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Antiarrhythmic Drug (Pharmacology (Class 1C (No ANS effects, Drug:
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Antiarrhythmic Drug
Pharmacology
Class 1C
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Drug:
- Flecainide
º Limited use because of proarrhythmogenic effects, leading to ↑ in
sudden death post-MI and when used prophylactically in VT
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Block fast Na+ channels (↓ INa), especially His-Purkinje tissue
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Class 1B
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Block inactivated channels—preference for tissues partly depolarized (slow conduction in hypoxic and ischemic tissues). This results in an increased threshold for excitation and less excitability of hypoxic heart muscle.
↓ APD—due to block of the slow Na+ “window” currents, but this increases diastole and extends the time for recovery.
Lidocaine
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Side effects:
- CNS toxicity (seizures)
- least cardiotoxic of conventional anti-arrhythmics
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For the exam, you should understand which effect is antiarrhythmic (slows heart) and which is proarrhythmic (speeds up heart).
Physiology
Cardiac action potential
Fast-Response fibers: Cardiac Muscle, His-Purkinje System
Phase 1
- Na+ channels are inactivated.
- In some His-Purkinje cells, transient outward K+ currents and inward Cl- currents contribute to the “notch” and overshoot.
- Antiarrhythmic drugs have no significant effects on these transient currents.
Phase 2
- Plateau phase in which a slow influx of Ca2+ (ICa-L) is “balanced” by a late-appearing outward K+ current (the delayed rectifier current IK).
- Antiarrhythmic drugs have no significant effects on these currents during,this phase of the action potential (AP).
Phase 3
- Repolarization phase in which the delayed rectifier K+ current rapidly increases as the Ca2+ current dies out because of time-dependent channel inactivation.
- Class III antiarrhythmic drugs slow this repolarization phase.
- Note that during phases 0 through 3 a slow Na+ current (“window current”) occurs, which can help prolong the duration of the action potential.
Phase 4
- Return of membrane to resting potential—maintained by activity of the Na+/K+-ATPase.
Responsiveness
- Capacity of a cell to depolarize, associated with the number of Na+ channels in a ready state. See Mechanism of Action of Voltage-Gated Na+ Channels
https://drive.google.com/drive/folders/0B4QFyVsok-aCMUg4ZWVBZUhqbzg
- This in turn depends on resting membrane potential: the more negative the resting potential (RP), the faster the response.
Conductance
Rate of spread of an impulse, or conduction velocity—three major determinants:
- Rate of phase 0 depolarization—as Vmax decreases, conduction velocity
decreases and vice versa.
- Threshold potential—the less negative, the slower the conduction velocity.
- Resting potential—the more negative the RP, the faster the conduction.
Phase 0
- Na+ channels open—sodium enters the cell down its concentration gradient (fanny I Na), causing membrane depolarization.
- Rate of depolarization depends on number of Na+ channels open, which in turn depends on resting membrane potential of the cell.
- Class I antiarrhythmic drugs can slow or block phase 0 in fast-response fibers.
Slow-Response Fibers SA and AV Nodes, Specialized Cells
- During repolarization, the Ca2+ currents are opposed and overcome by the delayed rectifier K+ current. The relative magnitudes of these opposing currents determine the “shape” of the action potential.
- The major distinctive feature of slow fibers is their spontaneous depolarization, shown by the rising slope of phase 4 of the AP, referred to as the pacemaker potential or “pacemaker current.” Although not completely understood, pacemaker potential is a composite of inward Na+ (I funny) and Ca2+ (ICa-T) currents and outward K+ currents (IK).
- Class IV antiarrhythmic drugs can slow or block phase 0 in slow response fibers.
- Depolarization depends on activation of Ca2+ channels (I Ca-L and I Ca-T).
- No appreciable (значного) Na+ current during phase 0 in these cells because the Na channels are either absent or in an inactive form because of the existing voltage.
- Class II and IV antiarrhythmic drugs can slow phase 4 in pacemaker fibers
Automaitcity
- The ability to depolarize spontaneously confers automaticity on a tissue.
- The fastest phase 4 slope will determine the pacemaker of the heart, which is normally the SA node.
Effective Refractory Period (ERP)
- No stimulus, of any magnitude, can elicit a response.
- Lasts into late stage 3 of the AP because Na+ channels are effectively inactivated and not in the “ready” state.
- Blockers of K+ channels prolong the ERP.
Relative Refractory Period (RRP)
- A strong stimulus can elicit a response, but the timing will be out of
sync with the rest of the heart and arrhythmias may occur.
- Ratio of ERP to the action potential duration (APD) is a measure of
refractoriness, as illustrated in Figure III-4-3. Decreases in ERP favor the formation and propagation of premature impulses.
Na+ Channels
Activation
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This voltage-gated channel, which is responsible for the fast Na current (INa), exists in three conformations:
- Resting or ready state
- Open or active state
- Inactivated or refractory state
The channel has two gates: M (activating) and h (inactivating), both of which are sensitive to voltage changes.
- At approx. –50mV ‘M’ gate closes.
- At approx. –85mV ‘h’ gate opens.
Inactivation of the h gate is slower; therefore, it stays open longer and the Na channel is active.
Recovery
Fastest rate of recovery occurs at normal RP, and recovery slows as membrane voltage increases.
Rate of recovery is slower in ischemic tissue because cells may be partly depolarized at rest. This reduces the number of channels able to participate in the next depolarization, which leads to a decrease in conduction rate in ischemic tissue.
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