AntiArrhythmic Drugs Flashcards
Antiarrhythmic Drug Characteristics
- ALL target ion channels in the heart either directly or indirectly
- many are both anti-and pro-arrhythmic. Some are associated with severe or even life threatening adverse effects
- blockade for cardiac ion channels also contributes to the proarrhythmic adverse effects of a large number of non-cardiac drugs
- ONLY beta-blockers (class II) have been shown to be associated with a significant reduction of mortality
- radiofrequency catheter ablation may produce permanent cures in many forms of Arrhythmias, implantable cardioverterdefibrillator (ICD) has the potential for prolonging survival by terminating VT/VF
2 major differences in AP (pacemakers vs. working myocytes)
- resting potential (diastolic potential is more depolarized in nodal cells)
- conduction velocity is almost 100x’s faster than pacemaker cells
allows for selectivity for anti-arrhythmic drugs
Major classes of ion channels in the heart
Na Channel Transient Outward K channel (Ito) Sustained K channels (Ik [split into IKr and IKs]) IK1 channels (or inward rectifier IK1) L-type Ca channels Pacemaking channel (If)
5 Phases of AP
0: upstroke (rapid opening and inactivation of Na channels. Very large but brief inward Na current)
1: initial repolarization (activation and inactivation of transient outward K current)
2: plateau phase (opposing Ca and K current): they balance each other and relatively small net current going on, which is hwy you have a prolonged plateau phase
3: final repolarization (inward rectifier K current, brings the voltage back to the resting phase. Sustained outward current that holds the voltage at a hyperpolarized level)
4: diastolic phase
Propagation of Action Potential (factors)
Speed
Magnitude
***larger inward current—
Na channel Blockers (e.g. Quinidine) (class I antiarrhythmics)
AP conduction is determined by the size of inward current, blockade of Na current reduces conduction
- the membrane potential of DISEASED CELLS is less negative, as a result, more Na channels are inactivated, generating a slow-conducting abnormal AP
- Na channel blockers target open or inactivated Na channel, suppressing abnormal AP but leaving normal AP alone
K channel Blockers (class III antiarrhythmics) (e.g. ibutilide)
- if you apply these, tilts the balance of K and Ca currents in the plateau phase (2) toward Ca influx. Prolongs the entire AP duration and refractory period
- prevents tachycardia and normal myocardium being triggered by diseased areas
- excessive prolongation of APD is pro-arrhythmic and can lead to arrhythmogenic triggered activities and polymorphic VT, torsade de points
- genetic mutations of cardiac K channels prolongs APD and QT interval, resulting in idiopathic Long QT Syndrome
Ca channel blockers (Class IV arrhythmics) (e.g diltiazem)
- SA and AV node cell AP upstroke mediated entirely by L-type Ca current
- Ca Blockers decrease conduction velocity, mainly in the AV node. This controls the transmission of high atrial rate to ventricles in Afib (rate control)
- iCaL blockade reduces AP duration and contractility in working myocytes. Negative inotropic effects will WORSEN HF
Beta-Blockers (class II arrhythmics) (e.g. metoprolol)
- decrease pacemaker activity, and is effective in treating sinus tachycardia
- modulates If current that is activated or inhibited by sympathetic/parasympathetics
Cholinergic Blocker (e.g. atropine)
-increases If, and is effective in treating sinus bradycardia
Abnormal Automaticity
Simple: either too fast or too slow
-increased vagaries tone inhibits If, leads to Sinus bradycardia
Tx: either atropine (muscarinic receptor blocker) or B agonist (isoproterenol)
-increased sympathetic tone stimulates If, leads to Sinus Tachycardia
Tx: B-blocker (metoprolol), Ca Channel Blocker (Diltiazem):reduces conduction veloicty, increases AP threshold and time to threshold (greater effect on AVN), K channel blocker (amiodarone): prolong APD thus decreases AP rate
Triggered Activity
-NOT a self-generating rhythm (unlike automaticity)
-spontaneous excitation of myocyte “triggered” by preceding impulse
-theses are single cell phenomena that can propagate and lead to cardiac arrhythmias
Requires 2 things
-voltage has to be above threshold or the channels will never open
-AND you need enough Na channels in the closed state to be re-opened
Early Afterdepolarization (EAD)
- occurs during excessive prolongation of AP
- due to very long AP, the Na and even Ca channels have enough time to recover back into closed state. The voltage spends quite a long time above threshold. Not a full recovery of Na channels but enough to fire an AP. We have the 2 conditions necessary to fire spontaneously
- the cell will fire a second AP on rope of the first AP
- associated with slow HR and AP prolongation
- happens DURING an AP
- might be underlying mechanisms of arrhythmogenesis in Long QT syndrome
Tx:
- treat offending condition (ischemia, K channel blockade)
- Na channel blockers (e.g. Lidocaine)
- B-blockers: in long QT syndrome (suppress L-type Ca channel, stimulate K channels: net increase in outward current)
- ***K channel blockers are contraindicated
Delayed Afterdepolarization (DAD)
- associated with fast rate and is the result of CA overload of cell
- happens AFTER the complete repolarization of an AP and can trigger a second or a series of additional APs
- more likely in the presence of catecholamines
Tx:
- B-Blockers: lower HR and reduce Ca influx and uptake
- Na Channel Blockers: to block the generation of spontaneous AP
Long QT Syndrome
- caused by mutations of cardiac channel genes (IKs, IKr, Na, L-type or Ik1), which result in decreased in outward K current or increase in inward Na/Ca current. Leads to longer cardiac APD and development of EADs
- syncope attacks, SCD due to TdP, a polymorphic VT
Tx:
- B-blockers: suppress Ca current and stimulates IKr)
- ICD
