Plant Arrhythmia & AADs

SA node function

initiates heartbeat, sets rhythm

AV node function

delays signal from SAN so ventricles can fill before ejection

His-Pukinje network

distributes excitation for synchronized ventricular contraction

How do right and left sides of the heart contract?

Simultaneously

Importance of timing & synchronicity of heart’s conduction pathway?

Part of pump performance/efficiency

Necessary to pump oxygenated blood to tissues

What happens to the heart’s conduction pathway in arrhythmia and what does this cause?

Arrhythmia: disruption of timing/synchronicity

Causes less efficient pumping of oxygenated blood to tissues

cardiac output equation

CO = SV x HR

SNS dominant signaling results in

increased HR

PNS dominant signaling results in

decreased HR

phase 4

rest

HCN2/4

phase 0

depolarization

Nav1.5

phase 1

rapid repolarization

Kv4.2/4.3

Kv1.5

phase 2

plateau

calcium entry window → muscle contraction

phase 3

Kv7.1

hERG

Kir2.1

depolarization

what does depolarization initiate

systole (contraction)

what does repolarization initiate

diastole (relaxation)

arrhythmia impact on AP

Disrupts conduction speed, sequence, AP shape

Changes duration of phase 2, changing contraction of the heart

What are APs in SAN driven by

I_f (funny current)

Difference in AP phase 4 in SAN vs ventricular cells

SAN: never flat b/c instability of funny current

ventricular cells: flat b/c Na+ currents and rectified by K+ currents

where does the AP flow through to travel across cells

through connexions in one direction (highly organized

connexions in AF

found on the wrong interfaces of cells, travel in different directions

chronotropy

speed of HR

(positive chronotropy = increases HR)

dromotropy

speed of conduction through the AV node

ionotropy

force of contraction

(positive ionotropy = greater force)

lusitropy

relaxation of myocardium; preserves filling at high heart rates

(more lusotropic = more relaxation)

QT interval

measures time for ventricles to depolarize

What can LQTs lead to?

Torsades de Pointes / TdP

LQT1 gene mutation

KCNQ1 loss of function

LQT3 mutation & what it results in

known or silent SCN5A/Nav1.5 variant

gain of function in Nav1.5 channel

What can LQT3 be triggered by?

ischemia and intense fever

pathophysiological switch in LQT3

Na+ channels in heart never fully reset, can lead to sudden cardiac arrest

LQT2 cause

adverse drug reactions

all new drugs are tested against hERG

LQT2 gene and channel/mutation

KCNH2 gene

hERG channel loss of function, impacts Ikr current

Class I AADs

Nav block → decreases phase 0 current (less flow into cell) → decreases conduction

Class 1A & example

intermediate Nav channel blocker and K+ channel block

procainamide

Class 1B & example

shortens AP, limited effect on phase 2 initiation (state-dependent block)

lidocaine

dosage form for lidocaine

IV use

(no oral formulation)

oral equivalent of lidocaine

mexiletine

Class 1C & example

no effect on AP length, strongly act on phase 0 initiation (state-dependent block)

flecainide

Class 2 AADs

beta blockers (negative chronotropes)

decrease pacemaker drive / AV conduction

sotalol class activity

class 2 (B1 and B2 receptor agonists)

class 3 (K+ channel blocker, increases AP duration)

Class 3 and example

K+ channel blockers

increase AP duration / ERP (increase QT risk)

amiodarone

major side effect of amiodarone

anti-thyroid action due to iodine

drodenarone

class 3 AAD

similar to amiodarone but no iodine

dofetilide class & risk

class 3 AAD

risk of polymorphic ventricular tachyarrhythmia (monitor via EKG)

ibutilide class and risk

class 3 AAD (also increases persistent Na+ current)

risk of TdP (monitor)

Class 4 AAD & example

L-type Ca2+ block in nodal tissue, slows AV conduction

non-DHPs (verapamil)

adenosine

used IV for terminating cardio version, causes temporary cardiac systole