16. Action of Drugs on the Cardiovascular System

Question 1

Which parts of the cardiovascular system can be altered by drugs?

Answer 1

The rate and rhythm of the heart.
The force of myocardial contraction.
Peripheral resistance and blood flow.
Blood volume.

Question 2

What are some of the possible causes of arrhythmias?

Answer 2

Ectopic pacemaker activity, afterdepolarisations, re-entry loop.

Question 3

How can ectopic pacemaker activity cause arrhythmias?

Answer 3

A damaged area of myocardium becomes depolarised and spontaneously active. Latent pacemaker region activated due to ischaemia.

Question 4

How can afterdepolarisations cause arrhythmias?

Answer 4

Abnormal depolarisation following the action potential, triggered activity.

Question 5

How can re-entry loops cause arrhythmias?

Answer 5

Conduction delay, accessory pathway.

Question 6

What is the difference between delayed and early after-depolarisations?

Answer 6

Delayed AD are from prolonged action potentials and are more likely to happen if intracellular Ca2+ concentration is high.
Early AD can lead to oscillations and is more likely to happen if action potential is prolonged, leads to longer QT interval.

Question 7

How can a block in conduction cause arrhythmias?

Answer 7

Normally when a spread of excitation reaches a branch, it splits and any bits that meet cancel each other out. But when there is incomplete conduction damage (unidirectional block) excitation can take a long route to spread the wrong way through the damages area to set up a circus of excitation.

Question 8

What can multiply re-entry loops in the atria lead to?

Answer 8

Atrial fibrillation.

Question 9

What are the four classes of anti-arrhythmic drugs?

Answer 9

I - drugs that block sensitive sodium channels.
II - antagonists of B-adrenoreceptors.
III - drugs that block potassium channels.
IV - drugs that block calcium channels.

Question 10

How does the local anaesthetic lidocaine work?

Answer 10

It is a type I antiarrhythmic. It only blocks voltage gated Na+ channels when open or inactive. They dissociate rapidly in time for the next action potential. This causes a use-dependent block.

Question 11

What type of tissue does lidocaine not affect in a healthy person?

Answer 11

Normal cardiac tissue.

Question 12

When is lidocaine given with MI and why?

Answer 12

Following the MI if the patient sows signs of ventricular tachycardia and it’s given intravenously. This is because damaged myocardium can be depolarised and fire automatically so more Na+ are open so lidocaine blocks these and prevents automatic firing of depolarised ventricular tissue.

Question 13

How do B-adrenoceptor antagonists work?

Answer 13

They block sympathetic action by acting on the B1-adrenoceptors in the heart. They decrease the slope of pacemaker potential in the SA node.

Question 14

Why are B-adrenoceptor antagonists used following a MI?

Answer 14

MI causes increased sympathetic activity but B-blockers prevent ventricular activity which takes away some cause of arrhythmias. It also reduces O2 demand and so reduces myocardial ischaemia. Finally it slows conduction in the AV node, this can prevent supraventricular tachycardias and slows ventricular rate in patients with AF.

Question 15

How does class III antiarrhythmia drugs work?

Answer 15

By blocking the K+ channel so prolonging the action potential. This lengthens the absolute refractory period and theoretically prevents another action potential happening soon.

Question 16

Why are class III antiarrhythmia drugs not used commonly?

Answer 16

They can actually cause arrhythmias.

Question 17

What is the one safe exception of class III antiarrhythmia drugs?

Answer 17

Amiodarone.

Question 18

How does amiodarone work and why is it safer than other class III antiarrhythmics?

Answer 18

It blocks K+ channels but has other actions too so not pro-arrhythmic. It treats tachycardia associated with Wolff-Parkinson-White syndrome.

Question 19

How do class IV anti-arrhythmic drugs work?

Answer 19

They block Ca2+ channels so decrease the slope of action potentials at SA node and at the AV node, this decreases the force of contraction.

Question 20

How does adenosine work as an antiarrhythmic?

Answer 20

It acts of A1 receptors at the AV node. This enhances K+conductance, so hyperpolarises cells on conducting tissue.

Question 21

What is heart failure?

Answer 21

Chronic failure of the heart to provide sufficient output to meet the body’s requirements.

Question 22

What are the features of heart failure?

Answer 22

Reduced force of contraction, reduced cardiac output, reduced tissue perfusion, and oedema.

Question 23

What are the two approaches to treating heart failure?

Answer 23

Positive inotropes increase cardiac output - cardiac glycosides and B-adrenergic agonists.
Drugs which reduce work load of the heart - reduce afterload and preload.

Question 24

Which drugs increase myocardial contractility?

Answer 24

Cardiac glycosides, and digoxin.

Question 25

What is the action of cardiac glycosides?

Answer 25

Ca2+ is extruded via the Na+Ca2+ exchanger, driven by Na+ moving down its concentration gradient. Cardiac glycosides block Na+K+ATPase so [Na+]in rises, which in turn decreases activity of Na+Ca2+ exchanger as it depends on the Na+ concentration gradient which is now lower. This raises [Ca2+]in and thus increases force of contraction.

Question 26

How do cardiac glycosides act specifically in the heart?

Answer 26

Cause increased vagal activity via action in the central nervous system, this slows AV conduction and therefore heart rate.

Question 27

Which group of drugs increase myocardial contractility?

Answer 27

B-adrenoreceptor agonists, e.g. dopamine that acts on B1-receptors.

Question 28

Why have cardiac glycoside been used less frequently in cardiac failure in recent years?

Answer 28

Because they work in the short term but not in the long run, so it’s now thought to be better to reduce workload.

Question 29

What is the mechanism of action of ACE-inhibitors?

Answer 29

They inhibit the action of angiotensin converting enzyme. This prevents the conversion of the physiological inert angiotensin I to the strong vasoconstrictor angiotensin II. Angiontensin II acts on the kidney to increase Na+ and water reabsorption so stopping it’s conversion lowers blood pressure.

Question 30

Which drugs reduce the workload of the heart?

Answer 30

B-adrenoceptor antagonists (B-blockers), diuretics (reduce blood volume).

Question 31

What is angina?

Answer 31

Myocardial ischaemia, the supply of O2 to the heart does not meet its need for a limited duration.

Question 32

What is the underlying cause of angina?

Answer 32

Narrowing of the coronary arteries, atheromatous disease.

Question 33

What are the two mechanisms of treating heart failure?

Answer 33

Reduce the work load of the heart - B-adrenoreceptor blocks, Ca2+ channel antagonists, organic nitrates.
Improve the blood supple to the heart - organic nitrates, Ca2+ channel antagonists.

Question 34

What do organic nitrates react with?

Answer 34

Thiols (-SH groups) in vascular smooth muscle to cause NO2- release, this is reduced to NO (nitric oxide).

Question 35

What is the action of nitric oxide?

Answer 35

It is a powerful vasodilator.

Question 36

What is the mechanism of action of nitric oxide?

Answer 36

It actives guanylate cyclase increases cGMP, lowers [Ca2+]in, and causes relaxation of vascular smooth muscle.

Question 37

How does nitric oxide alleviate symptoms of angina?

Answer 37

Primary action - venodilation in venous system so lower preload and work load of the heart, the force of contraction is reduced and lowers O2 demand.
Secondary action - improves O2 delivery to ischaemic myocardium via coronary arteries by dilating collateral arteries.

Question 38

Why don’t organic nitrates work by perfusing arterioles?

Answer 38

Because it there is a block, dilating the vessel before or after the block will make no difference, so it has to be dilation of the collateral artery more distal to the block to increase arteriole supply to the myocardium.

Question 39

Why is the effect of organic nitrate on collateral arteries in the heart a minor one in treating angina?

Answer 39

Because the coronary arteries are end arteries so there are not many collateral ligaments therefore they have a limited overall effect.

Question 40

What are the two types of antithrombotic drugs?

Answer 40

Anticoagulants and antiplatelet drugs.

Question 41

What are some anticoagulant drugs that lower risk of thrombus formation?

Answer 41

Heparin (given IV) - inhibits thrombin, used acutely.
Fractionated heparin (given as SC injection).
Warfarin (given orally) - antagonises action of vitamin K, used long term.

Question 42

What is an example of an antiplatelet drug that lowers risk of thrombus formation?

Answer 42

Aspirin - following acute MI, or high risk of MI.

Question 43

What is hypertension caused by?

Answer 43

Increased blood volume and increased total peripheral resistance.

Question 44

What is the equation for working out blood pressure?

Answer 44

BP = CO x TPR.

Question 45

What are the possible targets for treating hypertension?

Answer 45

Lower blood volume (so lowers CO via Starling’s Laws), lower cardiac output directly, and lower peripheral resistance.

Question 46

What are the five groups of drugs for managing hypertension?

Answer 46

Diuretics - decrease Na+ and water retention by kidney so decrease blood volume.
ACE-inhibitors - decrease Na+ and water retention by kidney and decrease total peripheral resistance by vasodilation.
B-blockers - decrease cardiac output.
Ca2+ channel blockers in vascular smooth muscle - cause vasodilation.
a1-adrenoceptor antagonists - cause vasodilation.