6. Arrythmia Flashcards
What is Atrial Fibrillation
-Rapid, irregular heartbeat
-Most common heart rhythm irregularity
-May cause blood clot formation
Name the sequence of sinoatrial node pacemaker potential
-Phase 4 (pacemaker potential)
-Phase 0 (depolarisation)
-Phase 3 (repolarisation)
Describe phase 4 of the sinoatrial node pacemaker potential
-The SA node lacks a stable resting membrane potential.
-Instead, the membrane potential gradually depolarizes due to the opening of funny (If) sodium channels, allowing Na⁺ influx.
-As depolarization progresses, T-type calcium channels open, allowing Ca²⁺ influx, further depolarizing the cell.
-The progressive depolarization eventually reaches the threshold (~-40 mV), triggering an action potential.
Describe phase 0 of the sinoatrial node pacemaker potential
-Once the threshold is reached, L-type calcium channels open, leading to a rapid Ca2+ influx and depolarisation
-This phase is slower than in ventricular myocytes, where fast Na+ channels dominate
Describe phase 3 of the sinoatrial node pacemaker potential
-As the membrane potential becomes more positive, L-type Ca2+ channels close, and K+ channels open, allowing K+ efflux
-The membrane repolarises back towards the most negative potential (-60mV) closing K+ channels and restarting the cycle
Describe the relationship between the SAN and the rhythm of the heart rate
-This automatic rhythmic depolarization of the SA node dictates heart rate, making it the primary pacemaker of the heart.
-Modulation by the autonomic nervous system can alter pacemaker potential dynamics, with sympathetic stimulation (β1-adrenergic activation) increasing firing rate and parasympathetic stimulation (via the vagus nerve and M2 receptors) slowing it down.
What mediates the funny current?
HCN gated channels
(hyperpolarisation activated cyclic nucleotide dependent nonspecific channels)
Name the phases of the ventricular myocyte action potential
-Phase 0 (rapid depolarisation)
-Phase 1 (initial repolarisation)
-Phase 2 (plateau phase)
-Phase 3 (repolarisation)
-Phase 4 (resting membrane potential)
Describe phase 0 and 1 of ventricular myocyte action potential
Phase 0: -Triggered by an action potential from adjacent cells
-Fast voltage gated Na+ channels open, causing a rapid influx of Na+ which depolarises the membrane to approximately +30mV
Phase 1: -Na+ channels inactivate, stopping further depolarisation
-Transient outward K+ channels (Ito) open briefly, allowing K+ efflux, causing a small drop in membrane potential
Describe phase 2, 3 and 4 of ventricular myocyte action potentials
Phase 2 (Plateau Phase):
-L-type Ca²⁺ channels open, allowing Ca²⁺ influx, which balances K⁺ efflux from delayed rectifier K⁺ channels.
-This maintains the plateau and triggers calcium-induced calcium release (CICR) from the sarcoplasmic reticulum, leading to contraction.
Phase 3 (Repolarization):
-L-type Ca²⁺ channels close, while K⁺ efflux (via delayed rectifier K⁺ channels) increases, leading to repolarization.
-The membrane potential returns to its resting state (~-90 mV).
Phase 4 (Resting Membrane Potential):
-The cell remains at ~-90 mV, maintained by inward rectifier K⁺ channels (IK1), while the Na⁺/K⁺ ATPase and Na⁺/Ca²⁺ exchanger restore ion gradients.
-The myocyte is ready for the next action potential.
Key features of ventricular myocyte action potentials
-Long duration (~200-300 ms) compared to neurons or skeletal muscle.
-The plateau phase prevents tetany, ensuring coordinated contraction and relaxation.
-Modulated by the autonomic nervous system, with β1-adrenergic stimulation increasing Ca²⁺ influx (stronger contraction) and parasympathetic activity having minimal direct effect.
Describe the molecular mechanism of sympathetic nerves affecting heart rate
-Sympathetic nerve terminals release noradrenaline, binding to β₁-adrenergic GPCR receptors
-This activates Gs protein which activates Adenylyl cyclase, producing cAMP, which activates PKA
-cAMP acts on HCN channels, and PKA acts on L-type calcium channels and delayed rectifier potassium channels
-The combined effects of increased If (faster depolarization), ICaL (enhanced depolarization), and IKs (faster repolarization) shorten the duration of the pacemaker potential.
Describe the action of cAMP on HCN channels
-cAMP directly binds to hyperpolarisation-activated cyclic nucleotide gated channels, increasing open probability
-This enhances the inward Na+ current (funny current) accelerating phase 4 of the SA node action potential
-Leading to positive chronotropy
Describe the action of PKA on L-type calcium channels
-PKA phosphorylates voltage gated Ca2+ channels, increasing influx during depolarisation
-This shortens the pacemaker potential and hastens the threshold for the next action potential
Describe the action of PKA on delayed rectifier potassium channels
-PKA phosphorylates K⁺ channels, increasing K⁺ efflux during repolarization.
-This facilitates quicker resetting of the pacemaker cells, preparing them for the next cycle.
Describe the net effect of noradrenalines effect on heart rate
-The combined effects of increased If (faster depolarization), ICaL (enhanced depolarization), and IKs (faster repolarization) shorten the duration of the pacemaker potential.
-This increases the frequency of action potentials in the SA node, leading to an increased heart rate (tachycardia)
Describe the molecular mechanism of parasympathetic nerves affecting heart rate
-Vagus nerve releases ACh, binding M2 GPCR muscarinic receptors on SAN cells
-These activate Gi protein (inhibiting Adenylyl cyclase) and activate Gprotein-gated inward rectifier potassium channels (GIRK)
-Lower cAMP reduces HCN activation, decreasing funny current leading to slower diastolic depolarisation, as well as decreasing phosphorylation of L-type Ca2+ channels
-GIRK channels are activated, increasing K+ efflux, hyper polarising the SAN
Describe the net effect of acetylcholine’s effect on heart rate
-Slower phase 4 depolarisation (due to decreased If and ICaL).
-More negative resting membrane potential (due to increased IKAch).
-Longer time to reach threshold → Fewer action potentials per minute → Reduced heart rate (bradycardia).
Describe the dominance of vagal tone to the heart
-At rest, the human heart is under a dominant vagal (parasympathetic) tone, meaning the parasympathetic nervous system exerts greater influence than the sympathetic nervous system over baseline heart rate.
-This results in a lower resting heart rate (typically 60–70 bpm) than the intrinsic pacemaker rate of the sinoatrial (SA) node (~100 bpm)
What are early afterdepolarisations?
-Abnormal, spontaneous depolarisations
-Occuring during the repolarisation phase (phases 2 or 3) of the cardiac action potential
-Can contribute to arrhythmias, particularly in conditions of prolonged action potentials
Name and describe some mechanisms of early afterdepolarisations
-Delayed repolarisation: Reduced outward K+ currents, slower repolarisation prolongs action potential duration, increasing chance of spotaneous depolarusation
-Reactivation of L type Ca2+ channels: Normally inactivate during repolarisation, but prolonged APD allows reactivation, allowing Ca2+ influx triggering an extra depolarisation
Name and describe some mechanisms of early afterdepolarisations
-Persistant late sodium current: Mutations in SCN5A cause prolonged Na+ influx, preventing full repolarisation
-Increased intracellular Ca2+: Excess Ca2+ can activate Na/Ca exchange, generating inward depolarising current, seen in digoxin toxicity
What are delayed afterdepolarisations?
-Abnormal. spontaneous depolarisations
-Occur after full repolarisation (during phase 4)
-If any reach threshold, they can trigger ectopic action potentials and arrhythmias
Name and describe some mechanisms of delayed afterdepolarisations
-Intracellular Ca2+ overload: Excessive Ca2+ accumulation occurring due to β-adrenergic stimulation, Hyperactive ryanodone receptors, Reduced Ca2+ reuptake by SERCA
-Na/Ca Exchanger activation: Spontaneous Ca2+ release from the SR activates the Na/Ca exchanger, which extrudes Ca in exchange for Na, generating an inward depolarising current
-If DADs reach threshold, they can generate premature action potentials, leading to ventricular or atrial arrhythmias
Describe the Vaughan Williams classification of antiarrhythmic drugs
Categorises drugs based on their primary mechanism of action:
-Class I: Na+ blockers
-Class II: Beta blockers
-Class III: K+ blockers
-Class IV: L-type Ca2+ blockers
Describe atropine as an anti-arrhythmic
-Muscarinic antagonist, blocking vagal stimulation at the SAN and AVN, increasing heart rate and improving AVN conduction
-Primarily affects phase 4 depolarisation in pacemaker cells by inhibiting M2 receptors, increasing cAMP and slowing HR
What is the distinction between the 3 subclasses of class I antiarrhythmics?
-Class Ia: Lengthen action potential duration and refractory period
-Class Ib: Shorten action potential duration and refractory period
-Class Ic: No effect on potential duration and refractory period, but delay conduction velocity in Purkinje fibres
What is the mechanism of action of class I antiarrhythmics?
-Inhibit fast Na+ channels
-Slowing phase 0 (depolarisation) of the action potential and reducing conduction velocity
What is the mechanism of action of class II antiarrhythmics?
-Inhibit β₁-receptors, reducing sympathetic stimulation
-Decreasing SAN and AVN automaticity, decreasing (flattening) phase 4 depolarisation
-Reduces heart rate, blood pressure, cardiac work
-Also reduces renin secretion
What is the mechanism of action of class III antiarrhythmics?
-Blocks K+ channels, prolonging phase 3 repolarisation
-Increasing AP duration and QT interval
What is the mechanism of action of class IV antiarrhythmics?
-Blocks L type Ca2+ channels, slowing phase 0 depolarisation in SAN and AVN
-Slowing AVN condition, and decreasing HR and contractility
Give some examples of Class V (miscellaneous) antiarrhythmics
-Adenosine
-Digoxin
-Magnesium sulfate
-Atropine
Give examples of each subclass of class I antiarrhythmics
-Class Ia: Quinidine, Propafenone, Disopyramide
-Class Ib: Lignocaine/Lidocaine
-Class Ic: Flecainide
Give indications of class I antiarrhythmics
-Class Ia: Atrial and ventricular arrhythmias
-Class Ib: Ventricular arrhythmias
-Class Ic: atrial fibrillation, SVTs
Give indications of class II antiarrhythmics
-Treat supraventricular tachycardia
-Rate control in atrial fibrillations
Give types of class II antiarrhythmics
-Non cardioselective (also block β2 receptors) eg propranolol
-Cardioselective (less potent blockers of β2 receptors) eg atenolol
Give some adverse effects associated with lidocaine
-Hypotension
-Heart block
-Potential neurotoxicity
-Seizures
Describe adverse effects associated with β1 and β2 blockers
β1: Bradycardia and Heart failure
β2: Cool peripheries, muscular aches, worsening intermittent claudication
Give some adverse effects associated with class III antiarrhythmics
-Thyroid disturbances
-Pulmonary fibrosis
-Proarrhythmia and torsade de pointes
-Hepatitis
Blue grey skin discolouration
Give indications of class III antiarrhythmics
-Ventricular and Supraventricular tachycardia
-Ventricular fibrillation
-Recurrent ventricular tachycardia
Give the subclasses of class IV antiarrhythmics
-Dihydropyridines (nifedipine, amlodipine)
-Benzothiazepines (diltiazem)
-Phenylalkylamine (Verapamil)
Give indications of class IV antiarrhythmics
-Supraventricular arrhythmias
-Rate control in atrial fibrillation
Give some adverse effects of class IV antiarrhythmics
-Heart failure, hypotension due to stroke volume and heart rate reduced
-Constipation
-Vasodilation, Oedema, Flushing
What can adenosine be used to treat?
-AVN reentry supraventricular tachycardia (Wolff-Parkinson-White syndrome)
-Paroxysmal supraventricular tachycardia
Describe the mechanism of action of adenosine as an antiarrhythmic
-Activating A1 adenosine receptors in the AV node
-Which opens inward rectifier K+ channels, hyperpolarisation of AV nodal cells, leading to transient AV block
-And inhibits L-type Ca2+ channels, decreasing inward Ca2+ current and suppressing AVN conduction
-This temporarily stops AVN conduction, effectively resetting reentrant arrhythmias that depend on the AVN
What is the drug treatment for Asystolic cardiac arrest
Adrenaline
What is the drug treatment for ventricular fibrillation cardiac arrest
-Lignocaine/lidocaine
-Amiodarone
What is the difference between asystolic and ventricular fibrillation cardiac arrest
-Asystolic: No contractions, no systole
-Venticular fibrillation: Still electrically active muscle
What are torsades de pointes
-Torsades de Pointes (TdP) is a type of polymorphic ventricular tachycardia (VT) characterized by a distinctive twisting pattern of the QRS complexes around the isoelectric line on an ECG.
-It is associated with prolonged QT interval and can lead to life-threatening arrhythmias, including ventricular fibrillation and sudden cardiac death.
