Arrhythmias Mechanisms & Drugs Flashcards
Describe the gene defects and molecular basis of long QT syndrome
Ion channel mutations!! (dom or rec)
LQT1: Ik-s (slow)
LQT2: Ik-r (rapid)
LQT3: Ina
Prolong QT by…
LOF K+channels (fewer expressed) and
GOF Na+ channels (improper inactivation)
Electrically, a prolonged plateau phase incites torsades de pointes –> v-fib (often after fright, shock, excitement, exercise etc. anything that increases sympathetic tone.) –> syncope and cardiac death.
Treat with beta blockers.
- List the cardiac ion channels and the phases of the slow and fast responses that are targeted by the various antiarrhythmic drugs
Class I: Na+ channel blockers
- Ia: slow 0, lengthen 2
- Ib: slow 0, shorten 2, lengthen 4
- Ic: SLOW 0, mildly lengthen 2, SAME LENGTH
Class II: beta-adrenergic receptor blockers:
- LTCC, and K+ current
- Reduces the rate of diastolic phase 4 depol in pacing cells, reduces the upstroke rate and slows repolarization.
Class III: K+ channel blockers
- prolongation of fast response phase 2 and prominent prolongation of refractory period.
Class IV: Ca2+ channel blockers
- slow the Ca2+ -dependent upstroke in slow response tissue (slow rise of action potential)
- prolong the refractory period (prolonged repolarization)
- Describe the cellular mechanism of triggered (early and delayed) afterdepolarizations
During prolonged phase 2
- Excessive Ca2+ entry triggers further Ca2+ release from the SR (CDCR).
- The high level of intracellular Ca2+ requires increased Na/Ca exchange via NCX1 exchanger.
- NCX takes in 3 Na+ for 1 Ca2+, so it adds one positive charge to the inside of the myocyte each time
- This depolarizes the myocyte and thereby initiates delayed or early afterdepolarizations.
Describe how a re-entrant, or circus, arrhythmia originates
Requires:
- Uni-directional conduction block in a functional circuit.
- Conduction time around the circuit is longer than the refractory period.
After the slow reentry the previously depolarized tissue has recovered and reentry into it will occur.
Describe the basis of use-dependent block of Na+ channels by class I antiarrhythmic drugs
Channels must open before they can be blocked.
The channel must be open for the blocker to enter the pore, bind and thereby block the Na+ channel
Mechanism of block of cardiac Na+ channels is identical to local anesthetic block of neuronal Na+channels.
THEREFORE: Na+ channels in myocytes with abnormally high firing rates or abnormally depolarized membranes will be blocked to a greater degree than Na+ channels in normal, healthy myocytes.
Describe how class I antiarrhythmics increase Na+ channel refractory period, whether or not they prolong phase 2 of the fast response
These drugs also have a higher affinity for the inactivated state of the Na+ channel, thereby stabilizing it
Alternately… prolonging phase 2 means that the myocyte membrane is depolarized for a longer period of time and therefore more Na+ channels become inactivated, making the refractory period longer.
Describe how beta-adrenergic receptor blockers help suppress arrhythmias
They reduce Ih, ICa,L and IK which reduces the rate of diastolic depolarization in pacing cells, which reduces the upstroke rate and slows repolarization.
Pacing rate is reduced and refractory period is prolonged in the SA and AV nodal cells.
Beta-blockers are used to terminate arrhythmias that involve AV nodal re-entry, and in controlling ventricular rate during atrial fibrillation.
Describe how class III drugs increase refractory period
They block cardiac K+ channels.
The consequences of which are prolongation of fast response phase 2, and a prominent prolongation of refractory period (¯ reentry).
Prolongation of refractory period occurs because the prolonged duration of phase 2 leads to an increased inactivation of Na+ channels.
This mechanism of increasing refractoriness is different from the use-dependent block mechanism of all class I drugs, but is similar to the secondary mechanism of increasing refractoriness exhibited by class Ia drugs.
Describe how class IV antiarrhythmic drugs (Ca2+ channel blockers) reduce re-entry via effects on conduction velocity through the AV node and refractory period of the AV node
They reduce upstroke rate which slows conduction velocity. Slower conducting action potentials are more likely to fail to propagate through a depressed region.
Prolonged refractoriness can help suppress re-entrant arrhythmias for the straightforward reason that refractory tissue will not generate an action potential, and so the re-entrant wave of excitation is extinguished.
Describe how some antiarrhythmic drugs can suppress arrhythmias by decreasing cardiac automaticity
Some arrhythmias are generated by rogue cardiomyocytes that generate their own action potential without getting “directions” from the action potential propagated by the pacemaker cells of the AV or SA nodes.
Decreasing cardiac automaticity, generally by decreasing the rate at which a cell fires, ensures that cells do not generate their own “pacemaking” activityàthereby suppressing these arrhythmias.
Class II (beta blockers) and Class III (K+ channel blockers) drugs are particularly good at this.Describe how adenosine can help suppress cardiac arrhythmias
Increase a K+ current, while also decreasing both L-type Ca2+ current and Ih in SA and AV nodes.
Adenosine induced changes in membrane currents cause a reduction in SA node and AV node firing rate as well as a reduced conduction rate in the AV node.
