca levels
  2. slight depolarisation of the MP
  3. Because there is an increased Ca concentration there is a decreased driving force for Na to enter the cell
83
Q

why can Ca not be transported out of the cell as effectively in the presence of digoxin? why dont you get increased Ca in the cell though?

what does digoxin do to the interaction between Ca and troponin C

A

The decreased energy from Na pump means that Ca cannot be transported out of the cell as effectively as normal

BUT you don’t get increased Ca because the excess Ca is actively transported into the sarcoplasmic reticulum

During the plateau of the AP the Ca channels that open Ca mean that there is a increased Ca release. This means that with digoxin there is increased Ca interaction with troponin

84
Q

Digoxin binds to the ___ subunit of Na/K ATPase in competition with _

A

Digoxin binds to the alpha subunit of Na/K ATPase in competition with K

85
Q

when can the effects of digoxin be dangerously enhanced?

A

enhanced by low plasma K because K and digoxin are effectively in competition and when there is low K, digoxin can bind. This is particularly important because D has a very low therapeutic ratio.

86
Q

what is the indirect effect of digoxin on electrical activity? 2 things

A
  • increased vagal activity

- it slows SA node discharge and slows AV node conduction; increases the refractory period

87
Q

what is the direct effect of digoxin on electrical activity?

A

shortens the action potential and refractory period in atrial and ventricular myocytes

88
Q

what is the danger of digoxin for electrical activity ?

A

is pro-arrhythmatic; toxic concentration cause membrane depolarisation and oscillatory afterpotential

89
Q

what is the afterpotential caused by digoxin likely due to?

A

likely due to Ca overload. D promotes the accumulation of Ca in the cell meaning that a second AP can be conducted outwith the control of the SA node.

90
Q

what is the danger if you have an afterpotential from digoxin?

A

after a second triggered AP - get another ectopic beat and this could lead to ventricular tachycardia which is self sustaining to produce fibrillation

91
Q

what is digoxin used to treat clinically ?

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)
92
Q

why is digoxin useful in heart failure with AF?

A

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

93
Q

what are 2 cardiac side effects of digoxin?

A
  • excessive depression of AV node conduction (heart block)

- propensity to cause arrhythmias

94
Q

Extracardiac effects are numerous: this is because ___ ase is in LOADS of cells

A

Extracardiac effects are numerous: this is because ATP ase is in LOADS of cells

95
Q

what does levosimendan do?

A
  • Increases the force of contraction

- vasodilates vascular smooth muscle

96
Q

why does levosimendan increase the force of contraction?

A

binds to troponin c in cardiac muscle sensitising the contractile proteins to action of Ca -this promotes Cross bridge formation increasing the force of contraction

97
Q

how does levosimendan cause vascular smooth muscle vasodilation ?

A

it opens K atp channels in the vascular smooth muscle

  • when open this hyperpolarizes the cell
  • if you hyperpolarize smooth muscle vasculature you get vasodilation
98
Q

what are two examples of Inodilators?

A

amrinone and milrinone

99
Q

what do inodilators do? 2 things

A
  • increases the force of contraction

- it decreases peripheral resistance

100
Q

how do inodilators increase the force of contraction?

A

they inhibit PDE in cardiac and smooth muscle cells and hence increase cAMP

101
Q

what are inodilators used for clinically?

A

its use is limited to IV administration in acute heart failure

Cardiovascular: pharmacology (6 decks)

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