Drugs and the cardiovascular system: The heart

Question 1

Name the cells which comprise the primary pacemaker site within the heart. Unlike most other cells that elicit action potentials, how is the depolarising current carried into these cells?

Answer 1

Sinoatrial (SA) nodal cells

• They are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials
• The depolarizing current is carried into the cell primarily by relatively slow Ca2+ currents instead of by fast Na+ currents (no fast Na+ channels and currents operating in SA nodal cells)

Question 2

SA nodal action potentials are divided into three phases. What do they each represent?

Answer 2

Phase 4 = the spontaneous depolarisation that triggers the action potential once the membrane potential reaches threshold
Phase 0 = depolarisation
Phase 3 = repolarisation; once the cell is completely repolarised at about -60 mV, the cycle is spontaneously repeated.

Question 3

In the SA node, three ions are particularly important in generating the pacemaker action potential. State the role of these ions in the different action potential phases.

Answer 3

• At the end of phase 3, I(f) channels open that conduct slow, inward (depolarizing) Na+ currents = ‘funny’ currents (initiating phase 4)
• At about -50 mV membrane potential, transient or T-type Ca2+ channels open and the inward directed Ca2+ currents further depolarise the cell
• At about -40mV membrane potential, long-lasting or L-type Ca2+ channels open => more Ca2+ influx depolarises the cell further until threshold is reached.
• Phase 0 depolarisation is caused by increased Ca2+ influx through L-type channels (other channels close during this phase)
• Phase 3 repolarisation occurs as K+ channels open => K+ efflux; at the same time, the L-type Ca2+ channels become inactivated and close.

Question 4

Although pacemaker activity is spontaneously generated by SA nodal cells, how can the rate of this activity be modified by SNS/PNS?

Answer 4

Sympathetic activation of the SA node (via noradrenaline acting on beta adrenoceptors which increase cAMP) increases pacemaker firing rate by increasing “funny” pacemaker currents (If) and increasing slow inward Ca2+ currents (the slope of phase 4 is steeper, which decreases the time to reach threshold)

Parasympathetic activation of the SA node (via ACh acting on muscarinic receptors, which decrease cAMP) decreases pacemaker firing rate by having opposite effects to above + increasing K+ efflux.

Question 5

Stat the sequential steps that occur following membrane depolarisation (due to action potentials arising from the SA node) of a cardiac myocyte.

Answer 5

1. Voltage-gated calcium channels (aka Dihydropyridine receptors) open => small release of Ca2+ into cell
2. The small Ca2+ current induces Ca2+ release from the SR through ryanodine receptors
3. Local release causes Ca2+ spark which sum up to create a Ca2+ signal
4. Ca2+ binds to troponin to initiate contraction; relaxation occurs when Ca2+ unbinds
5. Ca2+ is actively pumped back into SR and is also released from the cell via exchange with Na+
6. Na+ gradient is maintained by the Na+/K+ ATPase pump

Question 6

Which method is responsible for the majority of calcium removal?

Answer 6

SR ATPase uptake responsible for >70% of calcium removal

Question 7

What regulates the action of the SR ATPase Ca2+ pump (SERCA) and how does it do this? State the consequences of upregulation in terms of rate of relaxation and contractility.

Answer 7

Phospholamban (PLN)

• Phospholamban phosphorylation by PKA is stimulated by beta-adrenergic activity
• When dephosphorylated it is an inhibitor of SERCA
• When phosphorylated it dissociates from SERCA and activates the Ca2+ pump

=> rate of cardiac relaxation is increased
=> increase in contractility is in proportion to the increase in the size of the SR calcium store

Question 8

What are the determinants of myocardial oxygen supply?

Answer 8

Arterial oxygen content

Coronary blood flow

Question 9

What are the determinants of myocardial oxygen demand?

Answer 9

Heart rate
Contractility
Preload
Afterload

Poor supply and high demand => angina

Question 10

What effect do beta-blockers and calcium channel blockers have on the channels responsible for the SA node action potential, and hence heart rate? What effect do they have on contractility? What makes them excellent antianginal drugs?

Answer 10

• Beta-blockers decrease If and calcium channel activity
• Calcium channel blockers only decrease calcium channel activity

They both decrease heart rate and contractility which leads to a reduction in myocardial oxygen demand. CCBs can also dilate coronary arteries thereby increasing myocardial oxygen supply

Question 11

Name a drug that decreases If channel activity. Does it affect contractility?

Answer 11

Ivabradine (blocks the If channel)

No

Question 12

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

Answer 12

Rate slowing which have cardiac and smooth muscle actions:

• Phenylalkylamines (e.g. verapamil)
• Benzothiazepines (e.g. diltiazem)

Non-rate slowing which only have smooth muscle actions:
- Dihydropyridines (e.g. amlodipine)

Question 13

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

Answer 13

By blocking calcium entry into the smooth muscle cell => Profound systemic vasodilation => Reflex tachycardia (baroreceptor reflex)

Question 14

How do organic nitrates cause vasodilation?

Answer 14

• Organic nitrates are substrates for nitric oxide production.
• NO activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP.
• Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation
• NO also activates K+ channels, which leads to hyperpolarization and relaxation.

Question 15

Why are the organic nitrates useful in treating angina?

Answer 15

• Organic nitrates can dilate both arteries and veins (venous dilation > arterial dilation). Venous dilation reduces venous pressure and decreases ventricular preload. This reduces ventricular wall stress and oxygen demand by the heart, thereby enhancing the oxygen supply/demand ratio.
• Mild coronary dilation will further enhance the oxygen supply/demand ratio
• Systemic arterial dilation reduces afterload, which can enhance cardiac output while at the same time reducing ventricular wall stress and oxygen demand

Question 16

How do potassium channel openers work? Why are they good for angina?

Answer 16

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

They have the same effect as organic nitrates on preload, afterload and coronary blood flow

Question 17

Under what circumstance must caution be taken when giving beta-blockers? How would avoid/reduce the problem but still use beta-blockers?

Answer 17

Cardiac failure would be worsened because of the:

• CO reduction
• Increased vascular resistance (due to reduced vasodilation)
• Bradycardia

Give a beta-blocker with intrinsic sympathomimetic activity or alpha 1 blocking effects

Question 18

Why is cold extremities a side effect of beta blocker use?

Answer 18

Loss of β2 receptor mediated cutaneous vasodilation in extremities

Question 19

What are the side effects of verapamil?

Answer 19

Bradycardia and AV block

Constipation

Question 20

What are the side effects of dihydropyridines?

Answer 20

Ankle oedema (vasodilation means more pressure on capillary vessels)
Headaches/flushing (vasodilation)
Palpitations

Question 21

What is a simple classification of arrhythmias?

Answer 21

Based on its point of origin

Supraventricular, Ventricular and Complex (both)

Question 22

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

Answer 22

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

Question 23

What is adenosine used to treat?

Answer 23

It is used intravenously to terminate supraventricular tachycardia

Question 24

How does adenosine work?

Answer 24

• 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 => decreased chronotropy and dromotropy

Question 25

What is verapamil used for? and why?

Answer 25

Reduction of ventricular responsiveness to atrial arrythmias
It decreases the firing rate of aberrant pacemaker sites within the heart, and decreases conduction velocity at the AV node.

Question 26

Why is adenosine safer than verapamil?

Answer 26

Its actions are short-lived (20-30s)

Question 27

What is amiodarone used to treat?

Answer 27

Supraventricular tachyarrhythmia

Ventricular tachyarrhythmia

Question 28

How does amiodarone work?

Answer 28

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 29

Name the mechanism that accounts for most tachyarrhythmias found in patients. Describe this phenomenon.

Answer 29

Re-entry mechanism

• 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 (unidirectional block)
• The AP travels retrograde through the unidirectional block
• When the action potential exits the block, if it finds the tissue excitable, then the action potential will continue by travelling down an re-exciting the tissue

Question 30

What are the important adverse effects of amiodarone?

How long is its half-life and what is the significance of this?

Answer 30

photosensitive skin rashes
hypo- or hyper-thyroidism
pulmonary fibrosis

Amiodarone accumulates in the body (t½ = 10 - 100 days)

Question 31

What is the target of cardiac glycosides like digoxin?

Answer 31

Na+/K+ ATPase

Question 32

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

Answer 32

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
=> positive inotropic effect

It also causes central vagal stimulation => increased refractory period and reduced rate of conduction through the AV node (fewer impulses reach the ventricles and ventricular rate falls)

Question 33

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

Answer 33

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 34

What is digoxin used to treat?

Answer 34

Atrial fibrillation

Atrial flutter

Question 35

What is an adverse effect of digoxin?

Answer 35

Dysrrhythmias