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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

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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
An increased heart rate is what type of effect?
Chronotropic effect (positive for increase)
26
Increased calcium influx into ventricular myocardial cells has what type of effect?
Inotropic effect (positive) * Increased contractility * Increased sensitivity of contractile proteins to calcium
27
In sympathetic stimulation the end diastolic volume is _______ per stroke volume than normal
Greater
28
During sympathetic stimulation how is conduction velocity affected and why?
Increased (decreased delay) If and ICa currents are enhanced
29
What is automaticity and when does it increase?
The tendency for the heart to adopt spontaneous activity from latent pacemakers besides the SA node. This increases under sympathetic stimulation
30
What is a lusitropic action?
An action that alters the duration of systole caused by uptake rate of calcium into the sarcoplasmic reticulum.
31
How is cardiac efficiency affected under sympathetic innervation?
Decreases ## Footnote Oxygen consumption increases disproportionally to increased work
32
What is a long term impact on increased cardiac muscle workload?
Hypertrophy
33
Which neurotransmitter is associated with parasympathetic post ganglionic neurones?
Acetylcholine
34
Acetylcholine acts on which type of receptors in nodal cells
Type 2 muscarinic cholinoceptors
35
Describe what happens when acetylcholine activates type 2 muscarinic cholinoceptors in nodal cells?
A G protein coupled receptor is activated (Gi) Gi decreases adenylyl cyclase activity (by the beta and gamma subunits) and decreases cAMP levels
36
Which channel opens as a result of decreased cAMP levels in nodal cells?
Potassium channels (GIRK - G protein inward rectifier potassium channel) open causing SA node hyperpolarisation - efflux of potassium occurs
37
Decreased cAMP levels have what effect in nodal cells? (2)
1. Decreased heart rate 2. Decreased pacemaker potential slope (If and ICa are reduced, lengthening time between APs)
38
Contractility of myocardial cells decreases under the parasympathetic system, why?
The phase 2 component is decreased and calcium entry is reduced due to lower ICa activity This is a negative inotropic effect
39
Atrial tachycardia is treated by increasing parasympathetic system activity. How is this easily done without pharmacological action utilising the baroreceptor response? (2)
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
40
HCN (hyperpolarisation-activated cyclic nucleotide) channels are dual regulated by which two factors?
1. Hyperpolarisation 2. Cyclic AMP (cAMP)
41
HCN (hyperpolarisation-activated cyclic nucleotide) channels mediate which current?
Funny current (If) (sodium in, potassium out) Overall it is a depolarising current
42
What effect does cAMP have on HCN (hyperpolarisation-activated cyclic nucleotide)?
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
Pharmacologically, what is the benefit of blocking HCN channels and which drug can do so?
Ivabradine ## Footnote 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
What is the purpose of the drug Ivabradine?
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
To enable cardiac muscle contraction, which receptors are activated to allow for calcium induced calcium release?
Ryodine type 2 receptors (RyR2)
46
After cardiac muscle contraction, which two methods remove calcium from cells?
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
After cardiac muscle contraction, what is the effect of reduced calcium concentration?
1. Calcium dissociates from troponin C 2. Cross bridges break between actin and myosin
48
Sympathetic stimulation has what effect on the heart?
1. Increases heart rate 2. Increases contractile force
49
Which two neurotransmitters act frequently in the heart as part of the sympathetic system?
Adrenaline and noradrenaline
50
What happens when a B1 receptor is activated?
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
Protein kinase A has which 3 main effects when activated?
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
How is cAMP degraded?
Phosphodiesterase enzymes break down cAMP to 5'AMP
53
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)
Milrinone - too many side effects Potentially only used in absolute emergencies
54
Name thee catechloamines and state their function
1. Adrenaline 2. Noradrenaline 3. Dobutamine All increase heart rate and contractility
55
What is one negative impact of the catechloamines?
They can cause disturbances in heart rhythm
56
Adrenaline acts on which type of receptors?
Both alpha and beta adrenoceptors It is a mixed agonist
57
How can adrenaline be administered?
IM, IV or subcutaneously
58
What effects does adrenaline have in cardiac arrest?
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
Which receptors does dobutamine act on?
Beta 1 (weak B2 activity)
60
How is dobutamine administered?
IV
61
In what way are the effects conferred by dobutamine different to other catechloamines?
Has less effect on heart rate, and instead predominantly increases cardiac contractile force
62
Name a non-selective B adrenoceptor blocker
* Propranolol * Alprenolol (partial agonist, does not completely block B1 receptor activity)
63
Name a selective (B1) B adrenoceptor blocker
1. Atenolol 2. Bisoprolol 3. Metoprolol
64
How do B adrenoceptor antagonists affect a patient's heart rate and contractile force at rest?
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
Why are B-blockers prescribed to treat arrhythmias?
Excess adrenaline/noradrenaline release is what causes the sympathetic overdrive that manifests as an arrhythmia
66
B-blockers are used to treat which heart conditions?
1. Atrial fibrillation 2. Supraventricular tachycardia 3. Angina 4. Heart failure
67
Why would B-blockers be used to treat heart failure?
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
Name a drug in the B-blocker class for arrythmias and describe its properties
Carvedilol Is also an alpha-1 antagonist allowing dilation of systemic vasculature reducing blood pressure and improving cardiac function.
69
Why must B-blockers be administered at low initial doses and rise up to higher doses later for arrhythmia treatment?
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
When would B-blockers be considered first line treatment?
When hypertension is present alongside a co-morbidity such as angina
71
What are some adverse effects of B-blockers?
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
In a patient, with hypoglycaemia (low blood glucose due to diabetes), why is the use of B-blockers dangerous?
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
What is atropine?
A non-selective muscarinic antagonist
74
What is the main effect of atropine?
To increase heart rate (at moderate to high doses)
75
Why does atropine increase heart rate?
* Acts on M2 receptors in SA node preventing acetylcholine binding (from parasympathetic neurones) - vagal tone is reduced * This increases action potential discharge rate
76
Why does atropine have increased effect on athletes or highly physically trained individuals?
These people have increased vagal tone which atropine prevents - hence a larger difference in heart rate would be noticed
77
Which drug is used as first line treatment for bradycardia?
Atropine
78
Why does atropine have little effect on blood pressure?
Parasympathetics do not innervate arterioles - the main resistance vessels
79
What is an alternative drug to atropine used to treat bradycardia?
Glycopyrronium bromide
80
What is the range of doses for atropine and how is it administered?
300-600mg ## Footnote IV It is important that low doses are not given - these can slow heart rate and worsen the condition
81
What is anticholinesterase poisoning?
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
How is anticholinesterase poisoning treated?
Atropine
83
Digoxin is which type of drug?
Cardiac glyoside
84
Digoxin is a drug used in _____ \_\_\_\_\_\_\_ which acts mainly to increase _______ \_\_\_\_\_\_\_\_\_\_\_\_
Heart failure Cardiac contractility
85
In heart failure, how is cardiac output affected?
It is decreased to the point where it is insufficient to meet the demands of the body
86
How does heart failure affect the ventricular function curve?
The curve become depressed
87
In cardiac myocytes, where does digoxin act?
Na+/K+ ATPase
88
Why does digoxin increase contractility?
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
On the Na+/K+ ATPase, digoxin binds to which binding site?
Potassium (alpha subunit) - digoxin will compete for this site
90
Why must diuretic drugs be used carefully with digoxin?
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
What are the main direct effects of digoxin?
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
What are the main indirect effects of digoxin?
1. SA node discharge is reduced 2. Propagation of impulse through AV node is slowed - increases refractory period
93
How is digoxin adminstered alone?
IV - acute heart failure Orally - Chronic heart failure
94
In what situation would digoxin be used more frequently?
When heart failure is combined with atrial arrhythmias (drug slows impulses from atria to ventricles)
95
What are the side effects of digoxin?
1. Heart block - excessive AV node conduction depression 2. Can cause arrhythmias (high doses) 3. Nausea, vomiting, diarrhoea, vision disturbances
96
Name a drug which sensitises troponin C to calcium
Levosimendan
97
How does Levosimendan work?
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
When would levosimendan be used?
Acute decompensated heart failure (by IV)
99
What are inodilators?
Drugs which can block phosphodiesterase enzymes therefore preventing cAMP degradation. This allows heart force and increased vasodilation to occur
100
Give an example of an inodilator
1. Amrinone 2. Milrinone Administered by IV - used rarely due to increased incidence of arrhythmias

The Cardiovascular System (24 decks)

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