L14: Understanding arrhythmias and Action of drugs on CVS

Question 1

What are the different types of abnormalities you can have to the heart rhythm?

Answer 1

Bradycardia
Atrial fibrillation 
Atrial flutter
Tachycardia--> Ventricular and supraventricular
Ventricular fibrillation

Question 2

What are some of the causes of tachycardia?

Answer 2

Ectopic pacemaker activity
Afterdepolarisations–> abnormal depolarisation following AP (delayed and early)
Atrial flutter/ atrial fibrillation
Re-entry loop–> conduction delay, accessory pathway

Question 3

How does ectopic pacemaker activity arise?

Answer 3

Damaged area of myocardium –> depolarised and spontaneously active, or latent pacemaker region activated due to ischaemia (dominates over SA node)

Question 4

What is delayed after-depolarisations (triggered activity)?

Answer 4

Occur after repolarisation phase
More likely to happen if intracellular Ca2+ increased (activate Cl- channels or Na+/Ca2+ exchanger–> brief inward current–> threshold reached–> AP generated)

Question 5

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

Answer 5

Delay–> after repolarisation

Early–> During repolarisation

Question 6

What are early after-depolarisations?

Answer 6

Interupts normal repolarisation
Occurs if prolonged AP
Leads to oscillations

Question 7

What is the re-enterant mechanism for generating cardiac arrhythmias?

Answer 7

Occurs when point of divergence with incomplete conduction damage
Unidirectional block
Excitation (impulse) takes the long route around
Can spread through the damaged area in opposite direction (unidirectional block) leading to the formation of a circuit–> areas re-excited quickly
Damage to atria, excessive stretch–> Multiple re-entrant circuits in atria–> atrial fibrillation

Question 8

How may re-entry occur at the AV node?

Answer 8

AV node has fast and slow pathway in AV node → common pathway at end
- Slow pathway repolarisation faster than the fast pathway
Premature beat- slow pathway activated → reaches common pathway by which time fast has recovered from refractory period
Fast pathway activated in opposite direction → Sets up circuit
Depolarisation goes round the circuit
Many depolarisations down the bundle of His etc… → ventricles activated much faster rate than normal

Question 9

What are supraventricular tachycardias?

Answer 9

Arise above the ventricles in the atria
Atrial fibrillation
AV node re-entry

Question 10

What causes ventricular pre-excitation?

Answer 10

Accessory pathway between atria and ventricles
Creates a re-entry route
Depolarisation from atria to ventricles without passing through AV node
Wolff-Parkinson-White syndrome

Question 11

What are some of the causes of brachycardia?

Answer 11

Sinus brachycardia

Conduction block

Question 12

What causes sinus brachycardia?

Answer 12

Physiological–> fit, healthy athlete
Pathological
Sick sinus syndrome (intrinsic SA node dysfunction)
Extrinsic factors–> drugs–> beta blockers, some Ca2+ channel blockers

Question 13

What is a conduction block?

Answer 13

Problems at AV node or bundle of His

Slows conduction at AV node due to extrinsic factors –> beta blockers, some Ca2+ channel blockers

Question 14

What are the different classes of drugs that affect the rate and rhythm of the heart?

Answer 14

1- Block voltage sensitive Na+ channels
2- Antagonist of β-adrenoreceptors
3- Block K+ channels (not used–> pro-arrhythmic)
4- Block Ca2+ channels

Question 15

How do Na+ channel blockers (Class one) work?

Answer 15

Prevent Na+ influx and depolarisation
e.g. Lidocaine –> Local anaesthetic
Use dependent block
Blocks channel in open or inactivated state
Little effect in normal cardiac tissue as it dissociates rapidly
Help prevent ventricle tachycardia

Question 16

What is lidocaine used for?

Answer 16

Local anaesthetic
Propholyaxis–> prevent ventricle tachycardia after MI
Damaged areas of myocardium might depolarise and fire auomatically
More Na+ channels open during depolarisation–> lidocaine blocks then preventing depolarisation
Not commonly used–> other drugs avaliable

Question 17

How do β-adrenoreceptor antagonist (class two) work?

Answer 17

Block sympathetic action –> β1 adrenoreceptors in the heart
Decrease slope of pacemaker potential in SA node and slows conduction at AV node
Propanolol, atenolol

Question 18

What are β-blockers used to treat?

Answer 18

Supraventricular tachycardia–> slow conduction in AV node
–> slow ventricular rate in AF
MI–> causes increased sympathetic activity–> arrhythmias–> β-blockers stop
–> also reduced O2 demand preventing ischaemia

Question 19

What do K+ channel blockers do?

Answer 19

Theory should prolong action potential (prevent hyperpolarisation)
Lengthen the absolute refractory period
Reality–> pro-arrhythmic–> pro-long QT interval–> early after depolarisation

Question 20

What is the one K+ channel blocker that is an exception?

Answer 20

Amiodarone
Treat tachycardia
Other actions as well as K+ channel blocker
Suppression of ventricular arrhythmias
Treat tachycardia–> Wolff-Parkinson-White syndrome

Question 21

How do drugs that block the Ca2+ channels (class IV) work?

Answer 21

Decrease slope of AP at SA node
Decrease AV nodal conduction
Decrease force of contraction (negative iontropy)
Verapamil, dilitiazem (non-dihydropyridine types)

Question 22

What is the function of the dihydropyridines?

Answer 22

Ca2+ channel blockers
BUT do not prevent arrhythmias
Act on vascular smooth muscle
Amlodipine, nifedipine, nicardipine etc…

Question 23

What is the function of adenosine?

Answer 23

Endogenously produced
Injected intravenously
Acts on alpha 1 receptors in AV node
Short half life
Enhances K+ conduction--> hyperpolarises
Anti-arrhythmic
Prevents supraventricular tachycardia

Question 24

What other drugs that act on the CVS that are not used to specifically treat arrhythmias?

Answer 24

ACHi and angiotensin II receptor blockers
Diuretics
Calcium channel antagonists
Positive inotropes
Alpha adrenoreceptor blockers and beta blockers
Antithrombotic drugs

Question 25

How do ACEi work? What are they used to treat?

Answer 25

Inhibit ACE action Prevents conversion of AngI to AngII Treatment of hypertension and heart failure AngII acts on kidney--> increase Na+ absorption and H20 absorption, vasoconstrict vessels, aldosterone production Perindopril

Question 26

How does ACEi prevent heart failure?

Answer 26

``` Heart unable to provide sufficient output to meet body demand ACEi --> decrease vasomotor tone (↓ BP) --> reduce afterload --> decrease fluid retention (↓BP) --> reduce preload reduce work load on heart ```

Question 27

What is a side effect of ACEi?

Answer 27

Dry cough | Excess bradykinin

Question 28

What are AngII receptors blockers used for?

Answer 28

Treatment of HF and hypertension Block the receptors so AngII can't bind --> no vasodilation, reduced Na+ reabsorption and H2O reabsorption, no aldosterone Losartan

Question 29

What are diuretics used for? How do they work?

Answer 29

Treatment of heart failure and hypertension Congestive heart failure--> oedema in lungs--> difficulty breathing --> both sides of heart failing --> Furosemide, thiazide Act on the Loop of Henle--> Loop diuretics Reduce oedema

Question 30

How are Ca2+ channel blockers used to treat hypertension?

Answer 30

Dihydropyridine Ca2+ channel blockers--> vascular smooth muscle --> decrease peripheral resistance --> decrease arterial BP --> reduce workload of heart by reducing after load Amlopidine, nicardipine

Question 31

What are Ca2+ blockers used to treat in the CVS?

Answer 31

Hypertension, angina, coronary artery spasms, supraventricular tachycardia Non-dihydropyridine Ca2+ blocker--> heart Dihydropyridine Ca2+ blockers--> vascular smooth muscle

Question 32

What are positive inotropes?

Answer 32

Drugs used to increase contractility--> CO

Question 33

What are the two types of positive inotropes?

Answer 33

Cardiac glycoside--> digoxin | β-adrenergic agonists--> dobutamine

Question 34

How do cardiac glycosides work?

Answer 34

Primary action--> block Na+/K+ ATPase Na+ normally moves in down concn gradient whilst Ca2+ out via Na+/Ca2+ exchanger Na+/K+ ATPase blocked --> ↑ [Na+] intracellular --> ↓ Na+/Ca2+ activity [Ca2+] intracellular increase--> stored in SR --> increased force of contraction Secondary action Increase vagal nerve activity via CNS Slow AV conduction Slow HR

Question 35

What other conditions can cardiac glycosides be used to treat?

Answer 35

Arrhythmias in AF

Question 36

How do β1-adrenoreceptor agonists work? When are they used?

Answer 36

Stimulates β1 receptors in SA and AV node Treat cardiogenic shock Acute but reversible HF

Question 37

What is the problem with cardiac glycosides?

Answer 37

Relieve symptoms by making the heart contract harder Not sustainable--> No long term benefit Need to treat underlying cause Reduce the workload (pre-load and after load)

Question 38

What is angina?

Answer 38

O2 supply to heart does not meet demand Limited duration--> no death of myocytes Ischaemia of heart

Question 39

What is used to treat angina? Why?

Answer 39

Organic nitrates Nitrates react with thiols (-SH groups) in vascular smooth muscle causing NO2- to be released Reduced to NO (nitric oxide) --> powerful vasodilator of VEINS Endogenously released from endothelial cells Exogenously delivered as GTN spray (glycerol trinitrate)--> quick short acting Or Isosorbide dinitrate--> longer acting

Question 40

Why do organic nitrates act on veins?

Answer 40

Less endogenous nitric oxide in veins Therapeutic dose most effective on veins No action on arterioles

Question 41

How does nitric oxide cause vasodilation of veins?

Answer 41

NO activates Guanylate cyclase Increase cGMP Lowers intracellular [Ca2+] Relaxation of vascular smooth muscle

Question 42

How does NO alleviate the symptoms of angina?

Answer 42

Primary action--> VENOdilation, lowers preload --> reduce workload of heart--> heart fills less--> force of contraction reduced (Starlings law)--> lowers O2 demand Secondary action--> acts on coronary collateral arteries to improve O2 delivery to tissue (NOT arterioles)--> increase blood flow to ischaemic area slightly

Question 43

In summary how is angina treated?

Answer 43

Reduce work load on heart--> - organic nitrates (venodilation), - β-adrenoreceptor blockers (block sympathetic action), - Ca2+ channel antagonists (reduce work load by vascular smooth muscle relaxation) Improve blood supply to the heart--> - Ca2+ channel antagonists (vascular smooth muscle relaxation), - minor effect of organic nitrates

Question 44

Which heart diseases carry an increased risk of thrombus formation? Why?

Answer 44

Atrial fibrillation--> atria quiver but don't fully contract, LA blood stuck in left appendage--> stasis forms clot Acute myocardial infarction--> blood stasis--> clot forms Mechanical prosthetic heart valves--> traps blood

Question 45

What drugs are used to prevent thrombus formation?

Answer 45

Anticoagulants--> prevents Factor Xa converting prothrombin to thrombin Venous thromboembolisms prevented by: --> Heparin--> inhibits thrombin, short term action (IV) --> Fractionated heparin (subcutaneous injection) --> Warfarin--> antagonises Vit K (oral) --> Direct oral thrombin inhibitors such as dabigatran Antiplatelet drugs--> aspirin, clopidogrel (given following MI) --> stops platelets aggregating