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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 by pacemaker cells within the sinoatrial (SA) node, which is located within the wall of the right atrium. SA nodal pacemaker activity normally governs the rhythm of the atria and ventricles. Normal rhythm is very regular, with minimal cyclical fluctuation. Furthermore, atrial contraction is always followed by ventricular contraction in the normal heart. When this rhythm becomes irregular, too fast (tachycardia) or too slow (bradycardia), or the frequency of the atrial and ventricular beats 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 the population). The most common disorders are atrial fibrillation and flutter. The incidence is highly related to age and the presence of underlying heart disease; the incidence approaches 30% following open heart surgery. What are the clinical symptoms? Patients may describe an arrhythmia as a palpitation or fluttering sensation in the chest. For some types of arrhythmias, a skipped beat might be sensed because the subsequent beat produces a more forceful 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 activity of the heart. Depending on the severity of the arrhythmia, patients may experience dyspnea (shortness of breath), syncope (fainting), fatigue, heart failure symptoms, chest pain or cardiac arrest. What causes arrhythmias? A frequent cause of arrhythmia is coronary artery disease because this condition results in myocardial ischemia or infarction. When cardiac cells lack oxygen, they become depolarized, which lead to altered impulse formation and/or altered impulse conduction. The former concerns changes in rhythm that are caused by changes in the

automaticity of pacemaker cells or by abnormal generation of action potentials at sites other than the SA node (termed ectopic foci). Altered impulse conduction is usually associated with complete or partial block of electrical conduction within the heart. Altered impulse conduction commonly results in reentry, which can lead to tachyarrhythmias. Changes in cardiac structure that accompany heart failure (e.g., dilated or hypertrophied cardiac chambers), can also precipitate 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 depending on the hemodynamic consequence of the arrhythmia and the possibility of evolving into a lethal arrhythmia. Occasional premature ventricular complexes (PVCs), while annoying to a patient, are generally considered benign because they have little hemodynamic effect. Consequently, PVCs if not too frequent, are generally not treated. In contrast, ventricular tachycardia is a serious condition that can lead to heart failure, or worse, to ventricular fibrillation and death. How are arrhythmias treated? When arrhythmias require treatment, they are are treated with drugs that suppress the arrhythmia. These drugs are called antiarrhythmic drugs. There are many different types of antiarrhythmic drugs and many different mechanisms of action. Most of the drugs affect ion channels that are involved in the movement of sodium, calcium and potassium ions in and out of the cell. These drugs include mechanistic classes such as sodium-channel blockers, calcium-channel blockers and potassium-channel blockers. By altering the movement of these important ions, the electrical activity of the cardiac cells (both pacemaker and non-pacemaker cells) is altered, hopefully in a manner that suppresses arrhythmias. Other drugs affect autonomic influences on the the heart, which may be stimulating or aggravating arrhythmias. Among these drugs are beta-blockers. More details on drug therapy and specific drugs can be obtained by clicking here. Membrane Potentials

If a voltmeter is attached to the two terminals of a battery, a voltage difference will be measured across the two terminals. Likewise, if a voltmeter is used to measure voltage across the cell membrane (inside versus outside) of a cardiomyocyte, it will be found that the inside of the cell has a negative voltage (measured in millivolts; mV) with respect to the outside of the cell

(which is referenced as 0 mV). Under resting conditions, this is called the resting membrane potential. With appropriate stimulation of the cell, this negative voltage inside the cell (negative membrane potential) may transiently become positive owing to the generation of an action potential. Membrane potentials result from a separation of positive and negative charges (ions) across the membrane, similar to the plates within a 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) the permeability 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 ion concentrations across the membrane. Cardiac cells, like all living cells, have different concentrations of ions across the cell membrane, the most important of which are Na +, K+, Cl-, and Ca++ (see figure to right). There are also negatively charged proteins within the cell to which the cell membrane is impermeable. In a cardiac cell, 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. The opposite situation is found for Na+ and Ca++ where their chemical gradients (high outside, low inside concentrations) favor an inward diffusion. Potassium ion. To understand how a membrane potential is generated, first consider a hypothetical cell in which K + is the only ion across the membrane other than the large negatively charged proteins inside of the cell. Because the cell has potassium channels through which K+ can move in and out of the cell, K+ diffuses down its chemical gradient (out of the cell) because its concentration is much higher inside the cell than outside. As K+ (a positively charged ion) diffuses out of the cell, it leaves behind negatively charged proteins. This leads to a separation of charges across the membrane and therefore a potential difference across the membrane. Experimentally it is possible to prevent the K + from diffusing out of the cell. This can be achieved by applying a negative charge to the inside of the cell that prevents the positively charged K + from leaving the cell. The negative charge across the membrane that would be necessary to oppose the movement of K+ down its concentration gradient is termed the 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 chemical gradient driving K+ out of the cell would be reduced, and therefore the membrane potential required to maintain electrochemical equilibrium (E K) would be less negative according to the Nernst relationship. In this example, the EK becomes -35 mV when the outside K+ concentration is 40

mM. In other words, when K+ is elevated 10-fold outside of the cell, the chemical gradient driving K+ out of the cell is reduced and therefore a less negative 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 is 4 mM. Since the equilibrium potential for K + is -96 mV and the resting membrane potential is -90 mV, there is a net driving force (difference between membrane potential and equilibrium potential) of 6 mV acting on the K+. The membrane potential is more positive than the equilibrium potential, therefore the net driving force is outward due to K + having a positive 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 out of the cell, its chemical gradient would be lost over time; however, a Na+/K+-ATPase pump brings the K+ back into the cell and thereby maintains the K+ chemical gradient. Sodium and calcium ions. Because the Na+ concentration is higher outside the cell, this ion diffuses down its chemical gradient into the cell. Experimentally, this inward diffusion of Na + can be prevented by applying a positive charge to the inside of the cell. When this positive change counterbalances the chemical diffusion force driving Na + into the cell, there will be no net movement of Na+ into the cell, and Na+ will therefore be in electrochemical equilibrium. The membrane potential required to produce this electrochemical equilibrium is called the equilibrium potential 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 directed chemical gradient for Na+, the cell interior needs to be +52 mV to prevent Na+ from diffusing into the cell. At a resting membrane potential of -90 mV, there is not only a large chemical driving force, but also a large electrical driving force acting upon external Na + to cause it to diffuse into the cell. The difference between the membrane potential and the equilibrium potential (-142 mV) represents the net electrochemical force driving 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 small amount Na+ leaks into the cell. During an action potential, the cell membrane become more permeable to Na+, which increases sodium entry into the cell through sodium channels. At the peak of the action potential in a cardiac cell (e.g., ventricular myocyte), the membrane potential is approximately +20 mV. Therefore, while the resting potential is far removed from the ENa, the peak of the action potential approaches ENa. Because a small amount of Na+ enters the cell at rest, and a relatively large amount of Na+ enters during action potentials, a Na+/K+-ATPase pump is required to transport Na+ out of the cell (in exchange for K+) in order to maintain the chemical gradient for Na+.

Similar to Na+, there is a large Ca++ concentration difference across the cell membrane. Therefore, Ca++ diffuses into the cell through calcium channels. Applying the Nernst equation to the calcium concentrations given in the figure results in an equilibrium potential of +134 mV. This value also includes that the fact that Ca++ is a divalent instead of a monovalent cation. Because the equilibrium potential is much more positive than the resting membrane potential, there is a net electrochemical force trying to drive Ca++ into the cell, which occurs when the calcium channels are open.

The above discussion shows how changes in the concentration of individual ions across the membrane can alter the membrane potential. However, to fully understand how multiple ions affect the membrane potential, and ultimately how the membrane potential changes during action potentials, it is necessary to learn how changes in membrane ion permeability, that is, changes in ion conductance, affect the membrane potential. Furthermore, electrogenic ion pumps such as the Na+/K+-ATPase pump contribute to the membrane potential as they transport ions across the membrane to maintain the ion concentrations across the membrane. Action Potentials

Many cells in the body have the ability to undergo a transient depolarization and repolarization that is either triggered by external mechanisms (e.g., motor nerve stimulation of skeletal muscle or cell-to-cell depolarization in the heart) or by intracellular, spontaneous mechanisms (e.g., cardiac pacemaker cells).

There are two general types of cardiac action potentials. Nonpacemaker action potentials, also called "fast response" action potentials because of their rapid depolarization, are found throughout the heart except for the pacemaker cells. The pacemaker cells generate spontaneous action potentials that are also termed "slow response" action potentials because of their slower rate of depolarization. These are found in the sinoatrial and atrioventricular nodes of the heart. Both types of action potentials in the heart differ considerably from action potentials found in neural and skeletal muscle cells. One major difference 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, the duration of cardiac action potentials range from 200 to 400 ms. Another difference between cardiac and nerve and muscle action potentials is the role of calcium ions in depolarization. In nerve and muscle cells, the depolarization phase of the action potential is caused by an opening of sodium channels. This also occurs in non-pacemaker cardiac cells. However, in cardiac pacemaker cells, calcium ions are involved in the initial depolarization phase of the action potential. In non-pacemaker cells, calcium influx prolongs the duration of the action potential 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 functional evidence for the existence of specialized conducting pathways within the atria (termed internodal tracts), although this is controversial. The conduction velocity of action potentials in the atrial muscle is about 0.5 m/sec. As the wave of action potentials depolarizes the atrial muscle, the cardiomyocytes contract by a process termed excitation-contraction coupling. Normally, the only pathway available for action potentials to enter the ventricles is through a specialized region of cells

(atrioventricular node, or AV node) located in the inferior-posterior region of the interatrial septum. The AV node is a highly specialized conducting tissue (cardiac, not neural in origin) that slows the impulse conduction considerably (to about 0.05 m/sec) thereby allowing sufficient time for complete atrial depolarization and contraction (systole) prior to ventricular depolarization and contraction. The impulses then enter the base of the ventricle at the Bundle of His and then follow the left and right bundle branches along the interventricular septum. These specialized fibers conduct the impulses at a very rapid velocity (about 2 m/sec). The bundle branches then divide into an extensive system of Purkinje fibers that conduct the impulses at high velocity (about 4 m/sec) throughout the ventricles. This results in depolarization of ventricular myocytes and ventricular contraction. The conduction system within the heart is very important because it permits a rapid and organized depolarization of ventricular myocytes that is necessary for the efficient generation of pressure during systole. The time (in seconds) to activate the different regions of the heart are shown in the figure to the right. Atrial activation is complete within about 0.09 sec (90 msec) following SA nodal firing. After a delay at the AV node, the septum becomes activated (0.16 sec). All the ventricular mass is activated by about 0.23 sec. Regulation of Conduction The conduction of electrical impulses throughout the heart, and particularly in the specialized conduction system, is strongly influenced by autonomic nerve activity. Sympathetic activation increases conduction velocity in nodal and non-nodal tissues by increasing the slope of phase 0 of the action potentials. This leads to more rapid depolarization of adjacent cells. This positive dromotropic effect of sympathetic activation results from norepinephrine binding to beta-adrenoceptors, which increases intracellular cAMP. Therefore, drugs that block betaadrenoceptors (beta-blockers) decrease conduction velocity and can produce AV block. Parasympathetic (vagal) activation decreases conduction velocity (negative dromotropy) in nodal and non-nodal tissues by decreasing the slope of phase 0 of the action potentials. This leads to slower depolarization of adjacent cells. Acetylcholine, released by the vagus nerve, binds to cardiac muscarinic receptors, which decreases intracellular cAMP. Excessive vagal activation can produce AV block. Drugs such as digitalis, which increase vagal activity to the heart, are used to reduce AV nodal conduction in patients that have atrial flutter or fibrillation. These atrial arrhythmias lead to excessive ventricular rate (tachycardia) that can be suppressed by partially blocking impulses being conducted through the AV node. Because conduction velocity depends on the rate of tissue depolarization, which is related to the slope of phase 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

occur during myocardial ischemia and hypoxia. Cellular hypoxia leads to membrane depolarization, inhibition of fast Na+ channels, a decrease in the slope of phase 0, and a decrease in action potential amplitude in nonnodal cardiac muscle. These membrane changes result in a decrease in speed by which action potentials are conducted within the heart. Antiarrhythmic drugs such as quinidine (a Class IA antiarrhythmic) that block sodium channels and cause a decrease in conduction velocity in nonnodal tissue. Phase 0 action potentials at the AV node is not dependent on fast sodium channels, but instead are generated by the entry of calcium into the cell through slow-inward, L-type calcium channels. Blocking these channels with a calciumchannel blocker such as verapamil or diltiazem reduces the conduction velocity of impulses through the AV node and can produce AV block. Conduction Defects If the conduction system becomes damaged or dysfunctional, as can occur during ischemic conditions or myocardial infarction, electrical conduction becomes impaired. This can have a number of consequences. First, activation of the heart will be delayed, and in some cases, the sequence of activation will be altered. This can seriously impair ventricular pressure development. Second, damage to the conducting system can precipitate tachyarrhythmias by reentry mechanisms. Altered Impulse Conduction Abnormal conduction of impulses within the heart can lead to arrhythmias. The most common pathophysiologic mechanism for abnormal conduction results from localized or regional depolarization due to hypoxia caused by impaired coronary blood flow. Depolarization decreases the action potential amplitude and rate of depolarization (phase 0 slope is decreased), both of which decrease the velocity of action potential conduction or completely stop the conduction of action potentials (i.e., conduction block). Conduction blocks can also be caused, especially at the AV node, by excessive vagal activation or because of drugs that reduce conduction such as beta-blockers and calcium-channel blockers.

Conduction blocks can occur at the AV node, bundle of His, or bundle branches as shown in the figure. There are three categories of conduction blocks: AV block, bundle branch block, and hemiblock. When there is an AV block, impulses originating in the SA node cannot enter the ventricles. This type of block can occur either at the AV node, at the common bundle of His, or when both bundle branches are blocked. When this occurs, a pacemaker site distal to the block will become the new pacemaker for the heart. These secondary pacemaker sites generally have an intrinsic rate (30-50 impulses/min depending 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 branch block), impulses still travel from the atria to the ventricles so there is no complete block and the ventricles will still be driven by the SA node. However, the sequence and timing of ventricular depolarization will be altered (see below). A hemiblock occurs when left anterior or posterior fascicle of the left bundle branch becomes blocked. When the conduction block is not a complete AV block (e.g., left bundle branch block), electrical impulses can travel along alternate conduction pathways to depolarize the ventricles. When this occurs, it takes longer for the ventricles to depolarize. This is manifested as an increase in the duration of the QRS complex, and a change in its shape. Sometimes, the abnormal conduction pathways can cause a self-perpetuating, circular movement of electrical activation. This is termed reentry and is a major cause of ventricular and supraventricular tachycardias.

Abnormal Rhythms - Definitions

General Terms:

Normal sinus rhythm - heart rhythm controlled by sinus node at a rate of 60-100 beats/min; each P wave followed by QRS and each QRS preceded by a P wave. Bradycardia - a heart rate that is lower than normal. Tachycardia - a heart rate that is higher than normal.

Paroxysmal - an arrhythmia that suddenly begins and ends. Sinus bradycardia - low sinus rate <60 beats/min. Sinus tachycardia - high sinus rate of 100-180 beats/min as occurs during exercise or other conditions that lead to increased SA nodal firing rate. Sick sinus syndrome - a disturbance of SA nodal function that results in a markedly variable rhythm (cycles of bradycardia and tachycardia). Atrial tachycardia - a series of 3 or more consecutive atrial premature beats occurring at a frequency >100/min; usually due to abnormal focus within the atria and paroxysmal in nature, therefore appearance of P wave is altered in different ECG leads. This type of rhythm includes paroxysmal atrial tachycardia (PAT). Atrial flutter - sinus rate of 250-350 beats/min. Atrial fibrillation - uncoordinated atrial depolarizations. Junctional escape rhythm - SA node suppression can result in AV node-generated rhythm of 40-60 beats/min (not preceded by P wave). AV nodal blocks - a conduction block within the AV node (or occasionally in the bundle of His) that impairs impulse conduction from the atria to the ventricles.

Specific Arrhythmias:

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 be caused by enhanced vagal tone, digitalis, beta-blockers, calcium channel blockers, or ischemic damage.

Second-degree AV nodal block - the conduction velocity is slowed to the point where some impulses from the atria cannot pass through the AV node. This can result in P waves that are not followed by QRS complexes. For example, 1 or 2 P waves may occur alone before one is followed by a QRS. When the QRS follows the P wave, the P-R interval is increased. In this type of block, the ventricular rhythm will be 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 transmitted from the atria to the ventricles. QRS complexes will still occur (escape rhythm), but they will originate from within the AV node, bundle of His,

or other ventricular regions. Therefore, QRS complexes will not be preceded by P waves. Furthermore, there will be complete asynchrony between the P wave and QRS complexes. Atrial rhythm may be completely normal, but ventricular rhythm will be greatly reduced depending upon the location of the site generating the ventricular impulse. Ventricular rate typically range from 30 to 40 beats/min.

Supraventricular tachycardia (SVT) - usually caused by reentry currents within the atria or between ventricles and atria producing high heart rates of 140-250; the QRS complex is usually normal width, unless there are also intraventricular conduction blocks (e.g., bundle branch block). Ventricular premature beats (VPBs) - caused by ectopic ventricular foci; characterized by widened QRS; often referred to as a premature ventricular complex, or PVC. Ventricular tachycardia (VT) - high ventricular rate caused by aberrant ventricular automaticity (ventricular foci) or by intraventricular reentry; can be sustained or non-sustained (paroxysmal); usually characterized by widened QRS (>0.14 sec); 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 a normal 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 normal rhythm and conduction. When it is not possible to revert to normal sinus rhythm, drugs may be used to prevent more serious and possibly lethal arrhythmias 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 ion conductances, which in turn alters the physical characteristics of cardiac action potentials. For example, some drugs are used to block fast sodium channels. 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 reduce conduction velocity. Decreasing conduction velocity can help to abolish tachyarrhythmias caused by reentry circuits. Other types of

antiarrhythmic drugs affect the duration of action potentials, and especially the effective refractory period. By prolonging the effective refractory period, reentry tachycardias can often be abolished. These drugs typically affect potassium channels and delay repolarization of action potentials (phase 3). Drugs that block slow inward calcium channels are used to reduce pacemaker firing rate by slowing the rate of rise of depolarizing pacemaker potentials (phase 4 depolarization). These drugs also reduce conduction velocity at the AV node, because those cells, like SA nodal cells, depend on the inward movement of calcium ions to depolarize. Because sympathetic activity can precipitate arrhythmias, drugs that block beta1-adrenoceptors are used to inhibit sympathetic effects on the heart. Because beta-adrenoceptors are coupled to ion channels through defined signal transduction pathways, beta-blockers indirectly alter membrane ion conductance, particularly calcium and potassium conductance. In the case of AV block, drugs that block vagal influences (e.g., atropine, a muscarinic receptor antagonist) are sometimes used. AV block can occur during beta-blocker treatment and therefore simply removing a betablocker in patients being treated with such drugs may normalize AV conduction. Sometimes ventricular rate is excessively high because it is being driven by atrial flutter or fibrillation. Because it is very important to reverse ventricular 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 conduction velocity in an attempt to normalize ventricular rate during atrial flutter or fibrillation. 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 the pharmacology of that drug class and specific drugs. Please note that many of the drugs comprising the first five listed classes have considerable overlap 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)

- digitalis compounds (cardiac glycosides) - atropine (muscarinic receptor antagonist)

Sodium-Channel Blockers (Class I Antiarrhythmics) Effects on depolarization. Sodiumchannel blockers comprise the Class I antiarrhythmic compounds according to the Vaughan-Williams classification scheme. These drugs bind to and block the fast sodium channels that are responsible for the rapid depolarization (phase 0) of fast-response cardiac action potentials. This type of action potential is found in non-nodal, cardiomyocytes (e.g., atrial and ventricular myocytes; purkinje tissue). Because the slope of phase 0 depends on the activation of 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. In contrast, 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, sodiumchannel blockers have no direct effect on nodal tissue, at least through the blockade of fast sodium-channels. The principal effect of reducing the rate and magnitude of depolarization by blocking sodium channels is a decrease in conduction velocity in nonnodal tissue (atrial and ventricular muscle, purkinje conducting system). The faster a cell depolarizes, the more rapidly adjacent cells will become depolarized, leading to a more rapid regeneration and transmission of action potentials between cells. Therefore, blocking sodium channels reduces the velocity of action potential transmission within the heart (reduced conduction velocity; negative dromotropy). This can serve as an important mechanism for suppressing tachycardias that are caused by

abnormal conduction (e.g., reentry mechanisms). By depressing abnormal conduction, reentry mechanisms can be interrupted. Effects on repolarization. Besides affecting phase 0 of action potentials, sodium-channel blockers may also alter the action potential duration (APD) and effective refractory period (ERP). Because some sodium-channel blockers increase the ERP (Class IA), while others decrease the ERP (Class IB) or have no effect on ERP (Class IC), the Vaughan-Williams classification recognizes these differences as subclasses of Class I antiarrhythmic drugs. These effects on ERP are not directly related to sodium channel blockade, but instead are related to drug actions on potassium channels involved in phase 3 repolarization of action potentials. These channels regulate potassium efflux from the cell (K + out), and therefore repolarization. The drugs in these subclasses also differ in their efficacy for reducing the slope of phase 0, with IC drugs having the greatest and IB drugs having the smallest effect on phase 0 (IA drugs are intermediate 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 decrease arrhythmogenesis, 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 is unexcitable (its refractory period). This can prevent reentry currents from re-exciting the tissue. On the other hand, increasing the APD can precipitate torsades de pointes, a type of ventricular tachycardia caused by afterdepolarizations. Effects on automaticity. By mechanisms not understood and unrelated to blocking fast sodium channels, Class I antiarrhythmics can suppress abnormal automaticity by decreasing the slope of phase 4, which is generated by pacemaker currents. Indirect vagal effects. The direct effect of Class IA antiarrhythmic drugs on action potentials is significantly modified by their anticholinergic actions. Inhibiting vagal activity can lead to both an increase in sinoatrial rate and atrioventricular conduction, which can offset the direct effects of the drugs on these tissues. Although a IA drug may effectively depress atrial rate during flutter, it can lead to an increase in ventricular rate because of an increase in the number of impulses conducted through the atrioventricular node (anticholinergic effect), thereby requiring concomitant treatment with a beta-blocker or calcium-channel blocker to slow AV nodal conduction. These anticholinergic actions are most prominent at the sinoatrial and atrioventricular nodes because they are extensively innervated by vagal efferent nerves. Different drugs within the IA subclass differ in their anticholinergic actions (see table below).

Specific Drugs and Therapeutic Indications The following table summarizes Class I compounds in terms of their therapeutic use and some special or distinguishing characteristics. More detailed information on specific drugs can be found at

Class IA: atrial fibrillation, flutter; supraventricular & ventricular tachyarrhythmias quinidine* anticholinergic (moderate) cinchonism (blurred vision, tinnitus, headache, psychosis); cramping and nausea; enhances digitalis toxicity lupus-like syndrome in 25-30% of patients negative inotropic effect

anticholinergic (weak); relatively procainamide short half-life anticholinergic disopryamide (strong)

Class IB: ventricular tachyarrhythmias (VT) lidocaine* tocainide mexiletine phenytoin IV only; VT and PVCs good efficacy in ischemic myocardium

orally active lidocaine can cause pulmonary fibrosis analog orally active lidocaine good efficacy in ischemic analog myocardium digitalis-induced arrhythmias

Class IC: life-threatening supraventricular tachyarrhythmias (SVT) and ventricular tachyarrhythmias (VT) flecainide* propafenone moricizine SVT SVT & VT; VT; IB activity can induce life-threatening VT -blocking and Ca++-channel blocking activity can worsen heart failure

* prototypical drug Abbreviations: IV, intravenous; PVC, premature ventricular complex. Side Effects and Contraindications The anticholinergic effects of IA drugs can produce tachycardia, dry mouth, urinary retention, blurred vision and constipation. Diarrhea, nausea, headache and dizziness are also common side effects of many Class I drugs. Quinidine enhances digitalis toxicity, especially if hypokalemia is present. Quinidine, by delaying repolarization, can precipitate torsades de pointes (especially in patients with long-QT syndrome), a ventricular tachyarrhythmia caused by afterdepolarizations.

Disopyramide is contraindicated for patients with uncompensated heart failure because of its negative inotropic actions; propafenone can also depress inotropy. IC compounds can cause increased risk of sudden death in patients with a prior history of myocardial infarction or sustained ventricular arrhythmias. Beta-Adrenoceptor Antagonists (Beta-Blockers)

General Pharmacology Beta-blockers are drugs that bind to beta-adrenoceptors and thereby block the binding of norepinephrine and epinephrine to these receptors. This inhibits 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 receptor while preventing norepinephrine from binding to the receptor. These partial agonists therefore provide some "background" of sympathetic activity while preventing normal and enhanced sympathetic activity. These particular beta-blockers (partial agonists) are said to possess intrinsic sympathomimetic activity (ISA). Some beta-blockers also possess what is referred to as membrane stabilizing activity (MSA). This effect is similar to the membrane stabilizing activity of sodium-channels blockers that represent Class I antiarrhythmics.

The first generation of beta-blockers were non-selective, meaning that they blocked both beta1 (1) and beta2 (2) adrenoceptors. Second generation beta-blockers are more cardioselective in that they are relatively selective for 1 adrenoceptors. Note that this relative selectivity can be lost at higher drug doses. Finally, the third generation betablockers are drugs that also possess vasodilator actions through blockade of vascular alpha-adrenoceptors. Heart. Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both 1 and 2 adrenoceptors, although the predominant receptor type in number and function is 1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulates in the blood. Betablockers 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 adenylyl cyclase to form cAMP from ATP. Increased cAMP activates a cAMPdependent protein kinase (PK-A) that phosphorylates L-type calcium channels, which causes increased calcium entry into the cell. Increased calcium entry during action potentials leads to enhanced release of calcium by the sarcoplasmic reticulum in the heart; these actions increase inotropy (contractility). Gs-protein activation also increases heart rate (chronotropy). PK-A also phosphorylates sites on the sarcoplasmic reticulum, which lead to enhanced release of calcium through the ryanodine receptors (ryanodine-sensitive, calcium-release channels) associated with the sarcoplasmic reticulum. This provides more calcium for binding the troponin-C, which enhances inotropy. Finally, PK-A can phosphorylate myosin light chains, which may contribute to the positive inotropic 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 normally stimulate chronotropy (heart rate), inotropy (contractility), dromotropy (electrical conduction) and lusitropy (relaxation). Therefore, beta-blockers cause decreases in heart rate, contractility, conduction velocity, and relaxation rate. These drugs have an even greater effect when there is elevated sympathetic activity. Blood vessels. Vascular smooth muscle has 2-adrenoceptors that are normally activated by norepinephrine released by sympathetic adrenergic nerves or by circulating epinephrine. These receptors, like those in the heart, are coupled to a Gs-protein, which stimulates the formation of cAMP. Although increased cAMP enhances cardiac myocyte contraction (see above), in vascular smooth muscle an increase in cAMP leads to smooth muscle relaxation. The reason for this is that cAMP inhibits myosin light chain kinase that is responsible for phosphorylating smooth muscle myosin. Therefore, increases in intracellular cAMP caused by 2-agonists inhibits myosin light chain kinase thereby producing less contractile force (i.e., promoting relaxation).

Compared to their effects in the heart, beta-blockers have relatively little vascular effect because 2-adrenoceptors have only a small modulatory role on basal vascular tone. Nevertheless, blockade of 2-adrenoceptors is associated with a small degree of vasoconstriction in many vascular beds. This occurs because beta-blockers remove a small 2-adrenoceptor vasodilator influence that is normally opposing the more dominant alphaadrenoceptor mediated vasoconstrictor influence.

Therapeutic Indications Beta-blockers are used for treating hypertension, angina, myocardial infarction, arrhythmias and heart failure. Hypertension. Beta-blockers decrease arterial blood pressure by reducing cardiac output. Many forms of hypertension are associated with an increase in blood volume and cardiac output. Therefore, reducing cardiac output by beta-blockade can be an effective treatment for hypertension, especially when used in conjunction with a diuretic. Hypertension in some patients is caused by emotional stress, which causes enhanced sympathetic activity. Beta-blockers are very effective in

these patients. Beta-blockers are especially useful in treating hypertension caused by a pheochromocytoma, which results in elevated circulating catecholamines. Beta-blockers have an additional benefit as a treatment for hypertension in that they inhibit the release of renin by the kidneys (the release of which is partly regulated by 1-adrenoceptors in the kidney). Decreasing circulating plasma renin leads to a decrease in angiotensin II and aldosterone, which enhances renal loss of sodium and water and further diminishes arterial pressure. Acute treatment with a beta-blocker is not very effective in reducing arterial pressure because of a compensatory increase in systemic vascular resistance. This may occur because of baroreceptor reflexes working in conjunction with the removal of 2 vasodilatory influences that normally offset, to a small degree, alpha-adrenergic mediated vascular tone. Chronic treatment with betablockers lowers arterial pressure more than acute treatment possibly because of reduced renin release and effects of beta-blockade on central and peripheral nervous systems. Angina and myocardial infarction. The antianginal effects of betablockers are attributed to their cardiodepressant and hypotensive actions. By reducing heart rate, contractility, and arterial pressure, beta-blockers reduce 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 in the oxygen supply/demand ratio due to coronary artery disease. Furthermore, beta-blockers have been found to be very important in the treatment of myocardial infarction in that they have been shown to decrease mortality. Their benefit is derived not only from improving the oxygen supply/demand ratio and reducing arrhythmias, but also from their ability to inhibit subsequent cardiac remodeling. Arrhythmias. The antiarrhythmic properties beta-blockers (Class II antiarrhythmic) are related to their ability to inhibit sympathetic influences on cardiac electrical activity. Sympathetic nerves increase sinoatrial node automaticity by increasing the pacemaker currents, which increases sinus rate. Sympathetic activation also increases conduction velocity (particularly at the atrioventricular node), and stimulates aberrant pacemaker activity (ectopic foci). These sympathetic influences are mediated primarily through 1-adrenoceptors. Therefore, beta-blockers can 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 nonpacemaker action potentials by increasing action potential duration and the effective refractory period. This effect can play a major role in blocking arrhythmias caused by reentry. Heart failure. The majority of patients in heart failure have a form that is called systolic dysfunction, which means that the contractile function of the heart is depressed (loss of inotropy). Although it seems counterintuitive that cardioinhibitory drugs such as beta-blockers would be used in cases of systolic dysfunction, clinical studies have shown quite conclusively that some specific beta-blockers actually improve cardiac function and reduce mortality. Furthermore, they have been shown to reduce deleterious cardiac remodeling that occurs in chronic heart failure. Although the exact mechanism by which beta-blockers confer their benefit

to heart failure patients is poorly understood, it may be related to blockade of excessive, chronic sympathetic influences on the heart, which are 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) relatively selective 1 blockers ("cardioselective" beta-blockers). Some betablockers have additional mechanisms besides beta-blockade that contribute to their unique pharmacologic profile. The two classes of betablockers along with specific compounds are listed in the following table. Additional details for each drug may be found at The clinical uses indicated in the table represent both on and off-label uses of beta-blockers. For example, a given beta-blocker may only be approved by the FDA for treatment of hypertension; however, physicians sometimes elect to prescribe the drug for angina because of the class-action benefit that beta-blockers have for angina.

Clinical Uses Class/Drug Non-selective 1/2 carteolol X ISA; long acting; also used for glaucoma X X X X X X X X X X -blocking activity ISA; blocking activity long acting ISA ISA; MSA MSA; prototypical beta-blocker several other significant mechanisms X primarily used for glaucoma ISA HTN Angin Arrhy MI a CHF Comments

carvedilol labetalol nadolol penbutolol pindolol propranolol


sotalol timolol 1-selective acebutolol X X X X


atenolol betaxolol bisoprolol esmolol metoprolol




X MSA ultra short acting; intra or postoperative HTN X X MSA

Abbreviations: HTN, hypertension; Arrhy, arrhythmias; MI, myocardial infarction; CHF, congestive heart failure; ISA, intrinsic sympathomimetic activity. Side Effects and Contraindications Cardiovascular side effects. Many of the side effects of betablockers are related to their cardiac mechanisms and include bradycardia, reduced exercise capacity, heart failure, hypotension, and atrioventicular (AV) nodal conduction block. All of these 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 in conjunction with cardiac selective calcium-channel blockers (e.g., verapamil) because of their additive effects in producing electrical and mechanical depression. Except for those drugs specifically approved for use in heart failure, beta-blockers are contraindicated in heart failure patients. Beta-blockers are also contraindicated in patients with sinus bradycardia and partial AV block. Other side effects. Bronchoconstriction can occur, especially when nonselective beta-blockers are administered to asthmatic patients. Therefore, non-selective beta-blockers are contraindicated in patients with asthma or chronic obstructive pulmonary disease. Bronchoconstriction occurs because sympathetic nerves innervating the bronchioles normally activate 2-receptors that promote bronchodilation. Blockade of these receptors can lead to bronchoconstriction. Hypoglycemia can occur with betablockade because 2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glucose. Therefore, blocking 2adrenoceptors lowers plasma glucose. 1-blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia which serves as a 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)

General Pharmacology Effects on action potentials. The primary role of potassium channels in cardiac action potentials is cell repolarization. In non-nodal tissue (see figure), action potentials are initiated when a cell is depolarized to a threshold potential by an adjacent cell. This leads rapid opening of fast sodium channels and a slower opening of L-type calcium channels that permit calcium to enter the cell (phase 0 and 2, respectively). As these channels become inactivated, potassium channels open permitting potassium ions to leave the cell (Figure: K + out), which causes repolarization of the membrane potential (phase 3). Potassium channels remain open until the next action potential is triggered. There are also different potassium channels that are responsible for the initial repolarization (phase 1) that occurs as the fast sodium channels become inactivated. Potassium channels are also responsible for repolarizing slowresponse action potentials in the sinoatrial and atrioventricular nodes. Potassium-channel blockers comprise the Class III antiarrhythmic compounds according to the Vaughan-Williams classification scheme. These drugs bind to and block the potassium channels that are responsible for phase 3 repolarization. Therefore, blocking these channels slows (delays) repolarization, which leads to an increase in action potential duration and an increase in the effective refractory period (ERP). On the electrocardiogram, this increases the Q-T interval. This is the common effect of all Class III antiarrhythmic drugs. The electrophysiological changes prolong the period of time that the cell is unexcitable (refractory) and therefore make the cell less excitable. By increasing the ERP, these drugs are very useful in suppressing tachyarrhythmias caused by reentry mechanisms. Reentry occurs when an action potential reemerges into normal tissue when that tissue is no longer refractory. When this happens, a new action potential is generated prematurely (before normal activation) and a circular, repeating pattern of early activation can develop, which leads to a tachycardia. If the ERP of the normal tissue is lengthened, then the reemerging action potential may find 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 their therapeutic use and some special or distinguishing characteristics. More detailed information on specific drugs can be found at


Therapeutic Uses

Comments very long half-life (25-60 days); Class I, II, III & IV actions and therefore decreases phase 4 slope and conduction velocity; potentially serious side effects (e.g., pulmonary fibrosis; hypothyroidism) IV only; initial sympathomimetic effect (norepinephrine release) followed by inhibition, which can lead to hypotension

severe amiodaro supraventricular and ne ventricular arrhythmias life-threatening ventricular tachycardia and fibrillation

bretyliu m


ventricular arrhythmias; atrial also has Class II activity flutter and fibrillation slow inward Na+ activator, which delays repolarization; inhibits Na+-channel inactivation, which increases ERP; IV only

supraventricular arrhythmias; atrial ibutilide flutter and fibrillation conversion

supraventricular dofetilid arrhythmias; atrial very selective K+-channel blocker e flutter and fibrillation conversion Abbreviations: IV, intravenous. Side Effects and Contraindications All of these compounds, like Class I compounds, are proarrhythmic as well as being antiarrhythmic. For example, the increase in action potential duration can produce torsades de pointes (a type of ventricular tachycardia), especially in patients with long-QT syndrome. Amiodarone, because of its Class IV effects, can cause bradycardia and atrioventricular block, and therefore is contraindicated in patients with heart block, or sinoatrial node dysfunction. Calcium-Channel Blockers (CCBs)

General Pharmacology 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 for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, L-type calcium channels play an important role in pacemaker currents and in phase 0 of the action potentials. Therefore, by blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation (negative inotropy), decreased heart rate (negative chronotropy), and decreased conduction velocity within the heart (negative dromotropy), particularly at the atrioventricular node. Therapeutic Indications CCBs are used to treat hypertension, angina and arrhythmias. Hypertension. By causing vascular smooth muscle relaxation, CCBs decrease systemic vascular resistance, which lowers arterial blood pressure. These drugs primarily affect arterial resistance vessels, with only minimal effects on venous capacitance vessels. Angina. The anti-anginal effects of CCBs are derived from their vasodilator and cardiodepressant actions. Systemic vasodilation reduces arterial pressure, which reduces ventricular afterload (wall stress) thereby decreasing oxygen demand. The more cardioselective CCBs (verapamil and diltiazem) decrease heart rate and contractility, which leads to a reduction in myocardial oxygen demand, which makes them excellent antianginal drugs. CCBs can also dilate coronary arteries and prevent or reverse coronary vasospasm (as occurs in Printzmetal's variant angina), thereby increasing oxygen supply to the myocardium. Arrhythmias. The antiarrhythmic properties (Class IV antiarrhythmics) of CCBs are related to their ability to decrease the firing rate of aberrant pacemaker sites within the heart, but more importantly are related to their ability to decrease conduction velocity and prolong repolarization, especially at the atrioventricular node. This latter action at the atrioventricular node helps to block reentry mechanisms, which can cause supraventricular tachycardia. Different Classes of Calcium-Channel Blockers There are three classes of CCBs. They differ not only in their basic chemical structure, but also in their relative selectivity toward cardiac versus vascular L-type calcium channels. The most smooth muscle selective class of CCBs are the dihydropyridines. Because of their high vascular selectivity, these drugs are primarily used to reduce systemic vascular resistance and arterial pressure, and therefore are primarily used to treat hypertension. They are not, however, generally used to treat

angina because their powerful systemic vasodilator and pressure lowering effects can lead to reflex cardiac stimulation (tachycardia and increased inotropy), which can dramatically increase myocardial oxygen demand. Note that dihydropyridines are easy to recognize because the drug name ends in "pine." Dihydropyridines include the following specific drugs: (Go to for specific drug information)

amlodipine felodipine isradipine nicardipine nifedipine nimodipine nitrendipine

Non-dihydropyridines, of which there are only two currently used clinically, comprise the other two classes of CCBs. Verapamil (phenylalkylamine class), is relatively selective for the myocardium, and is less effective as a systemic vasodilator drug. This drug has a very important role in treating angina (by reducing myocardial oxygen demand and reversing coronary vasospasm) and arrhythmias. Diltiazem (benzothiazepine class) is intermediate between verapamil and dihydropyridines in its selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, diltiazem is able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines. Side Effects and Contraindications Dihydropyridine CCBs can cause flushing, headache, excessive hypotension, edema and reflex tachycardia. The activation of sympathetic reflexes and lack of direct cardiac effects make dihydropyridines a less desirable choice for angina. Long-acting dihydropyridines have been shown to be safer anti-hypertensive drugs, in part, because of reduced reflex responses. The cardiac selective, non-dihydropyridine CCBs can cause excessive bradycardia, impaired electrical conduction (e.g., atrioventricular nodal block), and depressed contractility. Therefore, patients having preexistent bradycardia, conduction defects, or heart failure caused by systolic dysfunction should not be given CCBs, especially the cardiac selective, non-dihydropyridines. CCBs, especially nondihydropyridines, should not be administered to patients being treated with a beta-blocker because beta-blockers also depress cardiac electrical and mechanical activity and therefore the addition of a CCB augments the effects of beta-blockade. Treatment of Arrhythmias The following table summarizes which antiarrhythmic drugs may be used to 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, it may precipitate other arrhythmias or adverse cardiovascular effects (e.g.,

cardiac depression, hypotension). Therefore, drug efficacy and safety must be carefully evaluated and individualized to the patient when treating arrhythmias. Condition Sinus tachycardia Drug Class II, IV Comments Other underlying causes may need treatment

Atrial fibrillation/flutterClass IA, IC, II, III, IV Ventricular rate control is digitalis; adenosine important goal; anticoagulation required Paroxysmal supraventricular tachycardia AV block Class IA, IC, II, III, IV adenosine atropine Acute reversal

Ventricular Class I, II, III tachycardia Premature ventricular Class II, IV; complexes Mg++ salts Digitalis toxicity Class IB Mg++ salts; KCl

PVCs are often benign and not treated

Adenosine: General Pharmacology Adenosine is a naturally occurring purine nucleoside that forms from the breakdown of adenosine triphosphate (ATP). ATP is the primary energy source in cells for transport systems and many enzymes. Most ATP is hydrolyzed to ADP, which can be further dephosphorylated to AMP. Most ADP and AMP that form in the cell is rephosphorylated in the mitochondria by enzymatic reactions requiring oxygen. If there are large amounts of ATP hydrolyzed, and especially if there is insufficient oxygen available (i.e., hypoxia), then some of the AMP can be further dephosphorylated to adenosine by the cell membrane associated enzyme, 5'-nucleotidase. Adenosine can bind to purinergic receptors in different cell types where it can produce a number of different physiological actions. One important action is vascular smooth muscle relaxation, which leads to vasodilation. This is a particularly important mechanism for matching coronary blood flow to the metabolic needs of the heart. In coronary vascular smooth muscle, adenosine binds to adenosine type 2A (A 2A) receptors, which are coupled to the Gs-protein. Activation of this G-protein stimulates adenylyl cyclase (AC in figure), increases cAMP and causes protein kinase activation. This stimulates KATP channels, which hyperpolarizes the smooth muscle, causing relaxation. Increased cAMP also causes smooth muscle relaxation by inhibiting myosin light chain kinase, which leads to decreased myosin phosphorylation and a decrease in contractile force. There is also evidence that adenosine inhibits calcium entry into the cell through L-type calcium channels. Since calcium regulates smooth muscle

contraction, reduced intracellular calcium causes relaxation. In some types of blood vessels, there is evidence that adenosine produces vasodilation through increases in cGMP, which leads to inhibition of calcium entry into the cells as well as opening of potassium channels. In cardiac tissue, adenosine binds to type 1 (A 1) receptors, which are coupled to Gi-proteins. Activation of this pathway opens potassium channels, which hyperpolarizes the cell. Activation of the Gi-protein also decreases cAMP, which inhibits L-type calcium channels and therefore calcium entry into the cell. In cardiac pacemaker cells located in the sinoatrial node, adenosine acting through A1 receptors inhibits the pacemaker current (If), which decreases the slope of phase 4 of the pacemaker action potential thereby decreasing its spontaneous firing rate (negative chronotropy). Inhibition of L-type calcium channels also decreases conduction velocity (negative dromotropic effect) particularly at the atrioventricular (AV) nodes. Finally, adenosine by acting on presynaptic purinergic receptors located on sympathetic nerve terminals inhibits the release of norepinephrine. In terms of its electrical effects in the heart, adenosine decreases heart rate and reduces conduction velocity, especially at the AV node, which can produce atrioventricular block. Adenosine has a very short half-life. In human blood, its half-life is less than 10 seconds. There are two important metabolic fates for adenosine. 1. Most importantly, adenosine is rapidly transported into red blood cells (and other cell types) where it is rapidly deaminated by adenosine deaminase to inosine, which is further broken down to hypoxanthine, xanthine and uric acid, which is excreted by the kidneys. Adenosine deamination also occurs in the plasma, but at a lower rate than that which occurs within cells. Dipyridamole is a vasodilator drug that blocks adenosine uptake by cells, thereby reducing the metabolism of adenosine. Therefore, one important mechanism for dipyridamole-induced vasodilation is its potentiation of extracellular adenosine. 2. Adenosine can be acted on by adenosine kinase and rephosphorylated to AMP. This salvage pathway helps maintain the adenine nucleotide pool in cells. Therapeutic Use and Rationale Although adenosine is a powerful vasodilator, especially in the coronary circulation, it is not used clinically as a vasodilator. The reason is that it is very short acting and in the heart it can produce coronary vascular steal. When administered by intravenous infusion, it can produce substantial hypotension. Adenosine is used, however, as an antiarrhythmic drug for the rapid treatment of supraventricular tachycardias. Its effects on atrioventricular conduction make it very useful in treating paroxysmal supraventricular tachycardia in which the AV node is part of the reentry pathway (as in Wolff-Parkinson-White Syndrome). Adenosine is administered either as bolus intravenous injection or as an intravenous infusion.

Adenosine is not effective for atrial flutter or fibrillation. Side Effects and Contraindications Most of adenosine's side effects are related to its vasodilatory properties. Patients can experience flushing and headache, both of which are related to vasodilation. Adenosine can produce rapid arterial hypotension; however, this is reversed shortly after ceasing the infusion of adenosine. Coronary vascular steal is of theoretical concern in some patients with coronary artery disease, although there is no clinical evidence supporting this adverse effect. Methylxanthines such as caffeine and theophylline competitively antagonize the binding of adenosine at its purinergic receptor. Finally, adenosine may produce undesirable AV block; however, this is usually rapidly corrected by stopping adenosine administration. Therefore, adenosine is contraindicated in patients with second or third degree AV block.

Electrolyte Supplements (Magnesium and Potassium) General Pharmacology

Magnesium is an important ion in many enzymatic reactions, including cardiac Na+-K+-ATPase. Hypomagnesemia can inhibit this vital ion transport system and lead to cellular depolarization. Potassium ion plays an important role in membrane potentials, particularly in the resting membrane potential. It is also very important in the repolarization phase of cardiac pacemaker and non-pacemaker action potentials (phase 3). Therefore, hypomagnesemia (serum concentration <1.5 mg/dl) and hypokalemia (serum concentration <3.5 mg/dl; severe hypokalemia, <2.5 mg/dl) can precipitate cardiac arrhythmias, which include ventricular tachycardia and fibrillation, premature ventricular complexes, supraventricular tachycardias (e.g., Wolff-Parkinson-White Syndrome), atrial tachycardias, including flutter and fibrillation, and arrhythmias associated with digitalis toxicity. Specific Drugs For treating hypomagnesemia-associated arrhythmias, magnesium sulfate may by administered intravenously. Oral magnesium supplementation can be administered using magnesium gluconate, oxide or hydroxide salts. Potassium chloride may be administered intravenously or orally.

Cardiac Glycosides (Digitalis Compounds)

General Pharmacology Cardiac glycosides represent a family of compounds that are derived from the foxglove plant (Digitalis purpurea). The therapeutic benefits of digitalis were first described by William Withering in 1785. Initially, digitalis was used to treat dropsy, which is an old term for edema. Subsequent investigations found that digitalis was most useful for edema that was caused by a weakened heart (i.e., heart failure). Mechanisms of action. Digitalis compounds are potent inhibitors of cellular Na+/K+-ATPase. This ion transport system moves sodium ions out of the cell and brings potassium ions into the cell. This transport function is necessary for cell survival because sodium diffusion into the cell and potassium diffusion out of the cell down their concentration gradients would reduce their concentration differences (gradients) across the cell membrane over time. Loss of these ion gradients would lead to cellular depolarization and loss of the negative membrane potential that is required for normal cell function. The Na +/K+-ATPase also plays an active

role in the membrane potential because this pump is electrogenic because it transports 3 sodium ions out of the cell for every 2 potassium ion that enter the cell. This can add several negative millivolts to the membrane potential depending on the activity of the pump. Cardiac myocytes, as well as many other cells, have a Na +-Ca++ exchanger (not an active energy-requiring pump) that is essential for maintaining sodium and calcium homeostasis. The exact mechanism by which this exchanger works is unclear. It is known that calcium and sodium can move in either direction across the sarcolemma. Furthermore, three sodium ions are exchanged for each calcium, therefore an electrogenic potential is generated by this exchanger. The direction of movement of these ions (either inward or outward) depends upon the membrane potential and the chemical gradient for the ions. We also know that an increase in intracellular sodium concentration competes for calcium through this exchange mechanism leading to an increase in intracellular calcium concentration. As intracellular sodium increases, the concentration gradient driving sodium into the cell across the exchanger is reduced, thereby reducing the activity of the exchanger, which decreases the movement of calcium out of the cell. Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a subsequent accumulation of intracellular calcium because of decreased exchange pump activity. By inhibiting the Na+/K+-ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na+-Ca++ exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy). Inhibition of the Na+/K+-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction. By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent activity to the heart. This parasympathomimetic action of digitalis reduces sinoatrial firing rate (decreases heart rate; negative chronotropy) and reduces conduction velocity of electrical impulses through the atrioventricular node (negative dromotropy). Pharmacokinetics and toxicity. The long half-life of digitalis compounds necessitates special considerations when dosing. With a halflife of 40 hours, digoxin would require several days of constant dosing to reach steady-state, therapeutic plasma levels (digitoxin with a half-life of 160 hours, would require almost a month!). Therefore, when initiating treatment, a special dosing regimen involving "loading doses" is used to rapidly increase digoxin plasma levels. This process is termed "digitalization." For digoxin, the therapeutic plasma concentration range is 0.5 - 1.5 ng/ml. It is very important that therapeutic plasma levels are not exceeded because digitalis compounds have a relatively narrow therapeutic safety window. Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity, which is manifested as arrhythmias, some of which may be life-threatening. If toxicity occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels because of the long half-life. There is available for digoxin toxicity an immune Fab

(Digibind) that can be used to rapidly reduce plasma digoxin levels. Potassium supplementation can also reverse the toxic effects of digoxin, especially if the toxicity is related to hypokalemia (see below). Drug Interactions. Many commonly used drugs interact with digitalis compounds. The Class IA antiarrhythmic, quinidine, competes with digoxin for binding sites and depresses renal clearance of digoxin. These effects increase digoxin levels and can produce toxicity. Similar interactions occur with calcium-channel blockers and nonsteroidal anti-inflammatory drugs. Other drugs that interact with digitalis compounds are amiodarone (Class III antiarrhythmic) and betablockers. Diuretics can indirectly interact with digoxin because of their potential for decreasing plasma potassium levels (i.e., producing hypokalemia). Because potassium competes with digoxin for binding sites on the Na+/K+-ATPase, hypokalemia results in increased digoxin binding and thereby enhances its therapeutic and toxic effects. Hypercalcemia enhances digitalis-induced increases in intracellular calcium, which can lead to calcium overload and increased susceptibility to digitalis-induced arrhythmias. Hypomagnesemia also sensitizes the heart to digitalisinduced arrhythmias. Therapeutic Uses Heart failure. Digitalis compounds have historically been used in the treatment of chronic heart failure owing to their cardiotonic effect. Although newer and more efficacious treatments for heart failure are available, digitalis compounds are still widely used. Clinical studies in heart failure patients have shown that digoxin, when used in conjunction with diuretics and vasodilators, improves cardiac output and ejection fraction, and reduces filling pressures and pulmonary capillary wedge pressure (this reduces pulmonary congestion and edema); heart rate changes very little. These effects are to be expected for a drug that increases inotropy. Although the direct effect of digoxin on blood vessels is vasoconstriction, when given to patients in heart failure, the systemic vascular resistance falls. This most likely results from the improvement in cardiac output, which leads to withdrawal of compensatory vasoconstrictor mechanisms (e.g., sympathetic adrenergic activity and angiotensin II influences). Digitalis compounds have a small direct diuretic effect on the kidneys, which is beneficial in heart failure patients. Atrial fibrillation and flutter. Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output. Furthermore, chronic ventricular tachycardia can lead to heart failure. Digitalis compounds, such as digoxin, are useful for reducing ventricular rate when it is being driven by a high atrial rate. The mechanism of this beneficial effect of digoxin is its ability to activate vagal efferent nerves to the heart (parasympathomimetic effect). Vagal activation can reduce the conduction of electrical impulses within the atrioventricular node to the point where some of the impulses will be blocked. When this occurs, fewer impulses reach the ventricles and ventricular rate falls. Digoxin also increases the effective refractory period within the atrioventricular node. Specific Drugs

Three different digitalis compounds (cardiac glycosides) are listed in the table below. The compound most commonly used in the U.S. is digoxin. Ouabain is used primarily as a research tool.

Drug Digoxin Digitoxin Ouabain

Oral Availability * 75% >90% 0%

Half-life (hours) 40 160 20

Elimination kidneys liver kidneys

* percent absorption Side Effects and Contraindications The major side effect of digitalis compounds is cardiac arrhythmia, especially atrial tachycardias and atrioventricular block. Digitalis compounds are contraindicated in patients who are hypokalemic, or who have atrioventricular block or Wolff-Parkinson-White (WPW) syndrome. Impaired renal function leads to enhanced plasma levels of digoxin because digoxin is eliminated by the kidneys. Lean, elderly patients are more susceptible to digitalis toxicity because they often have reduced renal function, and their reduced muscle mass increases plasma digoxin levels at a given dose because muscle Na +/K+-ATPase acts as a large binding reservoir for digitalis.

Atropine (Muscarinic Receptor Antagonist)

General Pharmacology

The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells comprising the sinoatrial (SA) and atrioventricular (AV) nodes. Muscarinic receptors are coupled to the Gi-protein; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells. Increases in vagal activity to the SA node decreases the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential (phase 4 of the action potential); this decreases heart rate (negative chronotropy). The change in phase 4 slope results from alterations in potassium and calcium currents, as well as the slowinward sodium current that is thought to be responsible for the pacemaker current (If). By hyperpolarizing the cells, vagal activation increases the cell's threshold for firing, which contributes to the reduction the firing rate. Similar electrophysiological effects also occur at the AV node; however, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node (negative dromotropy). In the resting state, there is a large degree of vagal tone on the heart, which is responsible for low resting heart rates. There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and even smaller decreases in ventricular contractility. Muscarinic receptor antagonists bind to muscarinic receptors thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate and conduction velocity.

Specific Drugs and Therapeutic Indications

Atropine is a muscarinic receptor antagonist that is used to inhibit the effects of excessive vagal activation on the heart, which is manifested as sinus bradycardia and AV nodal block. Therefore, atropine can temporarily revert sinus bradycardia to normal sinus rhythm and reverse AV nodal blocks by removing vagal influences.

Side Effects and Contraindications

The anticholinergic effects of atropine can produce tachycardia, pupil dilation, dry mouth, urinary retention, inhibition of sweating (anhidrosis), blurred vision and constipation. However, most of these side effects are only manifested with excessive dosing or with repeated dosing. Atropine is contraindicated in patients with glaucoma.