CVPR 03-25-14 10am-Noon Molecular Mechanisms of Arrhythmias and Anti-Arrhythmin Drugs - Sather Flashcards
Acquired cardiac arrhythmias…from what?
Acquired arrhythmias are much mroe common than congenital, and arise subsequent to MI, ischemia, acidosis, alkalosis, electrolyte abnormalities, or excessive catecholaminexposure
Antiarrhythmic Drug toxicity often causes
Arrhythmic activity, as well as greater mortality when used prophylatically post-MI….EX: Cardiac glycosides (digoxin), some antihistamines (astemizole, terfenadine), and antibiotics (sulfamethoxazole)
Common replacements for antiarrhythmic drugs
Catheter ablation of ectopic foci, Implantable cardioverter-debrillator devices (ICDs)
Uses for antiarrhythmic drugs
1) 1st line for certain arrhythmias…..2) Often used in conjunction w/ICDs (decrease frequency of arrhythmic episodes –> prolong battery life. reduce # of painful shocks)…..3) May be useful if elsewhere once research give more info on mechanisms/molecular targets.
Primary targets of antiarrhythmic drugs
Cardiac Na+ channels (INa), Ca2_ channels (ICa-L), K+ channels (IKs, IKr), and beta-adrenergic receptors (all are direct drug targets)
Indirect targets of antiarrhymthmic drug action
Via beta-adrenergic receptor pathways, pacemaker current, If, and ICa-L, and IKs
Only drug demonstrated to reduce incidence of sudden cardiac death
Beta blockers
Sudden cardiac death
Occurs during episodes of increased sympathetic tone/increased adrenergic receptor activation; Often have family members that suddenly died before the age of 40 (most likely also from sudden cardiac death)
Familial long QT syndrome - overview
Prolongation of the duration of cardiac action potential (QT interval –> can lead to ventricular arrhythmia and sudden death
Mechanism of long QT syndrome problems
Prolongation of the plateau phase (phase 2) of the fast response AP in ventricular myocytes –> torsades de pointes (polymorphic V tach) –> degenerates into V fib –> syncope & sudden cardiac death.
Triggering of Torsades de pointes in Familial long QT syndrome & reasoning for treatment
Typically triggered by an abrupt increase in sympathetic tone (emotional excitement, fright, or physical activity)… For this reason, current clinical practice includes treating long QT patients with β-adrenergic receptor blockers (β-blockers)
Constellation of Symptoms in Long QT syndrome
The Na+ and K+ channels involved in long QT syndrome are also found in other areas of the body, and thus can cause other problems than with the heart
Finding the underlying causes of long QT syndrome
Extensive human pedigrees were screened for families w/Hx of sudden death early in life —>Genetic linkage analysis of IDed pedigrees revealed variety of different mutations, depending upon pedigree, but nearly all were found in cardiac ion channels
Romano-Ward syndrome (RWS)
Autosomal dominant form of long QT syndrome; Genetically heterogeneous: more than 200 mutations IDed, with the most prevalent ones found in slow cardiac K+ channel IKs (LQT1), rapid cardiac K+ channel IKr (LQT2), and cardiac Na+ channel INa (LQT3).
Jervell-Lange-Nielson syndrome (JLNS)
Autosomal recessive form of long QT syndrome; Homozygous carriers of mutations in IKs (LQT1) suffer in addition from congenital deafness, while the heterozygous carriers are asymptomatic.
2 ways QT interval is lengthened in Long QT syndrome
- Loss of function mutation in K+ channel (not enough Phase 2 K+ release, leading to reduced current amplitude)…..2. Gain of function mutations in Na+ channel (incomplete inactivation)….May not see an ECG difference (must sequence), but they are two opposite problems (over and under activation)! So, must make sure drugs match specific problem in long QT syndrome.
Long QT mutations in cardiac K+ channel subunits
Generally reduce the number of K+ channels expressed in the myocyte plasma membrane (loss of function mutations), thereby reducing the size of the K+ current (IKr + IKs) that helps terminate the plateau phase of the fast response and return the membrane to resting potential during diastole.
Long QT mutations in the cardiac Na+ channel (INa)
Prevent Na+ channels from inactivating completely (gain of function mutations), thereby prolonging phase 2 of the fast response.
Long QT mutations in cardiac channels & antiarrhythmia treatment
Long QT mutations have been IDed in almost all of major kinds of cardiac ion channels; Thus, antiarrhythmic drugs should be selected based on specific molecular basis of long QT syndrome…. For patients with the LQT3 mutations, drugs that block Na+ channels should be used…. For patients with LQT1 or LQT2 mutations, drugs that open K+ channels ought to be used, ideally (none are currently approved)
Brugada syndrome
Congenital arrhythmia linked to cardiac Na+ channel mutations (different than in long QT syndrome), in which ventricular fibrillation develops… very poor prognosis (40% die by age 5);
Na+ channel abnormalities in Brugada syndrome
Rather than prolonged activation of I-Na as in long QT syndrome, Brugada syndrome reduces the amount of inward Na+ current that drives the AP upstroke in ventricular myocytes
2 types of arrhythmia problems:
(1) inappropriate impulse initiation in SA node or elsewhere (ectopic focus), and (2) disturbed impulse conduction in nodes, conduction cells (Purkinje cells) or myocytes.
Inappropriate impulse initiation in arrhythmias – identified by…
IDed by abnormally depolarized diastolic membrane potential
Inappropriate impulse initiation in arrhythmias – 2 Causes:
a.) Ectopic Foci, b) triggered afterdepolarizations
Ectopic Focis initiating inappropriate impulses in arrhythmias
B/c normal SA nodal pacemaker is abnormally slow, or ectopic focus is abnormally fast; Infarct causes membrane to depolarize (decrease in [K+]i occurs as Na/K-ATPase fails)
Triggered Afterdepolarizations
Lead to too much Ca2+ inside cardiac myocytes; may be early (EAD) or late/delayed (DAD); Both can trigger fatal arrhythmias
Early afterdepolarizations (EAD): Cause
Attributed to reactivation of I-Ca-L in response to increased intracellular Ca2+, during late phase 2 & phase 3 (prolongation of Phase 2, i.e. long QT, contributes to increase in Ca2+)
Delayed afterdepolarizations (DAD): Cause
Attributed to late increase in Na+-K+ exchange (by NCX, causing I-NCX), initiated by intracellular Ca2+ increase during early phase 4…Na/K exchange is electrogenic (net inward flow of +1 increase positive charge in myocytes & cause depolarization
Re-entry or “Circus Rhythm”
Normally AP starts at the top then moves through heart & dies at the end; Then, an new AP against starts at the top…..NOT a loop normally; BUT in reentry, a loop of current flows
2 requirements of re-entrant arrhythmias
- uni-directional conduction block in functional circuit (bi-directional would block circuit)…….2. conduction time around circuit must be greater than refractory period (if drug could increase refractory period, could prevent this)
Antiarrhythmic Drugs: Class IA, IB, IC drugs
= Na+ channel blockers —> Slow upstroke (esp. IC) —> decrease conduction velocity, increase refractory period, decrease reentry
Antiarrhythmic Drugs: Class IB
= slowed upstroke + shortened (faster) repolarization (~pure class 1 action = Na+ channel blocking)
Antiarrhythmic Drugs: Class IA
= slowed upstroke + prolonged (delayed) repolarization
Antiarrhythmic Drugs: Class IC
= very slowed upstroke + slight prolongation of repolarization
Antiarrhythmic Drugs: Class IA drug examples
quinidine, procainamide, disopyramide
Antiarrhythmic Drugs: Class IB drug examples
lidocaine, mexiletine, phenytoin
Antiarrhythmic Drugs: Class IC drug examples
propafenone, flecainide, encainide
Local anesthetic block of Na+ channels by lidocain
Inactive drug enters passively through membrane then is protonated & enters channel from inside, where it gets stuck –> it both blocks entry of Na+ & prolongs channel inactivation –> prolongs inactivation of the tissue (longer refractory period to prevent arrhythmia)
Antiarrhythmic drug classes
Classified by dominant action of teh drug; BUT drug can do more than one class of action……Class I: blockers of voltage-gated Na+ channels…..Class II: Beta-adrenergic receptor blockers…..Class III: drugs that prolong fast response phase 2 by delayed repolarization….. Class IV: blockers of voltage-gated cardiac Ca2+ channels
Unclassified antiarrhythmic drug - important example
adenosine
Use-dependence of Na+ channel blocking antiarrhythmic drugs (class I)
- The more frequently a channel is used (activated), the greater the chance that it will become blocked by the drug (more likely will block over-active cardiac tissue —> slowed conduction)
Refractory period affects of use-dependent Na+ channel blocking antiarrhythmic drugs (class I)
The bound drug not only blocks the channel, but increases the time required for Na+ channels to recover from inactivation …. Thus, in the presence of a use-dependent blocker, over-active cardiac tissue will exhibit a longer refractory period.
How to Defeat Reentry
Either by 1) Slowed conduction velocity (convert uni- to bi-direction block)…. 2) Longer refractory period
Ways to convert unidirectional block of the circuit to bidirectional block & thus prevent reentry
- Slow AP conduction velocity….. 2. Prolong refractory period…..Both are accomplished by Class I antiarrhythmic drugs
Terminating re-entry via slowed conduction velocity
Drugs can decrease upstroke & thus conduction velocity…. decreased upstroke –> slower AP propagation, less voltage —> AP May not propagate through depressed regions or at least will not be able to excite the tissue beyond it (thus, uni- is converted to bi-directional block)
Na+ channel block & conduction
Partial block of I-Na (by Class I antiarrhythmic drugs) causes retrograde conduction to fail in the depressed region, which is why we use these drugs
Prolonged refractory period can suppress reentrant arrhytmias b/c
Refractory tissue will not generate an AP, so the re-entrant wave of excitation is extinguished.
Paradox in combating re-entry
Slowing conduction to convert uni- to bi-directional block causes the conduction time around the circuit to be shorter than the refractory period –> i.e., the two fundamental means of terminating re-entry (slowing conduction & prolonging refraction) work via conflicting processes; doesn’t necessarily mean the drug won’t work, but it might
Class 2 antiarrhythatic drugs - Beta blockers - examples
propranolol, metoprolol, esmolol
Beta-adrengergic receptor blockers - action
Decrease If current, I-Ca-L, K+ current –> slow pacing rate, slow upstroke rate, slow repolarization (prolong refractory period) in nodal cells
When to use beta blockers in arrhythmias
To terminate arrhythmias involving AV nodal re-entry and in controlling ventricular rate during atrial fibrillation
Effects of beta-blockers on the slow response
- Decrease phase 4 slope —> decrease firing rate —> decrease Automaticity……. 2. Prolong AV node repolarization —> increase refractory period —> decrease Re-entry
Class III antiarrhythmic drugs - examples
ibutilide, dofetilide, AMIODARONE, sotalol, bretylium
Action of Class III antiarrhythmic drugs
Block K+ channels (ibutilide & dofetilide do so specifically) —> prolongs fast response phase 2 —> increases inavtivation of na+ channels —> prolongs refractory period
Amiodarone (Class III) - special actions
As a class III drug, prolong fast response phase 2 via delayed repolarization, BUT also has an important class I action (Na+ channel blocker) —> Reduces conduction velocity (decreases Re-entry), Increases refractory period by blocking Na+ channels, Decreases rate of diastolic depolarization in automatic cells, thus reducing firing rate (decreases Automaticity)
Sotalol (Class III) - special actions
Not only blocks K+ channels as a class III drug, but also acts as a beta-blocker
effects of class III drugs on fast response
Increase refractory period (prolonged repolarization) —> decrease reentry
Class IV drugs - examples
verapamil, diltiazem
Class IV drugs - actions
= use-dependent blockers of L-type Ca2+ channels, mostly those in nodal cells also block in fast response myocytes —> ↓ upstroke rate in slow response tissue —> ↓ conduction velocity (esp. in AV node) ………… Prolong refractory period & thereby suppress re-entrant arrhythmias
Effects of Class IV Ca2+ channel blockers on AV node APs
Decrease conduction velocity of AV node, Increase refractory period of AV node —> Decrease Re-entry….. Slowed upstroke & reduced AP amplitude are direct results of I-CaL block; Slowed repolarization (phase 3) is an indirect result (reduced AP amplitude –> fewer K+ channels activated)
Unclassified antiarrhythmic drugs: Adenosine - actions
In SA & AV node, adenosine (via A1 adenosine receptor): ↑ I-K, ↓ I-CaL (slow inward), ↓ nodal If……….Actions are similar to β-blockers……
Adenosine-induced changes in membrane currents: ↓ SA & AV node firing rate, ↓ AV node conduction rate
Antiarrhythmic drugs as primary therapy
Primary therapy for atrial fibrillation only; Ablation/ICD are equal or superior in all other arrhythmias
Pathophysiology & Treatment of Paroxysmal supraventricular tachycardia (PSVT)
Pathophys is via re-entry….Acutely, treated with adenosine (advantageous short half-life)….Chronically, treat with Class II-IV drugs and catheter ablation of ectopic focus
Pathophysiology & Treatment of Atrial fibrillation
Pathophys via re-entry …. Acute: AV nodal blockers, electrical cardioversion……. Chronic: AV nodal blockers + long-term anticoagulation (warfarin); Cardioversion (electrical/ibutilide) + drug maintenance of rhythm; or Class III (amiodarone)
Pathophysiology & Treatment of Ventricular tachycardias/fibrillation
Pathophys via afterdepolarizations & re-entry….. Acute: amiodarone, lidocaine
Half-lives of Esmolol (class II) vs. Amiodarone (class III) vs. Unclassified Adenosine
Adenosine (10 sec; given IV bolus) < Esmolol (10 min; metabolized by blood esterase) < Amiodarone (13-100 days)
