Drugs and the heart

Question 1

What are the mechanisms regulating heart rate?

Answer 1

Cells within the sinoatrial (SA) node are the primary pacemaker site within the heart. These cells are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials.
Unlike non-pacemaker action potentials in the heart, and most other cells that elicit action potentials (e.g., nerve cells, muscle cells), the depolarizing current is carried into the cell primarily by relatively slow Ca++ currents instead of by fast Na+ currents. There are, in fact, no fast Na+ channels and currents operating in SA nodal cells.

Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the AP

Pacemaker cells:
Sympathetic - B1 receptors –> upregulate cAMP which upregulate If and Ica = Increases HR. Shortens the time frame between 4 and 0. See diagram
Parasympathetic - downregulate cAMP and upregulate IK = promotes repolarisation

Question 2

What are the three types of membrane ion channels?

Answer 2

1) Mixed sodium-potassium current - [If] (Hyperpolarisation-activated cyclic nucleotide-gated channel (HCN channels))
2) L-type calcium channels (slow sodium-calcium channels) - [Ica]
3) Potassium channels 0 - [IK]

In ventricular muscle cells the fast sodium channels cause a rapid upstroke AP. Then a ‘plateau’ occurs due to a slower opening Ica. Finally repolarisation occurs with the opening of the IK (potassium) channels.

Question 3

Describe the mechanisms regulating contractility

Answer 3

Electrical excitation of the cell from action potentials arising from the sino-atrial node induce membrane depolarization that promotes gating of Ca2+ channels, which open and cause a small release of Ca2+ into the cytoplasm. The small Ca2+ current induces a release of Ca2+ from the SR by a process called Ca-induced Ca-release. The release occurs through Ca2+ release channels commonly referred to as ryanodine receptors (RyR2).

Depolarization-induced influx of Ca2+ current (ICa) through the L-type channels contributes approximately 20–25% of the free Ca2+ in a cardiac twitch. The release of Ca2+ through the RyRs contributes the remaining 75–80% of Ca2+ necessary for cardiac contraction.

There is a Ca2+/Na+ exchange protein and Na+/K+ ATPase which maintains the membrane potential

Question 4

Describe the concept of myocardial oxygen supply and demand

Answer 4

The heart isn’t particularly well perfused compared to the brain so it’s relatively easy for myocardial oxygen demand to exceed the supply

The coronary vessels deliver oxygen and nutrients to the heart muscle depending on how hard the heart is working. Work –> myocaridial oxygen demand

This depends on: (these all make the heart work harder = increase in demand for oxygen)

• Heart Rate
• Preload
• Afterload
• Contractility

Myocyte contraction = primary determinant of myocardial oxygen demand
↑ H.R. = more contractions; ↑ afterload or contractility = greater force of contraction; ↑ preload = small ↑ in force of contraction ( 100% ↑ ventricular
volume would only ↑ F.O.C. by 25%)

See slides

Question 5

What drugs influence (decrease) heart rate?

Answer 5

B-blockers - decrease If and Ica
Calcium antagonists - decrease Ica
Ivabradine - Decrease If

Calcium and ivabradine are direct channel blockers

Question 6

What drugs influence contractility?

Answer 6

B-blockers - decrease contractility. Block B1 –> decreases cAMP –> decreases Ica
Calcium antagonists - blocks Ica

Question 7

What are the classes of calcium channel antagonists?

Answer 7

Rate slowing (Cardiac and smooth muscle actions) (rate limiting)

• Phenylalkylamines (e.g. Verapamil)
• Benzothiazepines (e.g. Diltiazem)

Non-rate slowing (smooth muscle actions – more potent on smooth muscle)
- Dihydropyridines (e.g. amlodipine)

Non-rate slowing calcium channel blockers cause REFLEX TACHYCARDIA. They only effect the vasculature not the heart - cause vasdilation –> decreases BP –> baroreceptors detect

Rate slowing calcium channel blockers will reduce heart rate and cause vasodilation. Amlodipine has no effect on the heart so vasodilation causes reflex tachycardia

Question 8

Describe the used of organic nitrates and potassium channel openers?

Answer 8

Organic nitrates are substrates for nitric oxide production.

Entering endothelial cells they promote NO production. The NO then enters smooth muscle causing smooth muscle relaxation by activating guanylate cyclase. cGMP = relaxation

Potassium channels openers promote potassium efflux so it’ll hyperpolarise the smooth muscle and reduce its ability to contract.

Overall they cause smooth muscle relaxation = increase coronary blood flow

Question 9

What are organic nitrates used for?

Answer 9

Angina when there is profound atherosclerosis reducing the blood flow to the heart. Before they exercise organic nitrates are used because it dilates coronary vessels so blood flow is improved.

Increased coronary blood flow

Question 10

Describe the effects of vasodilation and venodilation

Answer 10

Vasodilation reduces TPR hence reduces afterload

This means that the heart has to work less hard against the resistance

The drugs also cause venodilation, which reduces venous return to the heart and hence reduces preload and contractility

The reduction in afterload and preload causes a decrease in myocardial oxygen demand

Question 11

Draw a diagram showing the effects of nitrate, potassium channel opener, Ivabradine , beta blockers and CCB on myocardial oxygen demand/supply.

Answer 11

See diagram on slides

All these drugs aim to improve coronary blood flow.

Question 12

How do you treat angina?

Answer 12

ANGINA TREATMENT: (Angina = Myocardial Ischaemia)
Beta blocker or calcium antagonist as background anti-angina treatment.
Ivabradine is a newer treatment
Nitrate as symptomatic treatment (short acting)
Other agents e.g. potassium channel opener if intolerant to other drugs

All these drugs are also used with heart failure - use Ivabradine and beta blockers

Question 13

What are the side effects of beta blockers?

Answer 13

Beta 2 receptors blockade will reduce vasodilation and increase TPR which can worsen heart failure.

Bradycardia - heart block decreased conduction through AV node.

Pindolol (beta blocker) will have some beta 2 stimulating effects due to ISA or carvedilol with alpha 1 blocking effects can decrease TPR and alleviate this problem.

• Bronchoconstriction - B2 receptors in lungs dilate them
• Hypoglycaemia - B2 stimulation causes gluconeogenesis and glycogenolysis
• Cold extremities - reduced vasodilation

[ - Fatigue

• Impotence (sexual dysfunction)
• Depression
• CNS effects (lipophilic agents) e.g. nightmares]

See side effects of beta blockers in SNS antagonists lecture

Question 14

What are the side effects of calcium channel blockers?

Answer 14

Verapamil

• Bradycardia and AV block (Ca2+ channel block)
• Constipation (Gut Ca2+ channels) – 25 % patients

Dihydropyridines – 10-20% patients
- Ankle Oedema – vasodilation means more pressure on capillary vessels
- Headache / Flushing – vasodilation
- Palpitations
Ankle oedema and headache flushing are also the side effects of K+ channel opener and nitrate since these drugs also affect the blood vessels.

CCBs that target the heart are going to have similar side effects to beta blockers

With any drug that causes profound vasodilation, you have to think about fluid accumulation

If you have loads of vasodilation then you’re going to get more leakage through the capillaries into the tissues

It is worse the further you get from the heart (hence why you get ankle oedema)

Vasodilation/reflex adrenergic activation

Question 15

Describe rhythm distubrances

Answer 15

These are abnormalities of cardiac rhythm (arrhythmias/dysrhythmias).

Aims of treatment are

• Reduce sudden death
• Prevent stroke
• Alleviate symptoms

Question 16

How do you classify arrhythmias?

Answer 16

This is done based on the site of origin

• Supraventricular arrhythmias (e.g. amiodarone, verapamil)
• Ventricular arrhythmias (e.g. flecainide, lidocaine).
• Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide).

Question 17

Describe the Vaughan-Williams classification of anti-arrhythmic drugs

Answer 17

See diagram

Class I - Sodium channel blockade
Class II - Beta adrenergic blockade
Class III - Prlongation of repolarisation (Membrane stabilisation mainly due to potassium channel blockade)
Class IV - Calcium channel blockade

Question 18

List some anti-arrhythmic drugs

Answer 18

Adenosine
Verapamil
Amiodarone
Digoxin (cardiac glycoside)

Question 19

When is adenosine used for?

Answer 19

Used intravenously to terminate supraventricular tachyarrhythmias (SVT). Its actions are short-lived (20-30s) and it is consequently safer than verapamil.

Question 20

What is the mechanism of action of adenosine on cardiac smooth muscle?

Answer 20

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. 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).

Question 21

What is the mechanism of action of adenosine on vascular smooth muscle?

Answer 21

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), increases cAMP and causes protein kinase activation. This stimulates KATP channels, which hyperpolarizes the smooth muscle, causing relaxation. This relaxation gives the heart more time to fill = more efficient contraction.

[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 22

What is verapamil used for?

Answer 22

Reduction of ventricular responsiveness to atrial arrythmias

Question 23

What is the mechanism of action of verapamil?

Answer 23

Depresses SA autonmaticity and subsequent AV node conduction.

This mainly targets the L-type calcium channels

This slows down the ability of the nodal tissue to depolarise

If you have rapid excessive depolarisations, as in tachyarrhythmias, you want to reduce that effect

CCBs block the membrane calcium channels so there is less calcium entry so the speed with which tissue can depolarise is reduced

This restores some normal contraction

Question 24

What is amiodarone used for?

Answer 24

superventricular and ventricular tachyarrhythmias – often due to re-entry

Question 25

What is the mechanism of action of amiodarone?

Answer 25

Complex action involving multiple ion channel block - main action is K+ channel block.

It prolongs repolarisation. By prolonging repolarisation, you’re prolonging the time during which the heart can NOT depolarise, thus restoring normal rhythm. See basis of arrythmias

t1/2 = 10-110 days

Adverse side effects:

• Photosensitive skin rashes
• hypo- or hyper-thyroidism (Thyroid malfunction)
• Pulmonary fibrosis

Question 26

What is the basis of arrythmias?

Answer 26

With cardiac tissue, as the action potential is propagated through the tissue you can have damaged bits of tissue where the action potential struggles to pass through

IMPORTANT POINT: THIS IS USUALLY UNIDIRECTIONAL

The action potential will struggle to go one way but then it is fine to go back in the opposite direction

In the bottom left diagram, the action potential (red) passes around the bottom left corner and because the damaged tissue (shaded blue) has not been depolarised by the action potential on the way down from the top, the action potential can pass back up the tissue and you get cyclical depolarisation. It goes back and then reactivates that particular part of tissue. Amiodarone causes the the tissue to still be hyperpolarised meaning even if the reentry current passes through it will not cause depolarisation.

See slides for diagram

Question 27

How do cardiac glycosides work?

Answer 27

Digoxin - Inhibition of Na-K-ATPase (Na/K pump). This results in increased intracellular Ca2+ via effects on Na+/Ca2+ exchange → positive inotropic effect. The Na+ needs to be removed so the Na+/Ca2+ pump is used remove Na+. It binds to the extracelluar K+ binding site.

Therefore the heart slows down and contracts more forcefully (increased intropy).

Digoxin also has an effect on vagal stimulation. It stimulates the parasympathetic innervation of the heart so it slows the heart rate via this route as well. Causes an increased refractory period and reduced rate of conduction through the AV node .

Question 28

Why does hypokalaemia lowers the threshold for digoxin toxicity?

Answer 28

The protein works by sodium binding to the intracellular component of the channel and potassium binding to the extracellular component, then the protein flip flops

Digoxin accesses the pump from outside the cell (from the blood) - as it is on the outside, the digoxin interferes with the potassium binding site

If you’re HYPOKALAEMIC then there is less competition between the potassium and digoxin so the digoxin has a far more powerful effect on this protein and that’s where the toxicity comes from

So when giving digoxin, you need to know the plasma potassium levels to adjust the dose

Question 29

What is digoxin used for?

Answer 29

Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output

Question 30

What are the adverse effects of digoxin?

Answer 30

• Dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
• Hypokalaemia toxicity