Nordgren: Anti-arrhythmic Drugs Flashcards
What is an arrhythmia?
A condition of the heart in which the electrical is faster, slower or irregular.
What is tachycardia?
Faster heart beat
What is bradycardia?
Slower heart beat
What are three ways that arrhythmias can deviate from normal?
- Rate of impulse
- Impulse at the site of origin
- Conduction of Impulse
Arrhythmias are also examples of…
cardiac depolarizations
The transmembrane potential through cells is determined by the concentrations of what three ions?
Na, K, Ca
Water soluble so don’t pass through membrane without specific ion channels
What accounts for the differences in the shape of observed AP for pacemaker and contractile cardiac cells?
Differences in ion permeability
What regulates the flow of ions though ion specific channels?
Ion channels are controlled by “gates” that are voltage sensitive and can be modulated by ion concentration and metabolic conditions.
What causes the depolarization of atrial, purkinje and ventricular cells?
Na current
What causes the depolarization of SA and AV nodal cells?
Ca current
What is difference between the depolarization of SA/AV nodal cells and atrial/purkinje/ventricular cells?
Ca and Na channels are activated/inactivated in the same way BUT the transitions in Ca channels occur more slowly and at more positive membrane potentials.
What causes the final repolarization of the action potential in all cell types?
Na/Ca inactivation and the growth of K permeability
When does the final repolarization of the action potential occur?
Phase 3
What are three factors that help to bring the membrane potential back to the K equilibrium potential?
- Rapidly activating K current
- Slowly activating K Current
- Ikr + Iks collectively called “Ik”
Why may some drugs that block Ik have little effect on the repolarization of SA nodal cells?
SA nodal cells may be controlled by a different K current
What is one of the most important relationships to consider when looking at the pathophysiology of arrhythmias and the drugs used to treat them?
The relation between RESTING potential of the cell and the number of APs that can be evoked.
What determines how many ion channels are open?
Membrane potential through activation and inactivation gates
Na channel inactivation gates close between -75 and -55. How many Na channels will be available for diffusion of Na at -60? At -80?
Fewer Na channels will be available for diffusion of Na than if AP occurred at -80.
At a positive membrane potential (ex. the plateau of phase 2), how many Na channels are available?
None!
What happens to Na channels during repolarization?
Na channels recover from inactivation and become available.
What is the refractory period?
The time phase between Phase 0 and sufficient recovery of Na channels in Phase 3 to allow another AP.
What happens to the AP if you add a drug that BLOCKS Na channels?
- Total # channels available at optimal conditions will be decreased (phase 4).
- At subotimal conditions, channels will be unavailable d/t both inactivation gate closure and drug blockade.
Why does Na channel recovery time increase w/ depolarization of the membrane potential?
- Depolarized cells recover more slowly!
2. Increases the refractory period of the cell.
What does a Na channel blockade do to recovery time? Where is the recovery time the greatest?
It PROLONGS the recovery time at any given membrane potential.
At depolarized potentials
What happens to Na currents if the resting potential depolarizes to -55mV?
It abolishes Na current–all Na channels are inactivated.
Depolarization of resting potential to -55 mV usually abolishes Na currents. What is an exception to this rule? What cells are an example of this exception?
Severely depolarized cells support special APs under circumstances that INCREASE Ca or DECREASE K permeability.
SA and AV nodal cells because they have a normal RMP in the range of -50 to -70.
What factors lead to arrhythmia?
Ischemia Drug toxicity Hypoxia Acidosis/alkalosis Electrolyte abnormalities Overstretching of cardiac fibers Excessive catecholamine exposure Autonomic influences Scarred or diseased tissue
Factors that cause arrhythmia do so by disturbing what to necessary cardiac processes?
- Impulse formation
2. Impulse conduction
What are pacemaker cells responsible for?
Impulse formation
What are the two phases of impulse formation described as?
- Diastolic Interval
2. Action Potential Phases
What will shortening of either the diastolic interval or the action potential phase do?
Increase pacemaker rate leading to an increase in heart rate.
Out of the two phases of initial impulse formation which is the more important of the two?
Diastolic Interval
What are two ways to slow the pacemaker cell?
- Alter the slope of the diastolic interval (phase 4 of the pacemaker potential)
- Hyperpolarize the diastolic interval so it takes longer to reach the threshold
How does vagal discharge of acetylcholine affect impulse formation?
It SLOWS the pacemaker.
How do beta-adrenoceptor blocking affect impulse formation?
They release NE (catecholamines)/sympathetic innervation leading to a reduced slope of diastolic interval, ultimately slowing the pacemaker.
How do you increase the speed of the pacemaker?
Alter the slop of the diastolic interval (more rapid change)
What are examples of physiological processes that speed up the pacemaker?
- Hypokalemia
- Beta-adrenoceptor stimulation
- Positive chronotropic drugs
- Fiber stretch
- Acidosis
What are afterdepolarizations?
Membrane voltage oscillations that result in transient, abnormal depolarizations of cardiac myocytes during phase 2, 3, or 4 of the cardiac AP.
What are the two ways to describe afterdepolarizations?
- Early afterdepolarization
2. Delayed afterdepolarization
When do early afterdepolarizations occur and what do they do?
Occur DURING and AP and interrupt orderly repolarization of the myocyte.
What causes early afterdepolarization?
- Late phase 2- opening of more Ca channels
- Early phase 3: Opening of Na channels
- Both: inhibition of K channels
When is early afterdepolarization exacerbated? Why?
At SLOW heart rates. There is a better chance another can happen on top of it.
When does a delayed afterpolarization occur?
- AFTER the Ap, when the cell is nearly or fully repolarized, but before another AP would occur.
What causes delayed afterdepolarization?
Elevated cytosolic Ca levels overloads the SR and causes a spontaneous release of Ca and leads to depolarizing current.
What exacerbates delayed afterdepolarization?
Fast heart rates
Why are afterdepolarizations bad? When are they most likely to occur?
They lead to arrythmias!
When AP duration is abnormally long.
What is a block?
When an electrical signal is slowed or disrupted as it moves through the heart.
Where can blocks occur?
SA node AV node Bundle of His (Infra-hisian block) Bundle Branch Fascicles (hemiblocks)
What is a partial block?
When electrical impulses are DELAYED or ocassionaly stopped.
What is a complete block?
Electrical impulses are completely STOPPED.
What is re-entry?
When an impulse reenters and excites areas of the heart more than once.
*Also called circus movement
What are the three things that must happen in order for re-entry to occur?
- There must be an obstacle to homogenous conduction
- There must be a unidirectional block at some point in the circuit
- The conduction time (how long it takes for the signal to go through/around) must exceed the effective refractory period
What is a unidirectional block?
Prevents the passage of an impulse when it approaches from one direction but not from the other.
What is a bidirectional block?
A block that prevents passage of an impulse in both directions.
What is Wolff Parkinson-White syndrome?
When a heart has an extra anatomical feature called a BUNDLE OF KENT that leads to an abnormal electrical accessory connection between the atria and ventricle.
What does the bundle of kent do?
- It allows for impulse to be conducted without going through the AV node and causing a ventricle to prematurely contract.
- It can also be a conduit for re-entry to the atria.
When is the only TIME reentry can occur?
When conduction has been depressed for some critical amount of time.
What happens when conduction is too slow or twoo fast?
Both lead to bidirectional blocks and therefore NO reentry.
What happens when an impulse travels around a unidirectional block too quickly?
Reaches tissue that are still refractory> no reentry
What causes conduction to slow down?
Decreased Ca or Na current
What causes arrhythmias?
- Abnormal pacemaker activity
2. Abnormal impulse propagation
What do antiarrhythmic drugs aim to do?
- Reduce pacemaker activity
2. Modify conduction/refractoriness
What are the 4 major pharmacologic mechanisms for arrhythmias?
- Na channel blockade (class I)
- β-Adrenoceptor Blockade (class II)
- K+ channel blockade (Class III drugs)
- Ca channel blockade (Class IV)
What is the MOA of a Na channel blockade do? Class?
Alters AP duration and kinetics of Na channel blockade.
Class I
What is the MOA of a Beta adrenoceptor blockade do? Class?
Blockade the SNS effects in the heart.
Class II
What is the MOA of a K channel blockade do? Class?
Prolongation of the effective refractory period.
Class III
What is the MOA of a Ca channel blockade? Class?
Slows conduction where depolarization is Ca dependent.
Class IV
What drugs are 1A Na channel blockers?
Quinidine
Procainamide
Disopyramide
What drugs are subgroup 1B Na channel blockers?
Lidocaine
Mexilitine
What drugs are 1C Na channel blockers?
Flecainide
Propafenone
What drugs are K channel blockers?
Amiodarone
Dofetilide
Ibutilide
What drugs are Ca channel blockers?
Verapamil
Diltiazem
What drugs are Beta adrenergic blockers?
Propanolol
Acebutolol
Esmolol
Sotalol.
What two drugs are misc arrhythmic?
Adenosine
Digitalis
When are “use” or “state dependent” drugs useful?
They are good channel blocking drugs.
- Bind readily to activated (phase 0)/inactivated channels (Phase 2)
- Bind poorly or not at all to rested channels (prevent drug from binding in this state/promotes drug dissociation from receptors when channel becomes rested.)
When can “state dependent” drugs block electrical activity?
- Fast tachycardia- many channel activations/inactivations per unit time
- Significant loss of resting potential- many inactivated channels during rest (lose RP channels are transformed to inactivated state when they should be in a resting state)
What is the goal of antiarrythmic drugs?
To suppress ectopic atuomaticity adn abnormal conduction occurring in depolarized cells, while minimally affecting the electrical activity of normally polarized parts of the heart.
What is the approach for antiarrhythmic drugs?
Identify the specific mechanism of arrhthmia and exploit what makes it different.
What does a reentry arrhthmia depend on?
- Depressed conduction
- Unidirectional block
*Slow conduction speed> bidirectional block> no reentry > not a problem
What are two ways to address reentry arrhythmias?
- Na and Ca channel blockade
2. K channel blockade
How does a Na and Ca channel blockade address a reentry arrhythmia?
It causes a steady state reduction in the number of available unblocked channels, which reduces excitatory currents to a level below that required for propagation.
How does a K channel blockade address a reentry arrhythmia?
Prolongs recovery time of channels still able to reach the rested and available state, which increases refractory period.
What do you have to worry about with many of the antiarrhythmetic drugs, particularly the Na channel blockers?
Many of these drugs lack channel specificity, so as you increase the dose, there is a greater spillover to secondary channels. Also, channel specificity is inversely related to dose, so at high doses the drugs can effect all the channels.
