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Introduction

INTRODUCTION

Digoxin , also known as digitalis, is a purified cardiacglycoside extracted from the foxglove plant, Digitalis lanata .Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin. Digoxin is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication. Digoxin preparations are commonly marketed under the trade names Lanoxin, Digitek, and Lanoxicaps.


Basics of kinetics

Basics of kinetics:

Bioavailability

  • 60 to 80% (Oral)

  • Protein binding capability

  • Hepatic (16%)

  • Half-life:

    36 to 48 hours(patients with normal renal function)3.5 to 5 days(patients with impaired renal function)

  • Excretion:Renal

  • Routes:Oral, Intravenous


Mechanism of action

MECHANISM OF ACTION:

  • Digoxin binds to a site on the extracellular aspect of the α-subunit of the Na+/K+ATPase pump in the membranes of heart cells (myocytes) and decreases its function. This causes an increase in the level of sodium ions in the myocytes, which leads to a rise in the level of intracellular calcium ions. This occurs because of a sodium/calcium exchanger on the plasma membrane, which depends on a constant inward sodium gradient to pump out calcium. Digoxin decreases sodium concentration gradient and the subsequent calcium outflow, thus raising the calcium concentration in myocardiocytes and pacemaker cells.

  • Increased intracellular calcium lengthens Phase 4 and Phase 0 of the cardiac action potential, which leads to a decrease in heart rate. Increased amounts of Ca2+ also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility, the force of contraction, of the heart.

  • There is also evidence that digoxin increases vagal activity, thereby decreasing heart rate by slowing depolarization of pacemaker cells in the AV node. . This negative chronotropic effect would therefore be synergistic with the direct effect on cardiac pacemaker cells. Digoxin is used widely in the treatment of various arrhythmias


Indications

INDICATIONS:

  • Today, the most common indications for digoxin are probably atrial fibrillation and atrial flutter with rapid ventricular response, but beta- or calcium channel- blockers should be the first choice.High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves owing to improved filling.

  • The use of digoxin in heart problems during sinus rhythm . In theory the increased force of contraction should lead to improved pumping function of the heart. Digoxin is no longer the first choice for congestive heart failure, but can still be useful in patients who remain symptomatic despite proper diuretic and ACE inhibitor treatment. It has fallen out of favor because it was proven to be ineffective at decreasing morbidity and mortality in congestive heart failure


Use of digoxin in heart failure

USE OF DIGOXIN IN HEART FAILURE:

Patients with more severe heart failure, a third heart sound gallop, left ventricular enlargement and a depressed left ventricular ejection fraction are more likely to respond to digoxin therapy.

  • Many compensatory mechanisms, including the sympathetic nervous system and salt- and water-retaining systems, become activated in the setting of a depressed cardiac output. The compensatory systems can maintain left ventricular function for days to months. However, when patients become overtly symptomatic, they begin to experience a striking increase in morbidity and mortality. The transition to symptomatic heart failure is accompanied by further activation of the neurohormonal system, including the sympathetic nervous system and a series of adaptive changes in the myocardium.

  • Digoxin-Induced Neurohormonal Modulation

  • In the past, digoxin was considered to be solely a positive inotropic agent. In patients with heart failure, digoxin exerts its positive inotropic effect by inhibiting sodium-potassium adenosine triphosphatase (ATPase). Inhibition of this enzyme in cardiac cells results in an increase in the contractile state of the heart. it has been shown that digoxin exerts a positive inotropic effect at higher dosages (0.25 mg or more per day); however, at lower dosages (less than 0.25 mg per day), this drug exerts a mainly neurohormonal effect and has little inotropic activity.21

  • The neurohormonal effect of digoxin showed that digoxin reduced plasma norepinephrine levels; these results were validated in other studies.The explanation for this effect was that digoxin improves impaired baroreceptor reflexes in heart failure.

  • Digoxin may also lower plasma renin levels, either because of a direct renal effect or secondary to inhibition of sympathetic activity. By inhibiting sodium-potassium ATPase in the kidney, digoxin decreases renal tubular reabsorption of sodium, thereby increasing delivery of sodium to the distal tubules and suppressing renin secretion.


Digoxin therapy in congestive heart failure

DIGOXIN THERAPY IN CONGESTIVE HEART FAILURE:

  • Digoxin has been shown to improve morbidity without any benefit on mortality.

  • Digoxin may act by decreasing sympathetic activity.

  • Digoxin may not be effective in patients who have normal left ventricular systolic function.

  • The benefits of digoxin therapy are greatest in patients with severe heart failure, an enlarged heart and a third heart sound gallop.

  • Digoxin may be used in patients with mild to moderate heart failure if they do not respond to an angiotensin-converting enzyme inhibitor or a beta blocker.

  • Low dosages of digoxin can be effective.

  • Renal function and possible drug interactions must be considered in deciding on an appropriate dosage of digoxin.

  • In general, digoxin therapy should be avoided in the acute phase after myocardial infarction.


Ecg of chf

ECG OF CHF


Atrial fibrillation

ATRIAL FIBRILLATION:

  • Atrial fibrillation (AF) is the most common type of heart arrhythmia. An arrhythmia is a problem with the rate or rhythm of the heartbeat.

  • Atrial fibrillation occurs when rapid, disorganized electrical signals cause the atria to fibrillate (contract very fast and irregularly). When this happens, the heart's upper and lower chambers don't work together as they should.


Introduction 2244797

If a clot (thrombus) forms in the left atrium of the heart, a piece of it can dislodge and travel to an artery in the brain, blocking blood flow through the artery. The lack of blood flow to the portion of the brain fed by the artery causes a stroke.


Atrial flutter

ATRIAL FLUTTER:

Atrial flutter refers to rapid and regular contractions (usually in the range of 120 to 350 times each minute) that is characterised on the ECG by a saw-tooth appearance. Not all atrial contractions are necessarily conducted to the ventricles due to a variable block within the atrioventricularnode. When conduction to the ventricles does occur, the QRScomplex morphology is regular but RR intervals may be random or follow a specific pattern.


Introduction 2244797

The ECG trace shows regular flutter waves (arrowed) at a rate of five per second. Ventricular conduction is occurring after every two (shaded RR intervals) or three (unshaded RR intervals) atrial contractions.


Dosing and tdm of digoxin

DOSING AND TDM of Digoxin:


Dosage form of digoxin

DOSAGE FORM OF DIGOXIN:


Bioavalability factor f of dosage

BIOAVALABILITY FACTOR (F)OF DOSAGE:


Crcl based maintance dosage and interval adjustment

CRCL-BASED MAINTANCE DOSAGE AND INTERVAL ADJUSTMENT:


Dosing

DOSING :

  • Digoxin may be taken with or without food. Digoxin is primarily eliminated by the kidneys; therefore, the dose of digoxin should be reduced in patients with kidney dysfunction. Digoxin blood levels are used for adjusting doses in order to avoid toxicity. The usual starting dose is 0.0625-0.25 mg daily depending on age and kidney function. The dose may be increased every two weeks to achieve the desired response.


Heart failure

HEART FAILURE:


Atrial fibrillation1

ATRIAL FIBRILLATION:


Usual pediatric dose in atrial fibrillation

Usual pediatric dose in atrial fibrillation:


Usual pediatric dose in atrial fibrillation c ont

Usual pediatric dose in atrial fibrillation:(cont.)


Dose adjustments

DOSE ADJUSTMENTS:

  • If patients are switched from intravenous to oral formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages. When changing from oral formulations to IM or IV therapy, dosage should be reduced by 20% to 25%. 

  • Divided dosage of the capsule formulation is preferred in patients that require a daily dose greater than 300 mcg, those with a previous history of digitalis toxicity, and in patients who may be more likely to become toxic.


General advice

GENERAL ADVICE:

  • Calculate doses based upon lean (ideal) body weight.

  • Consider the differences in bioavailability between digoxin injection, tablets, and oral solution when changing patients from one dosage form to another.

  • For IV administration, digoxin injection may be diluted (4-fold or more) with normal saline, dextrose 5% in water, or sterile water for injection. Infuse slowly, 5 min or longer.

  • IM injection can lead to severe pain at the injection site. If the drug must be administered IM, inject it deeply into the muscle and follow with massage. Do not inject more than 2 mL (500mcg) into a single site.


Therapeutic drug monitoring of digoxin

THERAPEUTIC DRUG MONITORING OF DIGOXIN:

  • Digoxin is one of the most commonly used drugs in medicine. Despite this widespread use and a history of over 200 years of clinical use and research, much controversy continues concerning its efficacy and safety. Two of the most prominent features of the clinical use of digoxin are :

  • 1.Its narrow therapeutic index

  • 2.An endpoint of therapy which is difficult to define and measure.

    Digitalis toxicity is one of the most frequently encountered drug-related causes of hospitalization. Conversely, the effect of serum digoxin concentrations below 0.8 ng/ml is clinically unimportant in most patients.


Calculation of individual patient doses

Calculation of individual patient doses:

  • The great variability in serum digoxin concentrations in patients given the same dose has led to the development of nomograms and equations designed to estimate the optimal digoxin dosage. These methods include factors such as age, weight, sex, renal function, disease state, and concurrent drug therapy to calculate the dose and corresponding serum concentration. An accurate method could decrease the potential for drug toxicity, which can be life-threatening, and decrease the time period required to optimize therapy, which is otherwise done by trial and error.


Why do we need a loading dose

WHY DO WE NEED A LOADING DOSE?

  • An adequate loading dose is necessary for rapid attainment of therapeutic serum levels. Choosing to initiate therapy with out a loading dose means that, because of digoxin's long half-life, therapeutic serum levels may not be achieved for weeks.


Monitoring parameters

Monitoring parameters:

  • The following patient parameters should be monitored during digoxin therapy:

    • Digoxin serum levelObtain level within 24 hours of digitalization, weekly until stable, and at steady state.

    • BUN and serum creatinineMeasure every two days, or every day in unstable renal function.

    • Weigh patient daily.

    • Measure and monitor urine output daily Monitor apical pulse daily


Precautions predisposing factors

PRECAUTIONS & PREDISPOSING FACTORS:

  • Proper timing of serum sampling is critical.Serum samples should be drawn just prior to the daily dose and no sooner than six hours after administration of the drug.

  • Factors affecting digoxin pharmacokinetics

    • Factors which predispose to digoxin toxicity:Hypokalemia, uncorrected hypothyroidism, renal dysfunction, and interacting drugs which decrease digoxin clearance (e.g: verapamil).

    • Factors which predispose to suboptimal clinical response:Hyperkalemia, uncorrected hyperthyroidism, interacting drugs which delay or prevent oral absorption (e.g antacids,).


How to design a regimen

HOW TO DESIGN A REGIMEN?

  • Before calculating an initial dose or adjusting the maintenance dose one must know the target digoxin serum level, whether the patient is in acute congestive failure and whether any interacting drugs are being concurrently administered.

  • Initial dosing(using a TDM software)

    The program first calculates an ideal loading dose, enter a practical dose and the desired dosage form of the loading dose. Enter 0 if no loading dose is desired. The program calculates an ideal maintenance dose, the user enters a practical maintenance dose and interval. The program then displays an estimated steady-state serum level.


Dosage adjustment based on serum levels

Dosage adjustment based on serum levels:

  • First enter the measured serum digoxin concentration, the dosage form, digoxin dose and interval. The program then requires the date and time the current dosage regimen was initiated, this is used to determine whether the patient’s digoxin level is at a steady-state. The program then calculates an incremental loading dose or temporary interruption, depending upon whether the serum level is below or above the target level. The user enters a practical loading dose or temporary interruption. The program calculates an ideal maintenance dose and the user enters a practical maintenance dose and interval. The program then displays an estimated steady-state serum level.


Digoxin dosing flow chart

DIGOXIN DOSING FLOW CHART:


Digitalizing a patient

DIGITALIZING A PATIENT:

  • Initial dosing:

    • Estimation volume of distribution (jusko equation)

    • Calculate loading dose

    • Estimate clearance(koda –kimble)

    • Calculate maintance dose

    • Estimate steady -state trough level


Estimate volume of distribution jusko equation

ESTIMATE VOLUME OF DISTRIBUTION (JUSKO EQUATION):

Vd = 226 + [(298 x CrCl) / (29.1 + CrCl)] x (BSA / 1.73)where

CrCl = normalized creatinine clearance (ml/min)BSA = Body surface area (square meters)


Calculate loading dose

CALCULATE LOADING DOSE:

LD = Vd x Cp/F where Vd = Volume of distribution (liters)Cp = target serum level (mcg/l)F = bioavailability factor

  • IV push = 1

  • capsules= 0.95

  • elixir = 0.8

  • tablets = 0.75


Estimate clearance koda kimble

ESTIMATE CLEARANCE (KODA KIMBLE):

Cl =[(A x CrCl) +B] x C

Where;

A =0.88 for aute CHF ,otherwise =1

B=23 for acute CHF ,otherwise=40

C=corrective factor for interacting drugs:

Quinidine =0.65

Spirolatone =0.75

Verapamil=0.7

Other =0.71


Calculate maintenance dose

CALCULATE MAINTENANCE DOSE:

  • MD = (Cl x Cp x tau) / F

  • where Cl = Clearance (liters/hour)Cp = target serum level (mcg/l)tau = dosing interval (hours)F = bioavailability factor


Estimate steady state trough level

Estimate steady-state trough level:

Cpss = (MD x F) / (Cl x tau)where

MD = Maintenance dose (mcg)F = bioavailability factorCl = Clearance (liters/hour)tau = dosing interval (hours)


Adjust maintenance dose

ADJUST MAINTENANCE DOSE:

  • Estimate Volume of Distribution (Jusko Equation)

  • Calculate digoxin clearanceCl = [(MD x F) / Cp] / tauwhere MD = Maintenance dose (mcg)F = Bioavailability factorCp = Steady-state serum digoxin concentration (mcg/l)tau = Dosing interval (hours)

  • Calculate Maintenance Dose

    MD = (Cl x Cp x tau) / Fwhere Cl = Digoxin clearance (l/hr)Cp = target serum level (mcg/l)tau = dosing interval (hours)F = bioavailability factor


Estimate steady state trough level1

Estimate steady-state trough level:

  • Cpss = (MD x F) / (Kel x Vd x tau)where MD = Maintenance dose (mcg)F = bioavailability factorKel = Elimination rate (1/hours)Vd = Volume of distribution (liters)tau = dosing interval (hours)


Significance of tdm

SIGNIFICANCE OF TDM:

  • Therapeutic drug monitoring (TDM) is only of value for a limited number of drugs. For such measurements to be clinically worthwhile, the following criteria should be fulfilled:

  • 1. Established relationship between plasma drug concentration and therapeutic response and/or toxicity;

  • 2. Poor relationship between plasma concentration and drug dosage;

  • 3. A good clinical indication for the test such as : no response to treatment; suspected non-compliance; signs of toxicity;

  • 4. The collection of an appropriately timed and dated specimen with proper patient information;

  • 5. Adequate clinical information to allow the interpretation of results.


Contraindications

CONTRAINDICATIONS:


Contraindications to digoxin are many

CONTRAINDICATIONS TO DIGOXIN ARE MANY:

  • 1.Hypertrophic obstructive cardiomyopathy (hypertrophic subaorticstenosis, asymmetrical septal hypertrophy) is a contraindication (unless there is atrial fibrillation and severe myocardial failure), because the inotropic effect can worsen outflow obstruction,hypokalemia,ventricular tachycardia.


Introduction 2244797

2.In some cases of Wolff-Parkinson-White syndrome with atrial fibrillation, digitalization may accelerate anterograde conduction over the bypass tract to precipitate ventricular tachycardia or ventricular fibrillation.

3.Significant AV nodal heart block. Intermittent complete heart block or second-degree AV block or sick sinus syndrome may be worsened by digitalis, especially if there is a history of Stokes-Adams attacks or when conduction is likely to be unstable, as in AMI or acute.


Hypertrophic cardiomyopathy

HYPERTROPHIC CARDIOMYOPATHY:

  • Hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle becomes thick. The thickening makes it harder for blood to leave the heart, forcing the heart to work harder to pump blood.

  • Hypertrophic cardiomyopathy is often asymmetrical, meaning one part of the heart is thicker than the other parts. The condition is usually passed down through families (inherited). It is believed to be a result of several problems (defects) with the genes that control heart muscle growth.


Why digoxin is contraindicated in hypertrophic obstructive cardiomyopathy

Why digoxin is contraindicated in hypertrophic obstructive cardiomyopathy?

  • Because the inotropic effect can worsen outflow obstruction.


Wolff parkinson white syndrome wpw

WOLFF-PARKINSON-WHITE SYNDROME (WPW):

  • Wolff-Parkinson-White (WPW) syndrome, digoxin and verapamil may result in extremely fast heart rates that can lead to lightheadedness, fainting (syncope), and even death. These drugs are only dangerous when given in an emergency when someone with Wolff-Parkinson-White syndrome is having atrial fibrillation.Treatment of WPW frequently requires antiarrhythmic medicines, such as propafenone (Rythmol) or flecainide (Tambocor), that slow electrical conduction over the extra connection.


Ventricular fibrillation and other heart diseases

VENTRICULAR FIBRILLATION AND OTHER HEART DISEASES:

  • Digoxin is contraindicated in patients with ventricular fibrillation. Ventricular fibrillation is a condition in which the heart beats rapidly causing the ventricles to stop pumping blood. This causes the blood pressure to fall and the supply of blood to the other parts of the body gets cut off.

  • Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased.


Second degree artioventicular block

SECOND-DEGREE ARTIOVENTICULAR BLOCK:

  • Second-degree AV block is a disease of the electrical conduction system of the heart. It refers to a conduction block between the atria and ventricles.


Why digoxin is contraindicated in av block

WHY DIGOXIN IS CONTRAINDICATED IN AV BLOCK:

  • Digoxin inhibits the sodium/potassium ATPase pump resulting in increased intracellular sodium leading to impaired sodium/calcium exchange in increased intracellular calcium. This increased intracellular calcium is stored in the sarcoplasmic reticulum of the cardiac muscle , resulting in increased calcium reserve stronger muscle contraction. Digoxin also potentiates the vagally mediated slowing of AV conduction and increased atrial ventricular block.

  • Patients with hypokalemia, second-degree AV block, third-degree AV block, and patients with atrial fibrillation , who also have Wolfe-Parkinson-White syndrome should not be given digoxin.


Sick sinus syndrome

SICK SINUS SYNDROME:

  • Sick sinus syndrome is a collection of conditions in which the ECG indicates sinus node dysfunction. It is characterised by sinus node dysfunction with an atrial rate inappropriate for normal requirements. Sick sinus syndrome is usually caused by idiopathic fibrosis of the sinus node.


Causes

CAUSES:

  • Hyperkalaemia, hypoxia, hypothermia, hypothyroidism, hyperthyroidism

  • Drugs, e.g. digoxin, calcium-channel blockers, betablockers, sympatholytic agents, antiarrhythmic drugs

  • Toxins, e.g. result of sepsis

  • In some cases of sinoatrial disorder (i.e. Sick Sinus Syndrome) digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block.


  • Stokes adams attack

    STOKES ADAMS ATTACK:

    • Sudden collapse into unconsciousness due to a disorder of heart rhythm in which there is a slow or absent pulse resulting in syncope (fainting) with or without convulsions.

    • In this condition, the normal heartbeat passing from the upper chambers of the heart to the lower chambers is interrupted. This results in a condition called a "heart block." When a heart block occurs, the heart rate usually slows considerably. This can cause inadequate blood flow to the brain and result in fainting.


    Special warnings and precautions for use

    Special warnings and precautions for Use

    • Hypokalaemiasensitises the myocardium to the actions of cardiac glycosides.Hypoxia, Hypomagnesemia and marked hypercalcemia increase myocardial sensitivity to cardiac glycosides.

    • Rapid intravenous injection can cause vaso-constriction producing hypertension and/or reduced coronary flow. A slow injection rate is therefore important in hypertensive heart failure and acute myocardial infarction.


    Hypokalemia why hypokalemia cause digoxin toxicity

    HYPOKALEMIA WHY HYPOKALEMIA CAUSE DIGOXIN TOXICITY

    • Usually, hyperkalemia is associated with usage of digoxin. This is due to the blocking action of digoxin on the Na/K ase which results in accumulation of extracellular K+.Most of the times, patients presenting with heart problems are already on diuretics before they are prescribed with digoxin. Diuretics cause hypokalemia as they result in excessive excretion of K+ from the body. Hypokalemia in turn causes digoxin toxicity. Digoxin toxicity does not cause hypokalemia, but hypokalemia can worsen digoxin toxicity.


    Kidney disease and other medical conditions

    KIDNEY DISEASE AND OTHER MEDICAL CONDITIONS:

    • Digoxin should be used with caution in patients with kidney diseases. Since renal impairment leads to slower removal of the excess medication from the body, the effects of the drug may be more than required. also says that digoxin should be used with caution in patients with diseases related to the blood vessels or the thyroid glands. The drug could also worsen conditions such as the presence of high amounts of calcium or oxygen and low amounts of potassium or magnesium in blood.


    Digoxin pregnancy and breastfeeding warnings

    Digoxin Pregnancy and Breastfeeding Warnings:

    • Digoxin has been assigned to FDA .pregnancy catageory “C” by the FDA digoxin has been used successfully to treat maternal chf and arrhythmias throughout gestation without report of fetal harm .Digoxin should be given during pregnancy only when benefit out weighs risk.

    • Digoxin is excreted into human milk, however, nursing infant exposure is limited. Pharmacologic and/or adverse effects are not anticipated. However, the manufacturer recommends caution when administering digoxin to nursing women.


    Drug interactions

    DRUG INTERACTIONS:

    • Amiodarone

    • Antacids

    • Antibiotics such as erythromycin and clarithromycin

    • Asthma medications

    • Calcium-containing supplements or medications

    • Decongestant medications for colds or allergies

    • Diarrhea medications

    • Diet pills

    • Diuretics (water pills)

    • Itraconazole

    • Kaolin-pectin

    • Laxatives

    • Other heart medications

    • Quinidine

    • Sulfasalazine

    • Thyroid medications

    • Verapamil


    Interactions

    INTERACTIONS:


    Drug to drug interactions

    DRUG TO DRUG INTERACTIONS:

    • Drugs rising digoxin concentration:

    • Amiodarone ↔ Digoxin

    • ADJUST DOSE:Coadministration with amiodarone may increase serum digoxin concentrations by up to 100%, frequently resulting in clinical toxicity.Amiodarone has been suggested to increase intestinal transit time, reduce renal clearance and volume of distribution, displace digoxin from protein binding sites, as well as induce hypothyroidism, both drugs may have additive bradycardic effects.

    • MANAGEMENT:The need for continued digitalis therapy should be evaluated if amiodarone is prescribed to patients treated with digitalis. Empirical reduction of digitalis dosage by one-third to one-half should be considered in patients who require concomitant treatment with these drugs.


    Introduction 2244797

    ANTIBIOTICS (Clarithromycin,Erythromycin) ↔ Digoxin

    • MONITOR:antibiotics may increase plasma concentrations of orally administered digoxin in about 10% of the population. The mechanism may be related to altered intestinal flora effect on gut-wall metabolism or absorption and/or inhibition of renal P glycoprotein secretion of digoxin.

    • MANAGEMENT:Patients should be advised to notify their physicians if they experience nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.

    • Quinine↔ Digoxin

    • MONITOR:High doses of quinine (greater than 600 mg/day) may decrease the plasma clearance of digoxin in some patients. Serum digoxin levels and risk of toxicity may be increased. The mechanism is believed to be decreased biliary clearance of digoxin. MANAGEMENT:During coadministration, the patient should be monitored for signs and symptoms of digoxin toxicity and serum digoxin levels should be checked when clinically necessary. Patients should be advised to notify their physician if they experience nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.


    Introduction 2244797

    • ACE INHIBATORS (Captopril) ↔ Digoxin

    • MONITOR:Some ACE inhibitors may decrease the renal clearance of digoxin. Increased plasma digoxin levels may result. The proposed mechanism is reduced tubular secretion of digoxin. Some occurrences of decreased digoxin levels also have been reported. Patients with CHF or renal impairment may have a greater risk of developing digoxin toxicity. MANAGEMENT:While this combination has demonstrated benefits in some CHF patients, their clinical response and digoxin levels should be monitored.


    Introduction 2244797

    • ANTIFUNGALS (Itraconazole) ↔ Digoxin

    • MONITOR:The coadministration of itraconazole or ketoconazole and digoxin may result in increased plasma concentrations of the latter. Two- to fourfold increases in digoxin concentrations have been reported after initiation of itraconazole. Toxicity has occurred in some cases, most with an onset of 9 to 13 days following the start of azole therapy. The exact mechanism of the interaction is unknown but may be related to azole-induced inhibition of the P-glycoprotein transport of digoxin, resulting in reduced renal clearance. MANAGEMENT:Caution is advised during concomitant therapy. Serum digoxin levels should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of the antifungal agent in patients who are stabilized on their digoxin regimen. Patients should be advised to notify their doctor if they experience signs of digoxin toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeats.


    Introduction 2244797

    • BETA-BLOCKERS (Propranolol) ↔ Digoxin

    • MONITOR:Concomitant use of digitalis glycosides and beta-blockers may increase the risk of bradycardia. These agents slow atrioventricular conduction and decrease heart rate, hence they may have additive cardiac effects during coadministration. Some beta-blockers have also been reported to increase the systemic bioavailability of digoxin. The mechanism may involve enhanced absorption as well as reduced renal excretion of digoxin due to inhibition of intestinal and renal P-glycoprotein efflux transporter.

    • MANAGEMENT:Caution is advised during coadministration of digitalis glycosides and beta-blockers. Serum digitalis levels, heart rate, and blood pressure should be monitored closely, particularly during the first few weeks of concomitant therapy. Beta-blockers should not be used in patients with overt or decompensated congestive heart failure.


    Introduction 2244797

    • CALCIUM CHANNEL BLOCKERS (Verapamil)↔ Digoxin

    • ADJUST DOSE:Verapamil increases digoxin levels significantly in most patients. Verapamil decreases renal and extrarenal clearance of digoxin. Serum digoxin levels may increase by 50% to 75% during the first week of concomitant verapamil therapy. Increases may be larger in patients with hepatic cirrhosis. Digoxin and verapamil have additive effects in slowing AV conduction.Synergistic effect of slowing impulse conduction and muscle contractility, leading to bradycardia and possible heart block.MANAGEMENT:If verapamil and digoxin are used together to control a supraventricular tachyarrhythmia, the dosage of each drug may have to be reduced. Despite the possible negative inotropic effects of verapamil, digoxin dosage probably will not have to be increased when a patient with congestive heart failure is given verapamil.


    Introduction 2244797

    • Drugs lowering digoxin concentration:

    • ANTINEOPLASTICS (Vincristine)↔ Digoxin

    • MONITOR: Some antineoplastic agents have been associated with decreased gastrointestinal absorption of digoxin. The suspected mechanism is alteration of the gastrointestinal mucosa. The risk of an interaction is expected to be less with digoxin solution in capsules because absorption occurs rapidly in the upper GI tract. MANAGEMENT: During coadministration, the patient should be monitored for digoxin effectiveness. Serum digoxin levels should be monitored and the digoxin dosage adjusted as necessary.

    • Antacids_Digoxin

    • MONITER: Digoxin has a well-defined interaction with aluminum-salt--based antacid treatments, such as aluminum hydroxide, kaolin-pectin and other stomach-coating medications. These antacid medicines may lower absorption of digoxin through the gastric system.

    • MANAGEMENT:digoxin should be taken at least 2 hours before the antacids. Similar interactions between digoxin and other drugs that affect stomach emptying and acidity are also likely.


    Minor food interaction

    MINOR FOOD INTERACTION:

    • Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits.

    • MANAGEMENT: Administer digoxin 1 hour before or 2 hours after such a meal


    Disease interactions

    DISEASE INTERACTIONS:

    • Digoxin ↔ Bradyarrhythmia/Av Block

    • Digoxin slows sinoatrial and AV conduction, commonly prolonging the PR interval. When treated with digoxin, patients with preexisting sinus node disease may develop severe sinus bradycardia or sinoatrial block, and patients with incomplete AV block may progress to advanced or complete heart block. In such patients, consideration should be given to the insertion of a pacemaker prior to initiating treatment with digoxin. Digoxin may be administered to patients with complete, stable AV block who have congestive heart failure, provided the block was not induced by cardiac glycosides.

    • Digoxin ↔ Hypercalcemia

    • Calcium and digoxin have additive inotropic effects. Therefore, hypercalcemia from any cause will predispose patients to digoxin toxicity and serious arrhythmias. Hypercalcemia should be corrected prior to initiating treatment with digoxin, and serum calcium levels should be monitored during therapy.


    Introduction 2244797

    • Digoxin ↔ Hypocalcemia

    • Hypocalcemia can nullify the effects of digoxin. The drug may be ineffective in hypocalcemic patients until serum calcium levels are restored to normal.

    • Digoxin ↔ Hypokalemia/Hypomagnesemia

    • Potassium and/or magnesium depletion sensitizes the myocardium to digoxin. In patients with hypokalemia or hypomagnesemia, digoxin toxicity may occur despite serum drug concentrations below 2.0 ng/ml. Therapy with digoxin should be administered cautiously in patients with or predisposed to potassium and/or magnesium deficiency, including patients on diuretic therapy; those with primary or secondary aldosteronism (may have low potassium levels); those with severe or prolonged diarrhea or vomiting; those with malnutrition; and renal dialysis patients. Electrolyte imbalances should be corrected prior to initiation of treatment. Serum potassium and magnesium concentrations should be monitored during therapy


    Introduction 2244797

    • Digoxin ↔ Renal Dysfunction

    • Digoxin is primarily eliminated by the kidney. Patients with renal impairment may be at increased risk for digoxin toxicity, including ventricular arrhythmias and AV conduction disturbances, due to decreased drug clearance.Therapy with digoxin should be administered cautiously in patients with impaired renal function. Dosage adjustments should be made according to product package labeling and patient attributes such as age, ideal body weight and other concomitant disease states and medication usage. Dosage increments should be made very gradually, since the elimination half-life may be prolonged in these patients and a longer period of time is required to establish steady-state serum concentrations than normal. These patients should be monitored closely for manifestations of toxicity, and dosages further adjusted as necessary. If toxicity occurs, clinicians should be aware that the adverse effects may also be prolonged.

    • Digoxin ↔ Acute MI

    • The use of inotropic drugs in some patients with acute myocardial infarction may lead to increases in myocardial oxygen demand and ischemia. Therapy with digoxin should be administered cautiously in this setting.


    Introduction 2244797

    • Digoxin↔ Hyperthyroidism

    • Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states such as hyperthyroidism, hypoxia, or arteriovenous shunt are best managed by treating the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly refractory to digoxin, possibly due to altered pharmacokinetics. Specifically, the apparent volume of distribution and renal elimination of the drug may be increased, resulting in lower serum concentrations. Therapy with digoxin should be administered cautiously in patients with hyperthyroidism. Serum digoxin levels should be monitored regularly and dosage adjustments may be required secondary to changes in their thyroid condition.

    • Digoxin ↔ Hypothyroidism

    • Hypothyroidism may reduce the requirements for digoxin due to decreased volume of distribution and plasma clearance of the drug. Therapy with digoxin should be initiated at lower dosages in patients with hypothyroidism to avoid toxicity. Serum digoxin levels should be monitored regularly and dosage adjustments may be required secondary to changes in their thyroid condition


    How can drug interactions be avoided

    HOW CAN DRUG INTERACTIONS BE AVOIDED?

    • Give health care practitioners a complete list of all of the drugs that you are using or have used within the last few weeks. This should include over-the-counter medications, vitamins, food supplements, and herbal remedies.

    • Inform health care practitioners when medications are added or discontinued.

    • Inform health care practitioners about changes in lifestyle (for example, exercise, diet, alcohol intake).

    • Ask your health care practitioners about the most serious or frequent drug interactions with the medications that you are taking.

    • Since the frequency of drug interactions increases with the number of medications, work with your health care practitioners to eliminate unnecessary medications


    Adverse effects

    ADVERSE EFFECTS:


    Adverse effects1

    ADVERSE EFFECTS:

    • The frequency and severity of adverse reactions to digoxin depend on the dose and route of administration,as well as on the patient's underlying disease or concomitant therapies.

    • The overall incidence of adverse reactions have been reported as 5 to 20% with 15 to 20% of them being considered serious (1 to 4% of patients receiving digoxin).

    • Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. 


    Causes of digoxin toxicity

    CAUSES OF DIGOXIN TOXICITY:

    • Therapeutic administration can cause toxicity:

      • Usual therapeutic doses

      • Doses with errors in prescription, dispensing, or administration

    • Acute non-therapeutic overdose can cause toxicity:

      • Unintentional

      • Suicidal

        The main causes of digitalis toxicity in the pediatric population include the following:

      • Erroneous dosing in infants, which is usually parenteral and frequently fatal

      • Unintentional ingestion in younger children, which is rarely fatal


    Causes of digoxin toxicity1

    CAUSES OF DIGOXIN TOXICITY:

    • Electrolytic abnormalities can worsen digitalis toxicity.

      • Hypokalemia can worsen toxicity. Hypokalemia is usually observed with chronic toxicity or in patients taking diuretics. Hypokalemia reduces the rate of sodium-activated and potassium-activated adenosine triphosphatase (Na+ K+ATPase) pump turnover and exacerbates pump inhibition due to digitalis.

      • Hyperkalemia can also worsen toxicity. In pediatric patients, hyperkalemia is usually a complication of acute toxicity rather than a cause; however, preexisting hyperkalemia increases the risk of morbidity and mortality.

      • Hypomagnesemia, hypercalcemia, can aggravate toxicity.4


    Causes of digoxin toxicity2

    CAUSES OF DIGOXIN TOXICITY:

    • Concomitant use of the following drugs can exacerbate digitalis toxicity:

      • Quinidine, procainamide, amiodarone, calcium channel blockers, beta-blockers

      • Diuretics, including spironolactone

      • Erythromycin and tetracycline: These agents can increase serum digoxin levels by inactivating an enteric bacterium (Eubacterium species) that is present in 10% of the population. This bacterium inactivates digoxin in the GI tract.


    Causes of digoxin toxicity3

    CAUSES OF DIGOXIN TOXICITY:

    • Other risk factors include the following:

      • Renal dysfunction

      • Hypothyroidism

      • Acidosis

      • Myocardial disease

      • Extremes of age


    Adverse effects on gi

    ADVERSE EFFECTS ON GI:

    • Nausea and vomiting.

    • Anorexia, weight loss.

    • Abdominal pain.

    • Diarrhea.


    Adverse effect on cns

    ADVERSE EFFECT ON CNS:

    • Lethargy or drowsiness

    • Confusion or giddiness

    • Headaches

    • Hallucinations

    • Visual changes, including aberrations in color vision (chromatopsia) and yellow halos around lights (xanthopsia), transient amblyopia or scotomata, and decreased visual acuity

    • Seizures (rare)

    • Syncope.


    Adverse effects on cvs

    ADVERSE EFFECTS ON CVS:

    • Ventricular tachycardia.

    •  Ventricular fibrillation.

    • Supraventricular extra beats.

    • Heart block.

    • Ventricular arrhythmias


    Adverse effects on hormones

    ADVERSE EFFECTS ON HORMONES:

    • Increased FSH (follicular stimulating hormone).

    • Increased estrogen.

    •  Decreased LH.

    • Decreased testosterone.


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