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 in response to depolarisation?

Answer 4

It binds to ryanodine receptors on the sarcoplasmic reticulum and cause calcium release from the SR Also contributes 20-30% of the free calcium binding to troponin

Question 5

How does the calcium stimulate contraction?

Answer 5

It binds to troponin on the thin filament This causes a conformational change in tropomyosin so it unblocks the myosin-actin binding site

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 and why?

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 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 phosphorylated and dephosphorylated by?

Answer 9

Phosphorylated by by protein kinase A dephosphorylated by 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.
• Sodium

Ica (T or L):

• Transient T-type Ca++ channel
• or Long Lasting L-type Ca++ channel

IK – Potassium K+ channels

Question 11

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

Answer 11

If channel is a slow release 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

Describe the intracellular pathway that beta adrenoceptors are coupled with in the heart

Answer 12

Adenylate cyclase:

• it increases cAMP.
• cAMP upregulates PKA production which in turn activates (through phosphorylation) Ica channels, RyRs and If channels

Question 13

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

Answer 13

It is negatively coupled with adenylate cyclase

Inhibition of adenylate cyclase causes decreased cAMP levels

This causes decreased opening of If and Ica channels

Decreased rate and strength of cardiac contraction

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 (least powerful determinate) Afterload

Question 16

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

Answer 16

Beta-blockers decrease If and calcium channel activity by blocking an increase in cAMP Calcium channel blockers decrease L-type calcium channel activity

Question 17

Name a drug that decreases If activity, what effect does it have on contracility?

Answer 17

Ivabradine (blocks the If channel) It has no effect on contractility because it doesn’t affect the calcium channels

Question 18

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

Answer 18

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

Question 19

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

Answer 19

Reflex tachycardia (baroreceptor reflex)

Question 20

How do organic nitrates cause vasodilation?

Answer 20

Organic nitrates are substrates for nitric oxide production

The NO then diffuses into the smooth muscle and activating guanylate cyclase

Guanylate cyclase converts GTP to cGMP

cGMP actiavtes the plasma membrane potassium channel - efflux of potassium from the cell causes hyperpolarization

Hyperpolarization inhibits the membrane calcium channel causes relaxtion

cGMP also causes direct relaxtion of the cell by an unknown mechanism

Question 21

How do potassium channel openers work?

Answer 21

They open the potassium channels and hyperpolarise the vascular smooth muscle This causes a closure of voltage-gated calcium (Ca2+) channels so the cell is less likely to contract

Question 22

How do vasodilation and venodilation reduce myocardial oxygen demand?

Answer 22

Vasodilation reduced TPR, so reduce the pressure against which the heart is pumping (reduce afterload) Venodilation increases the reservoir capacity of the venous system, reducing venous return to the heart (reduced preload) Decreases the work-load of the heart so decreased strength of contractility

Question 23

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

Answer 23

Angina pectoris

Question 24

State some unwanted effects of beta-blockers.

Answer 24

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

Question 25

When treating what condition must caution be taken when giving beta-blockers?

Answer 25

In the treatment of heart failure b blockers slow the heart to allow time to fill effectively but because they reduce heart rate and contractility it can have catastrophic consequences in cardiac failure patients if the dose is too high Can also be used to treat heart failure

Question 26

What are the side effects of verapamil?

Answer 26

Bradycardia

AV block

Constipation

Question 27

What are the side effects of dihydropyridines?

Answer 27

Ankle oedema Headaches/flushing Palpitations

Question 28

What is a simple classification of arrhythmias?

Answer 28

Based on its point of origin:

Supraventricular, Ventricular and Complex

Question 29

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

Answer 29

Vaughan-Williams classification

I – sodium channel blockers

II – beta-blockers

III – prolongation of repolarisation (mainly due to potassium channelblockade)

IV – calcium channel blockers

Question 30

What is adenosine used to treat?

Answer 30

It is used to terminate supraventricular tachycardia

Question 31

How does adenosine work in coronary vascular smooth muscle?

Answer 31

• In coronary vascular smooth muscle, adenosine binds to adenosine type 2A (A2A) receptors, which are coupled to the Gs-protein.
• Activation of this G-protein stimulates adenylyl cyclase (AC in figure),
• this increases cAMP and causes protein kinase activation.
• PKA activates K⁺ATP channels, which hyperpolarizes the smooth muscle, causing relaxation.
• Increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase, which leads to decreased myosin phosphorylation and a decrease in contractile force.
• There is also evidence that adenosine inhibits calcium entry into the cell through L-type calcium channels.

Question 32

What is verapamil used to treat?

Answer 32

Supraventricular tachycardia Atrial fibrillation

Question 33

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

Answer 33

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

Question 34

What is amiodarone used to treat?

Answer 34

Supraventricular tachyarrhythmia Ventricular tachyarrhythmia - often due to re-entry

Question 35

How does amiodarone work?

Answer 35

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 This reduces the chances of re-entry

Question 36

Describe re-entry.

Answer 36

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 37

What is the target of cardiac glycosides like digoxin?

Answer 37

Na+/K+ ATPase

Question 38

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

Answer 38

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 a positive inotropic effect

It also causes vagal stimulation, which has a negative chronotropic effect so reduces the conduction of electrical impulses within the AV node. Fewer impulses reach the ventricles and ventricular rate falls.

Question 39

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

Answer 39

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 40

What is digoxin used to treat?

Answer 40

Atrial fibrillation Atrial flutter

Question 41

What is an adverse effect of digoxin?

Answer 41

Dysrrhythmia e.g. AV conduction block, ectopic pacemaker activity

Question 42

What are cardiac inotropes? Name two.

Answer 42

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

Question 43

What are the ion currents responsible for the SA node depolarization?

Answer 43

If channel - slow leak sodium current to initiate depolarization Ica(t) - transient T-type calcium channel Ica(L) - Long lasting L-type calcium channel These channels generate a calcium current that is mainly responsible for depolarizion of the cell

Question 44

Whats the difference between the classes of calcium antagonist?

Answer 44

Rate slowing = effects primarily on the heart and some smooth muscle action Non-rate slowing = no effect on heart and stronger effect on vascular smooth muscle than rate slowing types

Question 45

When are organic nitrates often used?

Answer 45

They are often in angina patients before they exercise

Question 46

How does adenosine work in cardiac tissue?

Answer 46

• In cardiac tissue, adenosine binds to type 1 (A1) receptors, which are coupled to Gi-proteins.
• Activation of this pathway opens potassium channels, which hyperpolarizes the cell.
• Activation of the Gi-protein also decreases cAMP,
• which inhibits L-type calcium channels and therefore calcium entry into the cell. (negative ionotropy)
• In cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits the pacemaker current (If),
• which decreases the slope of phase 4 of the pacemaker action potential thereby decreasing its spontaneous firing rate (negative chronotropy).