Pathophysiology on Arrhythmia Cvphysio.com

8/22/2019 Pathophysiology on Arrhythmia Cvphysio.com

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Arrhythmias

What is an arrhythmia? How common are arrhythmias? What are the clinical symptoms?

What causes arrhythmias? What are the consequences of arrhythmias? How are arrhythmias treated?

What is an arrhythmia?

The rhythm of the heart is normally generated and regulated bypacemaker cells within the sinoatrial (SA) node, which is located withinthe wall of the right atrium. SA nodal pacemaker activity normallygoverns the rhythm of the atria and ventricles. Normal rhythm is veryregular, with minimal cyclical fluctuation. Furthermore, atrialcontraction is always followed by ventricular contraction in the normalheart. When this rhythm becomes irregular, too fast (tachycardia) ortoo slow (bradycardia), or the frequency of the atrial and ventricularbeats are different, this is called an arrhythmia. The term"dysrhythmia" is sometimes used and has a similar meaning.

How common are arrhythmias?

About 14 million people in the USA have arrhythmias (5% of thepopulation). The most common disorders are atrial fibrillation and

flutter. The incidence is highly related to age and the presence ofunderlying heart disease; the incidence approaches 30% followingopen heart surgery.

What are the clinical symptoms?

Patients may describe an arrhythmia as a palpitation or flutteringsensation in the chest. For some types of arrhythmias, a skipped beatmight be sensed because the subsequent beat produces a moreforceful contraction and a thumping sensation in the chest. A "racing"heart is another description. Proper diagnosis of arrhythmias requires

an electrocardiogram, which is used to evaluate the electrical activityof the heart.

Depending on the severity of the arrhythmia, patients may experiencedyspnea (shortness of breath), syncope (fainting), fatigue, heart failuresymptoms, chest pain or cardiac arrest.

What causes arrhythmias?

A frequent cause of arrhythmia is coronary artery disease because thiscondition results in myocardial ischemia or infarction. When cardiaccells lack oxygen, they become depolarized, which lead to altered

impulse formation and/or altered impulse conduction. The formerconcerns changes in rhythm that are caused by changes in the
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automaticity of pacemaker cells or by abnormal generation of actionpotentials at sites other than the SA node (termed ectopic foci).Altered impulse conduction is usually associated with complete orpartial block of electrical conduction within the heart. Altered impulseconduction commonly results in reentry, which can lead totachyarrhythmias. Changes in cardiac structure that accompany heartfailure (e.g., dilated or hypertrophied cardiac chambers), can alsoprecipitate arrhythmias. Finally, many different types of drugs(including antiarrhythmic drugs) as well as electrolyte disturbances(primarily K+ and Ca++) can precipitate arrhythmias.

What are the consequences of arrhythmias?

Arrhythmias can be either benign or more serious in nature dependingon the hemodynamic consequence of the arrhythmia and thepossibility of evolving into a lethal arrhythmia. Occasional prematureventricular complexes (PVCs), while annoying to a patient, are

generally considered benign because they have little hemodynamiceffect. Consequently, PVCs if not too frequent, are generally nottreated. In contrast, ventricular tachycardia is a serious condition thatcan lead to heart failure, or worse, to ventricular fibrillation and death.

How are arrhythmias treated?

When arrhythmias require treatment, they are are treated with drugsthat suppress the arrhythmia. These drugs are called antiarrhythmicdrugs. There are many different types of antiarrhythmic drugs andmany different mechanisms of action. Most of the drugs affect ion

channels that are involved in the movement of sodium, calcium andpotassium ions in and out of the cell. These drugs include mechanisticclasses such as sodium-channel blockers, calcium-channel blockersand potassium-channel blockers. By altering the movement of theseimportant ions, the electrical activity of the cardiac cells (bothpacemaker and non-pacemaker cells) is altered, hopefully in a mannerthat suppresses arrhythmias. Other drugs affect autonomic influenceson the the heart, which may be stimulating or aggravatingarrhythmias. Among these drugs are beta-blockers. More details ondrug therapy and specific drugs can beobtained by clicking here.

Membrane Potentials

If a voltmeter is attached to the twoterminals of a battery, a voltage differencewill be measured across the two terminals.Likewise, if a voltmeter is used to measurevoltage across the cell membrane (insideversus outside) of a cardiomyocyte, it willbe found that the inside of the cell has a

negative voltage (measured in millivolts;mV) with respect to the outside of the cell
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(which is referenced as 0 mV). Under resting conditions, this is called theresting membrane potential. With appropriate stimulation of the cell,this negative voltage inside the cell (negative membrane potential) maytransiently become positive owing to the generation of an actionpotential. Membrane potentials result from a separation of positive andnegative charges (ions) across the membrane, similar to the plates withina battery that separate positive and negative charges.

Membrane potentials in cells are determined primarily by three factors: 1)the concentration of ions on the inside and outside of the cell; 2) thepermeability of the cell membrane to those ions (i.e., ion conductance)through specific ion channels; and 3) by the activity of electrogenic pumps(e.g., Na+ /K+-ATPase and Ca++ transport pumps) that maintain the ionconcentrations across the membrane.

Cardiac cells, like all living cells, have different concentrations of ionsacross the cell membrane, the most important of which are Na+, K+, Cl-,

and Ca++ (see figure to right). There are also negatively charged proteinswithin the cell to which the cell membrane is impermeable. In a cardiaccell, the concentration of K+ is high inside the cell and low outside.

Therefore, there is a chemical gradient for K+ to diffuse out of the cell. Theopposite situation is found for Na+ and Ca++ where their chemicalgradients (high outside, low inside concentrations) favor an inwarddiffusion.

Potassium ion. To understand how a membrane potential is generated,first consider a hypothetical cell in which K+ is the only ion across themembrane other than the large negatively charged proteins inside of the

cell. Because the cell has potassium channels through which K

+

canmove in and out of the cell, K+ diffuses down its chemical gradient (out ofthe cell) because its concentration is much higher inside the cell thanoutside. As K+ (a positively charged ion) diffuses out of the cell, it leavesbehind negatively charged proteins. This leads to a separation of chargesacross the membrane and therefore a potential difference across themembrane. Experimentally it is possible to prevent the K+ from diffusingout of the cell. This can be achieved by applying a negative charge to theinside of the cell that prevents the positively charged K+ from leaving thecell. The negative charge across the membrane that would be necessaryto oppose the movement of K+ down its concentration gradient is termedthe equilibrium potential for K+ (EK; Nernst potential). The Nernst

potential for K+ can be calculated as follows:

EK = -61 log [K+]i / [K+]o = -96 mV

(where [K+]i = 150 mM and [K+]o = 4 mM)

The EK represents the electrical potential necessary to keep K+ from

diffusing out of the cell, down its chemical gradient. If the outside K+concentration were increased from 4 to 40 mM, then the chemicalgradient driving K+ out of the cell would be reduced, and therefore themembrane potential required to maintain electrochemical equilibrium (EK)

would be less negative according to the Nernst relationship. In thisexample, the EK becomes -35 mV when the outside K+ concentration is 40
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mM. In other words, when K+ is elevated 10-fold outside of the cell, thechemical gradient driving K+ out of the cell is reduced and therefore a lessnegative voltage is required to keep K+ from diffusing out of the cell.

The resting potential for a ventricular myocyte is about -90 mV, which is

near the equilibrium potential for K

+

when extracellular K

+

concentration is4 mM. Since the equilibrium potential for K+ is -96 mV and the restingmembrane potential is -90 mV, there is a net driving force (differencebetween membrane potential and equilibrium potential) of 6 mV acting onthe K+. The membrane potential is more positive than the equilibriumpotential, therefore the net driving force is outward due to K+ having apositive charge. Because the resting cell has a finite permeability to K+and the presence of a small net outward driving force acting upon K+,there is a slow outward leak of K+ from the cell. If K+ continued to leak outof the cell, its chemical gradient would be lost over time; however, aNa+/K+-ATPase pump brings the K+ back into the cell and therebymaintains the K+ chemical gradient.

Sodium and calcium ions. Because the Na+ concentration is higheroutside the cell, this ion diffuses down its chemical gradient into the cell.Experimentally, this inward diffusion of Na+ can be prevented by applyinga positive charge to the inside of the cell. When this positive changecounterbalances the chemical diffusion force driving Na+ into the cell,there will be no net movement of Na+ into the cell, and Na+ will thereforebe in electrochemical equilibrium. The membrane potential required toproduce this electrochemical equilibrium is called the equilibriumpotential for Na+(ENa) and is calculated by:

ENa = -61 log [Na

+

]i / [Na

+

]o = +52 mV

(where [Na+]i = 20 mM and [Na+]o = 145 mM)

The positive ENa means that in order to balance the inward directedchemical gradient for Na+, the cell interior needs to be +52 mV to preventNa+ from diffusing into the cell. At a resting membrane potential of -90mV, there is not only a large chemical driving force, but also a largeelectrical driving force acting upon external Na+ to cause it to diffuse intothe cell. The difference between the membrane potential and theequilibrium potential (-142 mV) represents the net electrochemical forcedriving Na+ into the cell at resting membrane potential. At rest, however,

the permeability of the membrane to Na+ is very low so that only a smallamount Na+ leaks into the cell. During an action potential, the cellmembrane become more permeable to Na+, which increases sodium entryinto the cell through sodium channels. At the peak of the actionpotential in a cardiac cell (e.g., ventricular myocyte), the membranepotential is approximately +20 mV. Therefore, while the resting potentialis far removed from the ENa, the peak of the action potential approachesENa. Because a small amount of Na

+ enters the cell at rest, and a relativelylarge amount of Na+ enters during action potentials, a Na+ /K+-ATPasepump is required to transport Na+ out of the cell (in exchange for K+) inorder to maintain the chemical gradient for Na+.
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Similar to Na+, there is a large Ca++ concentration difference across thecell membrane. Therefore, Ca++ diffuses into the cell through calciumchannels. Applying the Nernst equation to the calcium concentrationsgiven in the figure results in an equilibrium potential of +134 mV. Thisvalue also includes that the fact that Ca++ is a divalent instead of amonovalent cation. Because the equilibrium potential is much morepositive than the resting membrane potential, there is a netelectrochemical force trying to drive Ca++ into the cell, which occurs whenthe calcium channels are open.

The above discussion shows how changes in the concentration ofindividual ions across the membrane can alter the membrane potential.

However, to fully understand how multiple ions affect the membranepotential, and ultimately how the membrane potential changes duringaction potentials, it is necessary to learn how changes in membrane ionpermeability, that is, changes in ion conductance, affect the membranepotential. Furthermore, electrogenic ion pumps such as the Na+/K+-ATPasepump contribute to the membrane potential as they transport ions acrossthe membrane to maintain the ion concentrations across the membrane.

Action Potentials

Many cells in the body have the ability to undergo atransient depolarization and repolarization that is either triggered byexternal mechanisms (e.g., motor nerve stimulation of skeletal muscleor cell-to-cell depolarization in the heart) or by intracellular,spontaneous mechanisms (e.g., cardiac pacemaker cells).
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There are two general types of cardiac action potentials. Non-

pacemaker action potentials, also called "fast response" actionpotentials because of their rapid depolarization, are found throughoutthe heart except for the pacemaker cells. The pacemaker cellsgenerate spontaneous action potentials that are also termed "slowresponse" action potentials because of their slower rate ofdepolarization. These are found in the sinoatrial and atrioventricularnodes of the heart.

Both types of action potentials in the heart differ considerably fromaction potentials found in neural and skeletal muscle cells. One majordifference is in the duration of the action potentials. In a typical nerve,the action potential duration is about 1 ms. In skeletal muscle cells,

the action potential duration is approximately 2-5 ms. In contrast, theduration of cardiac action potentials range from 200 to 400 ms.Another difference between cardiac and nerve and muscle actionpotentials is the role of calcium ions in depolarization. In nerve andmuscle cells, the depolarization phase of the action potential is causedby an opening of sodium channels. This also occurs in non-pacemakercardiac cells. However, in cardiac pacemaker cells, calcium ions areinvolved in the initial depolarization phase of the action potential. Innon-pacemaker cells, calcium influx prolongs the duration of the actionpotential and produces a characteristic plateau phase.

Normal Impulse Conduction

Sequence of Cardiac Electrical Activation Regulation of Conduction Conduction Defects and their Treatment

Sequence of Cardiac Electrical Activation

The action potentials generated by the SA node spread throughout the

atria primarily by cell-to-cell conduction. There is some functionalevidence for the existence of specialized conducting pathways within theatria (termed internodal tracts), although this is controversial. Theconduction velocity of action potentials in the atrial muscle is about 0.5

m/sec. As the wave of actionpotentials depolarizes the atrialmuscle, the cardiomyocytescontract by a process termedexcitation-contraction coupling.

Normally, the only pathwayavailable for action potentials to

enter the ventricles is through aspecialized region of cells
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(atrioventricular node, or AV node) located in the inferior-posteriorregion of the interatrial septum. The AV node is a highly specializedconducting tissue (cardiac, not neural in origin) that slows the impulseconduction considerably (to about 0.05 m/sec) thereby allowing sufficienttime for complete atrial depolarization and contraction (systole) prior toventricular depolarization and contraction.

The impulses then enter the base of the ventricle at the Bundle of Hisand then follow the left and right bundle branches along theinterventricular septum. These specialized fibers conduct the impulses ata very rapid velocity (about 2 m/sec). The bundle branches then divideinto an extensive system ofPurkinje fibers that conduct the impulses athigh velocity (about 4 m/sec) throughout the ventricles. This results indepolarization of ventricular myocytes and ventricular contraction.

The conduction system within the heart is very important because itpermits a rapid and organized depolarization of ventricular myocytes that

is necessary for the efficient generation of pressure during systole. Thetime (in seconds) to activate the different regions of the heart are shownin the figure to the right. Atrial activation is complete within about 0.09sec (90 msec) following SA nodal firing. After a delay at the AV node, theseptum becomes activated (0.16 sec). All the ventricular mass is activatedby about 0.23 sec.

Regulation of Conduction

The conduction of electrical impulses throughout the heart, andparticularly in the specialized conduction system, is strongly influenced by

autonomic nerve activity. Sympathetic activation increases conductionvelocity in nodal and non-nodal tissues by increasing the slope of phase 0of the action potentials. This leads to more rapid depolarization ofadjacent cells. This positive dromotropic effect of sympathetic activationresults from norepinephrine binding to beta-adrenoceptors, whichincreases intracellular cAMP. Therefore, drugs that block beta-adrenoceptors (beta-blockers) decrease conduction velocity and canproduce AV block.

Parasympathetic (vagal) activation decreases conduction velocity(negative dromotropy) in nodal and non-nodal tissues by decreasing theslope of phase 0 of the action potentials. This leads to slower

depolarization of adjacent cells. Acetylcholine, released by the vagusnerve, binds to cardiac muscarinic receptors, which decreases intracellularcAMP. Excessive vagal activation can produce AV block. Drugs such asdigitalis, which increase vagal activity to the heart, are used to reduce AVnodal conduction in patients that have atrial flutter or fibrillation. Theseatrial arrhythmias lead to excessive ventricular rate (tachycardia) that canbe suppressed by partially blocking impulses being conducted through theAV node.

Because conduction velocity depends on the rate of tissue depolarization,which is related to the slope ofphase 0 of the action potential, conditions

(or drugs) that alter phase 0 will affect conduction velocity. For example,conduction can be altered by changes in membrane potential, which can
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occur during myocardial ischemia and hypoxia. Cellular hypoxia leads tomembrane depolarization, inhibition offast Na+ channels, a decrease inthe slope ofphase 0, and a decrease in action potential amplitude in non-nodal cardiac muscle. These membrane changes result in a decrease inspeed by which action potentials are conducted within theheart. Antiarrhythmic drugs such as quinidine (a Class IA antiarrhythmic)that block sodium channels and cause adecrease in conduction velocity in non-nodal tissue.

Phase 0 action potentials at the AV nodeis not dependent on fast sodiumchannels, but instead are generated bythe entry of calcium into the cell throughslow-inward, L-type calcium channels.Blocking these channels with a calcium-channel blocker such as verapamil or

diltiazem reduces the conduction velocityof impulses through the AV node and canproduce AV block.

Conduction Defects

If the conduction system becomesdamaged or dysfunctional, as can occurduring ischemic conditions or myocardialinfarction, electrical conduction becomesimpaired. This can have a number of

consequences. First, activation of theheart will be delayed, and in some cases,the sequence of activation will be altered.

This can seriously impair ventricularpressure development. Second, damageto the conducting system can precipitatetachyarrhythmias by reentrymechanisms.

Altered Impulse Conduction

Abnormal conduction of impulses within

the heart can lead to arrhythmias. Themost common pathophysiologicmechanism for abnormal conductionresults from localized or regionaldepolarization due to hypoxia caused byimpaired coronary blood flow.Depolarization decreases the actionpotential amplitude and rate ofdepolarization (phase 0 slope is decreased), both of which decreasethe velocity of action potential conduction or completely stop theconduction of action potentials (i.e., conduction block). Conduction

blocks can also be caused, especially at the AV node, by excessivevagal activation or because of drugs that reduce conduction such asbeta-blockers and calcium-channel blockers.
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Conduction blocks can occur at the AV node, bundle of His, or bundlebranches as shown in the figure. There are three categories ofconduction blocks: AV block, bundle branch block, and hemiblock.When there is an AV block, impulses originating in the SA nodecannot enter the ventricles. This type of block can occur either at theAV node, at the common bundle of His, or when both bundle branchesare blocked. When this occurs, a pacemaker site distal to the block willbecome the new pacemaker for the heart. These secondarypacemaker sites generally have an intrinsic rate (30-50 impulses/mindepending on the site), which is considerably slower than the SA node.

Therefore, an AV conduction block will lead to ventricular bradycardia.When either the left or right bundle branch is blocked (bundle branchblock), impulses still travel from the atria to the ventricles so there isno complete block and the ventricles will still be driven by the SA node.However, the sequence and timing of ventricular depolarization will bealtered (see below). A hemiblockoccurs when left anterior orposterior fascicle of the left bundle branch becomes blocked.

When the conduction block is not a complete AV block (e.g., left bundlebranch block), electrical impulses can travel along alternateconduction pathways to depolarize the ventricles. When this occurs, ittakes longer for the ventricles to depolarize. This is manifested as anincrease in the duration of the QRS complex, and a change in itsshape. Sometimes, the abnormal conduction pathways can cause aself-perpetuating, circular movement of electrical activation. This istermed reentry and is a major cause ofventricular andsupraventricular tachycardias.

Abnormal Rhythms - Definitions

General Terms:

Normal sinus rhythm - heart rhythm controlled by sinus nodeat a rate of 60-100 beats/min; each P wave followed by QRS andeach QRS preceded by a P wave.

Bradycardia - a heart rate that is lower than normal. Tachycardia - a heart rate that is higher than normal.
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Paroxysmal - an arrhythmia that suddenly begins and ends.

Specific Arrhythmias:

Sinus bradycardia - low sinus rate 100/min; usuallydue to abnormal focus within the atria and paroxysmal innature, therefore appearance of P wave is altered in differentECG leads. This type of rhythm includes paroxysmal atrialtachycardia (PAT).

Atrial flutter - sinus rate of 250-350 beats/min.

Atrial fibrillation - uncoordinated atrial depolarizations.

Junctional escape rhythm - SA node suppression can result inAV node-generated rhythm of 40-60 beats/min (not preceded byP wave).

AV nodal blocks - a conduction block within the AV node (oroccasionally in the bundle of His) that impairs impulseconduction from the atria to the ventricles.

First-degree AV nodal block- the conduction velocity is slowed so

that the P-R interval is increased to greater than 0.2 seconds. Can becaused by enhanced vagal tone, digitalis, beta-blockers, calciumchannel blockers, or ischemic damage.

Second-degree AV nodal block- the conduction velocity is slowedto the point where some impulses from the atria cannot pass throughthe AV node. This can result in P waves that are not followed by QRScomplexes. For example, 1 or 2 P waves may occur alone before oneis followed by a QRS. When the QRS follows the P wave, the P-Rinterval is increased. In this type of block, the ventricular rhythm willbe less than the sinus rhythm.

Third-decree AV nodal block- conduction through the AV node is

completely blocked so that no impulses are able to be transmittedfrom the atria to the ventricles. QRS complexes will still occur (escaperhythm), but they will originate from within the AV node, bundle of His,


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or other ventricular regions. Therefore, QRS complexes will not bepreceded by P waves. Furthermore, there will be complete asynchronybetween the P wave and QRS complexes. Atrial rhythm may becompletely normal, but ventricular rhythm will be greatly reduceddepending upon the location of the site generating the ventricularimpulse. Ventricular rate typically range from 30 to 40 beats/min.

Supraventricular tachycardia (SVT) - usually caused byreentry currents within the atria or between ventricles and atriaproducing high heart rates of 140-250; the QRS complex isusually normal width, unless there are also intraventricularconduction blocks (e.g., bundle branch block).

Ventricular premature beats (VPBs) - caused by ectopicventricular foci; characterized by widened QRS; often referred toas a premature ventricular complex, or PVC.

Ventricular tachycardia (VT) - high ventricular rate caused byaberrant ventricular automaticity (ventricular foci) or byintraventricular reentry; can be sustained or non-sustained(paroxysmal); usually characterized by widened QRS (>0.14sec); rates of 100 to 280 beats/min; life-threatening.

Ventricular flutter - very rapid ventricular depolarizations>250/min; sine wave appearance; leads to fibrillation.

Ventricular fibrillation - uncoordinated ventricular

depolarizations; leads to death if not quickly converted to anormal rhythm or at least a rhythm compatible with life.

Antiarrhythmic Drugs

Therapeutic Use and Rationale

The ultimate goal of antiarrhythmic drug therapy is to restore normalrhythm and conduction. When it is not possible to revert to normal sinusrhythm, drugs may be used to prevent more serious and possibly lethalarrhythmias from occurring. Antiarrhythmic drugs are used to:

decrease or increase conduction velocity alter the excitability of cardiac cells by changing the duration of the

effective refractory period suppress abnormal automaticity

All antiarrhythmic drugs directly or indirectly alter membrane ionconductances, which in turn alters the physical characteristics ofcardiacaction potentials. For example, some drugs are used to block fast sodiumchannels. These channels determine how fast the membrane depolarizes(phase 0) during an action potential. Since conduction velocity is related

to how fast the membrane depolarizes, sodium channel blockers reduceconduction velocity. Decreasing conduction velocity can help to abolishtachyarrhythmias caused by reentry circuits. Other types of
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antiarrhythmic drugs affect the duration of action potentials, andespecially the effective refractory period. By prolonging the effectiverefractory period, reentry tachycardias can often be abolished. Thesedrugs typically affect potassium channels and delay repolarization ofaction potentials (phase 3). Drugs that block slow inward calcium channelsare used to reduce pacemaker firing rate by slowing the rate of rise ofdepolarizing pacemaker potentials (phase 4 depolarization). These drugsalso reduce conduction velocity at the AV node, because those cells, likeSA nodal cells, depend on the inward movement of calcium ions todepolarize.

Because sympathetic activity can precipitate arrhythmias, drugs thatblock beta1-adrenoceptors are used to inhibit sympathetic effects on theheart. Because beta-adrenoceptors are coupled to ion channels throughdefined signal transduction pathways, beta-blockers indirectly altermembrane ion conductance, particularly calcium and potassiumconductance.

In the case of AV block, drugs that block vagal influences (e.g., atropine, amuscarinic receptor antagonist) are sometimes used. AV block can occurduring beta-blocker treatment and therefore simply removing a beta-blocker in patients being treated with such drugs may normalize AVconduction.

Sometimes ventricular rate is excessively high because it is being drivenby atrial flutter or fibrillation. Because it is very important to reverseventricular tachycardia, drugs are often used to slow AV nodal conduction.Calcium channel blockers and beta-blockers are useful for this indication.

Digitalis, because of its ability to activate the vagus nerve(parasympathomimetic effect), can also be used to reduce AV conductionvelocity in an attempt to normalize ventricular rate during atrial flutter orfibrillation.

Classes of Drugs Used to Treat Arrhythmias

Classes of drugs used in the treatment of arrhythmias are given below.Clicking on the drug class will link you to the page describing thepharmacology of that drug class and specific drugs. Please note that manyof the drugs comprising the first five listed classes have considerableoverlap in their pharmacologic properties.

Antiarrhythmic drug classes:

Class I - Sodium-channel blockers

Class II - Beta-blockers

Class III - Potassium-channel blockers

Class IV - Calcium-channel blockers

Miscellaneous

- adenosine

- electrolyte supplement (magnesium and potassium salts)
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- digitalis compounds (cardiac glycosides)- atropine (muscarinic receptor antagonist)

Sodium-Channel Blockers (Class IAntiarrhythmics)

Effects on depolarization. Sodium-channel blockers comprise the Class Iantiarrhythmic compounds according to the Vaughan-Williamsclassification scheme. These drugs bind to and block the fast sodiumchannels that are responsible for the rapid depolarization (phase 0) offast-response cardiac action potentials. This type of action potential isfound in non-nodal, cardiomyocytes (e.g., atrial and ventricular myocytes;purkinje tissue). Because the slope of phase 0 depends on the activationof fast sodium-channels and the rapid entry of sodium ions into the cell(Figure: Na+ in), blocking these channels decreases the slope of phase 0,which also leads to a decrease in the amplitude of the action potential. Incontrast, nodal tissue action potentials (sinoatrial and atrioventricular

nodes) do not depend on fast sodium channels for depolarization; instead,phase 0 depolarization is carried by calcium currents. Therefore, sodium-channel blockers have no direct effect on nodal tissue, at least throughthe blockade of fast sodium-channels.

The principal effect of reducing the rate and magnitude of depolarizationby blocking sodium channels is a decrease in conduction velocity in non-nodal tissue (atrial and ventricular muscle, purkinje conducting system).

The faster a cell depolarizes, the more rapidly adjacent cells will becomedepolarized, leading to a more rapid regeneration and transmission ofaction potentials between cells. Therefore, blocking sodium channelsreduces the velocity of action potential transmission within the heart(reduced conduction velocity; negative dromotropy). This can serve as animportant mechanism for suppressing tachycardias that are caused by
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abnormal conduction (e.g., reentry mechanisms). By depressing abnormalconduction, reentry mechanisms can be interrupted.

Effects on repolarization. Besides affecting phase 0 of actionpotentials, sodium-channel blockers may also alter the action potential

duration (APD) and effective refractory period (ERP). Because somesodium-channel blockers increase the ERP (Class IA), while othersdecrease the ERP (Class IB) or have no effect on ERP (Class IC), theVaughan-Williams classification recognizes these differences as subclassesof Class I antiarrhythmic drugs. These effects on ERP are not directlyrelated to sodium channel blockade, but instead are related to drugactions on potassium channels involved in phase 3 repolarization of actionpotentials. These channels regulate potassium efflux from the cell (K+ out),and therefore repolarization. The drugs in these subclasses also differ intheir efficacy for reducing the slope of phase 0, with IC drugs having thegreatest and IB drugs having the smallest effect on phase 0 (IA drugs areintermediate in their effect on phase 0). The following summarize these

differences:

Sodium-channel blockade:IC > IA > IB

Increasing the ERP:IA > IC > IB (decreases)

Increasing or decreasing the APD and ERP can either increase or decreasearrhythmogenesis, depending on the underlying cause of the arrhythmia.Increasing the ERP, for example, can interrupt tachycardia caused by

reentry mechanisms by prolonging the duration that normal tissue isunexcitable (its refractory period). This can prevent reentry currents fromre-exciting the tissue. On the other hand, increasing the APD canprecipitate torsades de pointes, a type of ventricular tachycardia causedby afterdepolarizations.

Effects on automaticity. By mechanisms not understood and unrelatedto blocking fast sodium channels, Class I antiarrhythmics can suppressabnormal automaticity by decreasing the slope of phase 4, which isgenerated by pacemaker currents.

Indirect vagal effects. The direct effect of Class IA antiarrhythmic drugs

on action potentials is significantly modified by their anticholinergicactions. Inhibiting vagal activity can lead to both an increase in sinoatrialrate and atrioventricular conduction, which can offset the direct effects ofthe drugs on these tissues. Although a IA drug may effectively depressatrial rate during flutter, it can lead to an increase in ventricular ratebecause of an increase in the number of impulses conducted through theatrioventricular node (anticholinergic effect), thereby requiringconcomitant treatment with a beta-blocker or calcium-channel blocker toslow AV nodal conduction. These anticholinergic actions are mostprominent at the sinoatrial and atrioventricular nodes because they areextensively innervated by vagal efferent nerves. Different drugs within the

IA subclass differ in their anticholinergic actions (see table below).
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Specific Drugs and Therapeutic Indications

The following table summarizes Class I compounds in terms of theirtherapeutic use and some special or distinguishing characteristics. Moredetailed information on specific drugs can be found at www.rxlist.com.

Class IA: atrial fibrillation, flutter; supraventricular &ventricular tachyarrhythmias

quinidine*anticholinergic(moderate)

cinchonism (blurred vision,tinnitus, headache, psychosis);cramping and nausea; enhancesdigitalis toxicity

procainamide

anticholinergic(weak); relatively

short half-life

lupus-like syndrome in 25-30% of

patients

disopryamide

anticholinergic(strong)

negative inotropic effect

Class IB: ventricular tachyarrhythmias (VT)

lidocaine* IV only; VT and PVCsgood efficacy in ischemicmyocardium

tocainideorally active lidocaineanalog

can cause pulmonary fibrosis

mexiletineorally active lidocaineanalog

good efficacy in ischemicmyocardium

phenytoindigitalis-inducedarrhythmias

Class IC: life-threatening supraventricular tachyarrhythmias(SVT) and ventricular tachyarrhythmias (VT)

flecainide* SVT can induce life-threatening VT

propafenone

SVT & VT;-blocking and Ca++-channelblocking activity can worsenheart failure

moricizine VT; IB activity

* prototypical drugAbbreviations: IV, intravenous; PVC, premature ventricular complex.

Side Effects and Contraindications

The anticholinergic effects of IA drugs can produce tachycardia, drymouth, urinary retention, blurred vision and constipation. Diarrhea,nausea, headache and dizziness are also common side effects of manyClass I drugs. Quinidine enhances digitalis toxicity, especially ifhypokalemia is present. Quinidine, by delaying repolarization, can

precipitate torsades de pointes (especially in patients with long-QTsyndrome), a ventricular tachyarrhythmia caused by afterdepolarizations.
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Disopyramide is contraindicated for patients with uncompensated heartfailure because of its negative inotropic actions; propafenone can alsodepress inotropy. IC compounds can cause increased risk of sudden deathin patients with a prior history of myocardial infarction or sustainedventricular arrhythmias.

Beta-Adrenoceptor Antagonists (Beta-Blockers)

General Pharmacology

Beta-blockers are drugs that bind to beta-adrenoceptors and thereby blockthe binding ofnorepinephrine and epinephrine to these receptors. Thisinhibits normal sympathetic effects that act through these receptors.

Therefore, beta-blockers are sympatholytic drugs. Some beta-blockers,when they bind to the beta-adrenoceptor, partially activate the receptorwhile preventing norepinephrine from binding to the receptor. These

partial agonists therefore provide some "background" of sympatheticactivity while preventing normal and enhanced sympathetic activity.

These particular beta-blockers (partial agonists) are said to possessintrinsic sympathomimetic activity (ISA). Some beta-blockers also possesswhat is referred to as membrane stabilizing activity (MSA). This effect issimilar to the membrane stabilizing activity ofsodium-channels blockersthat represent Class I antiarrhythmics.
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The first generation of beta-blockers were non-selective, meaning thatthey blocked both beta1 (1) and beta2 (2) adrenoceptors. Secondgeneration beta-blockers are more cardioselective in that they are

relatively selective for1 adrenoceptors. Note that this relative selectivitycan be lost at higher drug doses. Finally, the third generation beta-

blockers are drugs that also possess vasodilator actions through blockadeof vascular alpha-adrenoceptors.

Heart. Beta-blockers bind to beta-adrenoceptors located in cardiac nodaltissue, the conducting system, and contracting myocytes. The heart hasboth 1 and 2 adrenoceptors, although the predominant receptor type innumber and function is 1. These receptors primarily bind norepinephrinethat is released from sympathetic adrenergic nerves. Additionally, theybind norepinephrine and epinephrine that circulates in the blood. Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from

binding to the beta-adrenoceptor by competing for the binding site.

Beta-adrenoceptors are coupled to a Gs-proteins, which activate adenylylcyclase to form cAMP from ATP. Increased cAMP activates a cAMP-dependent protein kinase (PK-A) that phosphorylates L-type calciumchannels, which causes increased calcium entry into the cell. Increasedcalcium entry during action potentials leads to enhanced release ofcalcium by the sarcoplasmic reticulum in the heart; these actions increaseinotropy (contractility). Gs-protein activation also increases heart rate(chronotropy). PK-A also phosphorylates sites on the sarcoplasmicreticulum, which lead to enhanced release of calcium through the

ryanodine receptors (ryanodine-sensitive, calcium-release channels)associated with the sarcoplasmic reticulum. This provides more calciumfor binding the troponin-C, which enhances inotropy. Finally, PK-A canphosphorylate myosin light chains, which may contribute to the positiveinotropic effect of beta-adrenoceptor stimulation.

Because there is generally some level of sympathetic tone on the heart,beta-blockers are able to reduce sympathetic influences that normallystimulate chronotropy (heart rate), inotropy (contractility), dromotropy(electrical conduction) and lusitropy (relaxation). Therefore, beta-blockerscause decreases in heart rate, contractility, conduction velocity, andrelaxation rate. These drugs have an even greater effect when there is

elevated sympathetic activity.

Blood vessels. Vascular smooth muscle has 2-adrenoceptors that arenormally activated by norepinephrine released by sympathetic adrenergicnerves or by circulating epinephrine. These receptors, like those in theheart, are coupled to a Gs-protein, which stimulates the formation ofcAMP. Although increased cAMP enhances cardiac myocyte contraction(see above), in vascular smooth muscle an increase in cAMP leads tosmooth muscle relaxation. The reason for this is that cAMP inhibits myosinlight chain kinase that is responsible for phosphorylating smooth musclemyosin. Therefore, increases in intracellular cAMP caused by 2-agonists

inhibits myosin light chain kinase thereby producing less contractile force(i.e., promoting relaxation).
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Compared to their effects in the heart, beta-blockers have relatively littlevascular effect because 2-adrenoceptors have only a small modulatoryrole on basal vascular tone. Nevertheless, blockade of2-adrenoceptors isassociated with a small degree of vasoconstriction in many vascular beds.

This occurs because beta-blockers remove a small 2-adrenoceptorvasodilator influence that is normally opposing the more dominant alpha-adrenoceptor mediated vasoconstrictor influence.

Therapeutic Indications

Beta-blockers are used for treating hypertension, angina, myocardialinfarction, arrhythmias and heart failure.

Hypertension. Beta-blockers decrease arterial blood pressure byreducing cardiac output. Many forms of hypertension are associated withan increase in blood volume and cardiac output. Therefore, reducingcardiac output by beta-blockade can be an effective treatment forhypertension, especially when used in conjunction with a diuretic.

Hypertension in some patients is caused by emotional stress, whichcauses enhanced sympathetic activity. Beta-blockers are very effective in
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these patients. Beta-blockers are especially useful in treating hypertensioncaused by a pheochromocytoma, which results in elevated circulatingcatecholamines. Beta-blockers have an additional benefit as a treatmentfor hypertension in that they inhibit the release ofrenin by the kidneys(the release of which is partly regulated by 1-adrenoceptors in thekidney). Decreasing circulating plasma renin leads to a decrease inangiotensin II and aldosterone, which enhances renal loss of sodium andwater and further diminishes arterial pressure. Acute treatment with abeta-blocker is not very effective in reducing arterial pressure because ofa compensatory increase in systemic vascular resistance. This may occurbecause of baroreceptor reflexes working in conjunction with the removalof2 vasodilatory influences that normally offset, to a small degree,alpha-adrenergic mediated vascular tone. Chronic treatment with beta-blockers lowers arterial pressure more than acute treatment possiblybecause of reduced renin release and effects of beta-blockade on centraland peripheral nervous systems.

Angina andmyocardial infarction.The antianginal effects of beta-blockers are attributed to their cardiodepressant and hypotensive actions.By reducing heart rate, contractility, and arterial pressure, beta-blockersreduce the work of the heart and the oxygen demand of the heart.Reducing oxygen demand improves the oxygen supply/demand ratio,which can relieve a patient of anginal pain that is caused by a reduction inthe oxygen supply/demand ratio due to coronary artery disease.Furthermore, beta-blockers have been found to be very important in thetreatment of myocardial infarction in that they have been shown todecrease mortality. Their benefit is derived not only from improving theoxygen supply/demand ratio and reducing arrhythmias, but also from theirability to inhibit subsequent cardiac remodeling.

Arrhythmias.The antiarrhythmic properties beta-blockers (Class IIantiarrhythmic) are related to their ability to inhibit sympathetic influenceson cardiac electrical activity. Sympathetic nerves increase sinoatrial nodeautomaticity by increasing the pacemaker currents, which increases sinusrate. Sympathetic activation also increases conduction velocity(particularly at the atrioventricular node), and stimulates aberrantpacemaker activity (ectopic foci). These sympathetic influences aremediated primarily through 1-adrenoceptors. Therefore, beta-blockerscan attenuate these sympathetic effects and thereby decrease sinus rate,decrease conduction velocity (which can block reentry mechanisms), and

inhibit aberrant pacemaker activity. Beta-blockers also affect non-pacemaker action potentials by increasing action potential duration andthe effective refractory period. This effect can play a major role in blockingarrhythmias caused by reentry.

Heart failure. The majority of patients in heart failure have a form that iscalled systolic dysfunction, which means that the contractile function ofthe heart is depressed (loss of inotropy). Although it seemscounterintuitive that cardioinhibitory drugs such as beta-blockers would beused in cases of systolic dysfunction, clinical studies have shown quiteconclusively that some specific beta-blockers actually improve cardiacfunction and reduce mortality. Furthermore, they have been shown toreduce deleterious cardiac remodeling that occurs in chronic heart failure.Although the exact mechanism by which beta-blockers confer their benefit
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to heart failure patients is poorly understood, it may be related toblockade of excessive, chronic sympathetic influences on the heart, whichare known to be harmful to the failing heart.

Different Classes of Beta-Blockers and Specific Drugs

Beta-blockers that are used clinically can be divided into two classes: 1)non-selective blockers (block both 1and 2 receptors), or 2) relativelyselective 1 blockers ("cardioselective" beta-blockers). Some beta-blockers have additional mechanisms besides beta-blockade thatcontribute to their unique pharmacologic profile. The two classes of beta-blockers along with specific compounds are listed in the following table.Additional details for each drug may be found at www.rxlist.com. Theclinical uses indicated in the table represent both on and off-label uses ofbeta-blockers. For example, a given beta-blocker may only be approved bythe FDA for treatment of hypertension; however, physicians sometimeselect to prescribe the drug for angina because of the class-action benefit

that beta-blockers have for angina.

Clinical Uses

Class/Drug HTNAngin

aArrhy MI CHF Comments

Non-selective1/2

carteolol X

ISA; long

acting; alsoused forglaucoma

carvedilol X X-blockingactivity

labetalol X XISA; -blockingactivity

nadolol X X X X long acting

penbutolol X X ISA

pindolol X X ISA; MSA

propranolol X X X XMSA;prototypicalbeta-blocker

sotalol Xseveral othersignificantmechanisms

timolol X X X Xprimarily usedfor glaucoma

1-selective

acebutolol X X X ISA
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atenolol X X X X

betaxolol X X X MSA

bisoprolol X X X

esmolol X X

ultra short

acting; intra orpostoperativeHTN

metoprolol X X X X X MSA

Abbreviations: HTN, hypertension;Arrhy, arrhythmias; MI, myocardialinfarction; CHF, congestive heartfailure; ISA, intrinsicsympathomimetic activity.


Cardiovascular side effects.Many of the side effects of beta-blockers are related to their cardiacmechanisms and includebradycardia, reduced exercisecapacity, heart failure,hypotension, and atrioventicular(AV) nodal conduction block. All ofthese side effects result from

excessive blockade of normal sympathetic influences on the heart.Considerable care needs to be exercised if a beta-blocker is given inconjunction with cardiac selective calcium-channel blockers (e.g.,verapamil) because of their additive effects in producing electrical andmechanical depression. Except for those drugs specifically approved foruse in heart failure, beta-blockers are contraindicated in heart failurepatients. Beta-blockers are also contraindicated in patients with sinusbradycardia and partial AV block.

Other side effects. Bronchoconstriction can occur, especially when non-selective beta-blockers are administered to asthmatic patients. Therefore,non-selective beta-blockers are contraindicated in patients with asthma or

chronic obstructive pulmonary disease. Bronchoconstriction occursbecause sympathetic nerves innervating the bronchioles normally activate2-receptors that promote bronchodilation. Blockade of these receptorscan lead to bronchoconstriction. Hypoglycemia can occur with beta-blockade because 2-adrenoceptors normally stimulate hepatic glycogenbreakdown (glycogenolysis) and pancreatic release of glucagon, whichwork together to increase plasma glucose. Therefore, blocking 2-adrenoceptors lowers plasma glucose. 1-blockers have fewer metabolicside effects in diabetic patients; however, the tachycardia which serves asa warning sign for insulin-induced hypoglycemia may be masked.

Therefore, beta-blockers are to be used cautiously in diabetics.

Potassium-Channel Blockers (Class III Antiarrhythmics)
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Effects on action potentials. The primary role of potassium channels in

cardiac action potentials is cell repolarization. In non-nodal tissue (seefigure), action potentials are initiated when a cell is depolarized to athreshold potential by an adjacent cell. This leads rapid opening of fastsodium channels and a slower opening of L-type calcium channels thatpermit calcium to enter the cell (phase 0 and 2, respectively). As thesechannels become inactivated, potassium channels open permittingpotassium ions to leave the cell (Figure: K+ out), which causesrepolarization of the membrane potential (phase 3). Potassium channelsremain open until the next action potential is triggered. There are also

different potassium channels that areresponsible for the initial repolarization(phase 1) that occurs as the fast

sodium channels become inactivated.Potassium channels are alsoresponsible for repolarizing slow-response action potentials in thesinoatrial and atrioventricular nodes.

Potassium-channel blockers comprisethe Class III antiarrhythmic compoundsaccording to the Vaughan-Williamsclassification scheme. These drugsbind to and block the potassium

channels that are responsible for phase 3 repolarization. Therefore,blocking these channels slows (delays) repolarization, which leads to anincrease in action potential duration and an increase in the effectiverefractory period (ERP). On the electrocardiogram, this increases the Q-Tinterval. This is the common effect of all Class III antiarrhythmic drugs. Theelectrophysiological changes prolong the period of time that the cell isunexcitable (refractory) and therefore make the cell less excitable.

By increasing the ERP, these drugs are very useful in suppressingtachyarrhythmias caused by reentry mechanisms. Reentry occurs when anaction potential reemerges into normal tissue when that tissue is nolonger refractory. When this happens, a new action potential is generated

prematurely (before normal activation) and a circular, repeating pattern ofearly activation can develop, which leads to a tachycardia. If the ERP ofthe normal tissue is lengthened, then the reemerging action potential mayfind the normal tissue refractory and premature activation will not occur.

Specific Drugs and Therapeutic Indications

The following table summarizes Class III compounds in terms of theirtherapeutic use and some special or distinguishing characteristics. Moredetailed information on specific drugs can be found at www.rxlist.com.
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Drug Therapeutic Uses Comments

amiodarone

severesupraventricular andventricular

arrhythmias

very long half-life (25-60 days); Class I,II, III & IV actions and thereforedecreases phase 4 slope andconduction velocity; potentially serious

side effects (e.g., pulmonary fibrosis;hypothyroidism)

bretylium

life-threateningventriculartachycardia andfibrillation

IV only; initial sympathomimetic effect(norepinephrine release) followed byinhibition, which can lead tohypotension

sotalolventriculararrhythmias; atrialflutter and fibrillation

also has Class II activity

ibutilidesupraventriculararrhythmias; atrialflutter and fibrillationconversion

slow inward Na+

activator, which delaysrepolarization; inhibitsNa+-channel inactivation,which increases ERP; IVonly

dofetilide

supraventriculararrhythmias; atrialflutter and fibrillationconversion

very selective K+-channel blocker

Abbreviations: IV, intravenous.


All of these compounds, like Class I compounds, are proarrhythmic as wellas being antiarrhythmic. For example, the increase in action potentialduration can produce torsades de pointes (a type of ventriculartachycardia), especially in patients with long-QT syndrome. Amiodarone,because of its Class IV effects, can cause bradycardia and atrioventricularblock, and therefore is contraindicated in patients with heart block, orsinoatrial node dysfunction.

Calcium-Channel Blockers (CCBs)


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Currently approved CCBs bind to L-type calcium channels located on the

vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue(sinoatrial and atrioventricular nodes). These channels are responsible forregulating the influx of calcium into muscle cells, which in turn stimulatessmooth muscle contraction and cardiac myocyte contraction. In cardiacnodal tissue, L-type calcium channels play an important role in pacemakercurrents and in phase 0 of the action potentials. Therefore, by blockingcalcium entry into the cell, CCBs cause vascular smooth muscle relaxation(vasodilation), decreased myocardial force generation (negative inotropy),decreased heart rate (negative chronotropy), and decreased conductionvelocity within the heart (negative dromotropy), particularly at theatrioventricular node.

Therapeutic Indications

CCBs are used to treat hypertension, angina and arrhythmias.

Hypertension. By causing vascular smooth muscle relaxation, CCBsdecrease systemic vascular resistance, which lowers arterial bloodpressure. These drugs primarily affect arterial resistance vessels, with onlyminimal effects on venous capacitance vessels.

Angina.The anti-anginal effects of CCBs are derived from theirvasodilator and cardiodepressant actions. Systemic vasodilation reduces

arterial pressure, which reduces ventricular afterload (wall stress) therebydecreasing oxygen demand. The more cardioselective CCBs (verapamiland diltiazem) decrease heart rate and contractility, which leads to areduction in myocardial oxygen demand, which makes them excellentantianginal drugs. CCBs can also dilate coronary arteries and prevent orreverse coronary vasospasm (as occurs in Printzmetal's variant angina),thereby increasing oxygen supply to the myocardium.

Arrhythmias.The antiarrhythmic properties (Class IV antiarrhythmics) ofCCBs are related to their ability to decrease the firing rate of aberrantpacemaker sites within the heart, but more importantly are related to theirability to decrease conduction velocity and prolong repolarization,especially at the atrioventricular node. This latter action at theatrioventricular node helps to block reentry mechanisms, which can causesupraventricular tachycardia.

Different Classes of Calcium-Channel Blockers

There are three classes of CCBs. They differ not only in their basicchemical structure, but also in their relative selectivity toward cardiacversus vascular L-type calcium channels. The most smooth muscleselective class of CCBs are the dihydropyridines. Because of their highvascular selectivity, these drugs are primarily used to reduce systemic

vascular resistance and arterial pressure, and therefore are primarily usedto treat hypertension. They are not, however, generally used to treat
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angina because their powerful systemic vasodilator and pressure loweringeffects can lead to reflex cardiac stimulation (tachycardia and increasedinotropy), which can dramatically increase myocardial oxygen demand.Note that dihydropyridines are easy to recognize because the drug nameends in "pine."

Dihydropyridines include the following specific drugs: (Go towww.rxlist.com for specific drug information)

amlodipine felodipine isradipine nicardipine nifedipine nimodipine nitrendipine

Non-dihydropyridines, of which there are only two currently usedclinically, comprise the other two classes of CCBs. Verapamil(phenylalkylamine class), is relatively selective for the myocardium, and isless effective as a systemic vasodilator drug. This drug has a veryimportant role in treating angina (by reducing myocardial oxygen demandand reversing coronary vasospasm) and arrhythmias. Diltiazem(benzothiazepine class)is intermediate between verapamil anddihydropyridines in its selectivity for vascular calcium channels. By havingboth cardiac depressant and vasodilator actions, diltiazem is able toreduce arterial pressure without producing the same degree of reflexcardiac stimulation caused by dihydropyridines.


Dihydropyridine CCBs can cause flushing, headache, excessivehypotension, edema and reflex tachycardia. The activation of sympatheticreflexes and lack of direct cardiac effects make dihydropyridines a lessdesirable choice for angina. Long-acting dihydropyridines have beenshown to be safer anti-hypertensive drugs, in part, because of reducedreflex responses. The cardiac selective, non-dihydropyridine CCBs cancause excessive bradycardia, impaired electrical conduction (e.g.,atrioventricular nodal block), and depressed contractility. Therefore,patients having preexistent bradycardia, conduction defects, or heartfailure caused by systolic dysfunction should not be given CCBs, especiallythe cardiac selective, non-dihydropyridines. CCBs, especially non-dihydropyridines, should not be administered to patients being treatedwith a beta-blocker because beta-blockers also depress cardiac electricaland mechanical activity and therefore the addition of a CCB augments theeffects of beta-blockade.

Treatment of Arrhythmias

The following table summarizes which antiarrhythmic drugs may be usedto treat different types of arrhythmias. It is important to note that for a

given condition a particular drug may not be efficacious, and in fact, itmay precipitate other arrhythmias or adverse cardiovascular effects (e.g.,
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cardiac depression, hypotension). Therefore, drug efficacy and safetymust be carefully evaluated and individualized to the patient whentreating arrhythmias.

Condition Drug Comments

Sinus tachycardia Class II, IV Other underlying causes mayneed treatment

Atrial fibrillation/flutterClass IA, IC, II, III, IVdigitalis; adenosine

Ventricular rate control isimportant goal;anticoagulation required

Paroxysmalsupraventriculartachycardia

Class IA, IC, II, III, IVadenosine

AV block atropine Acute reversal

Ventriculartachycardia

Class I, II, III

Premature ventricularcomplexes

Class II, IV;Mg++ salts

PVCs are often benign andnot treated

Digitalis toxicity Class IBMg++ salts; KCl

Adenosine: General Pharmacology

Adenosine is a naturally occurring purine nucleoside that forms from thebreakdown of adenosine triphosphate (ATP). ATP is the primary energysource in cells for transport systems and many enzymes. Most ATP ishydrolyzed to ADP, which can be further dephosphorylated to AMP. MostADP and AMP that form in the cell is rephosphorylated in the mitochondriaby enzymatic reactions requiring oxygen. If there are large amounts ofATP hydrolyzed, and especially if there is insufficient oxygen available(i.e., hypoxia), then some of the AMP can be further dephosphorylated toadenosine by the cell membrane associated enzyme, 5'-nucleotidase.

Adenosine can bind to purinergic receptors in different cell types where itcan produce a number of different physiological actions. One importantaction is vascular smooth muscle relaxation, which leads to vasodilation.

This is a particularly important mechanism for matching coronary bloodflow to the metabolic needs of the heart. In coronary vascular smoothmuscle, adenosine binds to adenosine type 2A (A2A) receptors, which arecoupled to the Gs-protein. Activation of this G-protein stimulates adenylylcyclase (AC in figure), increases cAMP and causes protein kinaseactivation. This stimulates KATP channels, which hyperpolarizes the smoothmuscle, causing relaxation. Increased cAMP also causes smooth musclerelaxation by inhibiting myosin light chain kinase, which leads todecreased myosin phosphorylation and a decrease in contractile force.

There is also evidence that adenosine inhibits calcium entry into the cellthrough L-type calcium channels. Since calcium regulates smooth muscle
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contraction, reduced intracellular calcium causes relaxation. In some typesof blood vessels, there is evidence that adenosine produces vasodilationthrough increases in cGMP, which leads to inhibition of calcium entry intothe cells as well as opening of potassium channels.

In cardiac tissue, adenosine binds to type 1 (A1) receptors, which arecoupled to Gi-proteins. Activation of this pathway opens potassiumchannels, which hyperpolarizes the cell. Activation of the Gi-protein alsodecreases cAMP, which inhibits L-type calcium channels and thereforecalcium entry into the cell. In cardiac pacemaker cells located in thesinoatrial node, adenosine acting through A1 receptors inhibits thepacemaker current (If), which decreases the slope of phase 4 of thepacemaker action potential thereby decreasing its spontaneous firing rate(negative chronotropy). Inhibition of L-type calcium channels alsodecreases conduction velocity (negative dromotropic effect) particularly atthe atrioventricular (AV) nodes. Finally, adenosine by acting onpresynaptic purinergic receptors located on sympathetic nerve terminals

inhibits the release of norepinephrine. In terms of its electrical effects inthe heart, adenosine decreases heart rate and reduces conductionvelocity, especially at the AV node, which can produce atrioventricularblock.

Adenosine has a very short half-life. In human blood, its half-life is lessthan 10 seconds. There are two important metabolic fates for adenosine.

1. Most importantly, adenosine is rapidly transported into red bloodcells (and other cell types) where it is rapidly deaminated byadenosine deaminase to inosine, which is further broken down to

hypoxanthine, xanthine and uric acid, which is excreted by thekidneys. Adenosine deamination also occurs in the plasma, but at alower rate than that which occurs within cells. Dipyridamole is avasodilator drug that blocks adenosine uptake by cells, therebyreducing the metabolism of adenosine. Therefore, one importantmechanism for dipyridamole-induced vasodilation is its potentiationof extracellular adenosine.

2. Adenosine can be acted on by adenosine kinase andrephosphorylated to AMP. This salvage pathway helps maintain theadenine nucleotide pool in cells.

Therapeutic Use and Rationale

Although adenosine is a powerful vasodilator, especially in the coronarycirculation, it is not used clinically as a vasodilator. The reason is that it isvery short acting and in the heart it can produce coronary vascular steal.When administered by intravenous infusion, it can produce substantialhypotension.

Adenosine is used, however, as an antiarrhythmic drug for the rapidtreatment ofsupraventricular tachycardias. Its effects on atrioventricularconduction make it very useful in treating paroxysmal supraventriculartachycardia in which the AV node is part of the reentry pathway (as in

Wolff-Parkinson-White Syndrome). Adenosine is administered eitheras bolus intravenous injection or as an intravenous infusion.
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