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The Cardiovascular System > Pharmacology 2 - Drugs Modifying Cardiac Rate and Force > Flashcards

Pharmacology 2 - Drugs Modifying Cardiac Rate and Force Flashcards

1
Q

During a nodal action potential, which 5 different conductances are present?

A
  1. If - funny current (a mixed conductance, sodium influx, potassium efflux)
  2. Ib - background current (sodium influx)
  3. ICaT - transient calcium influx (short lasting)
  4. ICaL - calcium influx (long lasting)
  5. Ik - delayed rectifier outward potassium current
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2
Q

In the context of a nodal action potential what is the function of If - the funny current?

A

If is activated during the hyperpolarised state (after AP) and turns off when threshold is reached. It involves the mixed conductance of sodium influx and potassium efflux which aids the depolarisation of the cell - more positive charge enters than exits. The funny current utilises HNC channels (hyperpolarisation-activated cyclic nucleotide gated channels).

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3
Q

In the context of a nodal action potential what is the function of Ib - the background current?

A

Ib involves a background current of sodium into the cell and it is always present - a constitutive current. It contributes to cell depolarisation and the positive increase in voltage of the pacemaker potential.

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4
Q

In the context of a nodal action potential what is the function of ICaT - the short lasting transient calcium current?

A

ICaT willl activate around mid-way through the the pacemaker potential reaching threshold allowing for a final push towards the threshold voltage

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5
Q

In the context of a nodal action potential what is the function of ICaL - the long lasting calcium current?

A

As the pacemaker potential is achieves the long calcium current is activated mediating the upstroke of the AP

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6
Q

In the context of a nodal action potential what is the function of Ik - the delayed rectifier outward potassium current

A

Ik is involved in re-stabilising the cell after an AP. After the influx of calcium, the Ik current is activated causing potassium to move out of the cell - it is a hyperpolarising current. It is “delayed” as it take a while to become activated as potassium channels take time to open

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7
Q

What is depolarisation?

A

The tendency of the membrane potential to become less negative

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8
Q

What is the “pacemaker potential”?

A

This is a gradual depolarisation of a nodal cell that, when a threshold is reached, activates an action potential

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9
Q

During a myocyte action potential, which 5 different conductances are present?

A
  1. Ik1 - inward rectifier potassium current, constant tickle of potassium outwards - a hyperpolarising current
  2. INa - Na influx (dominant factor for depolarisation)
  3. Ito - transient (slow) outward potassium current
  4. ICaL - long inward calcium current
  5. Ik - delayed rectified outward potassium current
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10
Q

How many phases are present in myocardial cell action potential?

A

5 (0, 1, 2, 3, 4)

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11
Q

How many phases are present in a nodal cell action potential?

A

3 (4, 0, 3)

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12
Q

Describe phase 4 in a myocardial cell action potential

A

Diastolic potential is maintained (-90mv) by Ik1 which constantly hyperpolarises the cell

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13
Q

Describe phase 0 in a myocardial cell action potential

A

AP arrives from nodal tissue triggering depolarisation. Voltage gated sodium (INa) channels are activated causing rapid depolarisation. Sodium channels open very quickly

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14
Q

Describe phase 1 in a myocardial cell action potential

A

Ito involves the opening of potassium channels for efflux - a polarising current

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15
Q

Describe phase 2 in a myocardial cell action potential

A

INa channels will mostly switch off - those that don’t (INaL current contribute to depolarising influence) Only a slight decrease in potential is experienced as ICaL channels open maintaining the depolarised state and create the plateau phase. Calcium influx allows for ventricular contraction. NCX antiporter works in reverse (moves Ca++ into cell and 3 Na+ out of cell) - a repolarising influence aiding the end of the plateau phase. At the end of the plateau phase, calcium channels turn on (voltage activated) leading to Ca++ to leave the cell

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16
Q

Describe phase 3 in a myocardial cell action potential

A

Ik channels open including Ikr (rapid) and Iks (slow) producing an outward potassium flow aiding repolarisation. Ik1 channels also activate aiding this process

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17
Q

Describe phase 4 in a nodal cell action potential

A

Hyperpolarisation activates If (funny current) meaning a new action potential is prepared as soon as the previous finishes. If involves an inward sodium flow and an outward potassium flow - it is a depolarising current. ICaT turns on midway through the pacemaker potential giving the final push towards threshold. Ib is always present and involves the flow of sodium into the cell - a depolarising current

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18
Q

Describe phase 0 in a nodal cell action potential

A

Towards the end of the pacemaker potential ICaL current is activated mediating the upstroke of the action potential after threshold is reached

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19
Q

Describe phase 3 in a nodal cell action potential

A

Calcium activates Ik which allows potassium out of the cell - a hyperpolarising current. Ik activity is up-regulated in phase 3. This current is described as “delayed” since potassium channels take a while to open.

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20
Q

In the sympathetic nervous system, which neurotransmitter is released at the post-ganglionic neurone?

A

Noradrenaline

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21
Q

Pre-ganglionic neurones innervate which gland?

A

Adrenal gland (activates adrenal medulla which secretes adrenaline)

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22
Q

Adrenaline and noradrenaline activate which type of receptor in myocardial and nodal tissue

A

Beta 1 adrenoceptors

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23
Q

Describe what happens when adrenaline or noradrenaline activates beta 1 receptors in myocardial or nodal cells?

A

A G protein coupled receptor is activated (Gs). Gs activates adenylyl cyclase which boosts cAMP levels

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24
Q

Increased cAMP levels have what effect in nodal cells? (2)

A
  1. Increased heart rate
  2. Increase in pacemaker slope (If and calcium currents increase reducing time taken to reach threshold which speeds up firing rate)
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25
Q

An increased heart rate is what type of effect?

A

Chronotropic effect (positive for increase)

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26
Q

Increased calcium influx into ventricular myocardial cells has what type of effect?

A

Inotropic effect (positive)

  • Increased contractility
  • Increased sensitivity of contractile proteins to calcium
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27
Q

In sympathetic stimulation the end diastolic volume is _______ per stroke volume than normal

A

Greater

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28
Q

During sympathetic stimulation how is conduction velocity affected and why?

A

Increased (decreased delay) If and ICa currents are enhanced

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29
Q

What is automaticity and when does it increase?

A

The tendency for the heart to adopt spontaneous activity from latent pacemakers besides the SA node. This increases under sympathetic stimulation

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30
Q

What is a lusitropic action?

A

An action that alters the duration of systole caused by uptake rate of calcium into the sarcoplasmic reticulum.

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31
Q

How is cardiac efficiency affected under sympathetic innervation?

A

Decreases

Oxygen consumption increases disproportionally to increased work

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32
Q

What is a long term impact on increased cardiac muscle workload?

A

Hypertrophy

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33
Q

Which neurotransmitter is associated with parasympathetic post ganglionic neurones?

A

Acetylcholine

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34
Q

Acetylcholine acts on which type of receptors in nodal cells

A

Type 2 muscarinic cholinoceptors

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35
Q

Describe what happens when acetylcholine activates type 2 muscarinic cholinoceptors in nodal cells?

A

A G protein coupled receptor is activated (Gi) Gi decreases adenylyl cyclase activity (by the beta and gamma subunits) and decreases cAMP levels

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36
Q

Which channel opens as a result of decreased cAMP levels in nodal cells?

A

Potassium channels (GIRK - G protein inward rectifier potassium channel) open causing SA node hyperpolarisation - efflux of potassium occurs

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37
Q

Decreased cAMP levels have what effect in nodal cells? (2)

A
  1. Decreased heart rate
  2. Decreased pacemaker potential slope (If and ICa are reduced, lengthening time between APs)
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38
Q

Contractility of myocardial cells decreases under the parasympathetic system, why?

A

The phase 2 component is decreased and calcium entry is reduced due to lower ICa activity

This is a negative inotropic effect

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39
Q

Atrial tachycardia is treated by increasing parasympathetic system activity. How is this easily done without pharmacological action utilising the baroreceptor response? (2)

A
  1. Valsalva manouvre - baroreceptors in aortic arch activated. Achieved by attempting forceful exhalation to closed airway (closed mouth/pinched nose) - activates parasympathetic response
  2. Massage carotid artery bifurcation - stimulates baroreceptors in carotid sinus increasing parasympathetic response and preventing unwanted conduction to ventricles
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40
Q

HCN (hyperpolarisation-activated cyclic nucleotide) channels are dual regulated by which two factors?

A
  1. Hyperpolarisation
  2. Cyclic AMP (cAMP)
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41
Q

HCN (hyperpolarisation-activated cyclic nucleotide) channels mediate which current?

A

Funny current (If) (sodium in, potassium out) Overall it is a depolarising current

42
Q

What effect does cAMP have on HCN (hyperpolarisation-activated cyclic nucleotide)?

A

HCN becomes more sensitive to activation and switches on at less negative potentials. This means the funny current can begin sooner, reducing threshold and increasing AP generation by nodal cells

43
Q

Pharmacologically, what is the benefit of blocking HCN channels and which drug can do so?

A

Ivabradine

It acts by selectively blocking HCN channels increasing time between APs, due to the decreased slope of the pacemaker potential This is used to reduce heart oxygen consumption to treat patients with angina

44
Q

What is the purpose of the drug Ivabradine?

A

It acts by selectively blocking HCN channels (increased cAMP levels now have less effect). This increases time between APs, due to the decreased slope of the pacemaker potential This is used to reduce heart oxygen consumption to treat patients with angina

45
Q

To enable cardiac muscle contraction, which receptors are activated to allow for calcium induced calcium release?

A

Ryodine type 2 receptors (RyR2)

46
Q

After cardiac muscle contraction, which two methods remove calcium from cells?

A
  1. NCX pumps 1 Ca2+ out of the cell and allows entry for 3 Na
  2. Calcium-ATPase proteins transport Ca2+ from the cytoplasm to the sarcoplasmic reticulum (SERCA)
47
Q

After cardiac muscle contraction, what is the effect of reduced calcium concentration?

A
  1. Calcium dissociates from troponin C
  2. Cross bridges break between actin and myosin
48
Q

Sympathetic stimulation has what effect on the heart?

A
  1. Increases heart rate
  2. Increases contractile force
49
Q

Which two neurotransmitters act frequently in the heart as part of the sympathetic system?

A

Adrenaline and noradrenaline

50
Q

What happens when a B1 receptor is activated?

A

G protein Gs is activated which turns on adenylyl cyclase which converts ATP to cAMP. Increased cAMP acts as a secondary messenger to activate protein kinase A which has the overall effect of increasing heart rate

51
Q

Protein kinase A has which 3 main effects when activated?

A
  1. Phosphorylates volatge activated calcium channel making it more sensitive to voltage so it is open for longer - more calcium can be present to bind to troponin C
  2. Phosphorylates elements of contractile proteins making them more sensitive to Ca2+ (confers increased contractility)
  3. Phosphorylates phospholamban increasing activity of calcium ATPase allowing repolarisation (and relaxation) to occur more quickly
52
Q

How is cAMP degraded?

A

Phosphodiesterase enzymes break down cAMP to 5’AMP

53
Q

It is possible to inhibit phosphodiesterase enzymes, and therapeutically this was done in heart failure to aid contraction, but which drug would do this (now redundant)

A

Milrinone - too many side effects

Potentially only used in absolute emergencies

54
Q

Name thee catechloamines and state their function

A
  1. Adrenaline
  2. Noradrenaline
  3. Dobutamine

All increase heart rate and contractility

55
Q

What is one negative impact of the catechloamines?

A

They can cause disturbances in heart rhythm

56
Q

Adrenaline acts on which type of receptors?

A

Both alpha and beta adrenoceptors

It is a mixed agonist

57
Q

How can adrenaline be administered?

A

IM, IV or subcutaneously

58
Q

What effects does adrenaline have in cardiac arrest?

A
  1. Acts on alpha 1 receptors to constrict vessels in non-essential organs (skin, mucosa, abdomen) to return more blood to the heart
  2. Acts on beta 2 receptors in coronary arteries to cause dilation aiding perfusion
59
Q

Which receptors does dobutamine act on?

A

Beta 1 (weak B2 activity)

60
Q

How is dobutamine administered?

A

IV

61
Q

In what way are the effects conferred by dobutamine different to other catechloamines?

A

Has less effect on heart rate, and instead predominantly increases cardiac contractile force

62
Q

Name a non-selective B adrenoceptor blocker

A
  • Propranolol
  • Alprenolol (partial agonist, does not completely block B1 receptor activity)
63
Q

Name a selective (B1) B adrenoceptor blocker

A
  1. Atenolol
  2. Bisoprolol
  3. Metoprolol
64
Q

How do B adrenoceptor antagonists affect a patient’s heart rate and contractile force at rest?

A

There is little affect at rest (parasympathetic system dominant) During exercise, exercise tolerance is reduced as heart rate and contractile force cannot increase to cope with the exercise

65
Q

Why are B-blockers prescribed to treat arrhythmias?

A

Excess adrenaline/noradrenaline release is what causes the sympathetic overdrive that manifests as an arrhythmia

66
Q

B-blockers are used to treat which heart conditions?

A
  1. Atrial fibrillation
  2. Supraventricular tachycardia
  3. Angina
  4. Heart failure
67
Q

Why would B-blockers be used to treat heart failure?

A

This seems strange as they reduce sympathetic drive. Chronic sympathetic stimulation is detrimental causing decreased cardiac function and cardiac dysrhythmias may occur - B-blockers stop these unwanted effects

68
Q

Name a drug in the B-blocker class for arrythmias and describe its properties

A

Carvedilol

Is also an alpha-1 antagonist allowing dilation of systemic vasculature reducing blood pressure and improving cardiac function.

69
Q

Why must B-blockers be administered at low initial doses and rise up to higher doses later for arrhythmia treatment?

A

B-blockers have negative effects on the body when initially administered. To reduce these effects low doses are preferable. Higher doses can be given after these negative effects are not experienced later

70
Q

When would B-blockers be considered first line treatment?

A

When hypertension is present alongside a co-morbidity such as angina

71
Q

What are some adverse effects of B-blockers?

A
  1. Bronchospasm - non-selective blocker may be of more use
  2. Aggravation of cardiac failure - sympathetic drive may be required
  3. Bradycardia
  4. Hypoglycaemia - adrenaline breakdown does not occur as easily
  5. Fatigue - cardiac output is lowered
  6. Cold extremities - less vasodilatation occurs
72
Q

In a patient, with hypoglycaemia (low blood glucose due to diabetes), why is the use of B-blockers dangerous?

A

Hypoglycaemia - characterised by increased heart rate, trembling and sweating In diabetic patients, sympathetic drive may be required to allow the liver to break down glycogen into glucose (due to aid of adrenaline). With the blockade of the sympathetic response (by B-blockers), these symptoms can be masked leading to worsening of hypoglycaemia

73
Q

What is atropine?

A

A non-selective muscarinic antagonist

74
Q

What is the main effect of atropine?

A

To increase heart rate (at moderate to high doses)

75
Q

Why does atropine increase heart rate?

A
  • Acts on M2 receptors in SA node preventing acetylcholine binding (from parasympathetic neurones) - vagal tone is reduced
  • This increases action potential discharge rate
76
Q

Why does atropine have increased effect on athletes or highly physically trained individuals?

A

These people have increased vagal tone which atropine prevents - hence a larger difference in heart rate would be noticed

77
Q

Which drug is used as first line treatment for bradycardia?

A

Atropine

78
Q

Why does atropine have little effect on blood pressure?

A

Parasympathetics do not innervate arterioles - the main resistance vessels

79
Q

What is an alternative drug to atropine used to treat bradycardia?

A

Glycopyrronium bromide

80
Q

What is the range of doses for atropine and how is it administered?

A

300-600mg

IV It is important that low doses are not given - these can slow heart rate and worsen the condition

81
Q

What is anticholinesterase poisoning?

A

Anticholinesterases - drugs which block cholinesterase Cholinesterase - enzyme responsible for acetylcholine breakdown - Hence acetylcholine concentration increases allowing the parasympathetic system to have an overly pronounced effect

82
Q

How is anticholinesterase poisoning treated?

A

Atropine

83
Q

Digoxin is which type of drug?

A

Cardiac glyoside

84
Q

Digoxin is a drug used in _____ _______ which acts mainly to increase _______ ____________

A

Heart failure Cardiac contractility

85
Q

In heart failure, how is cardiac output affected?

A

It is decreased to the point where it is insufficient to meet the demands of the body

86
Q

How does heart failure affect the ventricular function curve?

A

The curve become depressed

87
Q

In cardiac myocytes, where does digoxin act?

A

Na+/K+ ATPase

88
Q

Why does digoxin increase contractility?

A
  1. Na+/K+ ATPase is blocked
  2. Sodium cannot exit the cell so builds in concentration
  3. The sodium calcium exchanger (NCX) is impacted - its function is decreased and calcium concentration is increased
  4. Calcium storage in the sarcoplasmic reticulm is increased (by action of Ca2+ ATPases)
  5. During calcium induced calcium release, more calcium is released allowing for a more pronouced contractile effect
89
Q

On the Na+/K+ ATPase, digoxin binds to which binding site?

A

Potassium (alpha subunit) - digoxin will compete for this site

90
Q

Why must diuretic drugs be used carefully with digoxin?

A

Both drugs decrease plasma K+ concentration

If this becomes too low, hypokalaemia may occur

This has many negative effects including increased blood pressure and abnormal heart rhythms

91
Q

What are the main direct effects of digoxin?

A
  1. Refractory period is reduced in myocytes
  2. High concentrations lead to oscillatory afterpotentials due to calcium overload (additional spike on ECG) - delayed after depolarisation can cause second action potential leading to tachycardia
92
Q

What are the main indirect effects of digoxin?

A
  1. SA node discharge is reduced
  2. Propagation of impulse through AV node is slowed - increases refractory period
93
Q

How is digoxin adminstered alone?

A

IV - acute heart failure

Orally - Chronic heart failure

94
Q

In what situation would digoxin be used more frequently?

A

When heart failure is combined with atrial arrhythmias

(drug slows impulses from atria to ventricles)

95
Q

What are the side effects of digoxin?

A
  1. Heart block - excessive AV node conduction depression
  2. Can cause arrhythmias (high doses)
  3. Nausea, vomiting, diarrhoea, vision disturbances
96
Q

Name a drug which sensitises troponin C to calcium

A

Levosimendan

97
Q

How does Levosimendan work?

A
  1. Binds to troponin C and increases its sensitivity to calcium
  2. Cross bridge formation is stimulated
  3. Activates KATP channels causing hyperpolarisation inducing relaxation and vasodilation
  4. Decreases TPR
98
Q

When would levosimendan be used?

A

Acute decompensated heart failure (by IV)

99
Q

What are inodilators?

A

Drugs which can block phosphodiesterase enzymes therefore preventing cAMP degradation.

This allows heart force and increased vasodilation to occur

100
Q

Give an example of an inodilator

A
  1. Amrinone
  2. Milrinone

Administered by IV - used rarely due to increased incidence of arrhythmias

The Cardiovascular System (24 decks)

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