CARDIOTONIC DRUGS. CARDIAC GLYCOSIDES AND OTHER INOTROPIC DRUGS. AGENTS USED FOR CONGESTIVE HEART FAILURE (Strophantinum, Corgliconum, Digoxinum, Digitoxinum, infusum herbae Adonodis vernalis, Dophaminum, Dobutaminum)

Cardiotonic drugs. Cardiac glycosides and other inotropic drugs

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 cao 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. 

Heart failure (HF), often called congestive heart failure (CHF) or congestive cardiac failure (CCF), occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body.^[1][2][3] Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition is diagnosed by patient physical examination and confirmed with echocardiography. Blood tests help to the etiology diagnosis. Treatment depends from severity and etiology of heart failure. In a chronic patient already in a stable situation, treatment commonly consists of lifestyle measures such as smoking cessation, light exercise, dietary changes, and medications. Sometimes, depending from etiology, it is treated with implanted devices (pacemakers or ventricular assist devices) and occasionally a heart transplant is required.

Common causes of heart failure include myocardial infarction and other forms of ischemic heart disease, hypertension, valvular heart disease, and cardiomyopathy.^[4] The term heart failure is sometimes incorrectly used for other cardiac-related illnesses, such as myocardial infarction (heart attack) or cardiac arrest, which can cause heart failure but are not equivalent to heart failure.

Heart failure is a common, costly, disabling, and potentially deadly condition.^[4] In developed countries, around 2% of adults suffer from heart failure, but in those over the age of 65, this increases to 6–10%.^[4][5]

Terminology

Heart failure is a global term for the physiological state in which cardiac output is insufficient in meeting the needs of the body and lungs. Often termed “congestive heart failure” or CHF, this is most commonly caused when cardiac output is low and the body becomes congested with fluid due to an inability of heart output to properly match venous return.^[6]

It may also occur in situations of high output, (termed “high output cardiac failure“) where the ventricular systolic function is normal but the heart can’t deal with an important augmentation of blood volume.^[7] This can occur in overload situation (blood or serum infusions), renal diseases, chronic severe anemia, beriberi (vitamin B₁/thiamine deficiency), thyrotoxicosis, Paget’s disease, arteriovenous fistulae, or arteriovenous malformations.

Fluid overload is a common problem for people with heart failure but is not synonymous with it. Patients with treated heart failure will often be euvolaemic (a term for normal fluid status), or more rarely, dehydrated.

Medical professionals use the words “acute” to mean of rapid onset and “chronic” of long duration. Chronic heart failure is therefore a long term situation, usually with stable treated symptomatology.

Acute decompensated heart failure is exacerbated or decompensated heart failure, referring to episodes in which a patient can be characterized as having a change in heart failure signs and symptoms resulting in a need for urgent therapy or hospitalization.^[8]

There are several terms which are closely related to heart failure, and may be the cause of heart failure, but should not be confused with it:

• Cardiac arrest and asystole refer to situations in which there is no cardiac output at all. Without urgent treatment these result in sudden death.

• Myocardial infarction (“Heart attack”) refers to heart muscle damage due to insufficient blood supply, usually as a result of a blocked coronary artery.

• Cardiomyopathy refers specifically to problems within the heart muscle, and these problems can result in heart failure. Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease. Dilated cardiomyopathy implies that the muscle damage has resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves enlargement and thickening of the heart muscle.

A man with congestive heart failure and marked jugular venous distension. External jugular vein marked by an arrow.

Heart failure symptoms are traditionally and somewhat arbitrarily divided into “left” and “right” sided, recognizing that the left and right ventricles of the heart supply different portions of the circulation. However, heart failure is not exclusively backward failure (in the part of the circulation which drains to the ventricle).

There are several other exceptions to a simple left-right division of heart failure symptoms. Left sided forward failure overlaps with right sided backward failure. Additionally, the most common cause of right-sided heart failure is left-sided heart failure. The result is that patients commonly present with both sets of signs and symptoms.

Left-sided failure

Common respiratory signs are tachypnea (increased rate of breathing) and increased work of breathing (non-specific signs of respiratory distress). Rales or crackles, heard initially in the lung bases, and when severe, throughout the lung fields suggest the development of pulmonary edema (fluid in the alveoli). Cyanosis which suggests severe hypoxemia, is a late sign of extremely severe pulmonary edema.

Additional signs indicating left ventricular failure include a laterally displaced apex beat (which occurs if the heart is enlarged) and a gallop rhythm (additional heart sounds) may be heard as a marker of increased blood flow, or increased intra-cardiac pressure. Heart murmurs may indicate the presence of valvular heart disease, either as a cause (e.g. aortic stenosis) or as a result (e.g. mitral regurgitation) of the heart failure.

Backward failure of the left ventricle causes congestion of the pulmonary vasculature, and so the symptoms are predominantly respiratory iature. Backward failure can be subdivided into failure of the left atrium, the left ventricle or both within the left circuit. The patient will have dyspnea (shortness of breath) on exertion (dyspnée d’effort) and in severe cases, dyspnea at rest. Increasing breathlessness on lying flat, called orthopnea, occurs. It is often measured in the number of pillows required to lie comfortably, and in severe cases, the patient may resort to sleeping while sitting up. Another symptom of heart failure is paroxysmal nocturnal dyspnea a sudden nighttime attack of severe breathlessness, usually several hours after going to sleep. Easy fatigueability and exercise intolerance are also common complaints related to respiratory compromise.

“Cardiac asthma” or wheezing may occur.

Compromise of left ventricular forward function may result in symptoms of poor systemic circulation such as dizziness, confusion and cool extremities at rest.

Right-sided failure

Physical examination may reveal pitting peripheral edema, ascites, and hepatomegaly. Jugular venous pressure is frequently assessed as a marker of fluid status, which can be accentuated by eliciting hepatojugular reflux. If the right ventricular pressure is increased, a parasternal heave may be present, signifying the compensatory increase in contraction strength.

Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin (termed peripheral edema or anasarca) and usually affects the dependent parts of the body first (causing foot and ankle swelling in people who are standing up, and sacral edema in people who are predominantly lying down). Nocturia (frequent nighttime urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and hepatomegaly (enlargement of the liver) may develop. Significant liver congestion may result in impaired liver function, and jaundice and even coagulopathy (problems of decreased blood clotting) may occur.

Biventricular failure

Dullness of the lung fields to finger percussion and reduced breath sounds at the bases of the lung may suggest the development of a pleural effusion (fluid collection in between the lung and the chest wall). Though it can occur in isolated left- or right-sided heart failure, it is more common in biventricular failure because pleural veins drain both into the systemic and pulmonary venous system. When unilateral, effusions are often right sided.

Causes

Congestive heart failure

The predominance of causes of heart failure are difficult to analyze due to challenges in diagnosis, differences in populations, and changing prevalence of causes with age.

A 19 year study of 13000 initially healthy adults (“A total of 13 643 men and women without a history of CHF at baseline examination were included in this prospective cohort study”) in the United States (the National Health and Nutrition Examination Survey (NHANES I) found the following causes ranked by Population Attributable Risk score:^[9]

1.     Ischaemic heart disease 62%

2.     Cigarette smoking 16%

3.     Hypertension (high blood pressure) 10%

4.     Obesity 8%

5.     Diabetes 3%

6.     Valvular heart disease 2% (much higher in older populations).

An Italian registry of over 6200 patients with heart failure showed the following underlying causes:^[10]

1.     Ischaemic heart disease 40%

2.     Dilated cardiomyopathy 32%

3.     Valvular heart disease 12%

4.     Hypertension 11%

5.     Other 5%.

Rarer causes of heart failure include:

• Viral myocarditis (an infection of the heart muscle)

• Infiltrations of the muscle such as amyloidosis

• HIV cardiomyopathy (caused by human immunodeficiency virus)

• Connective tissue diseases such as systemic lupus erythematosus

• Abuse of drugs such as alcohol and cocaine

• Pharmaceutical drugs such as chemotherapeutic agents

• Arrhythmias.

Obstructive sleep apnea (a condition of sleep wherein disordered breathing overlaps with obesity, hypertension, and/or diabetes) is regarded as an independent cause of heart failure.

Acute decompensation

Main article: Acute decompensated heart failure

Chronic stable heart failure may easily decompensate. This most commonly results from an intercurrent illness (such as pneumonia), myocardial infarction (a heart attack), arrhythmias, uncontrolled hypertension, or a patient’s failure to maintain a fluid restriction, diet, or medication.^[11] Other well recognized precipitating factors include anemia and hyperthyroidism which place additional strain on the heart muscle. Excessive fluid or salt intake, and medication that causes fluid retention such as NSAIDs and thiazolidinediones, may also precipitate decompensation.^[12]

Classification

There are many different ways to categorize heart failure, including:

• the side of the heart involved (left heart failure versus right heart failure). Right heart failure compromises pulmonary flow to the lungs. Left heart failure compromises aortic flow to the body and brain. Mixed presentations are common; left heart failure often leads to right heart failure in the longer term.

• whether the abnormality is due to insufficient contraction (systolic dysfunction), or due to insufficient relaxation of the heart (diastolic dysfunction), or to both.

• whether the problem is primarily increased venous back pressure (preload), or failure to supply adequate arterial perfusion (afterload).

• whether the abnormality is due to low cardiac output with high systemic vascular resistance or high cardiac output with low vascular resistance (low-output heart failure vs. high-output heart failure).

• the degree of functional impairment conferred by the abnormality (as reflected in the New York Heart Association Functional Classification^[27])

• the degree of coexisting illness: i.e. heart failure/systemic hypertension, heart failure/pulmonary hypertension, heart failure/diabetes, heart failure/renal failure, etc.

Functional classification generally relies on the New York Heart Association functional classification. The classes (I-IV) are:

• Class I: no limitation is experienced in any activities; there are no symptoms from ordinary activities.

• Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion.

• Class III: marked limitation of any activity; the patient is comfortable only at rest.

• Class IV: any physical activity brings on discomfort and symptoms occur at rest.

`This score documents severity of symptoms, and can be used to assess response to treatment. While its use is widespread, the NYHA score is not very reproducible and doesn’t reliably predict the walking distance or exercise tolerance on formal testing.^[28]

`In its 2001 guidelines the American College of Cardiology/American Heart Association working group introduced four stages of heart failure:^[29]

• Stage A: Patients at high risk for developing HF in the future but no functional or structural heart disorder.

• Stage B: a structural heart disorder but no symptoms at any stage.

• Stage C: previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment.

• Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative care.

`The ACC staging system is useful in that Stage A encompasses “pre-heart failure” — a stage where intervention with treatment can presumably prevent progression to overt symptoms. ACC Stage A does not have a corresponding NYHA class. ACC Stage B would correspond to NYHA Class I. ACC Stage C corresponds to NYHA Class II and III, while ACC Stage D overlaps with NYHA Class IV.

Algorithms

`There are various algorithms for the diagnosis of heart failure. For example, the algorithm used by the Framingham Heart Study adds together criteria mainly from physical examination. In contrast, the more extensive algorithm by the European Society of Cardiology (ESC) weights the difference between supporting and opposing parameters from the medical history, physical examination, further medical tests as well as response to therapy.

 

Drugs to treat Heart Failure

Cardiac glycosides represent a family of compounds that are derived from the foxglove plant (Digitalis purpurea). The therapeutic benefits of digitalis were first described by William Withering in 1785. Initially, digitalis was used to treat dropsy, which is an old term for edema. Subsequent investigations found that digitalis was most useful for edema that was caused by a weakened heart (i.e., heart failure).

Mechanisms of action

Digitalis compounds are potent inhibitors of cellular Na⁺/K⁺-ATPase. This ion transport system moves sodium ions out of the cell and brings potassium ions into the cell. This transport function is necessary for cell survival because sodium diffusion into the cell and potassium diffusion out of the cell down their concentration gradients would reduce their concentration differences (gradients) across the cell membrane over time. Loss of these ion gradients would lead to cellular depolarization and loss of the negative membrane potential that is required for normal cell function. The Na⁺/K⁺-ATPase also plays an active role in the membrane potential. this pump is electrogenic because it transports 3 sodium ions out of the cell for every 2 potassium ions that enter the cell. This can add several negative millivolts to the membrane potential depending on the activity of the pump.

Cardiac myocytes, as well as many other cells, have a Na⁺-Ca⁺⁺ exchanger (not an active energy-requiring pump) that is essential for maintaining sodium and calcium homeostasis. The exact mechanism by which this exchanger works is unclear.  It is known that calcium and sodium can move in either direction across the sarcolemma. Furthermore, three sodium ions are exchanged for each calcium, therefore an electrogenic potential is generated by this exchanger.  The direction of movement of these ions (either inward or outward) depends upon the membrane potential and the chemical gradient for the ions. We also know that an increase in intracellular sodium concentration competes for calcium through this exchange mechanism leading to an increase in intracellular calcium concentration. As intracellular sodium increases, the concentration gradient driving sodium into the cell across the exchanger is reduced, thereby reducing the activity of the exchanger, which decreases the movement of calcium out of the cell. Therefore, mechanisms that lead to an accumulation of intracellular sodium cause a subsequent accumulation of intracellular calcium because of decreased exchange pump activity.

By inhibiting the Na⁺/K⁺-ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na⁺-Ca⁺⁺ exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy). Inhibition of the Na⁺/K⁺-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction and vasoconstriction.

By mechanisms that are not fully understood, digitalis compounds also increase vagal efferent activity to the heart. This parasympathomimetic action of digitalis reduces sinoatrial firing rate (decreases heart rate; negative chronotropy) and reduces conduction velocity of electrical impulses through the atrioventricular node (negative dromotropy).

Pharmacokinetics and toxicity

The long half-life of digitalis compounds necessitates special considerations when dosing. With a half-life of 40 hours, digoxin would require several days of constant dosing to reach steady-state, therapeutic plasma levels (digitoxin with a half-life of 160 hours, would require almost a month!). Therefore, when initiating treatment, a special dosing regimen involving “loading doses” is used to rapidly increase digoxin plasma levels. This process is termed “digitalization.” For digoxin, the therapeutic plasma concentration range is 0.5 – 1.5 ng/ml. It is very important that therapeutic plasma levels are not exceeded because digitalis compounds have a relatively narrow therapeutic safety window. Plasma concentrations above 2.0 ng/ml can lead to digitalis toxicity, which is manifested as arrhythmias, some of which may be life-threatening. If toxicity occurs with digoxin, it may take several days for the plasma concentrations to fall to safe levels because of the long half-life. There is available for digoxin toxicity an immune Fab (Digibind) that can be used to rapidly reduce plasma digoxin levels. Potassium supplementation can also reverse the toxic effects of digoxin if the toxicity is related to hypokalemia (see below).

Drug Interactions

Many commonly used drugs interact with digitalis compounds. The Class IA antiarrhythmic, quinidine, competes with digoxin for binding sites and depresses renal clearance of digoxin. These effects increase digoxin levels and can produce toxicity. Similar interactions occur with calcium-channel blockers and nonsteroidal anti-inflammatory drugs. Other drugs that interact with digitalis compounds are amiodarone (Class III antiarrhythmic) and beta-blockers. Diuretics can indirectly interact with digoxin because of their potential for decreasing plasma potassium levels (i.e., producing hypokalemia). Because potassium competes with digoxin for binding sites on the Na⁺/K⁺-ATPase, hypokalemia results in increased digoxin binding and thereby enhances its therapeutic and toxic effects. Hypercalcemia enhances digitalis-induced increases in intracellular calcium, which can lead to calcium overload and increased susceptibility to digitalis-induced arrhythmias. Hypomagnesemia also sensitizes the heart to digitalis-induced arrhythmias.

Heart Failure

• ↑ inotropy

• ↑ ejection fraction

• ↓ preload

• ↓ pulmonary congestion/edema

Arrhythmias

• ↓ AV nodal conduction
  (parasympathomimetic effect)

• ↓ ventricular rate in atrial flutter
  and fibrillation

Heart failure

Digitalis compounds have historically been used in the treatment of chronic heart failure owing to their cardiotonic effect. Although newer and more efficacious treatments for heart failure are available, digitalis compounds are still widely used. Clinical studies in heart failure patients have shown that digoxin, when used in conjunction with diuretics and vasodilators, improves cardiac output and ejection fraction, and reduces filling pressures and pulmonary capillary wedge pressure (this reduces pulmonary congestion and edema); heart rate changes very little. These effects are to be expected for a drug that increases inotropy. Although the direct effect of digoxin on blood vessels is vasoconstriction, when given to patients in heart failure, the systemic vascular resistance falls. This most likely results from the improvement in cardiac output, which leads to withdrawal of compensatory vasoconstrictor mechanisms (e.g., sympathetic adrenergic activity and angiotensin II influences). Digitalis compounds have a small direct diuretic effect on the kidneys, which is beneficial in heart failure patients.

Atrial fibrillation and flutter

Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output. Furthermore, chronic ventricular tachycardia can lead to heart failure. Digitalis compounds, such as digoxin, are useful for reducing ventricular rate when it is being driven by a high atrial rate. The mechanism of this beneficial effect of digoxin is its ability to activate vagal efferent nerves to the heart (parasympathomimetic effect). Vagal activation can reduce the conduction of electrical impulses within the atrioventricular node to the point where some of the impulses will be blocked. When this occurs, fewer impulses reach the ventricles and ventricular rate falls. Digoxin also increases the effective refractory period within the atrioventricular node.

Specific Drugs

Three different digitalis compounds (cardiac glycosides) are listed in the table below. The compound most commonly used in the U.S. is digoxin. Ouabain is used primarily as a research tool. (See www.rxlist.com for more details on digoxin).

* percent absorption

Side Effects, Contraindications and Warnings

The major side effect of digitalis compounds is cardiac arrhythmia, especially atrial tachycardias and atrioventricular block. Digitalis compounds are contraindicated in patients who are hypokalemic, or who have atrioventricular block or Wolff-Parkinson-White (WPW) syndrome. Impaired renal function leads to enhanced plasma levels of digoxin because digoxin is eliminated by the kidneys. Lean, elderly patients are more susceptible to digitalis toxicity because they often have reduced renal function, and their reduced muscle mass increases plasma digoxin levels at a given dose because muscle Na⁺/K⁺-ATPase acts as a large binding reservoir for digitalis. A 2012 analysis of the AFFIRM trial determined that digoxin significantly increased all-cause mortality in patients with atrial fibrillation. This calls into question the practice of using digoxin for lowering ventricular rate in patients with atrial fibrillation.

Heart failure—it is the inability of the heart to meet the metabolic requirements of the peripheral system.

 

In heart failure the compensatory mechanisms are activated—

1.   Sympathetic nervous system—↑ pulse rate

2.   Renin angiotensin aldosterone system—leg oedema

3.   ADH secretion

 

Drugs used in the heart failure—

A.  Drugs with positive ionotropic action (↑ the force of contraction)

i.     Cardiac glycosides/digitalis

ii.  β-agonist

iii.   Phosphodiesterase enzyme inhibitors

( i and ii Advised in heart failure but not used in case of asthma)

 

B.  Drugs without positive ionotropic action

i.     Diuretics (↓ preload)

ii.  Vasodilators (↓ after load)

iii.   ACE inhibitor—angiotensin converting enzyme (↓ both preload and after load)

 

*** usually drugs of both groups are used in treatment.

*** in case abnormality of the ventricles, heart is unable to adequately pump blood. So, tissue perfusion ↓.

 

Types of heart failure—

·  Right and left heart failure

·  Acute and chronic heart failure

·  Forward and backward heart failure

Factors

o     Force of contraction

o     Heart rate

o     Preload

o     After load

 

 

Cardiac Glycosides—

Synthesized from the plant carbohydrate by hydrolysis. It has sugar and non-sugar parts.

These are the glycosidic compounds with cardiotonic action. They have—

1. Steroid nucleus & Lactone ring (non-sugar part)

2. Sugar moiety

 

*** the steroid nucleus contains Cyclo-Pentano Phenanthrene (CPP) ring

*** if the sugar part is glucose then it is called glycoside. (fructose—fructoside, pentose—pentoside)

*** sugar part = glycone part, lactone ring +CPP ring = Aglycone part.

 

Ø   Pharmacokinetic property depends upon sugar moiety glycone part.

Ø   Pharmacodynamic property depends upon glycine moiety /aglycone part.

 

Source of cardiac glycosides—

·   Digitalis lanata (Digoxin)

·   Digitalis purpura (Digitoxin)

·   Stropanthus gratus (Stropanthin)

·   Stropanthus kombe (Ouabian)

 

Name of the Cardiac glycosides—

1.    Digoxin (most commonly used)

2.    Digitoxin

3.    Ouabian

 

*** Digitalis—Digoxin and Digitoxin

 

Pharmacokinetics—

§    Digitalis may be given as tablets or capsules

§    Therapeutic index is very low so, low safety margin

§    Wide distribution to various tissues because of lipid solubility

{Advantage—reaches the target site very quickly, Disadvantage—goes to other tissues}

§    Digoxin mainly eliminated by the kidney (may be given to patients with liver diseases)

§    Digitoxin is mainly eliminated by hepatic metabolism (may be given to patients with renal failure)

§    The presence of enzyme inducers or inhibitors can change the extent of digitalis clearance

{so, digitalis and rifampicin is given together, acts as enzyme inducer}

 

Indication of use of cardiac glycosides—

1. CCF (congestive cardiac failure)

2. Atrial fibrillation

3. Atrial and nodal tachycardia

4. Ventricular tachycardia

 

Contraindication of use of cardiac glycosides—

1. Heart block

2. Obstructive cardiomyopathy

 

Mechanical effects of Cardiac Glycosides—

1. They inhibit Na⁺-K⁺-ATPase pump system on cardiac muscle cell membrane.

2. There is increased intracellular Na⁺ concentration.

3. Less expulsion of calcium from the cells by the Na⁺-Ca⁺ exchanger.

4. Also there is facilitation of Ca⁺ entry through the voltage gated calcium channel.

5. There is increased release of calcium from intracellular storage site (sarcoplasmic reticulum)

6. Net result is increased cardiac contractility, so the sign symptom of cardiac failure is corrected.

 

Pharmacological effects / Mechanism of Action of Digitalis (Digoxin and Digitoxin)—

 

On heart—the effects on the heart is of 2 types—

a.    Effects on contractility—cardiac contractility is increased and heart rate is decreased. Both of these effects in failing heart causes rise of cardiac output; thus symptoms are relieved. This increased contractility is due to greater availability of Ca⁺⁺ within the myocardial cells. The increased contractility of the heart causes greater evacuation of the ventricles; thus causes reduction of venous congestion and reduction of preload. Resulting in improvement of backward failure.

Increased contractility also causes increased cardiac output, leading to greater perfusion pressure, thus forward failure is relieved.

b.   Effects on rate and rhythm—Bradycardia; conductivity of A-V node is delayed. Slowing of rate of origin of impulses from the S-A node. In short heart rate becomes slow and threat of A-V block appears. These effects are largely due to parasympathetic stimulation.

 

On blood vessels—in presence of congestive heart failure, where there is sympathetic over activity (compensatory). Digitalis reduces the sympathetic over activity, so there is ↓ HR and vasodilatation.

*** iormal person digitalis cause both atrial and venous constriction.

 

On coronary circulation and myocardial O₂ supply—digitalis cause bradycardia, so cardiac metabolism is decreased. So, there is reduction of O₂ demand, it also reduces the heart size.

All theses will cause less O₂ demand by the failing heart. Coronary blood supply also improves.

 

On ANS—in congestive heart failure there is sympathetic over activity (compensatory). Digitalis reduces the sympathetic over activity and increases vagal activity.

In toxic dose digitalis causes sympathetic over activity by stimulating VMC. Iormal person it does the same thing iormal dose.

 

On CNS—in therapeutic dose the effects are minimal but higher (toxic) doses cause stimulation of the chemoreceptor trigger zone (CTZ) leading to nausea, vomiting, mental confusion and visual disturbances.

Digitoxin is more prone to CNS symptoms than Digoxin.

 

On kidneys—in congestive heart failure there is excessive renin production, which causes vasospasm and hypervolumia. Digitalis improves forward failure, Co and thus reduces renin production and there is natriuresis and reduction of hypervolumia. In congestive heart failure there is backward failure, as a result there is congestion in the renal venous circulation. And because there is less CO, less blood is available in the renal arteriolar side. So there is sluggishness in the renal circulation. All these cause stasis of circulation in the kidney, so more Na⁺ and H₂O is reabsorbed causing hypervolumia, oedema, ascities etc.

Digitalis by increasing cardiac contractility improves CO thus heart pumps more blood in the arterial side, as a result venous congestion is relieved, renal circulation is improved and diuresis starts in the kidney.

 

Influence of Glycosides on autonomic action—

Glycosides influences both sympathetic and parasympathetic effects on heart and it occurs throughout therapeutic and toxic dose range.

 

Electrical effects of cardiac glycosides—

§    On SA node and AV node and conducting tissues—decreased impulse discharge/generation from the SA node and decrease impulse propagation through the AV node.

§    In toxic doses cardiac glycosides can increase the sympathetic effect on heart.

*** cardiac glycosides also have pharmacological effects on kidney, CNS and GIT

*** cardiac glycosides cause anorexia in the GIT

*** cardiac glycosides ↑ perfusion and ↑ filtration, so has diuretic actions

*** digitalis are lipid soluble and therefore have effects in the CNS and eliminated by the liver

 

Digitalization—it is a process of dosing with digitalis which may be slow or rapid with the objective of attaining a steady state of plasma concentration of drug in cardiac patient.

 

Loading dose—it is the dose that is given to load the concentration of drug in blood.

Maintenance dose—it is the dose that is given to maintain the concentration of drug in blood.

 

 

Toxicity—

Cardiac effects—

1. Severe bradycardia—some persons can have even sino-atrial exit block. (these are all due to a combination of vagal stimulation and withdrawal of sympathetic over-activity)

2. Paroxysmal or non-paroxysmal atrial tachycardia—supra ventricular tachycardia. (due to increased automaticity or re-entry phenomenon)

3. A-V nodal rhythm due to development of after depolarization of AV node.

4. A-V block due to vagal over-activity.

5. Ventricular ectopic—premature beat. (due to re-entry phenomenon in Hiss perkinjee system or after depolarization)—this may lead to bigeminus pulse.

6. Ventricular tachycardia or fibrillation.

 

Non-cardiac effects—

1. Anorexia, nausea, vomiting (CNS effects)

2. Visual disturbance

3. Very rarely delirium or convulsion

 

Features of digitalis poisoning—

§    GIT problem—anorexia, nausea, vomiting

§    CVS problem—arrhythmia, bradycardia

§    CNS problem—visual haloes, hallucination

 

Management of digitalis poisoning / Toxicity—

1. Stop or correct the dose

2. Correct the electrolyte abnormality, that is hypokalemia (K⁺ therapy can be given)

3. Use drug like atropine to ↑ the HR if Bradycardia is present

4. Administer digitalis antibody

5. To prevent arrhythmia Lidocaine or Phenytoin can be given

6. To insert temporary pacemaker

*** now a days Digitalis antibody (Digibine) is used IV.

 

Differences between Digitoxin and Digoxin—

 

Indication of Digoxin—

1. Low output heart failure (where the rhythm is sinus rhythm)

2. Where CHF (congestive heart failure) is accompanied by atrial fibrillation

3. It may be used in cardiac arrhythmias like atrial flatter, atrial fibrillation, acute supraventricular tachycardia

 

Note:- when the heart failure is due to such cases like thyrotoxicosis (high output failure), Beriberi, Cor pulmonate—digitalis are not of great help. (although the drug is not contraindicated in such cases)

 

Contraindication of Digoxin—

1. Wolff Parkinson white (WPW)

2. In diastolic failure

3. Heart block

4. Previous history of stroke’s Adams syndrome

5. Obstructive cardiac myopathy

 

Relative contraindication of Digoxin—

1. Severe renal failure

2. Sinus bradycardia

3. After acute MI (myocardial infarction)

4. Cor pulmonate

 

Other drugs used in heart failure—

1. Other positive ionotropic drugs—

§    Dopamine / Dobutamine—β receptor stimulation. Used in acute heart failure, on patient it is refractory to other cardiac drugs (parenterally). They ↑ CO and ↑ force of contraction.

 

2. Phosphodiesterase inhibitors—drugs that inhibit phosphodiesterase and therefore ↑ intracellular cyclic-AMP. So it increases cardiac contractility, ↑ force of contraction. The newer phosphodiesterase inhibitors include Bipyridine.

They ↑ the intracellular influx of Ca⁺⁺ into the heart cells (Amrinone, Milrinone). But this drug does not inhibit Na⁺-K⁺-ATPase pump and does not activate adrenoceptors.

In acute heart failure if Bipyridine is given they will ↑ CO and ↓ pulmonary capillary pressure (lung congestion).

 

3. Drugs without positive ionotropic action—

§  Reduction of the preload. Such as diuretics. This drug ↓ preload (venous return) by increasing water and salt loss.

§  The nitrates dilate capacitans veins, thus reducing the ventricular filling pressure and ↓ the heart wall stretch and ↓ myocardial O2 demand. So can be used in acute left ventricular failure.

*** Hydralazine—it relaxes the arterioles, therefore ↓ peripheral vascular resistance.

 

4. Reduction of both preload and after load—

§    ACE inhibitors (angiotensinogen converting enzyme inhibitors)—here preload is decreased as reduced formation of aldosterone thus reducing water and salt retention. It decreases after load by preventing the conversion of angiotensin-I to angiotensin-II thus decreases angiotensin-II mediated vasoconstriction.

 

Cardiotonic drugs. Cardiac glycosides and other inotropic drugs

 

Drugs to treat Heart Failure

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

Stophantus

 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 p                             

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, wheot 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 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 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 centrallyIncreases 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

Pharmacokinetic properties

Digoxin is usually given by mouth, but can also be given by IV injection in urgent situations (the IV injection should be slow, and heart rhythm should be monitored). While IV therapy may be better tolerated (less nausea), digoxin has a very long distribution half-life into the cardiac tissue, which will delay its onset of action by a number of hours. The half-life is about 36 hours, digoxin is given once daily, usually in 125-μg or 250-μg doses.

In patients with decreased kidney function, the half-life is considerably longer, calling for a reduction in dose or a switch to a different glycoside, such as digitoxin (not available in the United States), which has a much longer elimination half-life of around seven days, elimination is mainly by renal excretion and involves P-glycoprotein which leads to significant clinical interactions with other drugs commonly used in patients with heart problems. These include: spironolactone, verapamil and amiodarone.

Effective plasma levels vary depending on the medical indication. For congestive heart failure, levels between 0.5 and 1.0 ng/ml are recommended.^[7] This recommendation is based on post hoc analysis of prospective trials, suggesting higher levels may be associated with increased mortality rates. For heart rate control (atrial fibrillation), plasma levels are less defined and are generally titrated to a goal heart rate. Typically, digoxin levels are considered therapeutic for heart rate control between 1.0 and 2.0 ng/ml. In suspected toxicity or ineffectiveness, digoxin levels should be monitored. Plasma potassium levels also need to be closely controlled (see side effects below).

Quinidine, verapamil, and amiodarone increases plasma levels of digoxin (by displacing tissue binding sites and depressing renal digoxin clearance), so plasma digoxin must be monitored carefully.

Researchers at Yale University looked at data from an earlier study to see if digoxin affected men and women differently. That study determined digoxin, which has been used for centuries and makes the heart contract more forcefully, did not reduce deaths overall, but did result in less hospitalization. Researcher Dr. Harlan Krumholz said they were surprised to find women in the study who took digoxin died “more frequently” (33%) than women who took a placebo pill (29%). They calculated digoxin increased the risk of death in women by 23%. There was no difference in the death rate for men in the study.

Digoxin is also used as a standard control substance to test for p-glycoprotein inhibition.

Adverse effects

The occurrence of adverse drug reactions is common, owing to its narrow therapeutic index (the margin between effectiveness and toxicity). Adverse effects are concentration-dependent, and are rare when plasma digoxin concentration is <0.8 μg/l.^[8] They are also more common in patients with low potassium levels (hypokalemia), since digoxiormally competes with K⁺ ions for the same binding site on the Na⁺/K⁺ ATPase pump.

Common adverse effects (≥1% of patients) include loss of appetite, nausea, vomiting and diarrhea as gastrointestinal motility increases. Other common effects are blurred vision, visual disturbances (yellow-green halos and problems with color perception), confusion, drowsiness, dizziness, insomnia, nightmares, agitation, and depression, as well as a higher acute sense of sensual activities.^[9] Less frequent adverse effects (0.1%–1%) include: acute psychosis, delirium, amnesia, convulsions, shortened QRS complex, atrial or ventricular extrasystoles, paroxysmal atrial tachycardia with AV block, ventricular tachycardia or fibrillation, and heart block.^[8] Rarely, digoxin has been shown to cause thrombocytopenia. Gynaecomastia (enlargement of breast tissue) is mentioned in many textbooks as a side effect, thought to be due to the estrogen-like steroid moiety of the digoxin molecule,^[10] but when systematically sought, the evidence for this is equivocal.^[11] The pharmacological actions of digoxin usually result in electrocardiogram changes, including ST depression or T wave inversion, which do not indicate toxicity. PR interval prolongation, however, may be a sign of digoxin toxicity. Additionally, increased intracellular Ca²⁺ may cause a type of arrhythmia called bigeminy (coupled beats), eventually ventricular tachycardia or fibrillation. The combination of increased (atrial) arrhythmogenesis and inhibited atrioventricular conduction (for example paroxysmal atrial tachycardia with A-V block – so-called “PAT with block”) is said to be pathognomonic (i.e. diagnostic) of digoxin toxicity.^[12]

An often described, but rarely seen, adverse effect of digoxin is a disturbance of color vision (mostly yellow and green) called xanthopsia. Vincent van Gogh‘s “Yellow Period” may have somehow been influenced by concurrent digitalis therapy. Other oculotoxic effects of digoxin include generalized blurry vision, as well as seeing a “halo” around each point of light.^[13] The latter effect can also be seen in van Gogh’s Starry Night. Evidence of van Gogh’s digoxin use is supported by multiple self portraits that include the foxglove plant, from which digoxin is obtained. (e.g. Portrait of Dr. Gachet)

Digoxin plasma concentrations may increase while on antimalarial medication hydroxychloroquine (based on two case reports from 1982).^[14]

In overdose, the usual supportive measures are needed. If arrhythmias prove troublesome, or malignant hyperkalaemia occurs (inexorably rising potassium level due to paralysis of the cell membrane-bound, ATPase-dependent Na/K pumps), the specific antidote is antidigoxin (antibody fragments against digoxin, trade names Digibind and Digifab).^[15] Toxicity can also be treated with higher thaormal doses of potassium. Digoxin is not removed by hemodialysis or peritoneal dialysis with enough effectiveness to treat toxicity.

Digoxin has potentially dangerous interactions with verapamil,^[16] amiodarone, erythromycin, and epinephrine (as would be injected with a local anesthetic).

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.

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.

Digitalis Glycosides (Systemic)

This monograph includes information on the following:

1) Digitoxin ^*

2) Digoxin

Arrhythmias, cardiac (prophylaxis and treatment)—Digitalis glycosides (digitalis) are indicated for the control of ventricular response rates in patients with chronic atrial fibrillation. ^{{01} {53}} Digitalis glycosides are also indicated for the control of paroxysmal atrioventricular (AV) nodal reentrant tachycardia; ^{64} digitalis glycosides may convert paroxysmal AV nodal reentrant tachycardia to normal sinus rhythm. ^{{01} {59} {64}}

Congestive heart failure (treatment)—Digitalis glycosides are indicated for the treatment of all degrees of congestive heart failure. Their positive inotropic action results in improved cardiac output and an improvement in the signs and symptoms of hemodynamic insufficiency such as dyspnea, edema, and/or venous congestion.

— Although digoxin has been shown to improve symptoms of heart failure, it does not prolong life, as was determined in a large, randomized, double-blind trial known as the Digitalis Investigation Group (DIG) study ^{124}. In this trial, the effect of digoxin on mortality and morbidity was evaluated in patients with heart failure ^{124}. It was concluded that digoxin did not reduce overall mortality, but that it did reduce the rate of hospitalization for worsening heart failure ^{124}.

Unaccepted

The use of digitalis glycosides in the treatment of obesity has been determined unwarranted and dangerous, since these drugs may cause potentially fatal arrhythmias or other adverse effects ^{01}.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Molecular weight—

Digitoxin: 764.96 ^{32}

Digoxin: 780.96 ^{32}

Mechanism of action/Effect:

Two major actions are produced by therapeutic doses of digitalis glycosides:

Force and velocity of myocardial contraction are increased (positive inotropic effect). This effect is thought to result from inhibition of movement of sodium and potassium ions across myocardial cell membranes by complexing with adenosine triphosphatase. As a result, there is enhancement of calcium influx and an augmented release of free calcium ions within the myocardial cells to subsequently potentiate the activity of the contractile muscle fibers of the heart.

(2) A decrease in the conduction rate and increase in the effective refractory period of the atrioventricular (AV) node is due predominantly to an indirect effect resulting from enhancement of parasympathetic tone and possibly from a decrease in sympathetic tone (the occurrence of the latter effect is controversial) ^{{127} {128} {129}}.

Digitalis glycosides differ predominantly in their pharmacokinetic properties, as opposed to their pharmacodynamic properties ^{73}.

Absorption:

Digitoxin—Highly lipophilic; almost completely absorbed after oral administration.

Digoxin—Absorption occurs by passive diffusion ^{01} in the proximal part of the small intestine ^{87}. Bioavailability is 60 to 80% (tablets), 70 to 85% (oral elixir), or 90 to 100% (capsules) ^{01}. The rate, but not the extent, of oral absorption is reduced when the tablets are taken after meals ^{01}.

Distribution:

Digitoxin—Estimated volume of distribution (Vol _D): 0.61 liter per kg (L/kg) (range, 0.53 to 0.74 L/kg); however, estimates vary considerably ^{86}.

Digoxin—Apparent Vol _D: 6 to 8 L/kg ^{{73} {87}}; digoxin concentrates in tissues, with a distribution space that correlates with lean body weight as opposed to total body weight ^{87}. Digoxin is distributed into cerebrospinal fluid, although to a lesser degree than into other tissues ^{87}.

Protein binding:

Digitoxin—High (> 90%) ^{60}.

Digoxin—Low (approximately 30%) ^{87}.

Biotransformation:

Digitoxin—Metabolism occurs in the liver and produces several metabolites ^{60}. The only active metabolite is digoxin, which makes up a small fraction of the total metabolites of digitoxin ^{60}.

Digoxin—Metabolism occurs partially in the stomach, but also may occur in the liver ^{90} and, although only about 16% of a dose of digoxin is metabolized ^{01}, several metabolites of digoxin and their metabolic pathways have been identified ^{90}. The bis-digitoxoside and mono-digitoxoside metabolites are considered to be cardioactive ^{90}. Other metabolites, such as digoxigenin, are considered to be less cardioactive than digoxin ^{90}. In some patients (estimated to be approximately 10% of patients taking digoxin ^{72}), other cardioinactive metabolites, such as dihydrodigoxin and dihydrodigoxigenin, may result from the metabolism of digoxin by intestinal bacteria ^{{23} {62} {90}}. In these individuals, as much as 40% or more of an oral dose of digoxin may be converted to these inactive reduction products ^{01}.

Drug interactions and/or related problems

The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Digitalis glycosides have a narrow therapeutic range and changes in digitalis pharmacokinetics and/or pharmacodynamics caused by a digitalis-drug interaction can result in toxicity or underdigitalization ^{74}. The presence of or a change in an underlying disease state also can cause changes in digitalis pharmacokinetics and/or pharmacodynamics and may complicate or contribute to a digitalis-drug interaction ^{{73} {74} {131}}. Although there are several consistent, well-known, digitalis-drug interactions ^{74}, numerous studies, reports, opinions, and conclusions about digitalis-drug interactions disagree on the existence or clinical significance of a number of interactions ^{130}. Because a risk of digitalis toxicity exists ^{73}, and the clinical significance of an interaction may be variable and not necessarily predictable ^{{73} {74} {130}}, it is important that the addition or withdrawal of a drug to or from a therapeutic regimen that includes digitalis be carefully evaluated in the context of the patient and the clinical situation ^{74}.

Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Albuterol^{91}{92} (concurrent use may decrease serum digoxin concentrations ^{91}, possibly by redistributing digoxin to other tissues ^{92}; albuterol may also decrease serum potassium concentrations, which may increase the risk of digoxin toxicity ^{92})

Alprazolam^{18}{19}{20} (concurrent use may increase serum digoxin concentrations, possibly by decreasing the renal clearance of digoxin ^{19}; although one small study performed in healthy volunteers concluded that alprazolam had no significant effect on digoxin clearance ^{18}, contradictory evidence has been reported in patients [primarily elderly patients] receiving long-term digoxin therapy ^{{19} {20}})

» Amiodarone^{01}{36}{38} (increases in serum digoxin concentrations by as much as 100% have been reported with concurrent use ^{74}. Although it is thought that amiodarone decreases renal and/or nonrenal clearance and/or the volume of distribution of digoxin, other contributing factors, such as amiodarone-induced displacement of digoxin from tissue binding sites ^{112}, also may be involved ^{115}. Amiodarone has a long elimination half-life [15 to 65 days or longer] ^{112} and digoxin toxicity may not appear until several weeks after the addition of amiodarone ^{{38} {112}} or may persist long after discontinuation of amiodarone ^{115})

Antacids^{01} orAntidiarrheal adsorbents (e.g., kaolin and pectin)^{01} orSulfasalazine^{01} (concurrent use may decrease digoxin bioavailability by decreasing digoxin absorption. In the case of antidiarrheal adsorbents and sulfasalazine, the digoxin dose may be administered 8 hours before the interacting medication ^{84})Antibiotics, oral, especiallyMacrolide antibiotics^{01} , such as:Clarithromycin^{01} orErythromycin^{{01}{33}{58}{72}{62}} orTetracycline^{01}{72} (concurrent use of some oral antibiotics may increase serum digoxin concentrations in patients who inactivate digoxin in the lower intestine by bacterial metabolism ^{01}; in these individuals, altering the bowel flora with certain antibiotics may diminish digoxin conversion to inactive metabolites, resulting in increased serum digoxin concentration; the increase in serum digoxin concentration has been as much as twofold in some cases and correlates with the extent of bacterial inactivation ^{01}. Although there are limited data, this interaction has been reported with oral use of clarithromycin, erythromycin, and tetracycline ^{{01} {33} {58} {62} {72} {100} {101} {102}})Anticancer medications^{01} (such as bleomycin, cyclophosphamide, cytarabine, doxorubicin, procarbazine, and vincristine^{74} ) or

Radiation therapy^{35}{74} (concurrent use may decrease digoxin bioavailability by decreasing digoxin absorption; the reduced absorption that occurs during concurrent use with anticancer medications or radiation therapy may be due to temporary damage to the gastrointestinal mucosa and may continue for several days after treatment ^{74}; in these patients, a dosage form with greater bioavailability, such as the capsule or solution, may help to minimize decreased bioavailability ^{{35} {74} {98} {99}}; digitoxin absorption does not appear to be affected by anticancer agents ^{74})Atorvastatin^{69} (concurrent use may increase digoxin serum concentrations; steady-state serum concentration increases of approximately 20% have been reported ^{69})» Beta-adrenergic blocking agents^{01} , including Atenolol Carvedilol^{95} Metoprolol and Propranolol (concurrent use with these agents may have additive effects on slowing atrioventricular [AV] nodal conduction ^{01}; concurrent use with carvedilol in patients with hypertension increased the steady-state area under the plasma concentration–time curve [AUC] and trough concentrations of digoxin by 14% and 16%, respectively ^{95}; monitoring of plasma digoxin concentrations is recommended ^{95}) Bran fiber, dietary^{{30}{31}{104}{105}} (it is uncertain whether concurrent administration of dietary bran fiber decreases digoxin bioavailability. In one small study, there was presumed to be a decrease in digoxin absorption when concurrent administration of digoxin with 5 grams of fiber resulted in a decrease in urinary excretion of digoxin. Another small study found no change in steady-state serum digoxin concentrations when digoxin was administered 15 to 30 minutes before administration of 11 grams of bran [as a bran muffin], with a second bran muffin administered several hours later ^{{30} {31} {104} {105}})

Verapamil^{01}{74} (concurrent use with calcium channel blocking agents may have additive effects on AV nodal conduction, which could result in complete heart block ^{01}; concurrent use also may increase serum digoxin concentrations by reducing digoxin renal clearance, possibly as a result of inhibition of active tubular secretion of digoxin ^{{79} {81}}; verapamil may increase serum digoxin concentrations by 30 to 200% ^{74}; bepridil may increase serum digoxin concentrations by approximately 34% ^{75}; some studies have reported no interaction with diltiazem while others have reported increases in serum digoxin concentrations of 20 to 60% ^{{74} {79} {80}}; contradictory evidence of an interaction also exists for nifedipine, although serum digoxin increases of 15 to 50% have been reported ^{{74} {77} {78}}; increases in serum digitoxin concentrations also have been reported with concurrent use of diltiazem and verapamil, although increases were less pronounced than with digoxin use and may be due to a reduction in extrarenal digitoxin clearance ^{81}; serum digitalis concentrations and electrocardiogram [ECG] should be monitored and dosages adjusted accordingly ^{22})

The following doses of digoxin are considered equivalent ^{01}:

For digoxin tablets Variability in the bioavailability of digoxin tablets was recognized as a clinical problem in the early 1970s. ^{{66} {67} {68}} These differences in bioavailability were reported among different brands of digoxin tablets as well as among different lots of digoxin tablets produced by the same manufacturer. ^{68} In response to the problems of bio-inequivalence, official dissolution standards were established. ^{68} Problems have not been reported following establishment of these standards. However, because bioavailability from any digoxin tablet is incomplete (£ 80%), clinicians should consider this as a possible source of the problem when unexplained difficulty is encountered in the digitalization or maintenance therapy of patients with digoxin tablets.

Oral Dosage Forms

DIGOXIN CAPSULES

Note: Digoxin capsules (digoxin solution in capsules) have an absolute bioavailability close to that of the intravenous injection dosage form ^{61}. However, the capsules have a greater bioavailability than the tablets or elixir because they are more completely absorbed ^{61}. The recommended oral dose of digoxin capsules is 80% of that for the tablets or elixir ^{61}. See Bioequivalence information section.

Usual adult dose

Congestive heart failure

Digitalization:

Rapid digitalization is achieved by administering a loading dose based upon projected peak digoxin body stores (body stores of 8 to 12 mcg per kg of body weight in patients with heart failure and normal sinus rhythm; body stores of 6 to 10 mcg per kg of body weight for heart failure patients with renal insufficiency) ^{61}. Roughly one half the total loading dose is given as the first dose, with the remaining portion divided and administered every six to eight hours (e.g., 400 to 600 mcg [0.4 to 0.6 mg] initially, followed by 100 to 300 mcg [0.1 to 0.3 mg] administered every six to eight hours) until an appropriate clinical response is achieved ^{61}. Before each additional dose is given, the patient’s clinical response should be assessed carefully ^{61}. If the patient’s clinical response requires a change from the calculated loading dose of digoxin, calculation of the maintenance dose should be based upon the amount actually given ^{61}. For a 70-kg patient to achieve peak body stores of 8 to 12 mcg per kg of body weight, the usual amount administered is 600 to 1000 mcg (0.6 to 1 mg) ^{61}.Slow digitalization is achieved by beginning an appropriate maintenance dose (allowing digoxin body stores to accumulate slowly) ^{61}. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives ^{61}. Depending upon the patient’s renal function, digitalization by this method will take between one and three weeks ^{61}.

Maintenance:

Digoxin maintenance doses for estimated peak body stores of 10 mcg per kg of body weight generally have ranged from 50 to 350 mcg (0.05 to 0.35 mg), administered orally as one or two doses per day, the dosage titrated according to the patient’s age, lean body weight, and renal function ^{61}. In patients digitalized with a loading dose, the subsequent maintenance dose can be calculated as a percentage of the loading dose ^{61}. Doses may be increased every two weeks according to clinical response ^{61}.Atrial fibrillation, chronicDoses should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects ^{61}.

Usual pediatric dose

Congestive heart failure

Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area ^{61}. Children older than 10 years of age require adult dosages in proportion to their body weight ^{61}. Some researchers have suggested that infants and young children tolerate slightly higher serum digoxin concentrations than do adults ^{61}. For digitalization and maintenance dosing of children younger than 2 years of age, see Digoxin Elixir USP or Digoxin Injection USP . The following digitalizing and maintenance doses are based on lean body weight for children with heart failure and normal renal function ^{61}:

Digitalizing dose:Digitalizing doses for the capsules are the same as intravenous digitalizing doses ^{61}. The following total amounts should be divided into three or more doses, with the initial portion representing approximately one half the total, and the remaining doses administered every six to eight hours, with careful assessment of clinical response before each additional dose ^{61}. If the patient’s clinical response requires a change from the calculated loading dose of digoxin, the calculation of the maintenance dose should be based upon the amount actually given ^{61}.

Cardiac glycoside toxicity continues to be a problem in the United States because of the wide availability of digoxin (a preparation of digitalis) and a narrow therapeutic window. Digitalis is a plant-derived cardiac glycoside commonly used in the treatment of congestive heart failure (CHF), atrial fibrillation, and reentrant supraventricular tachycardia.^{[1, 2]} Digoxin is the only available preparation of digitalis in the United States. (See Etiology and Epidemiology.)

Cardiac glycosides are found in certain flowering plants, such as oleander and lily-of-the-valley. Certain herbal dietary supplements also contain cardiac glycosides. Indigenous people in various parts of the world have used many plant extracts containing cardiac glycosides as arrow and ordeal poisons. The ancient Egyptians used squill as a medicine. The Romans employed it as a diuretic, heart tonic, emetic, and rat poison. Digitalis, or foxglove, was mentioned in AD 1250 in the writings of Welsh physicians. Fuchsius described it botanically 300 years later and gave it the name Digitalis purpurea.

William Withering published his classic account of foxglove and some of its medical uses in 1785, remarking upon his experience with digitalis. He recognized many of the signs of digitalis toxicity, noting, “The foxglove, when given in very large and quickly repeated doses, occasions sickness, vomiting, purging, giddiness, confused vision, objects appearing green or yellow; increased secretion of urine, slow pulses, even as low as 35 in a minute, cold sweats, convulsions, syncope, death.” (See Presentation and Workup.)

During the early 20th century, as a result of the work of Cushny, Mackenzie, Lewis, and others, the drug was gradually recognized as specific for treatment of atrial fibrillation. Only subsequently was the value of digitalis for treatment of CHF established. Cardiac glycosides enhance cardiac contractility and slow conduction through the atrioventricular (AV) junction by increasing vagal tone. (See Etiology.)^[3]

Cardiac glycoside toxicity has been known to result from ingestion of some plants, including yellow oleander (Thevetia peruviana) and foxglove, and a similar toxidrome has been associated with the use of herbal dietary supplements.

Digoxin is among the top 50 prescribed drugs in the United States.^[4] Cardiac glycosides account for 2.6% of toxic plant exposures in the United States.^{[5, 6]} Most of these exposures are in children. (See Epidemiology.)^[6]

Digoxin-specific fragment antigen-binding (Fab) antibody fragments have contributed significantly to the improved morbidity and mortality of toxic patients since their approval in 1986 by the US Food and Drug Administration (FDA). (See Prognosis, Treatment, and Medication.)

Mechanism of action

The positive inotropic effect of digitalis has the following 2 components:

• Direct inhibition of membrane-bound sodium- and potassium-activated adenosine triphosphatase (Na⁺/K⁺ -ATPase), which leads to an increase in the intracellular concentration of calcium ([Ca²⁺]i)
• Associated increase in a slow inward calcium current (iCa) during the action potential (AP); this current is the result of movement of calcium into the cell, and it contributes to the plateau of the AP

Digitalis glycosides bind specifically to Na⁺/K⁺ -ATPase, inhibit its enzymatic activity, and impair active transport of extruding sodium and transport of potassium into the fibers (3:2 ratio). As a result, intracellular sodium ([Na⁺]i) gradually increases, and a gradual, small decrease in intracellular potassium ([K⁺]i) occurs.

Cardiac fiber [Ca²⁺]i is exchanged for extracellular sodium (3:1 ratio) by a transport system that is driven by the concentration gradient for these ions and the transmembrane potential; increase in [Na⁺]i is related crucially to the positive inotropic effect of digitalis.

In addition, by a mechanism that is not defined clearly, the increase in [Ca²⁺]i increases the peak magnitude of iCa; this change parallels the positive inotropic action. The change in iCa is a consequence of the increase in [Ca²⁺]i and not of the increase in [Na⁺]i. Thus, more calcium is delivered during the plateau of each AP to activate each contraction.

A fall in intracellular pH accompanies the digoxin-induced increase in [Ca²⁺]i, which leads to activation of a sodium/hydrogen exchange pump. This results in extrusion of hydrogen, an increase in [Na⁺]i, and greater inotropy.

The mechanism described assumes that Na⁺/K⁺ -ATPase is the pharmacologic receptor for digitalis and that, when digitalis binds to these enzymes, it induces a conformational change that decreases active transport of sodium. Many studies have provided evidence that digitalis binds to ATPase in a specific and saturable manner and that the binding results in a conformational change of the enzyme such that the binding site for digitalis probably is on the external surface of the membrane. Furthermore, the magnitude of the inotropic effect of digitalis is proportional to degree of inhibition of the enzyme.

Digitalis, in therapeutic concentrations, exerts no effect on the contractile proteins or on the interactions between them.

Electrophysiologic effects

The electrophysiological effects of cardiac glycosides include (1) decreased resting potential (RP) or maximal diastolic potential (MDP), which slows the rate of phase-0 depolarization and conduction velocity; (2) decrease in action potential duration (APD), which results in increased responsiveness of fibers to electrical stimuli; and (3) enhancement of automaticity, which results from an increase in the rate of phase-4 depolarization and from delayed after-depolarization.^[7]

In general, cardiac glycosides slow conduction and increase the refractory period in specialized cardiac conducting tissue by stimulating vagal tone. Digitalis has parasympathetic properties, which include hypersensitization of carotid sinus baroreceptors and stimulation of central vagal nuclei.

Digoxin also appears to have variable effects on sympathetic tone, depending on the specific cardiac tissue involved.

Electrocardiographic/vasomotor effects

Digoxin and other cardiac glycosides cause direct vasoconstriction in the arterial and venous system through inhibition of the Na⁺/K⁺ -ATPase pump in vascular smooth muscle.

Dosage and toxicity

The therapeutic daily dose of digoxin ranges from 5-15mcg/kg. The absorption of digoxin tablets is 70-80%; its bioavailability is 95%. The kidney excretes 60-80% of the digoxin dose unchanged. The onset of action by oral (PO) administration occurs in 30-120 minutes; the onset of action with intravenous (IV) administration occurs in 5-30 minutes. The peak effect with PO dosing is 2-6 hours, and that with IV dosing is 5-30 minutes. Only 1% of the total amount of digoxin in the body is in the serum; of that amount, approximately 25% is protein bound.

Digoxin has a large volume of distribution, being 6-10L/kg in adults, 10L/kg ieonates, and as much as 16L/kg in infants and toddlers. At therapeutic levels, the elimination half-life is 36 hours with renal excretion. In acute digoxin intoxication in toddlers and children, the average plasma half-life is 11 hours. With acute intoxication, plasma concentrations extrapolated to time zero are lower in toddlers than in infants and older children because of their increased volume of distribution and clearance.

The lethal dose of digoxin is considered to be 20-50 times the maintenance dose taken at once. In healthy adults, a dose of less than 5mg seldom causes severe toxicity, but a dose of more than 10mg is almost always fatal. In the pediatric population, the ingestion of more than 4mg or 0.3mg/kg portends serious toxicity. However, plasma concentration does not always correlate with the risk of toxicity.^[8]

Digoxin in pregnancy

Digoxin is used widely in the acute management and prophylaxis of fetal paroxysmal supraventricular tachycardia, as well as in rate control of atrial fibrillation. It is a category C drug. Increased digoxin dosage may be necessary during pregnancy because of enhanced renal clearance and expanded blood volume.

No series has been published regarding toxicity in the pregnant woman. Digoxin-specific Fab fragments can be used in pregnancy with the caveat that careful monitoring of the fetus must be maintained. Fetal myocardium has an increased resistance to the toxic effects of digitalis.

Patient education

Increase patient awareness about the symptoms of digitalis toxicity. In addition, educate patients about drug interactions and about maintaining adequate hydration. Parents of pediatric patients should be educated about good home childproofing and preventive measures.

Congestive heart failure

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.

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 contractionPhosphodiesterase 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.

 

Congestive Heart Failure > Drugs Used to Treat Congestive Heart Failure

What Drugs Are Used For CHF and What Do They Do?

Heart failure can be treated with several different types of drugs. The choice of drugs depends on other disorders a person has and on the severity of congestive heart failure (CHF). Some commonly used drugs used to treat CHF are listed in Table 1.

Angiotensin-Converting Enzyme (ACE) inhibitors

The mainstay of heart failure treatment is a group of drugs called angiotensin-converting enzyme (ACE) inhibitors. These drugs not only reduce symptoms and the need for hospitalization but also prolong life. These drugs cause blood vessels to widen (dilate). Then, the heart can pump blood more easily. They also help the kidneys excrete excess water, thus decreasing the amount of work the heart has to perform. These drugs also may have direct beneficial effects on the heart and blood vessel walls.

Angiotensin II Receptor Blockers

Angiotensin II receptor blockers have effects similar to those of ACE inhibitors. Angiotensin II receptor blockers are used with ACE inhibitors in some people or are used alone in people who cannot tolerate ACE inhibitors because of cough, a side effect of ACE inhibitors. However, the role of angiotensin II receptor blockers is still being evaluated in the treatment of heart failure.

Other Vasodilators

Other drugs that dilate blood vessels (vasodilators) are not used as often as ACE inhibitors, which are more effective. Nonetheless, people who do not respond to or cannot take ACE inhibitors or angiotension II receptor blockers can benefit from vasodilators, such as hydralazine, isosorbide dinitrate, and nitroglycerin patches or spray.

Beta-blockers

Beta-blockers are often given with ACE inhibitors to treat heart failure. These drugs help the heart function better and prolong life. They are especially helpful for people who have had a heart attack. Doctors adjust the dose carefully and monitor the person’s response to the drug because these drugs may temporarily worsen symptoms.

Diuretics (water pills)

Diuretics are water pills that work by stimulating the kidneys to produce more urine. They are used to remove extra fluid from the body and to help prevent fluid from accumulating. If heart failure is very mild, a diuretic may be taken only on days when fluid accumulation is noticeable. If heart failure is more severe, a diuretic is usually taken every day. Furosemide and bumetanide are most commonly used.

Most diuretics can make you lose potassium in your urine.For this reason, doctors may recommend increasing the amount of potassium in the diet. Good sources of potassium are bananas, oranges, and other fruits. Alternatively, doctors may recommend a potassium supplement.

Potassium-sparing diuretics, such as spironolactone and triamterene, prevent potassium loss. These drugs are weak diuretics. Spironolactone prolongs life and reduces need for hospitalization in people with severe heart failure.

People who take a diuretic may need to urinate more often and more urgently. If they have urinary incontinence, taking a diuretic may cause problems. However, people can usually time when they take a diuretic so that a bathroom is available when they are likely to need to urinate. In general, to keep the increase in urine from affecting your sleep:

• If you are to take a single dose a day, take it in the morning after breakfast.

• If you are to take more than one dose a day, take the last dose prior to 4pm to prevent sleeplessness at night, unless otherwise directed by your doctor.

Sometimes the dose of a diuretic needs to be adjusted. For example, the dose may need to be decreased in hot weather because people sweat more. Or the dose may need to be increased if the body is retaining fluid. Weighing every day helps people notice these changes. The dose of a diuretic must be adjusted by a doctor.

Cardiac glycosides (Digoxin)

Digoxin , one of the oldest treatments for heart failure, increases the force of each heartbeat and slows a heart rate that is too rapid. Digoxin helps relieve symptoms, especially if atrial fibrillation is present.

Anticoagulants (blood thinners)

Anticoagulants (sometimes called blood thinners), such as warfarin, make blood less likely to clot. They can prevent clots from forming in the heart chambers. People who take warfarin must have blood tests periodically to check the blood’s ability to clot. If blood is taking too long to clot, bleeding can occur. People who have coronary artery disease or diabetics are often given aspirin, which makes blood clots less likely to form. People who have an abnormal heart rhythm may be given antiarrhythmic drugs.

Positive inotropic drugs (Drugs that make muscle contract more forcefully)

For people who have severe symptoms and have not responded well to the usual treatments, other drugs that help the heart pump more efficiently may be used. These drugs include dopamine, dobutamine, and milrinone.

Table 1. Some Drugs Used to Treat Heart Failure

 

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