INOTROPIC AGENTS. ANTIANGINAL AGENTS. ANTIDYSRYTHMIC AGENTS

Inotropic Agents

Heart diseases can be primarily grouped into three major disorders: cardiac failure, ischemia and cardiac arrhythmia. Cardiac failure can be described as the inability of the heart to pump blood effectively at a rate that meets the needs of the metabolizing tissues. This occurs when the muscles that perform contraction and force the blood out of heart are performing weakly. Thus cardiac failures primarily arise from the reduced contractility of heart muscles, especially the ventricles. Reduced contraction of heart leads to reduced heart output but new blood keeps coming in resulting in the increase in heart blood volume. The heart feels congested. Hence the term congestive heart failure. Congested heart leads to lowered blood pressure and poor renal blood flow. This results in the development of edema in the lower extremities and the lung (pulmonary edema) as well as renal failure.

Heart Failure occurs when decreases in contractility prevent the heart from contracting forcefully enough to deliver  blood to meet the demands of the body.  Decreases in C.O. activate reflex responses in the SNS which attempt to compensate for the reduced C.O.:  These reflex responses include 1. increases in heart rate (tachycardia), 2. increased preload (salt and water retention increase blood volume through activation of the renin-angiotensin-aldosterone pathway -this leads to peripheral and pulmonary edema.  Since the volume returned is greater than the ability of the heart to pump, blood remains in the heart with each stroke leading to enlargement of the heart), and 3. increased afterload (through vasoconstriction via a receptors as well as through the production of angiotensin II) resulting in compensated heart failure.  Ultimately, SNS activation can no longer compensate, and the heart fails.  Drug treatment  is directed towards 1) enhancing cardiac output with + inotropic drugs (cardiac glycosides), 2) decreasing preload with diuretics and  Angiotensin Converting Enzyme (ACE) inhibitors , and/or 3) decreasing afterload with vasodilators like organic nitrates and ACE inhibitors.

Drugs to treat Heart Failure

SYMPTOM/DEFECT	DRUG/PHARMACODYNAMICS	THERAPEUTIC VALUE
decreased contractility (decrease in ability of muscle to contract) results in SNS activation to compensate for  decreased cardiac output	cardiac glycosides inhibit the Na pump allowing Ca to inc. inside cells and increase the force of contraction non-selective/b1-selective agonists increase contractility	Increase contractility increases cardiac emptying, decreases preload, heart size and oxygen demand. Increase C.O. decreases SNS tone, heart rate  and venous tone     short-term support of a failing heart
increased preload  due to Na/water retention caused by    activation of the renin - angiotensin - aldosterone pathway.  Na/water retention lead to edema	diuretics - increase Na and water excretion ACE inhibitors -decrease pro- duction of angiotensin II (a potent vasoconstrictor).  Decreased  AngII decreases aldosterone thus decreasing salt and water retention	decreases preload (dec. blood volume  causes decreased venous return)                                       decreased afterload (dec. AngII causes vasodilation or decreased PVR) and decreased preload due to  decreased aldosterone and increase Na and water excretion)
increased vascular tone (increase blood pressure) due to SNS activation in an attempt to compensate for decreased contractility	ACE inhibitors - decrease production of AngII  which is a potent vasoconstrictor                                                   Nitrovasodilators - dilate both veins and arteries	decrease afterload due to arterial dilation (dec. PVR)  decrease preload and afterload due to venous and arterial dilation, respectively

Cardiac Glycosides

Increasing the force of contraction of the heart (positive inotropic activity) is very important for most heart failure patients. There are several mechanisms by which this could be achieved. Cardiac steroids are perhaps the most useful and are being discussed here. Phosphodiesterase inhibitors, such as amrinone and milrinone, have also been explored and so are direct adenylate cyclase stimulants, such as forskolin. These drugs all act by affecting the availability of intracellular Ca+2 for myocardial contraction or increasing the sensitivity of myocardial contractile proteins.

The cardiac glycosides are an important class of naturally occurring drugs whose actions include both beneficial and toxic effects on the heart. Plants containing cardiac steroids have been used as poisons and heart drugs at least since 1500 B.C. Throughout history these plants or their extracts have been variously used as arrow poisons, emetics, diuretics, and heart tonics. The therapeutic properties of cardiac glycosides (eg, digoxin, a product of the foxglove plant) have been known since the days of the Roman Empire. The ancient Romans used red squill, a cardiac glycoside derived from the sea onion, as a diuretic and heart medicine. Cardiac glycosides are found in certain flowering plants such as oleander and lily-of-the-valley. Certain herbal dietary supplements also contain cardiac glycosides. Cardiac steroids are widely used in the modern treatment of congestive heart failure and for treatment of atrial fibrillation and flutter. Yet their toxicity remains a serious problem.

Purple Foxglove Lily of the valley

Lychnis Stophantus

Structure

Cardiac glycosides are composed of two structural features : the sugar (glycoside) and the non-sugar (aglycone - steroid) moieties. (figure below)

The R group at the 17-position defines the class of cardiac glycoside. Two classes have been observed in Nature - the cardenolides and the bufadienolides (see figure below). The cardenolides have an unsaturated butyrolactone ring while the bufadienolides have an a-pyrone ring. 

Nomenclature : The cardiac glycosides occur mainly in plants from which the names have been derived. Digitalis purpurea, Digitalis lanata, Strophanthus grtus, and Strophanthus kombe are the major sources of the cardiac glycosides. The term 'genin' at the end refers to only the aglycone portion (without the sugar). Thus the word digitoxin refers to a agent consisting of digitoxigenin (aglycone) and  sugar moieties (three). The aglycone portion (figure below) of cardiac glycosides is more important than the glycone portion. The steroid nucleus has a unique set of fused ring system that makes the aglycone moiety structurally distinct from the other more common steroid ring systems. Rings A/B and C/D are cis fused while rings B/C are trans fused.

Such ring fusion give the aglycone nucleus of cardiac glycosides the characteristic 'U' shape as shown below. To view the 3-dimensional structure of the aglycone moiety click on the figure.

The steroid nucleus has hydroxyls at 3- and 14- positions of which the sugar attachment uses the 3-OH group. 14-OH is normally unsubstituted. Many genins have OH groups at 12- and 16- positions. These additional hydroxyl groups influence the partitioning of the cardiac glycosides into the aqueous media and greatly affect the duration of action. The lactone moiety at C-17 position is an important structural feature. The size and degree of unsaturation varies with the source of the glycoside. Normally plant sources provide a 5-membered unsaturated lactone while animal sources give a 6-membered unsaturated lactone.

Sugar moiety : One to 4 sugars are found to be present in most cardiac glycosides attached to the 3b-OH group. The sugars most commonly used include L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-vallarose, and D-fructose. These sugars predominantly exist in the cardiac glycosides in the b-conformation. The presence of acetyl group on the sugar affects the lipophilic character and the kinetics of the entire glycoside.  Because the order of sugars appears to have little to do with biological activity Nature has synthesized a repertoire of numerous cardiac glycosides with differing sugar skeleton but relatively few aglycone structures.

Structure - Activity Relationships

• The sugar moiety appears to be important only for the partitioning and kinetics of action. It possesses no biological activity. For example, elimination of the aglycone moiety eliminates the activity of alleviating symptoms associated with cardiac failure.
• The "backbone" U shape of the steroid nucleus appears to be very important. Structures with C/D trans fusion are inactive.
•  Conversion to A/B trans system leads to a marked drop in activity. Thus although not mandatory A/B cis fusion is important.
• The 14b-OH groups is now believed to be dispensible. A skeleton without 14b-OH group but retaining the C/D cis ring fusion was found to retain activity.
• Lactones alone, when not attached to the steroid skeleton, are not active. Thus the activity rests in the steroid skeleton.
• The unsaturated 17-lactone plays an important role in receptor binding. Saturation of the lactone ring dramatically reduced the biological activity.
• The lactone ring is not absolutely required. For example, using a,b-unsaturated nitrile (C=C-CN group) the lactone could be replaced with little or no loss in biological activity.

Pharmacokinetics of Cardiac Glycosides

The commercially available cardiac steroids differ markedly in their degree of absorption, half-life, and the time to maximal effect (see table below). 

Agent	GI absorption	Onset (m)	Peak (h)	Half-life
Ouabain	Unreliable	5-10	0.5-2	21 h
Deslanoside	Unreliable	10-30	1-2	33 h
Digoxin	55-75%	15-30	1.5-5	36 h
Digitoxin	90-100%	25-120	4-12	4-6 days

Usually this is due to the polarity differences caused by the number of sugars at C-3 and the presence of additional hydroxyls on the cardenolide. Although two cardiac glycosides may differ by only one sugar residue their partition co-efficients may be significantly different resulting in different pharmacokinetics. For example, lanatoside C and digoxin differ only by a glucose residue and yet the partition co-efficient measured in CHCl₃/16% aqueous MeOH are 16.2 and 81.5, respectively.

Glycoside	Partition Coefficient
Lanatoside C (glucose-3-acetyldigitoxose-digitoxose2-digoxigenin)	16.2
Digoxin (digitoxose3-digoxigenin)	81.5
Digitoxin (digitoxose3-digitoxigenin)	96.5
Acetyldigoxin (3-acetyldigitoxose-digitoxose2-digoxigenin)	98.0
G-Strophanthin (rhamnose-ouabagein)	very low

In general, cardiac glycosides with more lipophilic character are absorbed faster and exhibit longer duration of action as a result of slower urinary exretion rate. Lipophilicity is markely influenced by the number of sugar residues and the number of hydroxyl groups on the aglycone part of the glycoside. Comparison of digitoxin and digoxin structures reveals that they differ only by an extra OH group in digoxin at C-12, yet their partition coefficients differ by as much as 15 % points.

Biochemical Mechanism of Action

The mechanism whereby cardiac glycosides cause a positive inotropic effect and electrophysiologic changes is still not completely clear. Several mechanisms have been proposed, but the most widely accepted involves the ability of cardiac glycosides to inhibit the membrane bound Na⁺-K⁺-ATPase pump responsible for Na⁺-K⁺ exchange.

        The process of muscle contraction can be pictured as shown below.

The process of membrane depolarization / repolarization is controlled by the movement of three cations, Na⁺, Ca⁺², and K⁺, in and out of the cell. At the resting stage, the concentration of Na⁺ is high on the outside. On membrane depolarization sodium fluxes-in leading to an immediate elevation of the action potential. Elevated intracellular Na⁺ triggers the influx of free of Ca⁺⁺ that occurs more slowly. The higher intracellular [Ca⁺⁺] results in the efflux of K⁺. The reestablishment of the action potential occurs later by the reverse of the Na⁺-K⁺ exchange. The Na⁺ / K⁺ exchange requires energy which is provided by an enzyme Na⁺-K⁺-ATPase. Cardiac glycosides are proposed to inhibit this enzyme with a net result of reduced sodium exchange with potassium that leaves increased intracellular Na⁺. This results in increased intracellular [Ca⁺⁺]. Elevated intracellular calcium concentration triggers a series of intracellular biochemical events that ultimately result in an increase in the force of the myocardial contraction or a positive inotropic effect.

Digoxin

In 1785, Withering published an account of digitalis (dried leaves of the purple foxglove) and some of its medical uses.¹² Although digoxin continues to be viewed as beneficial in patients with heart failure and atrial fibrillation, its role in patients with heart failure and sinus rhythm has been increasingly challenged. Mackenzie and Christian, two eminent clinicians and coeditors of Oxford Medicine, debated this issue in 1922. Mackenzie advocated the use of digitalis only in heart failure with associated atrial arrhythmias, whereas Christian argued that digitalis was effective irrespective of an irregular pulse. In 1938, Cattell and Gold first showed a direct inotropic effect of digitalis on cardiac muscle. For many more years, digitalis continued to be an important part of heart failure management. The detrimental aspects of digoxin therapy were not considered important until excess mortality was reported in survivors of myocardial infarction who received digitalis. Uncontrolled observations that the withdrawal of digoxin produced no ill effects also raised concerns about the efficacy of the drug.

Pharmacology of digoxin

Action

§ Increases vagal tone (central effect), leading to slowed ventricular response in atrial fibrillation.

§ Reduces sympathetic tone, especially when this is abnormally high, as in heart failure. This is probably mediated partly via vagotonic actions and partly via direct effects.

§ Positive inotropic action mediated via direct blockade of Na+–K+-ATPase on cell membranes. This leads to increased intracellular Na+ concentration, which in turn increases intracellular Ca++ concentration via the Na+–Ca++ exchanger.

Negative Chronotropic Effect of Digoxin

• Stimulates vagus centrally
  Increases refractoriness of AV node

o Decreases ventricular response to atrial rate

o Controls heart rate in atrial fibrillation

Slows depolarization rate of SA node

o Decreases sinus rate

o Decreases heart rate in Sinus Tachycardia

Digoxin in Patients with Mild to Moderate Heart Failure

In the DIG trial, digoxin therapy was most beneficial in patients with ejection fractions of 25 percent or lower, patients with enlarged hearts (cardiothoracic ratio of greater than 0.55) and patients in NYHA functional class III or IV. The findings of the DIG trial also indicated that digoxin was clinically beneficial in subgroups of patients with less severe forms of heart failure. Using direct clinical measures of heart failure, the PROVED and the RADIANCE trials showed definite clinical improvement in patients who were treated with digoxin, even patients with mild heart failure. Based on the study findings, digoxin therapy may be effective in patients with mild or moderate heart failure, although the magnitude of the effect may be quite modest.

Digoxin in Patients with Preserved Left Ventricular Systolic Function

Much has been learned about the effective treatment of patients who have congestive heart failure associated with left ventricular systolic dysfunction. In contrast, little is known about how best to treat patients with preserved left ventricular systolic function. As many as 30 percent of patients with congestive heart failure have a normal or nearly normal left ventricular ejection fraction. In these patients, congestive heart failure is often described as "left ventricular diastolic dysfunction." Left ventricular diastolic dysfunction is considered to be a diagnosis of exclusion (or assumption) in patients with congestive heart failure and preserved left ventricular systolic function. Diagnostic tools such as radionuclide angiography and Doppler echocardiography have made it possible to identify patients who have normal or nearly normal left ventricular systolic function but abnormal left ventricular filling parameters. The majority of patients with congestive heart failure who have only diastolic dysfunction have no identified diagnosis. Most of these patients are elderly or have a history of hypertension. Some patients have coronary artery disease without extensive scar tissue. Such patients also commonly have diabetes mellitus.

Approach to Patients with Diastolic Dysfunction

In patients with diastolic dysfunction, appropriate measures include the diagnosis and treatment of myocardial ischemia (if present) and the aggressive treatment of hypertension (if needed). Digitalis therapy has been considered inappropriate in these patients. In some patients, treatment with diuretics and nitrates could reduce pulmonary congestion. In the DIG trial, a subgroup of nearly 1,000 patients with a left ventricular ejection fraction of 45 percent or greater experienced a reduction in congestive heart failure end points similar to patients with a left ventricular ejection fraction of 25 to 45 percent. One group of investigators suggested that this effect may be the result of digoxin's ability to reduce neurohormonal activities. However, they concluded that information about the effect of digoxin in patients with congestive heart failure and preserved left ventricular systolic function is limited and does not warrant routine use of the drug in this setting until the results of more studies are available. At present, the consensus is that digoxin therapy is probably inappropriate in patients with preserved left ventricular systolic function. In addition, digoxin therapy may not be useful in patients with congestive heart failure and a high cardiac output syndrome such as anemia or thyrotoxicosis.

Adverse Effects of Digoxin

Adverse reactions to digoxin are usually dose dependent and occur at dosages higher than those needed to achieve a therapeutic effect. The actual incidence of digoxin toxicity may be lower than is historically reported. Adverse reactions are less common when digoxin is used in the recommended dosage range and careful attention is given to concurrent medications and medical conditions. The principal manifestations of digoxin toxicity include cardiac arrhythmias (ectopic and reentrant cardiac rhythms and heart block), gastrointestinal tract symptoms (anorexia, nausea, vomiting and diarrhea) and neurologic symptoms (visual disturbances, headache, weakness, dizziness and confusion). Most adult patients with clinical toxicity have serum digoxin levels greater than 2 ng per mL (2.6 nmol per L). Conditions such as hypokalemia, hypomagnesemia or hypothyroidism may predispose patients to have adverse reactions even at lower serum digoxin concentrations.

Dosages of Digoxin

Although some investigators advocate the use of serum levels to guide digoxin dosing, little evidence supports this approach.³⁰ The serum level of digoxin may be used to assist in evaluating a patient for toxicity, but not to determine the efficacy of the drug. When digoxin was considered to be mainly an inotrope, higher dosages (greater than 0.25 mg per day) were generally used, and the incidence of toxicity was much higher. In the PROVED and RADIANCE trials, the mean digoxin dosage was 0.375 mg per day. However, a study of a subset of patients in the RADIANCE trial showed that increasing the digoxin dosage from a mean of 0.2 mg per day to 0.39 mg per day did not significantly improve heart failure symptoms, exercise time or serum norepinephrine levels. When lower dosages are used, the side effects of digoxin, especially ventricular arrhythmias, decrease. Use of lower dosages is particularly important in the elderly, because digitalis toxicity may be difficult to recognize in this patient population. It is generally agreed that digoxin should be given in a dosage of 0.125 to 0.25 mg per day. Dosages higher than 0.25 mg per day are probably unwarranted. Renal function plays a major role in the pharmacokinetics of digoxin and is an important factor in determining the dosage. Medications such as quinidine, amiodarone (Cordarone) and verapamil (Calan) can increase the serum digoxin concentration. Thus, safe and effective dosing requires recognition of concomitant disease states and medications that could change digoxin pharmacokinetics, along with a recognition of digoxin toxicity.

Digoxin and Other Medications for Congestive Heart Failure

ACE inhibitors, beta blockers and spironolactone have been shown to improve survival in patients with heart failure. Consequently, the role of digoxin in the treatment of heart failure remains secondary, despite renewed interest in its use. Digoxin has been shown to reduce the morbidity associated with congestive heart failure but to have no demonstrable effect on survival.

In the absence of a survival benefit, the goal of digoxin therapy is to improve quality of life by reducing symptoms and preventing hospitalizations. Digoxin should be used routinely, in conjunction with diuretics, ACE inhibitors, beta blockers and spironolactone, in all patients with severe congestive heart failure and reduced systolic function. It also should be added to the therapy of patients with mild to moderate congestive heart failure if they have not responded adequately to an ACE inhibitor or a beta blocker. If digoxin acts primarily by reducing neurohormonal activation, its value is in question in patients with heart failure who are already being treated with beta blockers.

Digoxin for arrhythmia

While there is little doubt that appropriate doses of digoxin will slow the resting ventricular rate in most patients with chronic atrial fibrillation (E1), it has been known for many years that digoxin is far less successful in controlling exercise-induced or stress-induced tachycardia in atrial fibrillation in many patients, even when plasma drug concentrations are near the upper end of the accepted therapeutic range.1 A study of 12 patients with chronic atrial fibrillation confirmed that medium-dose diltiazem was comparable, in terms of rate control at rest, to a therapeutic dose of digoxin and superior to digoxin during exercise. High-dose diltiazem (360 mg/day) was superior to digoxin, both at rest and during exercise

Digoxin Toxicity

Toxicity

§ Common (seen in 10%–20% of patients on long-term digoxin therapy).

§ Cardiotoxicity is most serious and may manifest as ventricular or supraventricular arrhythmias, including sudden increased prevalence of cardiac death (this was almost exactly balanced in Digitalis Investigation Group trial by reduction in "pump failure" deaths). Also, vagotonic actions can produce bradyarrhythmias, including prolonged PR interval and high-grade heart block.

§ Non-cardiac toxicity includes nausea, vomiting, diarrhoea, visual effects, including "yellow" vision, and gynaecomastia.

Digitalis toxicity can occur fairly easily and quickly. Digitalis can accumulate in tissues even when taken as prescribed. Symptoms of digoxin toxicity are:

• weakness
• nausea, vomiting, or diarrhea
• seeing colored lights
• loss of appetite or
• an uneven, very slow or very fast heartbeat

Several medications can affect the way digitalis works, causing either an increase or decrease in the drug's actions on the heart. Some of the medicines are:

• diuretics or water pills
• other cardiac medications
• antacids
• laxatives and some diarrhea medications
• thyroid and asthma medications
• decongestants found in cough, cold, and sinus products and
• diet pills

Physicians first studied digoxin in the 18th century. The syndrome of digoxin toxicity originally was described in 1785. Digoxin's inotropic effect results from the inhibition of the sodium-potassium adenosine triphosphatase (NA⁺/K⁺ ATPase) pump. The subsequent rise in intracellular calcium (Ca⁺⁺) and sodium (NA⁺) coupled with the loss of intracellular potassium (K⁺) increases the force of myocardial muscle contraction (contractility), resulting in a net positive inotropic effect. Digoxin also increases the automaticity of Purkinje fibers but slows conduction through the atrioventricular (AV) node. Cardiac dysrhythmias associated with an increase in automaticity and a decrease in conduction may result. The relationship between digoxin toxicity and the serum digoxin level is complex; clinical toxicity results from the interactions between digitalis, various electrolyte abnormalities, and their combined effect on the Na⁺/K⁺ ATPase pump. Cardiac glycoside toxicity from plants, such as oleander, foxglove, and lily-of-the-valley, is uncommon but potentially lethal. Case reports of toxicity from these sources implicate the preparation of extracts and teas as the usual culprit.

Frequency:

• In the US: Approximately 0.4% of all hospital admissions, 1.1% of outpatients on digoxin, and 10-18% of nursing home patients develop toxicity.

The overall incidence of digoxin toxicity has decreased because of a number of factors including increased awareness of drug interactions, decreased use of digoxin to treat heart failure and arrhythmias, and the availability of accurate rapid radioimmunoassays to monitor drug levels.

Internationally: Approximately 2.1% of inpatients on digoxin and 0.3% of all admissions develop toxicity.

Mortality/Morbidity:

• Morbidity is usually 4.6-10%; however, morbidity is 50% if the digoxin level is greater than 6 ng/mL.

• Mortality varies with the population studied. Adult mortality depends on underlying comorbidity. In general, older people have a worse outcome than adults who, in turn, have a worse outcome than children.

Age: Advanced age (>80 y) is an independent risk factor and is associated with increased morbidity and mortality.

Digitalis toxicity occurs in 5 to 20 percent of patients treated with digitalis glycosides. Because the therapeutic and toxic ranges are relatively narrow, toxicity may occur from an accidental overdose, unpredictable changes in renal function or electrolyte imbalance. Most cases of digoxin toxicity are minor, and treatment consists of temporary withdrawal or reduction in the dose. However, several thousand patients each year require more aggressive treatment, often in the coronary care unit. Mortality rates in patients with digoxin toxicity have ranged from 3 to 25 percent. Digoxin immune Fab (ovine) fragments (Digibind) have been shown to reverse digitalis toxicity and substantially reduce the risk of death. Fab fragments are presently indicated for use in patients with potentially life-threatening arrhythmias or other evidence of severe digitalis intoxication. Such patients require continuous monitoring until digoxin levels return to the therapeutic range. Mauskopf and Wenger used data from uncontrolled studies of patients treated with Fab fragments and data from symptomatically treated patients to estimate the difference in clinical outcomes and medical care costs when Fab fragments are used. Treatment with Fab fragments produces a greater reduction in mortality risk in patients with serious toxicity than in patients with less serious toxicity. Treatment is associated with increased total medical costs for patients with serious toxicity, because more of these patients survive and require further hospitalization and care. For these patients, the estimated cost per year of life saved is between $1,900 and $5,400. When Fab fragments are used to treat patients with less serious toxicity, total medical costs are decreased because the number of days in the coronary care unit and the need for pacemakers and other aggressive treatments are reduced.

Treatment of Toxicity

• Stop giving the drug (for a time)
• antiarrhythmics (lidocaine, procainamide, propranolol, phenytoin) IF the arrhythmias appear to be life-threatening in their own right (multi-focal pvcs, high rate ventricular tachycardia) or if the arrhythmias severely compromise cardiac output.
• Potassium (if hypokalemic)
• Cholestyramine, activated charcoal etc. to bind digoxin in GI tract and shorten half-life
• Digoxin Antibodies (therapeutic monitoring becomes irrelevant).

Phosphodiesterase inhibitors

Amrinone

Mechanism(s) of Action

Increased force of contraction
Phosphodiesterase inhibition increased cyclic AMP in myocardial cell (same biochemical effect as β-1,-2 stimulation)

• Reduced preload and afterload
  Direct inhibition of smooth muscle arterial and venous>

Pharmacokinetics (humans)

• Only 10 to 40% of the dose excreted unchanged in urine
• 4 conjugated metabolites have been detected
• considerable potential for species differences

Toxicity aggravates outflow obstruction (contraindicated with aortic or pulmonic valvular disease, hypotension (1.5%), arrhythmia (3% - consider other risks here), thrombocytopenia (dose dependent - decreased platelet survival> nausea, vomiting, abdominal pain, anorexia (1%), hepatic toxicity (9 - 32 mg/kg/day in dogs - enzyme elevation, hepatic cell necrosis>, hypersensitivity

Clinical Uses

• intravenous infusion only
• only for emergency situations
• clinical experience is slight

Topic Summary (Positive Inotropes)

1. Cardiac glycosides are definitely indicated for control of tachycardia associated with congestive heart failure. The heart rate effects can be monitored (contractility effects cannot).

2. Cardiac glycoside therapy is inherently risky and difficult. You will produce some toxicity in some patients or you are not treating aggressively enough.

3. Digoxin dosage must be individualized for each patient.

4. Bioavailability of digoxin dose forms varies considerably (relative to the therapeutic index). Patient monitoring should be increased when a change is made.

5. Non-glycoside inotropes are available for emergency treatment. Some evidence exists to suggest that a short course of dobutamine may have lasting (weeks) effects on patient performance.

Antianginal agents

Angina pectoris is chest pain due to ischemia (a lack of blood and hence oxygen supply) of the heart muscle, generally due to obstruction or spasm of the coronary arteries (the heart's blood vessels). Coronary artery disease, the main cause of angina, is due to atherosclerosis of the cardiac arteries. The term derives from the Greek ankhon ("strangling") and the Latin pectus ("chest"), and can therefore be translated as "a strangling feeling in the chest".

An anginal pain attack signals a transient hypoxia of the myocardium. As a rule, the oxygen deficit results from inadequate myocardial blood flow due to narrowing of larger coronary arteries. The underlying causes are: most commonly, an atherosclerotic change of the vascular wall (coronary sclerosis with exertional angina); very infrequently, a spasmodic constriction of a morphologically healthy coronary artery (coronary spasm with angina at rest; variant angina); or more often, a coronary spasm occurring in an atherosclerotic vascular segment.

http://www.musc.edu/bmt737/spring2001/Kate/angina2.html

The goal of treatment is to prevent myocardial hypoxia either by raising blood flow (oxygen supply) or by lowering myocardial blood demand (oxygen demand) (A).

Factors determining oxygen supply. The force driving myocardial blood flow is the pressure difference between the coronary ostia (aortic pressure) and the opening of the coronary sinus (right atrial pressure). Blood flow is opposed by coronary flow resistance, which includes three components. (1) Due to their large caliber, the proximal coronary segments do not normally contribute significantly to flow resistance. However, in coronary sclerosis or spasm, pathological obstruction of flow occurs here. Whereas the more common coronary sclerosis cannot be overcome pharmacologically, the less common coronary spasm can be relieved by

appropriate vasodilators (nitrates, nifedipine). (2)

The caliber of arteriolar resistancevessels controls blood flow through the coronary bed. Arteriolar caliber is determined by myocardial O2 tension and local concentrations of metabolic products, and is “automatically” adjusted to the required blood flow (B, healthy subject). This metabolic autoregulation explains why anginal attacks in coronary sclerosis occur only during exercise (B, patient). At rest, the pathologically elevated flow resistance is compensated by a corresponding decrease in arteriolar resistance, ensuring adequate myocardial perfusion. During exercise, further dilation of arterioles is impossible. As a result, there is ischemia associated with pain. Pharmacological agents that act to dilate arterioles would thus be inappropriate because at rest they may divert blood from underperfused into healthy vascular regions on account of redundant arteriolar dilation. The resulting “steal effect” could provoke an anginal attack. (3) The intramyocardial pressure, i.e., systolic squeeze, compresses the capillary bed. Myocardial blood flow is halted during systole and occurs almost entirely during diastole. Diastolic wall tension (“preload”) depends on ventricular volume and filling pressure. The organic nitrates reduce preload by decreasing venous return to the heart.

Factors determining oxygen demand. The heart muscle cell consumes the most energy to generate contractile force. O2 demand rises with an increase in (1) heart rate, (2) contraction velocity, (3) systolic wall tension (“afterload”). The latter depends on ventricular volume and the systolic pressure needed to empty the ventricle. As peripheral resistance increases, aortic pressure rises, hence the resistance against which ventricular blood is ejected. O2 demand is lowered by в-blockers and Ca-antagonists, as well as by nitrates. It is common to equate severity of angina with risk of fatal cardiac events. There is a weak relationship between severity of pain and degree of oxygen deprivation in the heart muscle (i.e. there can be severe pain with little or no risk of a heart attack, and a heart attack can occur without pain). Worsening ("crescendo") angina attacks, sudden-onset angina at rest, and angina lasting more than 15 minutes are symptoms of unstable angina (usually grouped with similar conditions as the acute coronary syndrome). As these may herald myocardial infarction (a heart attack), they require urgent medical attention and are generally treated as a presumed heart attack.

Most patients with angina complain of chest discomfort rather than actual pain: the discomfort is usually described as a pressure, heaviness, tightness, squeezing, burning, or choking sensation. Apart from chest discomfort, anginal pains may also be experienced in the epigastrium (upper central abdomen), back, neck, jaw, or shoulders. Typical locations for radiation of pain are arms (often inner left arm), shoulders, and neck into the jaw. Angina is typically precipitated by exertion or emotional stress. It is exacerbated by having a full stomach and by cold temperatures. Pain may be accompanied by breathlessness, sweating and nausea in some cases. It usually lasts for about 1 to 5 minutes, and is relieved by rest or specific anti-angina medication. Chest pain lasting only a few seconds is normally not angina.

Myocardial ischemia comes about when the myocardia (the heart muscles) fail to take in sufficient blood and oxygen to function correctly. This inadequate perfusion of blood and the resulting reduced delivery of oxygen and nutrients, is directly correlated to blocked or narrowed blood vessels.

Some experience "autonomic symptoms" (related to increased activity of the autonomic nervous system) such as nausea, vomiting and pallor. Major risk factors for angina include cigarette smoking, diabetes, high cholesterol, high blood pressure and family history of premature heart disease. A variant form of angina (Prinzmetal's angina) occurs in patients with normal coronary arteries or insignificant atherosclerosis. It is thought to be caused by spasms of the artery. It occurs more in younger women. Increase in heart rate results in increased oxygen demand by the heart. The heart has a limited ability to increase its oxygen intake during episodes of increased demand. Therefore, an increase in oxygen demand by the heart (eg, during exercise) has to be met by a proportional increase in blood flow to the heart.

Myocardial ischemia can result from:

1. a reduction of blood flow to the heart caused by the stenosis or spasm of the heart's arteries

2. resistance of the blood vessels

3. reduced oxygen-carrying capacity of the blood.

Atherosclerosis is the most common cause of stenosis (narrowing of the blood vessels) of the heart's arteries and, hence, angina pectoris. Some people with chest pain have normal or minimal narrowing of heart arteries; in these patients, vasospasm is a more likely cause for the pain, sometimes in the context of Prinzmetal's angina and syndrome X.

Myocardial ischemia also can be the result of factors affecting blood composition, such as reduced oxygen-carrying capacity of blood, as seen with severe anemia (low number of red blood cells), or long-term smoking. Angina is more often the presenting symptom of coronary artery disease in women than in men. The prevalence of angina rises with an increase in age. Similar figures apply in the remainder of the Western world. All forms of coronary heart disease are much less-common in the Third World, as its risk factors are much more-common in Western and Westernized countries; it could therefore be termed a disease of affluence. The increase of smoking, obesity and other risk factors has already led to an increase in angina and related diseases in countries such as China.

Antianginal Drugs

Antianginal agents derive from three drug groups, the pharmacological properties of which have already been presented in more detail, viz., the organic nitrates, the Ca2+ antagonists, and the в-blockers.

Organic nitrates (A) increase blood flow, hence O2 supply, because diastolic wall tension (preload) declines as venous return to the heart is diminished. Thus, the nitrates enable myocardial flow resistance to be reduced even in the presence of coronary sclerosis with angina pectoris. In angina due to coronary spasm, arterial dilation overcomes the vasospasm and restores myocardial perfusion to normal. O2 demand falls because of the ensuing decrease in the two variables that determine systolic wall tension (afterload): ventricular filling volume and aortic blood pressure.

Nitroglycerin (NG), also known as nitroglycerine, trinitroglycerin, and glyceryl trinitrate, is a chemical compound. It is a heavy, colorless, oily, explosive liquid obtained by nitrating glycerol. It is used in the manufacture of explosives, specifically dynamite, and as such is employed in the construction and demolition industries, and as a plasticizer in some solid propellants. It is also used medically as a vasodilator to treat heart conditions.Nitroglycerin was discovered by chemist Ascanio Sobrero in 1847, working under TJ Pelouze at the University of Torino. The best manufacturing process was developed by Alfred Nobel in the 1860s. His company exported a liquid combination of nitroglycerin and gunpowder as 'Swedish Blasting Oil', but it was extremely dangerous as a result of its extreme instability, as shown in a number of "appalling catastrophes," such as the explosion that destroyed a Wells Fargo office in San Francisco in 1866. The liquid was widely banned, and this led to the development of dynamite (and similar mixtures such as dualine and lithofracteur), by mixing the nitroglycerine with inert (Nobel used kieselguhr) absorption (chemistry)|absorbents]] (e.g., nitrocellulose gel, blasting gelatine).

Nitroglycerin in medicine, where it is generally called glyceryl trinitrate, is used as a heart medication (under the trade names Nitrospan®, Nitrostat®, and Tridil®, amongst others). It is used as a medicine for angina pectoris (ischaemic heart disease) in tablets, ointment, solution for intravenous use, transdermal patches (Transderm Nitro®, Nitro-Dur®), or sprays administered sublingually (Nitrolingual Pump Spray®, Natispray®). The principal action of nitroglycerin is vasodilation — that is, widening of the blood vessels. The main effects of nitroglycerin in episodes of angina pectoris are:

• subsiding of chest pain
• decrease of blood pressure
• increase of heart rate.
• fainting or loss of consciousness (side effect that may occur upon change of posture)

These effects arise because nitroglycerin is converted to nitric oxide in the body (by a mechanism that is not completely understood), and nitric oxide is a vasodilatator).

Infrequent exposure to high doses of nitroglycerin can cause severe headaches known as NG head: these headaches can be severe enough to incapacitate some people; however, humans develop a tolerance and addiction to nitroglycerin after long-term exposure. Withdrawal can (rarely) be fatal; withdrawal symptoms include headaches and heart problems; with re-exposure to nitroglycerin, these symptoms may disappear. For workers in nitroglycerin manufacturing facilities, this can result in a "Monday Morning Headache" phenomenon for those who experience regular nitroglycerin exposure in the workplace; over the weekend they develop symptoms of withdrawal, which are then countered by reexposure on the next work day.

Isosorbite mononitrate

Mechanism of Action

The isosorbide mononitrate extended release tablets product is an oral extended-release formulation of isosorbide mononitrate, the major active metabolite of isosorbide dinitrate; most of the clinical activity of the dinitrate is attributable to the mononitrate. The principal pharmacological action of isosorbide mononitrate and all organic nitrates in general is relaxation of vascular smooth muscle, producing dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood, decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, and systolic arterial pressure and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Isosorbide mononitrate is the major active metabolite of isosorbide dinitrate, and most of the clinical activity of the dinitrate is attributable to the mononitrate.

Pharmacodynamics

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored.

Immediate Release Tablets

The drug-free interval sufficient to avoid tolerance to isosorbide mononitrate has not been completely defined. In the only regimen of twice-daily isosorbide mononitrate that has been shown to avoid development of tolerance, the two doses of isosorbide mononitrate tablets are given 7 hours apart, so there is a gap of 17 hours between the second dose of each day and the first dose of the next day. Taking account of the relatively long half-life of isosorbide mononitrate this result is consistent with those obtained for other organic nitrates.

The same twice-daily regimen of isosorbide mononitrate tablets successfully avoided significant rebound/withdrawal effects. The incidence and magnitude of such phenomena have appeared, in studies of other nitrates, to be highly dependent upon the schedule of nitrate administration.

Extended Release Tablets

The isosorbide mononitrate extended release tablets during long-term use over 42 days dosed at 120 mg once daily continued to improve exercise performance at 4 hours and at 12 hours after dosing but its effects (although better than placebo) are less than or at best equal to the effects of the first dose of 60 mg.

Pharmacokinetics

Immediate Release Tablets

In humans, isosorbide mononitrate is not subject to first pass metabolism in the liver. The absolute bioavailability of isosorbide mononitrate from isosorbide mononitrate tablets is nearly 100%. Maximum serum concentrations of isosorbide mononitrate are achieved 30 to 60 minutes after ingestion of isosorbide mononitrate.

The volume of distribution of isosorbide mononitrate is approximately 0.6 L/Kg, and less than 4% is bound to plasma proteins. It is cleared from the serum by denitration to isosorbide; glucuronidation to the mononitrate glucuronide; and denitration/hydration to sorbitol. None of these metabolites is vasoactive. Less than 1% of administered isosorbide mononitrate is eliminated in the urine.

The overall elimination half-life of isosorbide mononitrate is about 5 hours; the rate of clearance is the same in healthy young adults, in patients with various degrees of renal, hepatic, or cardiac dysfunction, and in the elderly. In a single-dose study, the pharmacokinetics of isosorbide mononitrate were dose-proportional up to at least 60 mg.

Nitroglycerine Tolerance

• can be avoided in most patients if there is a nitrate- free interval of 10-12 hours per day.
• may be the result of depletion of intracellular suphydryl groups which prevents further nitrate metabolism and nitric oxide release.
• reversed within 18 hours of stopping nitrates.
• if tolerance is supected in the case of modified isosorbide dinitrate (and conventional preparations of isosorbide mononitrate) then the second of two daily doses can be given after about 8 hours rather than after 12 hours.
• there is no relationship to tolerance to adverse and therapeutic effects.
• toleance may develop in less than 48 hours after the initiation of treatment with nitrates.

Calcium antagonists (B) decrease O2 demand by lowering aortic pressure, one of the components contributing to afterload. The dihydropyridine nifedipine is devoid of a cardiodepressant effect, but may give rise to reflex tachycardia and an associated increase in O2 demand. The catamphiphilic drugs verapamil and diltiazem are cardiodepressant. Reduced beat frequency and contractility contribute to a reduction in O2 demand; however, AV-block and mechanical insufficiency can dangerously jeopardize heart function. In coronary spasm, calcium antagonists can induce spasmolysis and improve blood flow.

CCBs exert their clinical effects by blocking the L-class of voltage gated calcium channels. By blocking transmembrane entry of calcium into arteriolar smooth muscle cells and cardiac myocytes, CCBs inhibit the excitation-contraction process. CCBs are a heterogeneous group of drugs. Dihydropyridines are primarily potent vasodilators of peripheral and coronary arteries. Non-dihydropiridines Verapamil and Diltiazem are moderate vasodilators with significant cardiac effects

Adverse effects: Most common side effect of CCBs is ankle edema. This is caused by vasodilatation, which also causes headache, flushing and palpitation, especially with short-acting dihydropyridines. Some of these side effects can be offset by combining a calcium channel blocker with a beta blocker. Verapamil and Diltiazem cause constipation. More seriously, they can cause heart block, especially in those with underlying conduction problems. Verapamil, diltiazem and short-acting dihydropyridines should be avoided in patients with heart failure.

Amlodipine

Amlodipine (prolong acting) is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which amlodipine relieves angina have not been fully delineated, but are thought to include the following:

Exertional Angina: In patients with exertional angina, Amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina: Amlodipine has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A₂ analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of NORVASC in vasospastic (Prinzmetal’s or variant) angina.

в-Blockers (C) protect the heart against the O2-wasting effect of sympathetic drive by inhibiting в-receptormediated increases in cardiac rate and speed of contraction.

Beta-blockers act by blocking the action of catecholamines at adrenergic receptors throughout the circulatory system and other organs. BBs major effect is to slow the heart rate and reduce force of contraction. BBs via inhibition of receptors at justaglomerular cells inhibit renin release.

Beta-blockers may be classified based on their ancillary pharmacological properties. Cardioselective agents have high affinity for cardiac β _ and less affinity for bronchial and vascular β₂ receptors compared with non-selective agents and this reduces (but does not abolish) β ₂ receptor-mediated side effects. However, with increasing doses cardiac selectivity disappears. Lipid-soluble agents cross the blood-brain barrier more readily and are associated with a higher incidence of central side effects. Some beta-blockers have intrinsic sympathomimetic activity – ISA (i.e., they stimulate β receptors when background sympathetic nervous activity is low and block them when background sympathetic nervous activity is high). Adverse effects: BBs slow the rate of conduction at the atrio-ventricular node and are contraindicated in patients with second- and third-degree heart block. Sinus bradycardia is common and treatment should be stopped if patient is symptomatic or heart rate falls below 40 b/min. Because of blockade of pulmonary ß₂ receptors, even small doses of BBs can cause bronchospasm (less common with cardioselective agents), and all beta-blockers are contraindicated in asthma. Blockade of ß receptors in the peripheral circulation causes vasoconstriction and may induce particularly in patients with peripheral circulatory insufficiency adverse affects such as cold extremities, Raynaud’s phenomenon, and intermittent claudication. Nevertheless, they are reasonably tolerated in patient with mild peripheral vascular disease. Lipid-soluble agents can cause central nervous system side effects of insomnia, nightmares and fatigue. Exercise capacity may be reduced by BBs and patients may experience tiredness and fatigue. BBs can worsen glucose intolerance and hyperlipidemia and in diabetic patients mask signs of hypoglycemia. However, diabetic hypertensive patients with previous MI should not be denied BB because of concerns about metabolic side effects.

Uses of antianginal drugs (D). For relief of the acute anginal attack, rapidly absorbed drugs devoid of cardiodepressant activity are preferred. The drug of choice is nitroglycerin (NTG, 0.8–2.4 mg sublingually; onset of action within 1 to 2 min; duration of effect ~30 min). Isosorbide dinitrate (ISDN) can also be used (5–10 mg sublingually); compared with NTG, its action is somewhat delayed in onset but of longer duration. Finally, nifedipine may be useful in chronic stable, or in variant angina (5–20 mg, capsule to be bitten and the contents swallowed).

For sustained daytime angina prophylaxis, nitrates are of limited value because “nitrate pauses” of about 12 h are appropriate if nitrate tolerance is to be avoided. If attacks occur during the day, ISDN, or its metabolite isosorbide mononitrate, may be given in the morning and at noon (e.g., ISDN 40 mg in extended- release capsules). Because of hepatic presystemic elimination, NTG is not suitable for oral administration. Continuous delivery via a transdermal patch would also not seem advisable because of the potential development of tolerance. With molsidomine, there is less risk of a nitrate tolerance; however, due to its potential carcinogenicity, its clinical use is restricted. The choice between calcium antagonists must take into account the differential effect of nifedipine versus verapamil or diltiazem on cardiac performance. When в-blockers are given, the potential consequences of reducing cardiac contractility (withdrawal of sympathetic drive) must be kept in mind. Since vasodilating в2-receptors are blocked, an increased risk of vasospasm cannot be ruled out. Therefore, monotherapy with в-blockers is recommended only in angina due to coronary sclerosis, but not in variant angina.

Acute Myocardial Infarction

Myocardial infarction is caused by acute thrombotic occlusion of a coronary artery (A).

Therapeutic interventions aim to restore blood flow in the occluded vessel in order to reduce infarct size or to rescue ischemic myocardial tissue. In the area perfused by the affected vessel, inadequate supply of oxygen and glucose impairs the function of heart muscle: contractile force declines. In the great majority of cases, the left ventricle anterior or posterior wall) is involved. The decreased work capacity of the infarcted myocardium leads to a reduction in stroke volume (SV) and hence cardiac output (CO). The fall in blood pressure (RR) triggers reflex activation of the sympathetic system. The resultant stimulation of cardiac β-adrenoceptors elicits an increase in both heart rate and force of systolic contraction, which, in conjunction with an β-adrenoceptor- mediated increase in peripheral resistance, leads to a compensatory rise in blood pressure. In ATP-depleted cells in the infarct border zone, resting membrane potential declines with a concomitant increase in excitability that may be further exacerbated by activation of β-adrenoceptors. Together, both processes promote the risk of fatal ventricular arrhythmias. As a consequence of local ischemia, extracellular concentrations of H+ and K+ rise in the affected region, leading to excitation of nociceptive nerve fibers. The resultant sensation of pain, typically experienced by the patient as annihilating, reinforces sympathetic activation. The success of infarct therapy critically depends on the length of time between the onset of the attack and the start of treatment. Whereas some theraputic measures are indicated only after the diagnosis is confirmed, others necessitate prior exclusion of contraindications or can be instituted only in specially equipped facilities. Without exception, however, prompt action is imperative. Thus, a staggered treatment schedule has proven useful. The antiplatelet agent, ASA, is administered at the first suspected signs of infarction. Pain due to ischemia is treated predominantly with antianginal drugs (e.g., nitrates).

In case this treatment fails (no effect within 30 min, administration of morphine, if needed in combination with an antiemetic to prevent morphine-induced vomiting, is indicated. ECG If ECG signs of myocardial infarction are absent, the patient is stabilized by antianginal therapy (nitrates, β- blockers) and given ASA and heparin. When the diagnosis has been confirmed by electrocardiography, attempts are started to dissolve the thrombus pharmacologically (thrombolytic therapy: alteplase or streptokinase) or to remove the obstruction by mechanical means (balloon dilation or angioplasty). Heparin is given to prevent a possible vascular reocclusion, i.e., to safeguard the patency of the affected vessel. Regardless of the outcome of thrombolytic therapy or balloon dilation, a β-blocker is administered to suppress imminent arrhythmias, unless it is contraindicated.

Treatment of lifethreatening ventricular arrhythmias calls for an antiarrhythmic of the class of Na+-channel blockers, e.g., lidocaine.

To improve long-term prognosis, use is made of a β-blocker ( incidence of reinfarction and acute cardiac mortality) and an ACE inhibitor (prevention of ventricular enlargement after myocardial infarction) (A).

Antiarrhythmic agents

The past two decades have witnessed a rapid growth in understanding of the cellular and molecular basis of both normal and pathological electrophysiology. Elucidation of cardiac ion channel structure and function has contributed to many of these advances. As a result, we may be on the verge of an era where arrhythmia management will no longer be dominated by trial and error based observational treatment. Our aim in this article is to provide an overview of antiarrhythmic drug action, linking known actions at the level of cellular electrophysiology to clinical use. Taking particular examples, we shall also illustrate how molecular genetic advances have shown that some rhythm disturbances can result from specific defects in genes encoding cardiac ion channels. Making reference to investigational drugs under study, we will also consider the issue of whether advances in the understanding of cardiac cellular electrophysiology may improve rational approaches to antiarrhythmic drug design and treatment.

Lipitor Patient Information

http://heart.health.ivillage.com/arrhythmia/arrhythmia.cfm

The mechanism of drug action is central to the process of choosing a drug to treat any particular arrhythmia. Thus it is useful to consider first impulse generation at the cellular level. This in turn demands consideration of the ion channels underpinning impulse generation in different cardiac muscle cell types. It is the opening and closing of a range of different ion channels that leads to the distinct profiles of membrane potential which comprise cardiac action potentials. Therefore, we shall initially consider the electrophysiological characteristics of cardiac action potentials, aspects of ion channel function, and ion channels as sites of antiarrhythmic drug action.

Membrane and action potentials: conventions shows schematic representations of action potentials from pacemaker, ventricular, and atrial tissues. Whereas the membrane potential in pacemaker cells (typically from the sinus node, as this is usually the dominant pacemaker) constantly cycles , cells (myocytes) from ventricular and atrial tissue ( possess true resting potentials, which usually lie between 70 and 80 mV.

The negative value of the resting potential reflects the dominant effect of a steady net efflux of positively charged K⁺ ions in these cell types by way of an ionic current (I_K1), through a channel type called the inward rectifier.¹ Pacemaker cells from sinoatrial² and atrioventricular nodes³ appear to lack a significant I_K1, and as a resultalong with other ionic currentsthey do not show a true resting membrane potential; rather, a pacemaker potential precedes each action potential. Action potentials in all cell types result from positive shifts in membrane potential (depolarisation), caused by opening of ion channels, allowing positively charged sodium and calcium ions to enter the cell through channels selective for each ionic type. The rate of depolarisation during the action potential upstroke in atrial and ventricular cells is faster than in pacemaker cells, owing to the fact that a large and fast sodium current underlies the upstroke in these cell types, while the upstroke in pacemaker cells is predominantly carried by a calcium current.

After the peak of the action potential, the membrane potential is restored to its original value during the repolarisation phase, as channels passing depolarising current close and repolarising channels (largely a range of potassium channels) open. Ventricular cells in particular also possess a distinct plateau phase, and the relatively long duration of the ventricular action potential helps make the ventricular tissue refractory to overexcitation which might otherwise tetanise the ventricular myocardium. The distinct action potential phases discussed above are sometimes referred to as phases 0 to 4: phase 0 is the action potential upstroke, phase 1 is the early repolarisation "notch" (evident immediately after the ventricular action potential peak , phases 2 and 3 describe plateau and late repolarisation (pacemaker cell action potentials without a distinct notch or plateau may lack distinct phases 1 and 2), while phase 4 is the period after repolarisation is complete (the resting level in non-pacemaker cells, and the pacemaker depolarisation in pacemaker cells).

Ion channels: the basics Critical to action potential generation is the combined function of different membrane bound ion channels, together with ion exchange proteins and ATP driven pumps. ATPases for Na/K⁴ and Ca⁵ help sustain the normal transmembrane gradients for these ions, and a sodium-calcium exchange protein contributes to calcium and sodium homeostasis and membrane potential generation (for example, Allen and colleagues,⁶ Janvier and Boyett⁷).

To understand modifications of ionic currents by antiarrhythmic drugs, some basic properties of ion channel function need to be examined. In simple terms, transmembrane ion channels activated by membrane potential changes can be viewed as proteins comprising a voltage sensor coupled to a pore through which ions flow; the pore incorporates a "selectivity filter" which determines which types of ions will pass through the open pore.

FLOW OF IONIC CURRENT IN RELATION TO "EQUILIBRIUM POTENTIAL"
The direction of ion flow (and therefore of electrical current generation) is determined by the transmembrane concentration gradient established by the concentrations C_o outside and C_i inside the cell of the permeant ion, together with the electrical gradient resulting from the membrane potential.

For a particular ionic species and given values of C_o and C_i, there will be one membrane potential value), at which there is no net driving force for ions to flow across the membrane. For example, for sodium ions E_Na lies near +70 mV; at potentials negative to this, sodium ions will flow down their concentration gradient (from outside to inside the cell) and generate a depolarising or inward current Beyond E_Na (a situation encountered experimentally, but not physiologically), sodium ions would flow in the opposite direction Conversely, for potassium ions, E_K lies near -90 mV, and at potentials positive to this potassium ions will flow down their concentration gradient (from inside to outside the cell) and generate repolarising or outward current .

If the inside of the cell is made more negative than E_K the direction of ion flow will be reversed With a knowledge of the normal intracellular and extracellular ion concentrations, it is possible to predict the contributions of sodium, calcium, and potassium channels in generating membrane potential depolarisation or repolarisation.

One further aspect of ion channel function should be covered before considering the roles played by individual ion channel typeschannel gating. Voltage operated channels are usually referred to as voltage gated, as biophysical measurements indicate that specific membrane potential regulated processes determine the magnitude and time course of ionic current flow across the range of ion channel types. This can be explained by considering an ion channel that does not pass current until a depolarising stimulus is applied. At rest, the channel is therefore considered to be closed. When a depolarising stimulus is applied, the membrane potential change is detected by the voltage sensorthe channel undergoes a conformational change and opens in order to allow ionic current to flow.

The process describing the transition from the closed to open state is termed activation. The probability of channels moving to the open state usually depends on the magnitude of the voltage change (activation is therefore "voltage dependent"), and the speed with which channels move from the closed to the open state will determine the rate of activation. Some voltage dependent channels show only a voltage dependent activation process, but for many a second process also influences ionic current flow. If the depolarising stimulus is maintained, a second conformational change occurs in the ion channel. Part of the ion channel protein moves to occlude the channel pore such that, while the channel may be fully activated, it becomes poorly conducting. This process, which, like activation, is voltage and time dependent, is termed inactivation. Experimentally, the properties of channel activation, inactivation, voltage sensitivity, and ionic selectivity can be studied using voltage or patch clamp techniques. The important points here are as follows:

• Distinct ion channel types generate depolarising and repolarising currents during the action potential.
• From the existence of distinct ion channels with distinct roles arises the potential for drug classification and design.
• The fact that ion channels undergo voltage dependent state transitions means that, theoretically, drugs could bind to resting/closed (C), activated/open (O) or inactivated (I) states.⁸

Drugs which bind preferentially to open or inactivated channel states may exert effects that vary with stimulation frequency (or in vivo, with heart rate) and as such can show use dependence. For antiarrhythmic agents, an ideal channel blocking agent would have positive use dependenceshowing a greater inhibitory action at faster heart rates. Drugs binding preferentially to closed channels may either exert use independent actions or show "reverse use dependence," in which the drug dissociates from its binding site during channel activation. With reverse use dependent blockade, faster rates of channel stimulation (or indeed heart rate) encourage greater dissociation than slower rates, resulting in comparatively less channel inhibition at faster than at slower rates.

CHANNELS INVOLVED IN PACEMAKING

In the sinus node, the T type calcium current (I_Ca,T) and the hyperpolarisation activated current (I_f) both provide inward, depolarising current during the pacemaker depolarisation² that precedes each action potential upstroke (fig 1A). Agents that reduce these currents should therefore slow the rate of the pacemaker depolarisation and thereby have a negative chronotropic effect. Specific inhibitors of I_f produce rate reduction.^{9 10} Mibefradil is a blocker of I_Ca,T which preferentially relaxes coronary vasculature and slows heart rate without reducing contractility,¹¹ making it a potential bradycardic agent. This particular compound was voluntarily withdrawn because it was involved in several clinically relevant drug interactions.¹² In general, the use of selective bradycardic agents is likely to be of limited value except in inappropriate sinus tachycardia.

CHANNELS INVOLVED IN ACTION POTENTIAL DEPOLARISATION

L type calcium and sodium channels are of greater importance as antiarrhythmic targets. I_Ca,L appears to be the dominant depolarising current during action potentials from the sinoatrial² and atrioventricular (AV) nodes.^{3 13} The dependence of AV nodal conduction on I_Ca,L makes L type channel blockers such as verapamil and diltiazem important in the management of supraventricular tachycardias. In paroxysmal atrioventricular tachycardias, either anterograde or retrograde conduction through the AV node forms part of the circuit maintaining the arrhythmia; thus blockade of I_Ca,L can be effective in preventing recurrence ofthe arrhythmia.^14-16. L type channel blockers can also be effective against AV nodal reentrant tachycardias¹⁴ and atrial fibrillation.¹⁷

The importance of I_Na in generating the fast upstroke phase of both atrial and ventricular action potentials makes I_Na blockers potentially effective against both supraventricular and ventricular arrhythmias. Sodium channel-drug interactions are usefully considered within the "modulated receptor" model, which takes into consideration the channel state to which a drug preferentially binds.^{8 18} The action potential upstroke rate can become slowed when I_Na is reduced and as a result I_Na blockers can decrease impulse conduction velocity. In addition, agents that delay the recovery of I_Na from channel inactivation have the effect of prolonging tissue refractoriness.

Agents such as quinidine,¹⁹ propafenone,²⁰ and disopyramide²¹ preferentially bind to the open (activated) state of the sodium channel, while others including lignocaine (lidocaine)²² and mexiletine²³ show a preference for the inactivated channel. Open channel blockers are effective in generally reducing electrical excitability and impulse conduction, while inactivated channel blockers may show a blocking effect influenced by differences in atrial and ventricular action potential profile (fig 1). The comparatively longer and more depolarised ventricular action potential plateau results in a more prolonged inactivation of I_Na, with an increased level of block. This property may contribute to the selectivity of drugs such as mexiletine against ventricular arrhythmias; it might also be used in combination treatment by combining an inactivated state sodium channel blocker with a drug that delays repolarisation,²⁴ resulting in enhanced sodium channel inhibition and thereby prolonged refractoriness.

The kinetics of recovery from block are also critically important in determining the effects of sodium channel blockers. Agents associated with slow recovery from block (for example, flecainide²⁵) cause a block that accumulates rapidly on repetitive stimulation, and a stable steady state level of block is attained over a wide range of heart rates.²⁶ Agents with relatively fast recovery from block (for example, mexiletine) may show little cumulative block at slow heart rates, as block is relieved between action potentials.

At faster rates (tachycardias), block accumulates because there is too little time for unbinding to occur between action potentials. This produces the effect of "positive use dependence," which is beneficial in that little ECG alteration may be experienced at normal rates, whereas drug effects become important during tachyarrhythmias.

It is important to realise, however, that blocking efficiency and recovery can be affected by various factors. Open channel blockers may be less effective in damaged or ischaemic tissue; this is often depolarised, resulting in the inactivation of a proportion of channels, thereby rendering these unavailable for block. In contrast, inactivated state blockers may be more effective in conditions where tissue becomes depolarisedexperimental evidence suggests that the efficacy of lignocaine and the risk of proarrhythmia are both enhanced in acutely ischaemic myocardium.²⁷ In addition to the effects of membrane potential depolarisation on block, the low pH associated with ischaemia can also slow the time constant of drug dissociation, enhancing the cumulative level of channel block.²⁶

POTASSIUM CHANNELS

Some sodium channel blocking agents, for example disopyramide²⁸ and in particular quinidine,²⁹ are also associated with delayed repolarisation and QT prolongation on the ECG. For both disopyramide³⁰ and quinidine,^{31 32} this effect results from potassium channel blocking actions of the drug. Excessive action potential and QT prolongation (when the corrected QT interval (QT_c) exceeds ~440²⁹ to 460³³ ms), carries a risk of proarrhythmia. However, potassium channel blockade can also be antiarrhythmic, because moderately delayed action potential repolarisation can enhance the inactivation of depolarising currents (I_Na and I_Ca), thereby prolonging the period between successive action potentials. This can be effective in disrupting arrhythmias caused by reentrant mechanisms. Different potassium channel types, therefore, offer potential antiarrhythmic drug targets. Major potassium ion channel types involved in action potential repolarisation include the transient outward current, I_TO, responsible for the action potential notch in ventricular cells and prominent during atrial repolarisation.^{1 34} The rapid and slow components of delayed rectifier current (I_Kr and I_Ks, respectively³⁵) are important in plateau repolarisation.^{36 37} The inward rectifier potassium current is important for the final stage of repolarisation^{37 38} and for maintaining the cell resting potential. Owing to their roles in plateau repolarisation, I_Kr and I_Ks are of particular interest as antiarrhythmic targets.

As in the case of sodium channel blocking agents, the desirable potassium channel blocker is one that shows positive use dependence (that is, the drug effects are greatest at faster action potential rates). Unfortunately, many potassium channel blocking drugs appear to be associated with a reverse use dependent effect: action potential prolongation is greater at slower rather than at faster rates.³⁹ The problem with this is that action potential prolongation at slow rates can be proarrhythmic through the cellular mechanism of early afterdepolarisations. By a mechanism originally investigated by January and Riddle⁴⁰ and recently reviewed by Makielski and January,⁴¹ sufficiently slowed membrane repolarisation during the action potential facilitates calcium entry through L type calcium channels, which can result in early afterdepolarisations. These in turn could give rise to triggered activity and lead to torsade de pointes. Selective block of I_Kr (for example, by the drug E-4031) can be sufficient to induce early afterdepolarisations.⁴² Early afterdepolarisations are relieved at faster rates; therefore I_Kr block is most likely to be proarrhythmic at slow rates. The clinical implications of reverse use dependence and specific I_Kr block are exemplified by sotalol which, as the racemic D-L mix, possesses  blocking and I_K blocking actions and is indicated for the treatment of life threatening ventricular tachycardia. Racemic sotalol produces some QT prolongation and is bradycardic.⁴³ D-sotalol lacks the  blocking activity of the racemic mix, but is an I_Kr blocker³⁵ and shows reverse use dependent effects on the action potential.⁴⁴ Significantly, D-sotalol is associated with an increased risk of death from presumed arrhythmias.⁴⁵

A simple explanation for reverse use dependent drug effects on action potential prolongation involves drug binding to the resting channel (in the interval between action potentials) and dissociating during membrane depolarisation.⁴⁶ This would produce a greater relief of block at faster rates (at which there would be shorter intervals between action potentials for drug binding to occur). However, subsequent experiments on cloned channels are not consistent with this explanation (for example, Synders and colleagues⁴⁷). Moreover, agents such as almokalant block I_Kr in a use dependent fashion,⁴⁸ while producing reverse use dependent action potential prolongation.²⁴ In addition, dofetilide has been reported to produce rate independent effects on I_Kr, but reverse rate dependent effects on the action potential.⁴⁹ In the same study,⁴⁹ repetitive stimulation was observed to increase the magnitude of I_Ks but not of I_Kr. It has been proposed, therefore, that reverse use dependence may result from the interaction between I_Kr and I_Ks during repolarisation at different heart rates.⁴⁹ At slower rates I_Kr may be dominant; at faster heart rates the role of I_Ks increases owing to incomplete deactivation (the transition of channels from OC, fig 3A) of the current between action potentials. Thus specific I_Kr inhibition would have a greater effect on repolarisation at slower than at faster rates.

If this mechanism holds, then an agent which blocks I_Ks specifically might be better for treating tachycardias than an I_Kr blocker; moreover, an agent that blocks both components of I_K might have an improved safety profile over a specific I_Kr blocker. There are few experimental data yet available to support the first of these possibilities (selective I_Ks blockers are only beginning to appear); the second, however, does seem to hold true. Quinidine and sotalol do not appear to block I_Ks.⁵⁰ By contrast amiodarone, which has a much better cardiac safety profile, blocks both I_Kr and I_Ks,^{50 51} while also showing a more consistent effect on action potentials at different rates.⁵²

Side effects of amiodaron

A further potassium channel should be mentioned, as it is likely to mediate the antiarrhythmic actions of adenosine. The extremely short half life of adenosine makes intravenous administration valuable in terminating tachycardias involving the AV node (either AV nodal re-entry or AV re-entry). In bolus form, adenosine has been shown to be highly effective against paroxysmal supraventricular tachycardias that require AV nodal conduction for their maintenance.^{53 54} The cellular basis for the effect of adenosine appears to resemble that for acetylcholine. Acetylcholine activates a potassium current (I_KACh), which is important in mediating parasympathetic effects on the sinoatrial² and AV nodes.⁵⁵ When activated, I_KACh produces membrane potential hyperpolarisation; it thereby decreases automaticity and excitability. At the cellular level, adenosine activates a current (I_KAdo) with properties identical to those of I_KACh (for example, Belardinelli and colleagues⁵⁶). Cellular studies on rabbit AV node suggest that activation of I_KAdo is likely to be predominantly responsible for the action of adenosine, with possible supplementary effects on L type calcium channels.^{57 58}

Amiodaron Thyroiditis

Molecular insights into arrhythmogenesis Some of the most exciting cardiological developments of the last decade relate to advances in understanding the molecular biology underlying ion channel function, and the finding that defects in individual ion channels can underlie particular arrhythmias. This is no better exemplified than in congenital long QT syndrome. This syndrome illustrates how various different channelopathies can manifest themselves clinically as virtually identical electrocardiographic endpoints. Congenital long QT syndrome is characterised by abnormally prolonged ventricular repolarisation leading to QT_C prolongation (as discussed earlier), with an associated risk of malignant ventricular tachyarrhythmias (torsade de pointes).

Congenital long QT syndrome has been found to arise from a range of different genetic abnormalities^{33 59-67} (table 1). The two main forms are the autosomal dominant Romano-Ward syndrome (pure cardiac phenotype)⁶⁸ and the autosomal recessive Jervell-Lange-Nielsen syndrome (in which cardiac abnormalities coexist with congenital deafness).⁶⁹ Of the genetic abnormalities identified in the Romano-Ward syndrome, four are associated with identified ion channels. Most of the mutations causing congenital long QT (LQT) syndrome are missense mutations. However, substantial phenotypic heterogeneity remains, even with identical gene abnormalities. LQT1, 2, and 3 all result in prolongation of the action potential. The extent of prolongation depends not only upon the gene mutated, but also upon the exact location of the mutation.^{33 70} As discussed earlier, it is the risk of afterdepolarisations associated with QT interval prolongationrather than slowing of action potential repolarisation on its ownthat is arrhythmogenic. The involvement of L type I_Ca in the production of early afterdepolarisations and the widely known enhancement of I_Ca by  adrenergic stimulation may, at least in part, explain the clinical effectiveness of blockers in reducing the incidence of syncopal episodes and arrhythmias in the long QT syndrome.^{33 70}

As shown in table 1, alterations in the genes underlying I_Kr and I_Ks are associated with LQT-2 and LQT-1. The channels for both I_Kr and I_Ks are multimeric,³⁶ and alleles from both parents contribute to the channel complexes. Mutant channels expressed in oocytes or cell lines show loss of function.⁶¹ Channel kinetics, as well as reduced overall current, contribute to the loss of function (that is, a reduction in repolarising outward current). In contrast, mutations of sodium (SCN5A) channels cause a gain of function,^{71 72} in which a late persistent (depolarising) sodium current is produced because of defective inactivation of I_Na. Owing to the heterogeneous basis for congenital long QT syndrome, identification of the underlying cause is pivotal in deciding upon appropriate treatment. Provocation may distinguish between the different congenital LQT syndromes. While the QT interval shortens only minimally with exercise in LQT1 and LQT2, in patients with LQT3 it shortens significantly.^{70 73} Furthermore, torsade de pointes is precipitated by adrenergic stimulation (for example, during exercise) in LQT1, possibly because I_Ks normally predominates at high rates, and therefore reduced I_Ks would lead to inadequate shortening of the action potential.⁷⁰ In contrast, most patients with LQT 3 experience more events at rest than on exertion.^{70 73}

Another interesting group of patients providing a clear link between cellular abnormalities and clinical treatment are those with the Brugada syndrome.^{74 75} These patients have structurally normal hearts and right precordial ST segment elevation or right bundle branch block.⁷⁶ The ECG abnormalities probably reflect exaggerated transmural differences in action potential configuration, especially within the right ventricular outflow tract. The end result is an increased risk of ventricular fibrillation within these families. One variant of the Brugada syndrome arises from a mutation of the SCN5A gene (the same gene that is implicated in LQT3),⁷⁷ leading to a gain of function; hence drugs targeting the sodium channel may be clinically effective.

IMPLICATIONS OF GENETIC INSIGHTS?

In addition to the syndromes described above, our understanding of the role of genes in other conditions has also increased. The reader is referred to a recent and comprehensive review by Priori and colleagues.⁷⁰. A clear result of the arrival of molecular biology in the clinical arena is that genetic testing may be available not only for diagnostic purposes in patients presenting with arrhythmias but also possibly for individuals who could benefit from prophylactic treatment to avoid sudden death. Increased genetic knowledge may also influence treatment strategy. For example, sodium channel blockers such as lignocaine and mexiletine may be effective in LQT-3,^{71 72} while LQT-2 would be expected to be respond to a different approach. Cloned channels encoded by HERG (the gene underlying channels for I_Kr) show currents that increase in size as external potassium concentration ([K]_e) is raised and decrease as [K]_e is lowered.⁶⁰ Consistent with this experimental observation, Compton and colleagues⁷⁸ have shown that abnormal repolarisation in patients with LQT-2 can be corrected by raising serum potassium.⁷⁸

However, while long QT syndrome and the Brugada syndrome may provide a clear route from cell to clinic, some common arrhythmias are not yet so accommodating. Refractory arrhythmias, for example, may be refractory because of the complex processes involved in their pathogenesis. These may include both electrical and structural remodelling. Electrical remodelling may be physiological and unrelated to cardiac disease (for example, atrial fibrillation may become self sustaining⁷⁹), or pathological in origin (alteration in the distribution of gap junctions between cells in diseased tissue⁸⁰). Structural remodelling may also be either physiological (for example, initial ventricular hypertrophy in response to hypertension) or pathological (cell hypertrophy in peri-infarct zones and cell loss with replacement fibrosis within infarcted regions⁸¹). Therefore complex arrhythmias with a multifactorial aetiology may benefit from primary prevention targeted towards alleviation of diseases such as coronary occlusion or ventricular hypertrophy. A second line of attack may then be directed towards the electrophysiological sequelae of upstream events. Treatment must be tailored towards the aetiology of the arrhythmia, as drug treatment for ventricular tachycardia in one patient may be detrimental in another. Indeed, in the structurally abnormal heartfor example, after myocardial infarction or during congestive cardiac failuredrug efficacy has been limited and in these conditions antiarrhythmic drugs can have a significant proarrhythmic potential.^82-84

Re-evaluation of antiarrhythmic drug classification Another area that has experienced change owing to the increased information available from cellular cardiology is that of drug classification. Early approaches to antiarrhythmic drug development involved the identification of natural compounds with antiarrhythmic activity such as cinchona,⁸⁵ or identification of antiarrhythmic effects of drugs licensed for other uses, primarily local anaesthetics, including lignocaine and its derivatives. Clinical studies verified the acceptability as antiarrhythmic agents of synthetic molecules such as procainamide.⁸⁶ Further attempts were than made to produce related compounds with increased potency and reduced toxicity (for example, flecainide, lorcainide, and encainide^{82 87}). While this approach has provided many useful drugs for therapeutic use, the derived compounds have to varying degrees retained the adverse effect profiles of parent drugs. Progress in the development of newer antiarrhythmic drugs has not been as great as once anticipated, and the chance discovery of antiarrhythmic properties of drugs developed for other conditionsfor example, amiodarone (initially developed as an antianginal drug)has contributed significantly to the armoury available to the clinician.

In 1970, Vaughan Williams proposed a classification based on possible ways in which abnormal cardiac rhythms could be corrected or prevented.^{88 89} In this early classification, class I drugs act by reducing inward sodium current at concentrations not affecting the resting membrane potential. Class II drugs act by blocking sympathetic activity of the heart. Although not thought to affect the action potential of most myocardial cells, these drugs reduce the spontaneous rate of depolarisation of pacemaker cells under adrenergic stimulation and are therefore negatively chronotropic. They are also negatively dromotropic, as the AV node tends to be under greater sympathetic drive than the sinoatrial node for which vagal tone normally predominates. Class III drugs prolong action potential duration. They do not specifically affect any single factor involved in repolarisation (although in reality most class III drugs exert potassium channel blocking actions). They are able to alter the activity of several different ion channel conductances at a cellular level, making their impact upon the action potential quite complex. In general, they prolong action potential duration and hence prolong the length of the refractory period. In a separate class was placed diphenylhydantoin, a centrally acting drug.

In 1974, Singh and Hauswirth modified the classification, with two major changes.⁹⁰ First, lignocaine and diphenylhydantoin were placed in a separate class, because at low concentrations and at low external potassium concentrations, they had little effect upon the action potential or cardiac conduction. Secondly, a separate class (now denoted class IV) was introduced to accommodate calcium channel blockers, which (as described earlier) predominantly affect regions in which action potential depolarisation depends on I_Ca,L. In a further development, class I drugs were subclassified by Harrison⁹¹ according to their effect upon action potential upstroke and duration. Additional studies^{87 92 93} showed that the subclassification separated class I drugs according to the rate of recovery of I_Na channels from blockade. Class 1a drugs were intermediate between class Ib drugs, with fast recovery time constants less than one second, and class Ic drugs, with relatively slower recovery time constants of more than 15 seconds.

The "Singh-Hauswirth-Harrison-Vaughan Williams" (S-H-H-VW) classification is summarised in table 2. Many antiarrhythmic drugs have more than one class of action (for example, racemic sotalol has class II and class III activity and amiodarone has class I-IV actions). Moreover, some drugs within a particular class may differ in their clinical effects owing to subtle (but significant) differences in their mechanism of action at the ion channel level. In addition, there are some antiarrhythmic drugs (for example, digoxin and adenosine) which cannot be fitted into the S-H-H-VW I-IV classification.

While the S-H-H-VW classification has been valuable, the limitations of inadequate correlations between drug mechanism, arrhythmia mechanism, and therapeutic efficacy gave rise to the "Sicilian Gambit" approach to antiarrhythmic treatment. This approach to arrhythmia management, formulated by the European Society of Cardiology working group,⁹⁴ seeks the critical mechanisms responsible for arrhythmogenesis (table 3) to identify a "vulnerable parameter" or "Achilles heel" of the arrhythmia concerned. This would enable the clinician to select a drug on the basis of its mechanism of action and not empirically. This approach complements well those recent advances in our understanding of molecular biology (for example, cloning and sequencing of ion channels and receptors) that have raised hopes for a "target oriented" approach to antiarrhythmic treatment. There are, however, two fundamental issues that might hinder this approach to drug selection. First, an Achilles heel is not always (yet) identifiable for many arrhythmias, and in some cases there may be more than one Achilles heel, some of which are not involved in arrhythmogenesis. In addition, there are drugs classified within the S-H-H-VW classification that have multiple electrophysiological targets; this may preclude them from being selective for any one particular Achilles heel. Second, consideration of drug action based on multiple targets (ion channels, receptors, and second messenger systems) and the "spread sheet" approach advanced in the Sicilian Gambit⁹⁴ generates a degree of complexity absent from the S-H-H-VW classification, and which may hinder acceptance of this approach.⁹⁵ Against this, however, a major advantage of the Sicilian Gambit approach is that it provides a framework within which the ever increasing information on arrhythmogensis and drug action can be readily accommodated and considered.(for example, Members of the Sicilian Gambit⁹⁶)

Our increasing knowledge of the basic electrophysiological and genetic characteristics of ion channels, the cellular actions of antiarrhythmic agents, their effects on animal models, and the results of clinical trials should help guide future rational drug development and classification. In a recent article,⁹⁷ Camm and Yap summarise attributes for future antiarrhythmic agents, including: appropriate modification of the arrhythmia substrate, suppression of arrhythmia triggers, efficacy in pathologic tissues and states, positive rate/use dependent effects, similar efficacy in oral and parenteral formulations, similar efficacy in arrhythmias and their surrogates, few side effects, and cardiac selective ion channel blockade.

One of the central issues will be whether approaches which focus on a single ion channel target offer more promise than approaches based on compounds with "polypharmacological" (multiple ion channel) effects. Recently discovered ion channelssuch as the ultrarapid delayed rectifier (I_K,ur) in atrial tissue⁹⁸may offer new, alternative drug targets. Importantly, the reverse use dependence associated with some drugs with class III (predominantly I_Kr) blocking actions might be taken as suggesting that either drugs against alternative targets to I_Kr or drugs with multiple effects may be superior to selective I_Kr blockers alone.

Unfortunately, the emerging picture is not as clear as this. While the results of the SWORD (survival with oral d-sotalol) trial indicate that d-sotalol increases mortality and is therefore unsuitable for use,⁴⁵ the same does not appear to be true for dofetilide. Dofetilide is a potent and selective blocker of I_Kr, which, although associated with reverse use dependent effects on the action potential at the cellular level,⁴⁹ has a profile that is not clearly reverse use dependent in humans (for example, Bashir and colleagues⁹⁹). The drug appears to be reasonably well tolerated and at some concentrations is effective at suppressing ventricular tachycardia.⁹⁹ Moreover, its use does not seem to be associated with significantly increased mortality, and with only a low incidence of torsade de pointes.¹⁰⁰ Quite why dofetilide appears to be safer than d-sotalol is not entirely clear, though there is some experimental evidence that the class III effects of d-sotalol are much more sensitive to extracellular potassium levels than those of dofetilide.⁴⁴ At this stage, it would appear premature to rule out selective I_Kr blockade as a viable antiarrhythmic strategy.

I_Ks blockade may, in principle, offer an attractive alternative or supplementary approach to I_Kr inhibition. Azimilide is a relatively new agent effective at inhibiting both I_Kr and I_Ks.¹⁰¹ Data from experiments in which I_Ks blocking effects of the drug on the action potential have been estimated suggested that the I_Ks block alone was associated with rate independent action potential prolongation.¹⁰² The overall drug effect on the action potential (involving combined I_Kr and I_Ks actions) shows some variations between experimental studies, with reports of either some reverse use dependence^{102 103} or a rate independent action on effective refractory period.¹⁰⁴ Azimilide may be effective against both atrial and ventricular arrhythmias^{101 104} and, while it is too early to comment with certainty on its efficacy and safety in humans, initial signs appear promising.¹⁰¹ Several clinical trials including the ALIVE (azimilide post-infarct survival evaluation) study¹⁰⁵ were ongoing at the time of writing.

Other investigative agents with polypharmacological effects include ibutilide and tedisamil. Ibutilide has an interesting pharmacological profile in that in addition to affecting I_Kr it also appears to induce a sustained sodium current, an effect that would be synergistic in prolonging the action potential.¹⁰⁶ Tedisamil blocks I_Kr and the transient outward potassium current (I_TO).¹⁰⁷ It has been shown to be effective against ventricular fibrillation in a rabbit model¹⁰⁸ and it prolongs the monophasic action potential in humans.¹⁰⁹ Dronedarone, an investigational drug related to amiodarone, may be an agent of particular interest.⁹⁷ Like its parent compound, dronedarone may be expected to exert multiple S-H-H-VW effects and thereby have wide ranging efficacy. The results of trials of this and other agents with polypharmacological effects will be important in the debate about whether the future development of antiarrhythmic agents lies in single or multiple ion channel targets. As the underlying basis for the generation and maintenance of particular arrhythmias becomes increasingly understood, so will our understanding of the nature of any associated Achilles heel or vulnerable parameter. This knowledge, together with ongoing revision of drug classification according to target/action, is likely to refine pharmacotherapeutic approaches to clinical arrhythmia management.

This work was supported by grants from the British Heart Foundation, the United Bristol Healthcare Trust, and the Wellcome Trust. KCRP was supported by a British Heart Foundation clinical training fellowship, and JCH was supported by a Wellcome Trust research fellowship. We thank Kathryn Yuill for providing the ionic current record for figure 3B, and Helen Wallis for comments on the manuscript.

1. http://www.youtube.com/watch?v=JwB7VG6WaaY&feature=related
2. http://www.youtube.com/watch?v=oHTGtYsEJBo&feature=channel
3. http://www.youtube.com/watch?v=xw4nDMgTOrw&feature=related
4. http://www.youtube.com/watch?v=x67vRkooZDc&feature=related
5. http://www.youtube.com/watch?v=PwnpEoQDzo0&feature=related