The Toxicology and Forensic Chemistry

Digoxin
Toxicity
 Digoxin is a purified cardiac glycoside found in
the foxglove plant, Digitalis lanata.
Brand name: Lanoxin.

Introd
uction
 Digoxin is indicated in the following conditions:

1) For the treatment of mild to moderate heart failure in adult

patients.

Indica 2) To increase myocardial contraction in patients diagnosed

with heart failure.

tions In adults with heart failure, digoxin should be administered in

conjunction with a diuretic and an angiotensin-converting
enzyme (ACE) inhibitor for optimum effects.

3) To maintain the control of ventricular rate in adult patients

diagnosed with chronic atrial fibrillation.
 Narrow therapeutic index.
- Therapeutic levels are 0. 8 – 2
- The toxic level is >2.4 ng/mL.

Pharmaco
dynamics The elimination of digoxin is 50-70% of the dose is
measured excreted as unchanged digoxin in the
urine. Approximately 25 to 28% of digoxin is
eliminated outside of the kidney.
 - History of present illness:
A 78-year-old man with a complex medical history
on hemodialysis presents to the Emergency
Department after 2 days of worsening weakness,
nausea, and visual abnormalities. He reports
difficulty walking from the parking lot to the store
over the last 2 days, and that this morning’s
generalized weakness was severe enough that he

Case could not sit up in bed.

He has felt nauseated the entire time; however,

Presentation:
there has been no emesis. In regard to his vision,
he reports that staring at lights results in bright,
fuzzy spots. The patient was recently discharged
from the hospital on levofloxacin and
vancomycin following a bout of hospital-
associated pneumonia as well as surgical graft
infection. He has atrial fibrillation and takes
digoxin 0.125 mg three times a week after
hemodialysis.
 - Past Medical History: End-stage renal disease on
dialysis, congestive heart failure, heart block status
post-pacer placement, coronary artery disease,
diabetes mellitus, cerebrovascular accident, deep
venous thrombosis, and gastrointestinal bleeding.

Case - Medications: Lantus, digoxin, midodrine, lispro,

amiodarone, levothyroxine, simvastatin, tamusolin.

Presentation:
-

-
Allergies: Cefazolin, hydrocodone, neomycin

Family History: Father with heart attack and mother

with stroke history.

- Social History: Former smoker, denies recreational drug

use or alcohol consumption.
 - Physical Examination Blood pressure: 97/47 mmHg.
- Heart rate: 74 bpm,
- Respiratory rate: 16 breaths/min,
- Temperature: 36.5 °C,
- O2 saturation: 100% (room air)
- General: No acute distress. Alert, pleasant, interactive, and
communicative. Mild cachexia
- Head: Mild temporal wasting.
- Eyes: Pupils equal, round, and constricted.

Case -
-
-
ENT: moist mucous membranes.
Neck: Supple, no JVD.
Cardiovascular: Regular rate and rhythm. 3/6 harsh systolic

Presentation:
blowing murmur.
- Pulmonary: Clear to auscultation bilaterally. Normal effort.
- Abdomen: Soft, distended with chronic epigastric tenderness, no
rebound.
- Extremities: 1+ pitting edema to knees bilaterally.
- Neurologic: Awake, alert, and oriented to person, place, time. Mild
dysarthria.
- Diagnostic Testing: Sodium 131 mEq/L, Potassium 4.9 mEq/L,
Creatinine 5.56 mg/dL, Digoxin 12 ng/mL.
- Ancillary Testing EKG: Wide complex, Paced rhythm.
 - CNS symptoms of digitalis toxicity include the following:
• Drowsiness
• Lethargy
• Fatigue.
• Dysarthria.

Q1: What Are the - Vision:

Signs and he reports that staring at lights results in bright (photophopia),
Symptoms of fuzzy spots.
Digoxin Toxicity?
- GIT:
has felt nauseated the entire time.

- CVS:
Hypotension.
Dyspnea.
 - Digoxin inhibits Na/K pump , leading to increase level of
Na.

- In toxic doses, this excessive rise in Na also can cause

excessive rise in intracellular Ca. This rise in the
Q2: What Is the intracellular Ca modulates activity of number of
Mechanism of sarcolemmal ion channels and affect release of intracellular
Digoxin Ca from sarcoplasmic reticulum ,all of which might be
Toxicity? involved in causing arrhythmia.

- The increase in the contractile force that result from

intracellular Ca may initiate or exacerbate arrhythmia, this
will increase energy demand in the ventricle, and increase
wall stress may lead to arrhythmia.
  Amiodarone : may increase the amount of digoxin in
your blood and cause side effects.
 Atorvastatin: may increase the amount of digoxin in
Q3: What your blood and cause side effects.
Medications Were
Prescribed that May  Levothyroxin combination may cause a decrease in
Enable Digoxin digoxin levels. The dosage of digoxin may need to be
Toxicity? increased
 Tamsulosin may decrease the excretion rate of
Digoxin which could result in a higher serum level.
 • Prophylactic anti coagulation agent, acetly
salicylic acid 75 mg daily.

Q4: What • Dose adjustment of current medications.

Treatment Should
Be Pursued at This •Adding digoxin immune fab.
Time?
• K+ potassium) adjustment to control arrhythmia.

• Atropine to reverse muscarinic activity.

 -The Fab:
fragment is separated via enzymatic degradation to
yield smaller, less antigenic and
more mobile molecules that are able to bind digoxin
Q5: How Does and quickly remove digoxin
from its active binding site; thus isolating it within the
Digoxin Immune Fab extracellular compartment
Work?
What Treatment -The patient is presenting:
Should Be Pursued with hyperkalemia and a high level of digoxin
at This Time? suggesting severe toxicity. The presence of cardiac
dysrhythmias
is likely masked by the patient’s pacemaker and should
not prevent the
administration of the antidote.
 *Formula 1:
Dose (no. of vials)= total digoxin body load(mg) / 0.5 mg
of digoxin bound per vial.

*Formula 2:
Dose= (serum digoxin concentration in ng/mL) x (weight
Q6: How Is Digoxin in Kg)/100.
Immune Fab Dosing
Calculated in *Formula 3:
Chronic Toxicity? Dose (in mg)= (40 mg/vial) x ( (serum digoxin
concentration in ng/mL) x (weight in Kg)/100).

*Formula 4:
Dose (no. of vials)= (serum digitoxin concentration in
ng/mL) x (weight in kg)/1000.
 Renal metabolism is primarily responsible for the clearance
of digoxin as well as
the digoxin/digoxin immune Fab complex.

Thus, renal dysfunction leads to impaired

clearance of both digoxin and the digoxin/digoxin immune
Fab complex.
Q7: Does Renal
Dysfunction Patients with renal impairment may be at increased risk for
Change digoxin toxicity, and AV conduction disturbances, due to
Management? decreased drug clearance.

The drug can remain in the body for 36–48 h in individuals

with normal kidney function but may take between three and
five days to clear in patients with renal insufficiency.

Therapy with digoxin should be administered cautiously in

patients with impaired renal function.
Q8: What Special
Monitoring should Patients should be closely monitored, including
temperature, blood pressure,
Take Place Once a electrocardiogram, and potassium
Patient Has concentration, during and after administration
Received Digoxin of DIGIBIND (digoxin immune fab)
Immune Fab?
 In the management of this particular patient, the
poison center recommended monitoring free
digoxin levels to better assess his pharmacologic
burden. One day after admission and
administration of six vials of digoxin immune Fab,
the patient’s digoxin levels increased to 32.9
ng/mL;

Case Continued:
However, free digoxin level were only 1.1 ng/mL.
At this time, the patient had complete resolution of
symptoms, as demonstrated by resolution of
nausea, improvement in abdominal pain, and
ability to read as well as walk independently to the
bathroom. Review of his pill counts as well as his
medication history revealed that the patient had
mistakenly taken his digoxin three times daily for
several days, rather than three times weekly.
 *Some cases have evaluated the use of plasmapheresis or
plasma exchange for the management of digoxin toxicity.
Plasmapheresis involves the removal of the
digoxin/digoxin immune Fab complex from the plasma
where it has been seques- tered in those unable to really
Q9: Are There excrete the complex.
Alternatives to Aid in
the Clearance of *Another method for management of digoxin toxicity in the
Digoxin That Does setting of renal fail- ure involves charcoal intestinal
Not Involve Renal dialysis, or multi-dose activated charcoal.
Metabolism in the In char- coal intestinal dialysis, a high intraluminal
Anuric Patient? concentration of charcoal creates a gradient between the
plasma and the intestinal lumen, allowing the redistribution
and binding of the drug into the charcoal.

*Additional data suggest that digoxin may undergo active

secretion into the intestines; thus, charcoal may prevent
further reab- sorption .
Plasmapheresis
 At this time, the poison center recommended
considering multi-dose activated charcoal and
plasmapheresis with his next hemodialysis to aid in
the removal of digoxin/ digoxin immune Fab complex.

On the fourth day of admission, the patient’s

symptoms returned in spite of having received one

CaseContinued
round of plasmapheresis with his last hemodialysis. At
:
this time, repeated laboratory studies revealed a free
digoxin level 2.2 ng/mL, which increased to 2.7 ng/mL
upon repeat evaluation. Quantification of total digoxin
level was found to be 22.6 ng/mL, and upon repeat
testing, it was down to 12.5 ng/mL; thus demonstrating
a dissociation effect of the digoxin/digoxin immune
Fab complexes in this anuric patient.
 *Although data is limited, it is theorized that the timing
of plasmapheresis to digoxin immune Fab dosing
Q10: Is There a Preferred should reflect the time to peak of bound digoxin levels.
Timing for
Administration of *Thus, plasmapheresis would be best performed
Digoxin Immune Fab within
and Undergoing 1–3 h of administration of digoxin immune Fab
Plasmapheresis? so as to trap as much of the complex in the plasma just
prior to removal.
 *The cost of digoxin immune Fab varies by institution;
however, it is reported to be in the range of $2725 per 40 mg
vial (Lexicomp 2015).

*The cost of plasmapheresis again varies by institution, but

published reports suggest a cost of $4099. This cost includes
both a round of plasmapheresis and the replacement
Q11: Are There Cost
albumin required as part of the treatment (Heatwole et al.
Advantages to the Use of
2011).
Plasmapheresis Versus
Repeated Administration
*Thus, if a patient requires re-dosing, with a minimum of two
of Digoxin Immune Fab?
vials of digoxin immune Fab, the cost of the antidote would
already outweigh the cost of one round of plasmapheresis.

*Digoxin toxicity is rarely encountered in the setting of

hemodialysis-dependent end-stage renal disease; however,
the use of plasmapheresis ideally within 3 h of digoxin
immune Fab administration may provide a cost advantage
compared to repeated dosing of immune Fab
 Thank You .
Presented by:
Nada Abu El-Eneen .
Nadine Elassmy.
Sara Hegazy.
Nagham Akram.