Antiarrhythmics and contractility

Question 1

Class I antiarrhythmics

Answer 1

Fast sodium channel blockers -> spike is delayed, slope is lower.
Reduce conduction velocity (negative dromotropy).
Stabilize membrane decreasing its excitability.

Categorized into 3 subgroups based upon their effects on the Na+ channel and the action potential (AP) duration:
- Class IA (Quinidine, Disopiramide, procainamide): Moderate blockade of Na+ channels,
prolong AP duration, slow conduction velocity, prolong effective refractory period (ERP), weak blockade of the K+ channel

• Class IB (Lidocaine, fenitoina, mexiletine): weak blockade of Na+ channels, shorten AP duration (shortened repolatization), slow conduction velocity, no effect on or slight prolongation of ERP, strongest effect on ischemic myocardium
• Class IC (Flecainide, Propafenone): Strong blockade of Na+ channels → QRS prolongation; no to minimal effect on AP duration (no shift); slow conduction velocity; prolong ERP in AV node and accessory tract; ERP unaffected in Purkinje and ventricular tissue

Question 2

Class II antiarrhythmic drugs

Answer 2

Beta blockers

• Inhibit β-adrenergic activation of adenylate cyclase → ↓ cAMP → ↓ Ca2+ → ↓ SA and AV node activity
• Decrease slope of phase 4 in pacemaker cells
• Slow conduction velocity
• Prolong AV node repolarization
• Prolong PR interval

Metoprolol
Esmolol
Propranolol
Atenolol
Timolol
Carvedilol
Sotalol

Question 3

Class III antiarrhythmic drugs

Answer 3

Potassium channel blockers

• Inhibit delayed rectifier potassium currents
• Prolong QT interval
• Prolong AP duration (reverse use dependence) and ERP
• No effect on conduction velocity

Amiodarone

Question 4

Class IV antiarrhythmic drugs

Answer 4

Calcium channel blockers

• Inhibit slow calcium channels
• Decrease slope of phase 0 and 4 → slower conduction velocity → increased ERP
• Prolong AV node repolarization
• Prolong PR interval

Verapamil, Diltiazem -> contraindicated in HF since they interfere with contractility
Nifedipine -> this is used for HT because it mainly affect resistance of peripheral vessels

Question 5

Digoxin

Answer 5

Mechanism of action: inhibits Na+/K+-ATPases → higher intracellular Na+ concentration → reduced efficacy of Na+/Ca2+ exchangers → higher intracellular Ca2+ concentration → increased contractility, decreased heart rate
Improves symptoms but it doesn’t change the natural history of the disease.

Indications

• AFib
• Atrial flutter
• Chronic systolic heart failure

Digoxin has a very narrow therapeutic window. An antidote exists.

Question 6

PDE3 inhibitors

Answer 6

Amrinone
PDE3 is present in the heart. It is responsible for cAMP transformation in AMP.
It is used in acute HF but just for a short period of time becasue it is detrmental on the long run (prolonged high levels of cAMP are bad)

Question 7

Beta adrenergic agonist in HF

Answer 7

Different catecholamines, which are used ONLY in acute HF: dopamine, dobutamine, E, NE. The reason is that chronic stimulation of the heart is not a good thing because you work on beta1 receptors.

Question 8

Ivabradine

Answer 8

Mechanism of action: blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I(f) ‘funny’ current → duration of the diastolic phase increases →coronary vessels are open for a longer period of time

→ used in heart failure and ischemia (angina)

Question 9

Levosimendan

Answer 9

1. Calcium sensitizing agent, it sensitizes Troponin C to bind calcium ions → The ejection fraction is increased, and the left ventricular filling pressure is decreased.
2. Hyperpolarization: activation of potassium channels, especially ATP-dependent potassium channels. → Relaxation in the periphery and effect on the heart. In this way both pre and afterload are decreased, it has anti-ischemic effect and the neurohormone levels are normalised.
3. Protection of mitochondria in ischemic perfusion.

No chronic use of this drug. Widely used in surgery, but the use of this drug in chronic HF is delayed. In the future, this drug will be more used in chronic HF due to the advantages. Toxicity is not relevant.

Question 10

Lusitropy

Answer 10

Rate of myocardial relaxation

Question 11

Frank-starling law

Answer 11

The ejection volume is proportional to the distention of the fibres