DIGOXIN AND ITS

TOXICITY

Dr. Satyam Rajvanshi

SR Cardiology, Dr. RML Hospital, New Delhi

Introduction

Introduction

Cardiac Glycosides (or CardioactiveSteroids (CAS)) - organic compounds containing a glycoside (sugar) and a common steroid nucleus that act on the contractile force of the cardiac muscle.

Because of their potency in disrupting the function of the heart, most are extremely toxic.

The most common pharmaceutical product is digoxin. Other preparations available internationally include digitoxin, ouabain, lanatoside C, deslanoside, and gitaline.

Cardiac glycosides : Sources

Plants

Digitalis purpurea (Foxglove, Common

Foxglove, Lady's Glove)

Digitalis lanata (Woolly Foxglove or Grecian

Foxglove)

Cardiac glycosides : Sources

Insects

Some Buttefly species

Amphibians

Some toad species

History

There is evidence in the EbersPapyrus (Papyrus Smith) that the Egyptians used plants containing CAS at least 3000 years ago.

William Withering, an englishBotanist

noticed a person with dropsy (historical name of CHF) improve remarkably after taking a traditional herbal remedy

recognised that the active ingredient in the mixture came from foxglove

In 1785, published An Account of the Foxglove and some of its Medical Uses, which contained reports on clinical trials and notes on digitalis's effects and toxicity.

Pharmacology and

Mechanism of Action

Chemical structure

All cardiac

glycosides

Genin (active part) =

Steroid nucleus +

Lactone ring

“Digoxigenin”

Sugar (physical

properties)

Term ‘Digitalis’

refers to all cardiac

glycosides

Mechanism of Action

Positive Inotropic Action

Neurally Mediated Action

Electrophysiolocal Action

Digoxin is a cardiac glycoside that binds to and inhibits sarcolemma-bound (Naþ/Kþ-) Mg2þ-ATPase. This ATPase catalyses both an active influx of 2 K ions and an efflux of 3 Na ions against their respective concentration gradients, the energy being provided by the hydrolysis of ATP.

The inhibition induced by digoxin leads to an efflux of potassium from the cell and, in proportion to the extent of inhibition of the ATPase, an increase in internal sodium ion concentration [Na] at the inner face of the cardiac membranes.

This local accumulation of sodium causes an

increase in free calcium concentrations via the

Na – Ca exchanger. This free cellular calcium

concentration [Ca] is responsible for the

inotropic action of digoxin, secondary to the

release of Ca from the sarcoplasmic reticulum.

Positive Inotropic Action

Positive inotropic effect on the intact ventricle,

or isolated ventricular muscle

Resulting in an increase in the rate of rise of

intracavitary pressure during isovolumic systole at

constant heart rate and aortic pressure

Present in normal as well as failing cardiac

muscle.

Shifts ventricular-function (Frank-Starling) curve

upward and to the left, so that more stroke work

would be generated at a given filling pressure.

Inhibits Na-K ATPase Pump

Increases intracellular Na Concentration

Increases intracellular Ca concentration

Improved isolated myocyte contractile performance

(increased shortening velocity)

Improved overall left ventricular (LV) systolic function.

Shifts Frank starling curve upward and leftward

Neurally Mediated Actions

Intravenous ouabain increased mean arterial

pressure, forearm vascular resistance, and

venous tone in normal human subjects, probably

in part because of direct but transient effects on

vascular smooth muscle.

Patients with heart failure respond with a decline

in heart rate and other effects consistent with

enhanced baroreflex responsiveness.

In patients with moderate to severe heart failure,

cardiac glycosides increase forearm blood flow

and cardiac index and decreased heart rate

concomitant with a marked decrease in skeletal

muscle sympathetic nerve activity measured as

an indicator of centrally mediated sympathetic

nervous system activity.

In contrast, dobutamine, a sympathomimetic drug

that increased cardiac output to a similar degree,

did not affect muscle sympathetic nerve activity in

these patients.

Mason DT, Braunwald E. Studies on digitalis, X: effects of ouabain

on forearm vascular resistance and venous tone in normal

subjects and in patients in heart failure. J Clin Invest.

1964;43:532–543.

Therefore, Digoxin has parasympathomimetic

action, clinically manifests as increased central

and peripheral vagal tone.

In HF patients, digoxin also has anti-sympathetic

effect, it also restores baroreceptor sensitivity.

Electrophysiological effects

The major effect of digitalis preparations on cardiac rhythm is believed to be due to modulation of ANS.

At therapeutic levels of digoxin, Digoxin acts by enhancing both central and peripheral vagal tone.

These actions are largely confined to slowing of the sinus node discharge rate, shortening of atrial refractoriness, and prolongation of AV nodal refractoriness.

It decreases automaticity and increase maximum diastolic potential, effects that can be blocked by atropine.

Electrophysiologic effects on the His-Purkinje

system and ventricular muscle are minimal,

except in toxic concentrations.

In studies of denervated hearts, digoxin has

relatively little effect on the AV node and causes a

mild increase in atrial refractoriness.

The sinus rate and P wave duration are minimally

changed in most patients. The sinus rate may

decrease in patients with heart failure whose left

ventricular performance is improved by the drug;

individuals with significant underlying sinus node

disease also have slower sinus rates or even

sinus arrest.

Similarly, the PR interval is generally unchanged,

except in patients with underlying AV node

disease.

QRS and QT intervals are unaffected. The

characteristic ST and T wave abnormalities seen

with digoxin use do not represent toxicity.

ANS modulation is an important mechanism

contributing to the efficacy of cardiac glycosides in

the treatment of patients with heart failure (and

may occur at blood levels of these drugs that are

below those necessary to achieve a direct

inotropic effect).

Pharmacokinetics

The elimination half-life for digoxin is 36 to 48

hours in patients with normal or near-normal

renal function. This permits once-a-day dosing;

near steady-state blood levels are achieved one

week after initiation of maintenance therapy.

Digoxin is excreted by the kidney with a clearance

rate that is proportional to the glomerular filtration

rate.

In patients with congestive heart failure and marginal

cardiac reserve, an increase in cardiac output and

renal blood flow with vasodilator therapy or

sympathomimetic agents may increase renal digoxin

clearance, necessitating adjustment of daily

maintenance doses.

Conversely, the half-life of the drug is increased substantially in patients with advanced renal insufficiency (to approximately 3.5 to 5 days);

both the volume of distribution and the clearance rate of the drug are decreased in the elderly.

As a result, the drug must be used with caution in patients with renal insufficiency and in the elderly.

Despite renal clearance, digoxin is not removed effectively by hemodialysis due to the drug's large (4 to 7 liters/kg) volume of distribution. The principal tissue reservoir is skeletal muscle and not adipose tissue, and thus dosing should be based on estimated lean body mass.

Most digoxin tablets average 70% to 80% oral bioavailability; however, approximately 10% of the general population harbors the enteric bacterium Eubacterium lentum, which can convert digoxininto inactive metabolites, and this may account for some cases of apparent resistance to standard doses of oral digoxin.

Liquid-filled capsules of digoxin (LANOXICAPS) have a higher bioavailability than do tablets (LANOXIN) and require dosage adjustment if a patient is switched from one dosage form to the other.

Digoxin is available for intravenous administration,

and maintenance doses can be given

intravenously when oral dosing is impractical.

Digoxin administered intramuscularly is erratically

absorbed, causes local discomfort, and is not

recommended.

Serum Digoxin Concentration (SDC) should be

measured atleast after 6 hrs of dosing – after

initial serum distribution phase ends – to prevent

falsely high SDC; Ideally within 6-20 hrs.

Drug interactions

Drugs Magnitude of

interaction

Suggested

Intervention

Cholestyramine SDC decrease 25% Temporal separation 8

hr

Antacid Gels SDC decrease 25% Temporal separation 8

hr

High Fibre Supplements SDC decrease 25% Temporal separation 8

hr

Sulfasalazine SDC decrease 25% Increase dose

Erythromycin,

Tetracycline

SDC increase 50-

100%

Decrease dose

Quinidine, Amiodarone SDC increase 100% Decrease dose by 50%

Verapamil SDC increase 70-

100%

Decrease dose by 50%

Diltiazem, Nicardipine SDC increase 20% None

Nifedipine, Amlodipine None

Factors affecting SDC

Joglekar SJ, Thatte UM, Anand S,

Dahanukar SA, Tendolkar AG. Digoxin

concentrations in Indian patients. Lancet

1997; 347: 1326–27.

Indications and Evidence

HEART FAILURE WITH LOW EF

(HFLEF)

Digoxin has many beneficial characteristics Only inotrope whose chronic therapy does not

increase long term mortality

Does not lower BP or adversely affect renal function

Very low cost drug

Few side effects when dosed appropriately

PROVED was a 12-week placebo-controlled,

digoxin-withdrawal study. This study enrolled

patients in sinus rhythm with reduce systolic

function and stable heart failure symptoms

who were receiving digoxin and diuretics.

Patients in whom digoxin was discontinued

had a 2-fold increase in worsening heart

failure and a decrease in both exercise

capacity and LVEF compared with patients

who continued on digoxin therapy.

The RADIANCE trial followed a similar

protocol; however, patients were receiving

ACE inhibitors in addition to diuretics and

digoxin. Digoxin discontinuation was

associated with a 6-fold increase in worsening

heart failure, despite the fact that ACE

inhibitors and diuretics were continued after its

withdrawal. Functional capacity worsened in

the withdrawal group, as did quality of life and

ejection fraction.

A pooled analysis of the RADIANCE and PROVED trials suggested

a significant cost reduction related to hospitalizations was associated with digoxin therapy.

The efficacy of 3 levels of serum digoxin concentration (SDC) of 0.5 to 0.9 mg/mL, 0.9 to 1.2 ng/mL, and 1.2 ng/mL with regard to LVEF and patient outcomes were evaluated. LVEF fell in patients assigned not to receive digoxin and increased in those who received digoxin(P<0.0001); treadmill times were reduced in those not receiving digoxin and were unchanged in those receiving digoxin (P<0.0001).

Risk of worsening HF was significantly less for all 3 subgroups of patients who continued to receive digoxinafter adjustment for LVEF, cardiothoracic ratio, age, HF score, and ACE-I use.

There was no relation between SDC levels and changes in

LVEF, treadmill times, and development of worsening HF.

The incidence of worsening HF in the placebo group was

30% and in the 3 digoxin subgroups was 6%, 9%, and

12%, respectively (P<0.02 for no digoxin versus the digoxin

subgroups).

Triple therapy with digoxin, an ACE inhibitor, and a diuretic

was associated with the lowest risk of worsening heart

failure (5%).

The DIGITALIS INVESTIGATION GROUP

(DIG) trial is the largest trial of digitalis. It had

two parts: the main trial and the ancillary trial.

Main Trial

6800 patients with LVEF 0.45 were randomly assigned

to digoxin or placebo: The placebo group received

diuretics (82%) and ACE-I (95%) and the digoxin

group received digoxin, diuretics (81%), and ACE-I

(94%).

The main findings were that digoxin

Had no effect on total mortality rates

Reduced incidence of Death or hospitalization caused

by worsening HF [P<0.001 risk ratio was 0.75 in the

whole group and was 0.80 in all subgroups]

Reduced incidence of Hospitalization for worsening

HF (P<0.001)

Reduced incidence of Death caused by worsening HF

(P=0.06)

Benefits were incremental to use of diuretic and ACE-I

Ancillary Trial

988 patients with LVEF 0.45 were randomly assigned

to digoxin or placebo.

It showed Death or hospitalization for worsening HF

was lower in patients assigned to digoxin (risk ratio,

0.82; 95% CI, 0.63 to 1.07) and “were consistent with

the findings of the main trial”

Subgroup Analysis

At the end of 5 years that women had a higher mortality

rate than men (33.1% versus 28.9%; absolute difference,

4.2%)

At a 2-year follow-up, a reduction in total mortality and total

hospitalization was demonstrated in a prespecified

subgroup analysis of patients with an LVEF 25%,

cardiothoracic ratio 55%, or NYHA class III/IV symptoms. In

these subgroups, the relative reduction in heart failure

mortality or heart failure–related hospitalization was 39%

for patients with LVEF 25%, 35% for patients with

cardiothoracic ratio 55% on chest x-ray, and/or 35% for

patients with severe symptoms.

A recent comprehensive post hoc analysis of the DIG trial

that included all patients (preserved or reduced systolic

function) suggested a survival benefit for patients with

Digoxin in Women

Digoxin has not been well studied in women with heart

failure.

In the DIG trial, women made up only 22% of the study

population

One post hoc analysis of the DIG database suggested that

women randomized to digoxin had increased all-cause

mortality.

However, subsequent independent analyses of the same

database showed no evidence of increased mortality in

women with a serum concentration <1.0 ng/mL. A higher

risk of mortality (but not hospitalization) was observed only

in women with SDCs <1ng/mL.

An analysis of patients treated with digoxin in the Studies of

Left Ventricular Dysfunction (SOLVD) database also failed

to demonstrate a survival difference based on gender.

Digoxin in the Elderly

Advanced age may predispose patients to an increased risk

for digoxin intoxication that is related to decreased renal

function, low lean body mass, and electrical conduction

abnormalities.

In the DIG trial, however, advanced age was not associated

with an increased risk of digoxin intoxication. The beneficial

effects of digoxin were found to be similar across all age

groups regardless of LVEF (and maximum in Low EF).

Digoxin remains a useful agent in elderly heart failure

patients when variables such as lean body mass and renal

function are taken into account.

Digoxin with Beta Blockers

The DIG study was conducted before -blockers were

proved conclusively to reduce mortality and morbidity in

heart failure. Most patients enrolled in trials of Beta-

blockers, however, were receiving digoxin. It is not known if

the findings of these trials would have been similar without

background digoxin therapy.

Digoxin as Background therapy in HF trials

Digoxin in children Despite the lack of data regarding its use in children,

digoxin continues to be used by most clinicians in the management of pediatric heart failure.

Primary Myocardial disease HF is most acceptable indication of Digoxin in Pediatric HF.

Left to right shunts and Valvular heart disease patients are treated with digoxin only after they become symptomatic.

Also, any HF due to digoxin responsive Tachyarrhythmia is a strong indication – needs Rapid digitalisation

Lower starting dose (½ to ¾ maintenance) is indicated in acute phase of myocarditis, renal failure, and with drugs which increase SDC.

HEART FAILURE WITH Preserved

EF (HFpEF)

Approximately 50% of patients hospitalized for acute heart failure syndromes have relatively preserved systolic function. These patients are older and more likely to have a history of hypertension and atrial fibrillation.

To date, only 3 relatively large studies have been conducted in heart failure patients with preserved systolic function: DIG Ancillary - The effect of digoxin in 988 patients with heart

failure and preserved systolic function (mean LVEF, 55%) was examined in the ancillary component of the DIG trial.. The addition of digoxin to ACE inhibitors and diuretics resulted in a nonsignificant 12% reduction in heart failure mortality or heart failure hospitalizations. The direction and magnitude of this finding are similar to that observed in patients with decreased systolic function.

Effects of Candesartan in Patients With Chronic Heart Failure

and Preserved Left-Ventricular Ejection Fraction or (CHARM-

Preserved study) - Therapy with candesartan resulted in an

11% relative risk reduction in cardiovascular death or heart

failure hospitalization in patients with heart failure and

preserved systolic function. In this trial, however, patients

randomized to candesartan developed more hypotension,

worsening renal function, and hypokalemia compared with the

placebo group.

Treatment of Preserved cardiac function HF with an

Aldosterone Antagonist (TOPCAT study) - patients who took

the aldosterone inhibitor spironolactone failed to show benefit

for primary end point composite of death from cardiovascular

causes, aborted cardiac arrest, or hospitalization for heart

failure. But they did have significantly fewer heart-failure

hospitalizations, a part of the primary end point, over the

average follow-up of 3.3 years.

Acute Heart Failure Syndromes

Hospitalizations for worsening heart failure are a major problem in HF spectrum. Also This is associated with a readmission rate as high as 30% within 2 months after discharge.

To date, no single agent used to improve presenting symptoms has been shown to be safe and effective. These include nesiritide, milrinone, tezosentan, levosimendan, etc.

The effects of intravenous digoxin, alone or with other vasodilators, are seen within an hour of its administration and result in increasedcardiacoutput, decreased pulmonary wedge pressure, increased ejection fraction, and improved neurohormonal profile without changes in blood pressure. This therapy may be continued during hospitalization and after discharge.

Despite its potential benefits, no study to date has

evaluated digoxin in the setting of acute heart

failure.

Accordingly, digoxin is not recommended for the

management of acute heart failure syndromes by

the ACC/AHA heart failure guidelines. However,

given its acute positive hemodynamic effects and

long-term safety data, digoxin should be evaluated

in this setting by future trials.

Coronary Artery Disease

Myocardial ischemia may cause inhibition of the sodium potassium pump, rendering myocardial tissue more sensitive to the arrhythmogeniceffects of digitalis, even at lower doses.

In a retrospective analysis, digoxin has been associated with an increase in postdischargemortality in patients surviving myocardial infarction. However, in other studies, analysis failed to show that digoxin is an independent predictor of increased mortality.

In the DIG trial, 70% of patients had ischemic heart disease, 65% had a history of myocardial infarction, and 30% had angina at the time of enrollment. Patients with an ischemic origin had a reduction in heart failure–related death or hospitalization similar to that seen in nonischemic

The DIG trial, however, did not examine the effects

of digoxin in the settings of acute coronary

syndromes.

Because its safety has not been evaluated in this

setting, digoxin should be avoided if possible during

acute myocardial infarction or in patients with

ongoing ischemia.

Atrial Fibrillation

Atrial fibrillation is present in 30% of heart failure

patients.

At rest, digoxin can effectively control the ventricular

response in atrial fibrillation by enhancing vagal

tone. However, it may be less effective at controlling

the ventricular response during exercise or in the

setting of enhanced sympathetic tone.

In patients with heart failure and reduced systolic

function, the combination of digoxin and a -blocker

reduces symptoms, improves ventricular function,

and leads to better rate control than either agent

alone.

The best strategy for rate control is a 2-drug

combination, usually consisting of digoxin and a -

blocker. Using a -blocker and digoxin in combination

allows lower doses to be used, thus improving

tolerability and decreasing the risk of toxicity.

Diltiazem and verapamil also are options, but these

agents should not be used in the setting of systolic

dysfunction. Caution should be used when

combination therapy with digoxin and amiodarone is

chosen for rate control because amiodarone can

significantly increase SDC.

Dosing

Dosing

There are many problems encountered in writing a program to effectively dose a drug such as digoxin. It is inherently difficult because of such components as narrow therapeutic index, difficult to define therapeutic endpoints, inter and intra-patient variability, and varying effects of pathological states and drugs on digoxin's disposition.

In sum, there exists significant variability as far as a given dose and concentration produced in a given patient. It is important to be able to determine various patient attributes that may help predict drug concentrations for any given patient. There are several known attributes that have a direct correlation with the eventual therapeutic dose.

Variables such as ideal body weight, serum creatinine, age, concomitant drug therapy all have great influence on the eventual therapeutic dosing regimen.

Rapid digitalizing (loading dose) regimen

IV: 8-12 mcg/kg (0.0080.012 mg/kg) total loading dose; administer 50% initially; then may cautiously give 1/4 the loading dose q68hr twice; perform careful assessment of clinical response and toxicity before each dose

PO: 1015 mcg/kg total loading dose; administer 50% initially; then may cautiously give 1/4 the loading dose q68hr twice; peform careful assessment of clinical response and toxicity before each dose

Maintenance PO: 3.4-5.1 mcg/kg/day or 0.1250.5 mg/day PO; may increase dose every 2 weeks based on clinical response, serum drug levels, and toxicity

IV/IM: 0.10.4 mg qDay; IM route not preferred due to severe injection site reaction

As per ACCF/AHA guidelines, a loading dose

to initiate digoxin therapy in patients with heart

failure is not necessary

0.125-0.25 mg PO/IV qDay;

higher doses including 0.375-0.5 mg/day

rarely needed

Use lower end of dosing (0.125 mg/day) in

patients with impaired renal function or low

lean body mass

Dosing Modifications

Adjust maintenance dose by estimating CrCl

and measuring serum levels

In heart failure, higher dosages have no

additional benefit and may increase toxicity;

decreased renal clearance may lead to

increased toxicity

In geriatric patients, use lean body weight to

calculate dose

What all can

go wrong?

Toxicity and Adverse effects

Incidence and Causes

Incidence is decreasing

1970s – Upto 25-30% of all treated patients

1980s and 1990s – 4-5% of all treated patients

DIG trial – probable digoxin toxicity in about 12%

in digoxin group and about 8% in placebo group –

actual incidence about 4%

2000s – Reported incidence < 0.1%

Causes

Suicide gestures/purposeful overdoses

Incorrect Dosage

Risk factors

Renal dysfunction (Moderate to severe renal

failure – CrCl <60 ml/min in Males in <50 ml/min

in Females)

Elderly

Females

Concomitant drug interactions

Mechanisms

Most of digoxin effect in HF patients is thought to

be due to ANS modulation. But Toxic effects are

explained mainly by excessive Na-K pump

inhibition.

Toxic effects of digoxin (ie, arrhythmias) occur

when the cytoplasmic [Ca] increases to

concentrations exceeding the storage capacity of

the sarcoplasmic reticulum. As a consequence of

this internal [Ca] overload, several cycles of Ca

release–reuptake are required to restore the Ca

equilibrium between sarcoplasmic reticulum and

cytoplasm.

In addition, high internal concentrations of Ca activate a depolarizing (inward) current corresponding to the forward mode of the electrogenic Na–Ca exchanger (3Na/2Ca). This current generates delayed after-depolarizations that give rise to extra-systoles and sustained ventricular arrhythmias in vivo.

The toxicity of digoxin could also be amplified in human heart failure, because the Naþ–Ca2þ exchanger is upregulated in HF.

The pharmacological properties of the three main human cardiac Na/K-ATPase isoforms explain the role of hypokalemia in the toxic effects of digoxin.

The functional Na/K-ATPase is a heterodimer of alpha and beta subunits. The alpha subunit bears the catalytic site and binds digoxin, ATP, Na, and K. The three isoforms have the same apparent affinity for digoxin; however, their apparent affinities vary according to the concentration of potassium.

In the presence of physiological [K] concentrations, the alpha 1 and alpha 3 isoforms exhibit 3–5-fold lower sensitivities to digoxin; potassium exerts a protective effect. In contrast, the alpha 2 isoformremains highly sensitive to cardiac glycosides.

Furthermore, the alpha 2 isoform very rapidly

binds and releases digoxin (within a few minutes),

whereas the half-times for the dissociation of

digoxin from alpha 1 and alpha 3 are 80 and 30

min, respectively.

Thus, under physiological conditions, the alpha 2

isoform could be effectively inhibited at low

concentrations of digoxin.

Also, It has been assumed that, in the presence of

high concentrations of digoxin, alpha 1 and alpha

2 isoforms are inhibited and induce toxic effects.

Manifestations

Traditionally divided into extra cardiac and

cardiac

‘Definite’ Toxicity defined as

Nausea/Vomiting with

Cardiac effects with

Resolution of side effects on discontinuation

SDC not a necessary criterion – but SDC > 2.0

ng/ml helpful

Extracardiac SEs

Nonspecific but more common

Gastrointestinal (60-80%)

Nausea / Vomiting

Anorexia, Abdominal Pain, Diarrhoea

Malaise (30-40%)

Lethargy, Fatigue

Neurological (20-30%)

Dizziness, Confusion

Headache

Visual changes (flashing lights, halos, colourdisturbances in green – yellow spectrum, blurred vision)

Cardiac SEs

More specific but less common

Almost any permutations and combinations of

heart block, brady- and tachydysrhythmias are

possible.

The only dysrhythmia not assumed to be due

to Digoxin toxicity – Mobitz Type 2 Heart block

ECG manifestations

Effects on S-T segment

Inverse check mark

Inverse check mark: Digoxin effect

Digoxin toxicity signs

Inverse check mark

with proximal ST segment depressed

In leads other than those with tall R waves

With T wave not rising above baseline (Inverted T)

With shortened Qtc

Note that

Digoxin does not affect the QRS

Maximal therapeautic effect of digoxin is usually

present befoe the ECG effects appear

Management

If the evidence of toxicity is relatively minor

with, for example, symptoms of nausea,

withdrawal of the drug is often the only specific

treatment required.

If there is no evidence of serious cardiac

problems, such as heart block or significant

dysrhythmias, then following the withdrawal of

the drug and the correction of electrolyte

imbalance, symptomatic measures will usually

suffice.

More serious evidence of toxicity, particularly

with cardiac involvement, dysrhythmias, is

potentially life threatening, and requires

admission to hospital.

Measures

Hypokalemia correction - intravenous

supplementation of no more than 20 mmol/h of

potassium, to reduce digitalis binding to Na/K

ATPase. More rapid infusion may lead to

asystole.

Heart blocks – Atropine and Temporary cardiac

pacing

Malignant ventricular arrhythmias

Phenytoin (100 mg intravenously, repeated after

5 minutes if required) is a useful

antidysrhythmic as it opposes digitalis binding

and may improve atrioventricular conduction by

its anticholinergic properties.‘

Ultrashort acting beta blockers – Esmolol

Cardioversion should be avoided wherever

possible, due to the risk of precipitating

asystole, and when necessary should be

attempted using the lowest energy possible.

Digoxin-specific antibody fragments

Digoxin-specific fab antibody fragments (Digibind) are the most effective treatment available. However, this therapy is expensive and therefore should be reserved for treatment of serious toxicity, especially in the presence of malignant cardiac dysrhythmias.

These antibodies have a high affinity and specificity for cardiac glycosides and have been shown to reverse digoxin toxicity and reduce the risk of death.

In several large studies, approximately 80% of patients had complete resolution of all evidence of toxicity, 10% improved whilst 0% showed no response.

They appear effective for all age groups and also in patients with poor renal reserve (despite eventual renal elimination).

Pharmacokinetics

Half life 12-20 hrs

Vd 0.4 L/kg

After administration, SDC cannot be measured

without complete elimination from the body

Dosage: 2 methods

Side effects

Anaphylaxis, and allegies

Hypokalemia

Rebound digoxin toxicity

Exacerbation of HF