Cardiac Conductance and Arrythmogenesis and Antiarrhythmia Drugs Flashcards
How is the resting membrane potential maintained?
3Na+ is pumped in whilst 2K+ is pumped out of the cell
-causing a deficit of positive ions in the cell
what causes a low intracellular Ca2+ conc?
the Ca2+ pump and the Na+-Ca2+ exchanger
what is the resting membrane potential of the heart?
-90mV
what is the ion channel permeability in cell membranes controlled by?
voltage-gated channels
define membrane resting potential?
when electrical and chemical forces are exactly equal and there is no net movement of ions across cell
what channels are open at resting membrane potential and which are closed?
K+ channels open, Na+ channels closed
what causes voltage gated Na+ channels to open?
a less negative cytoplasm
what is an inward current?
Movement of +ve charge (e.g. Na+) into cell or -ve charge (e.g. Cl-) out of cell
(aka depolarisation)
what is an outward current?
Positive charge (e.g. Na+) leaving cell or negative charge (e.g. Cl-) entering cell (aka repolarisation)
explain how an action potential occurs?
-the excitatory stimulus causes membrane potential to become less negative
and beyond threshold
-Permeability of membrane to ions increases
-Cell rapidly depolarises
-Membrane potential reverses transiently prior to repolarisation
what are the two types of action potentials in the heart?
- heart muscle action potential
2. pacemaker action potential (SAN and AVN)
explain how an action potential works in heart muscles?
- heart at resting potential with Na and Ca channels closed and K rectifier channels open keeping potential at -90mV.
- Rapid influx of Na through fast opening Na channels - aka phase 0
- Transient K channels open and Na+ channels close (phase 1) causing K efflux hence reducing membrane potential
- influx of Ca, via L-type Ca channels, is balanced with efflux of K, via delayed rectifier K channels (phase 2).
- Ca channels close but delayed rectifier channel remains open to return transmembrane potential to -90mV (phase 3).
what is the threshold potential for an action potential to continue?
-70mV
what is the action potential rate of the SAN?
60-80 action potentials per minute
what is the action potential rate of the AVN?
40-60 action potentials per minute
what is the action potential rate of the bundle of His?
20-40 action potentials per minute
what is the action potential rate of the Bundle branches?
10-20 action potentials per minute
what do pacemaker cells do?
-cause adjacent cardiac
muscle cells to reach threshold voltage –
thus initiating cardiomyocyte action potential
-they have unstable membrane potentials so generate action potentials spontraneously
what do cardiomyocytes have that pacemakers don’t have?
an inward rectifier K+ channel
during the refractory period, why can’t an active potential be initiated and what would you need to initiate an AP during this period?
- the membrane of the cardiomyocytes aren’t repolarised and the Na+ channels haven’t recovered from their inactivated state
- a bigger stimulus required to initiate the AP
what happens during the supernormal period?
when the threshold potential is lower than the usual required to generate an AP
where does the heart muscle require Ca2+ to enter from for contraction in comparison to skeletal muscle?
heart muscle needs the Ca from outside the cell to enter via the voltage-gated L-type Ca channel to then stimulate the sarcoplasmic reticulum to release calcium, whilst skeletal muscles gets the Ca from the sarcoplasmic reticulum inside the cell straight away.
Explain how calcium causes heart muscle contraction?
- Ca enters through L-type channel
- Ca2+ -induced calcium release (CICR) occurs
- Stimulates Ca2+ release from sarcoplasmic
reticulum (SR). - Intracellular Ca2+ rises ~ 0.5-2μM
- Ca2+ interacts with troponin-C
- Myosin binding site on actin freed
- Actin moves over myosin causing myocyte
contraction
At the end of muscle contraction, what happens to the calcium?
-Intracellular Ca2+ reabsorbed into SR via the
sarco-endoplasmic reticulum Ca ATPase
(SERCA) pump and removed from the cell via
Na+/ Ca2+ exchanger and ATP-dependent
Ca2+ pump.
-Ca2+ dissociates from TN-C and the binding
site on actin is inhibited.
-ATP required to unbind myosin from actin and
reset the sarcomere to its normal length.
how is an impulse conducted through the heart?
- SA node activity and atrial activation begins
- stimulus spread across the arterial surface and reaches AV node
- After a delay at the AV node (100msec), atrial contraction begins.
- the impulse travels along the interventricular septum within the AV bundle and the bundle branches to the Purkinje fibres and the papillary muscles of the right ventricle via the moderator band.
- the impulse is distributed by purkinje fibres and relayed throughout the ventricular myocardium. Atrial contraction is completed and ventricular contraction begins.
where can ectopic (abnormal) pacemakers occur?
-Cells with spontaneous pacemaker activity that
develop more rapid spontaneous phase 4 depolarisation than normal SA node activity.
-Cells that normally lack pacemaker activity, e.g. ventricular cells, and have stable phase 4, rapid depolarisation
what causes an ectopic pacemaker?
change in microcellular environment e.g: -electrolyte disturbances causing reduced resting membrane potential and cells closer to threshold potential - Ischaemia -Xenobiotics
what are the types of spontaneous depolarisations?
- afterdepolarisation (requires a preceding impulse)
- Early afterdepolarisation (occurs during phase 2&3, associated with K+ channel being blocked)
- Delayed Afterdepolarisation (during phase 4 and associated with Ca2+ overload)
What is first degree impulse conduction disorder?
when the P-R interval is greater than the normal range caused by a delay in the AV node conductance
What is second degree impulse conduction disorder?
- type 1: P-R interval increased over a number of heartbeats until the P wave occurs without a QRS complex
- type2: more P waves than QRS complexes but relationship between P and QRS waves is fixed e.g. 2:1 or 3:1 etc
What is third degree impulse conduction disorder?
-when there’s a heart block and no relationship between atrial and ventricular rates. This occurs when there’s a loss of conduction through the AV node or proximal bundle of His.
What does the QRS wave width tell us?
the time taken for depolarisation through ventricles
what direction does depolarisation take place in the ventricles?
from the inside (endocardium) to the outside (epicardium)
what is the depolarisation route?
from the intraventricular septum to the inside of the left ventricle to the outside of it, then to the inside of the right ventricles then to the outside.
what is re-entry and what does it cause?
- impulse propagation by more than one anatomical pathway between 2 points in the heart
- causes arrhythmias where there’s non-conduction tissue and heterogeneous conduction in that region
explain how re-entry arrhythmias occur?
not sure if what I’ve wrote is correct????
- impulse arrives at myocardium refractory stimulus
- impulse bypasses the refractory tissue due to blockage
- this causes tachycardia
- impulse arrives at refractory tissue when it has repolarised due to the re-entry circuit acting as a pacemaker (re-entry)
what are supraventricular arrhythmias?
- Sinus Tachycardia
- Atrial Tachycardia
- Paroxysmal Atrial tachycardia (PAT)
- Atrial Flutter
- Atrial Fibrillation
- AV blocks
what is Sinus Tachycardia?
Rate of 100-180 beats/min, occurs during exercise or other conditions that lead to increased SA nodal firing rate
what is Atrial Tachycardia?
Series of 3 or more consecutive atrial premature beats
occurring at a frequency >100/min
what is Paroxysmal Atrial tachycardia (PAT)?
tachycardia which begins and ends acutely
what is Atrial Flutter?
sinus rate of 250-350 beats/min.
what is Atrial Fibrillation?
uncoordinated atrial depolarizations.
what is AV blocks?
Conduction block within the AV node or bundle of His. Impairs impulse conduction from the atria to the ventricles.
what are ventricular arrhythmias?
- ventricular fibrillation
- ventricular tachycardia
- ventricular flutter
- ventricular premature beats
what is ventricular fibrillation?
uncoordinated ventricular depolarizations
what is ventricular tachycardia?
high ventricular rate caused by abnormal ventricular
automaticity or by intraventricular re-entry; sustained or non-sustained
(paroxysmal); characterized by widened QRS; rates of 100 to 200 beats/min; life threatening
what is ventricular flutter?
ventricular depolarisations >200/min.
what is ventricular premature beats?
caused by ectopic ventricular foci;
characterized by widened QRS.
what are the objectives of antiarrhythmic drugs?
- to restore sinus rhythm and conduction
- to prevent more serious and lethal arrhythmias occurring
what are antiarrhythmic drugs used for?
- decrease conduction velocity
- change the duration of the effective refractory period (ERP)
- suppress abnormal automaticity
what is the Vaughan Williams Classification System based on?
the mechanism of drug action
what are the advantages of the Vaughan Williams Classification System?
- Convenient classification by primary mechanism of action
- Useful conversational shorthand
- Specific class or subclass often exhibit similar adverse effects
what are the disadvantages of the Vaughan Williams Classification System?
- Drugs within a class do not necessarily have clinically similar effects
- Almost all of the currently available drugs have multiple actions
- Metabolites contribute significantly to efficacy or adverse effects
- Empirical approach used to determine the most effective agent for patient
what is the Sicilian Gambit classification system?
a classification system that takes into consideration multiple antiarrhythmic
actions that most drugs possess and the mechanism of a patient’s arrhythmia
what are the advantages of the Sicilian Gambit classification system?
- Identifies one or more ‘vulnerable parameters’ associated with a specific arrhythmogenic mechanism
- System can readily accommodate drugs with multiple actions
(start from 38)
how do class IA antiarrhythmic drugs work?
-act on open Na+ channels and slightly work against K+channels to cause moderate phase 0 depression (prolonging repolarisation and increasing duration of action potential by slowing the impulse conduction rate)
what are class IA antiarrhythmics suitable treatments of?
supraventricular and ventricular arrhythmias
how do class IB antiarrhythmics work?
- cause weak phase 0 depression and have little effect on the K+ channels.
- shorten the phase 3 repolarisation (by slowing the impulse conduction in abnormal tissue and don’t affect healthy tissue).
- decreases the action potential
what are class IB antiarrhythmics suitable treatments of?
for ventricular arrhythmias
how do class IC antiarrhythmics work?
- cause a strong phase 0 depression by blocking Na+ and K+ channels. Also blocks inward Ca2+ channels
- minimal effect on repolarisation
- has no effect on action potential duration but slows down impulse conduction
what are class IC antiarrhythmics suitable treatments of?
both atrial (supraventricular) and ventricular arrhythmias
which class (IA, IB, IC) has the most and which has the least Na+ channel blocking ability?
IC has most, IB has least
Which class (IA, IB, IC) increases the effective refractory period the most and which reduces it?
IA increases it the most and IB lowers it. IC also increases it but not as much as IA.
how do class II antiarrhythmias work?
- they’re beta-adrenoreceptor blockers blocking catecholamine action on the receptors.
- block Na+ channels opening
- reduce rate of spontaneous depolarisation of SA and AV nodes and reduce conduction of AV node.
- Reduce spontaneous depolarisation of phase 4 (block adrenorecetor Ca2+ channels
what are class II antiarrhythmics suitable treatments of?
both supraventricular and ventricular
how do class III antiarrhythmias work?
- blok K+ channels
- prolong phase 3 repolarisation without altering phase 0 resting membrane potential.
- prolong action potential duration an effective refractory period
why were class III antiarrhythmias developed?
as some patients were negatively sensitive to Na+ channel blockers
what channels do class IA, IB, IC antiarrhythmias block?
Na+ channels
what channels do class II antiarrhythmias block?
B-receptors
what channels do class III antiarrhythmias block?
K+ receptors
what are class III antiarrhythmics suitable treatments of?
supraventricular and ventricular arrhythmias
what channels do class IV arrhythmics block?
Ca2+ channels
how do class IV channels work?
-stabilize action potential in phase 4 and slow the rate of spontaneous depolarisation of AV node by blocking L-tpe Ca2+ channels
what are proarrhythmias?
- drug induced arrhythmias that can develop into ventricular fibrillation rapidly.
- associated with the use of Class III and IA actions
what are use-dependent chanel blockers?
- Enhanced Na+ or Ca2+ channel blockers in rapidly depolarizing tissue
- Responsible for increased efficacy in slowing and converting tachycardias with minimal effects on tissues depolarizing at normal (sinus) rates
what is the theraeutic index of most antiarrhythmics like?
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