Lecture 12: Anti-arrhythmic drugs Flashcards
1
Q
What are the objectives of anti-arrhythmic drugs?
A
- Reduce morbidity
- Reduce mortality
- Ventricular arrhythmias lead to 70k deaths/year in the UK
2
Q
What are the phases of a cardiac cation potential in ventricular myocytes?
A
- Phase 0: rapid depolarisation, Na+ channels open, rapid influx into myocytes
- Phase 1: short depolarisation, K+ channels open, K+ efflux
- Phase 2: delay in repolarisation (Ca2+ entry via L-type channels) → small plateau
- Phase 3: rapid repolarisation, K+ channels open → K+ efflux → brings membrane potential back down
- Phase 4: automatically slow depolarisation → relatively flat as not peacemaker cells
3
Q
What are the phases of a cardiac action potential in SA nodes?
A
- Phase 4: slow depolarisation → causes pacemaker activity → mediated by if channels
- Phase 0: rapid influx of Ca via L type Ca channels
- Phase 3: repolarisation in channels → back to baseline
4
Q
What is the refractory period?
A
- Play crucial role in regulation of electrical impulses in heart, preventing arrhythmias
- Absolute refractory period → when there is an AP being fired, myocytes unresponsive to electrical stimulation
→ voltage-gated sodium channels inactivated - Relative refractory period (vulnerable period) → followed ARP, could get an extra AP, could drive arrhythmias
- Supranormal period → excitable due to which channels are open - high chance of an extra beat
5
Q
What are afterdepolarisations?
A
- Extra depolarisations - not a full AP
- Early → during repolarisation
- Delayed → following complete repolarisation
- If they get big enough can cause arrhythmias
- Can occur if you don’t have enough K+ - cells → hyper excitable
6
Q
What are the major modes of action to block arrhythmias?
A
- Decrease phase 4 slope → slow rate
- Increase threshold potential → slow phase 0
- Increase refractory period → lengthen AP
- Aim: to prevent re-entrant circuits (loops)
7
Q
What is the Vaughan-Williams classification of anti-arrhythmic drugs?
A
- Class I: sodium channel blockade
- Class II: catecholamine blockade
- Class III: lengthening of refractoriness
- Class IV: calcium channel blockade
8
Q
What do sodium channel (class I) blockade anti-arrhythmic drugs do?
A
- Restrict rapid inflow of Na+ during phase 0
- Slows depolarization n conduction esp in damaged tissue
- Can also block K+ channels
9
Q
Explain the 3 subtypes of sodium channel (class I) blockade anti-arrhythmic drugs
A
- Sodium channel block w lengthened refractoriness
- EFFECT: makes AP longer → slows repolarization
- Blocks K+ channels
- EXAMPLE: quinidine, disopyramide n procainamide
- Sodium channel block with reduced refractoriness
- Doesn’t change rising phase
- Stop premature beats by holding channel inactivated → block voltage gated Na+ channels→ local anaesthetics like lidocaine, supresses premature beats
- Binds and unbinds quickly
- Sodium channel block with little effect on refractory period
- Slows rising phase, slows QRS
- Bind and unbinds slowly, general reduction in excitability, suppress re-rentrant rhythms
- EXAMPLE: flecainide
10
Q
What do beta-andrenoceptor antagonist (class II) anti-arrhythmia drugs do?
A
- Used for ventricular dysrhythmias following MI often [the drug increases sympathetic activation]
- EFFECTS
- Inhibits the effects of catecholamines like epinephrine and noradrenaline
- Reduce delayed afterdpolarisations due to symptoms activity
- Some ectopic pacemakers depend on adrenergic drive (useful for ectopic beats)
- Increases refractory period of AV node → prevent re-entrant tachycardia
- Useful if tachyarrhythmias are driven by overactive sympathetic system
- Membrane stabilising activity → less excitable
11
Q
What do class III anti-arrhythmia drugs do?
A
- Long elimination half life (10-100 days) thus given as loading dose
- Block K+ channels (Phase 3) → lengthen refractory period
- e.g. amiodarone - prolongs cardiac action potential
→ useful in re-entrant tachycardias, suppress ectopic activity
- e.g. amiodarone - prolongs cardiac action potential
- ECG
- Prolongs QT, widens QRS
- Sotalol → non-selective beta-adrenoceptor blocker, prolongs cardiac AP
→ delays slow outward K+ current
→ not as effective as amiodarone but less adverse effects - SIDE EFFECTS
- Photosensitive rash, thyroid abnormalities, pulmonary fibrosis
12
Q
How can class III anti-arrhythmia drugs be pro-arrhythmic?
A
- Can produce polymorphic ventricular tachycardia
- Dangerous when
- Taken w other drugs that lengthen the QT interval (e.g. antipsychotic drugs)
- Disturbed electrolyte balance (hypokalaemia)
- Hereditary prolonged QT
- Occurs if amiodarone taken w other specific drugs
13
Q
What are class IV anti-arrhythmia drugs?
A
- Ca2+ channel antagonists → block L-type Ca2+ channels in the heart
- Half-life 6-8 hours
- Considerable first pass metabolism
- Slow release preparation available
- EXAMPLE: verapamil
- Slow conduction in SA and AV nodes - as AP is carried by Ca2+ ions
- Slow the heart and terminate supra ventricular tachycardia (partial AV block)
- Shorten plateau of AP (phases 1 and 2) - less Ca2+ influx
- Reduce force of contraction
- Reduce after depolarisations
- Suppress ectopic beats
- ECG
- PR interval prolonged → slows conduction through AV node
14
Q
What does adenosine do?
A
- Receptors for adenosine in the heart at AV node → opens K+ channels → hyperpolarises AV node → slows conduction of beat → negative dromotropic effect
- Endogenous chemical mediator in the body (vasodilator)
- Acts via A1 receptors on AV node (hyper polarises cardiac tissue)
- Slows the rate of rise of pacemaker potential
- Slows conduction through AV node (negative dromotropic)
- Terminates paroxysmal supraventricular tachycardias
- Given as IV bolus (half life 8-10 seconds) - broken down very quickly
15
Q
What do digoxin and other cardiac glycosides do?
A
- Act directly in the heart → inhibit Na+/K+ ATPase pump
→ reduction in Na+ and Ca2+ exchange → less Na+ extrusion, reduces Ca2+ extrusion - Increase in intracellular [Ca2+] increases excitability/contractility
- Decreases propagation and AP generation at SA and AV nodes
- Useful as slows conduction through AV node
- Enhances vagal activity by complex - indirect action bradycardia
- Useful in: atrial fibrillation, atrial flutter, heart failure
