Drugs and the Cardiovascular System – The Heart

Question 1

What is the major store of calcium within the cardiomyocyte?

Answer 1

Sarcoplasmic reticulum

Question 2

The heart has two signalling pathways that are involved in elevating the level of two intracellular second messengers. What are these second messengers?

Answer 2

Ca2+ and cAMP

Question 3

Which plasma membrane proteins allow calcium to enter the cell in response to depolarisation?

Answer 3

Dihydropyridine receptors

Question 4

What happens to the calcium once it has passes into the cell viathis channel?

Answer 4

It binds to ryanodine receptors on the sarcoplasmic reticulum and cause calcium release from the SR

Question 5

How does the calcium stimulate contraction?

Answer 5

It binds to troponin on the thin filament

Question 6

What are the different ways in which calcium is removed from the myoplasm after it has stimulated contraction? Which method is responsible for the majority of calcium removal?

Answer 6

Plasma membrane calcium ATPase
Na+/Ca2+ exchanger
SERCA2a (sarcoendoplasmic reticulum calcium ATPase) –responsible for >70% of calcium removal

Question 7

What features of contraction is SERCA2a responsible for andwhy?

Answer 7

Rate of calcium removal and so it’s responsible for the rate of cardiac muscle relaxation
Size of calcium store, which affects the contractility of the subsequent beat

Question 8

What regulates the action of SERCA2a and how does it do this?

Answer 8

Phospholamban (PLN)
Phospholamban phosphorylation is stimulated by beta-adrenergic activity
It is a target for phosphorylation by protein kinase A
When dephosphorylated it is an inhibitor of SERCA2a
When phosphorylated it dissociates from SERCA2a and activates the Ca2+ pump
As a result, the rate of cardiac relaxation is increased and, on subsequent beats, contractility is in proportion to the elevation in the size of the SR calcium store

Question 9

What is phospholamban dephosphorylated by?

Answer 9

Protein phosphatase 1

Question 10

What are the three main channels that are responsible for the action potential in the sinoatrial node?

Answer 10

If channel – hyperpolarisation-activated cyclic nucleotide-gated (HCN) channel 
Calcium channel (T and L type) 
Potassium channel

Question 11

Describe how these channels are responsible for the action potential of the sinoatrial node.

Answer 11

If channel is a sodium channel that opens at the most negative membrane potential
Opening of the sodium channel causes sodium influx, which begins to depolarise the membrane and stimulates the opening of calcium channels, which further depolarises the membrane
Potassium channels are responsible for repolarisation

Question 12

What are beta adrenoceptors coupled with?

Answer 12

Adenylate cyclase – it increases cAMP, which is important in the opening of the If channel to begin depolarisation

Question 13

How does the parasympathetic nervous system affect heart rate and contractility?

Answer 13

It is negatively coupled with adenylate cyclase

Question 14

What are the determinants of myocardial oxygen supply?

Answer 14

Arterial oxygen content

Coronary blood flow

Question 15

What are the determinents of myocardial oxygen demand?

Answer 15

Heart rate
Contractility
Preload
Afterload

Question 16

What effect do beta-blockers and calcium channel blockers haveon the channels responsible for the SA node action potential?

Answer 16

Beta-blockers decrease If and calcium channel activity

Calcium channel blockers only decrease calcium channel activity

Question 17

Name a drug that decreases If activity.

Answer 17

Ivabradine (blocks the If channel)

Question 18

What effect does this drug have on contractility?

Answer 18

It has no effect on contractility because it doesn’t affect the calcium channels

Question 19

What are the two types of calcium channel blocker? Name the drugs in each category including their drug class.

Answer 19

Rate slowing  
Phenylalkylamines – verapamil 
Benzothiazepines – diltiazem 
Non-rate slowing  
Dihydropyridines – amlodipine

Question 20

What is a consequence of non-rate slowing calcium channel blockers?

Answer 20

Reflex tachycardia (baroreceptor reflex)

Question 21

How do organic nitrates cause vasodilation?

Answer 21

Organic nitrates are substrates for nitric oxide production
The NO then diffuses into the smooth muscle and causes smooth muscle relaxation by activating guanylate cyclase
They are often in angina patients before they exercise

Question 22

How do potassium channel openers work?

Answer 22

They open the potassium channels and hyperpolarise the vascular smooth muscle so that it is less likely to contract

Question 23

How do vasodilation and venodilation reduce myocardial oxygen demand?

Answer 23

They reduce the pressure against which the heart is pumping (reduce afterload) and it also causes reduce venous return to the heart (reduced preload) meaning that contractility is decreased

Question 24

As these drugs reduce the myocardial oxygen demand, what condition can they all be used to treat?

Answer 24

Angina pectoris

Question 25

State some unwanted effects of beta-blockers.

Answer 25

``` Bradycardia Hypotension Hypoglycaemia in diabetics on insulin Cold extremities (because of beta-2 blockade) Bronchoconstriction Fatigue Impotence Depression CNS effects ```

Question 26

Under what circumstance must caution be taken when giving beta-blockers?

Answer 26

Cardiac failure – because they reduce heart rate and contractility it can have catastrophic consequences in cardiac failure patients

Question 27

What are the side effects of verapamil?

Answer 27

Bradycardia and AV block | Constipation

Question 28

What are the side effects of dihydropyridines?

Answer 28

Ankle oedema Headaches/flushing Palpitations

Question 29

What is a simple classification of arrhythmias?

Answer 29

Based on its point of origin | Supraventricular, Ventricular and Complex

Question 30

What is the main classification of anti-arrhythmic drugs and how are the drugs ordered?

Answer 30

``` Vaughan-Williams classification I – sodium channel blockers II – beta-blockers III – prolongation of repolarisation (mainly due to potassium channelblockade) IV – calcium channel blockers ```

Question 31

What is adenosine used to treat?

Answer 31

It is used to terminate supraventricular tachycardia

Question 32

How does adenosine work?

Answer 32

Adenosine binds to adenosine receptors in the cardiac muscle and vascular smooth muscle Adenosine receptors are negatively coupled with adenylate cyclase Reducing the cAMP in nodal tissue will impact on depolarisation within the AV node

Question 33

What is verapamil used to treat?

Answer 33

Supraventricular tachycardia | Atrial fibrillation

Question 34

What is the target of verapamil and how does it work?

Answer 34

L-type calcium channel | Reducing calcium entry means that the speed with which the tissue is depolarise is reduced

Question 35

What is amiodarone used to treat?

Answer 35

Supraventricular tachyarrhythmia | Ventricular tachyarrhythmia

Question 36

How does amiodarone work?

Answer 36

It works by blocking many ion channels Its main effect seems to be through potassium channel blockade This prolongs repolarisation, so you’re prolonging the time during which the tissue can’t depolarise

Question 37

Describe re-entry.

Answer 37

Some damaged cardiac tissue will make it difficult for depolarisation to pass through it in one direction, but it will allow the action potential to propagate in the opposite direction This could mean that you get a miniature circuit set up within the tissueand you get re-entry of action potentials

Question 38

What is the target of cardiac glycosides like digoxin?

Answer 38

Na+/K+ ATPase

Question 39

How does digoxin work and what are its effects on the heart?

Answer 39

By blocking Na+/K+ ATPase it causes an accumulation of Na+ in the cell The excess Na+ is then removed by Na+/Ca2+ exchanger, thus increasing the intracellular calcium concentration This has an inotropic effect It also causes vagal stimulation, which has a chronotropic effect

Question 40

What is an important factor to consider before starting treatment with digoxin?

Answer 40

Hypokalaemia Digoxin binds to the potassium binding site on the extracellular component of Na+/K+ ATPase so it competes with potassium for the binding site If hypokalaemic, there is less competition for digoxin and so the effects of digoxin are exaggerated

Question 41

What is digoxin used to treat?

Answer 41

Atrial fibrillation | Atrial flutter

Question 42

What is an adverse effect of digoxin?

Answer 42

Dysrrhythmia

Question 43

What are cardiac inotropes? Name two.

Answer 43

They increase the contractility of the heart (it is used in acute heart failure in some cases) Dobutamine (beta-1 agonist) Milrinone (phosphodiesterase inhibitor)