MEDICAL

TOXICOLOGY
DIGOXIN
DR.Eman Mantawy
 Digitalis
 Digitalis is one of cardiac glycosides,
present maily in Digitalis Purpurea
(foxglove)
 Cardiac glycosides comprise a group
of steroidal compounds used in the
treatment of congestive heart failure
(CHF).

 The two most commonly used

digitalis glycosides are digoxin and
digitoxin.
 Digoxin

Formulations
Lanoxin
(Tablets, Injections ,Elixir)

Therapeutic uses

- Congestive heart failure

- Atrial fibrillation
- Supraventricular tachycardia
 Toxicodynamics
1-They increase the cardiac output by exerting a
positive ionotropic action HOW ?????????????
A) Inhibiting Na+/K+ ATPase (sodium pump) which pumps 3
Na+ outside the cell in exchange with 2 K+ inside the cell
which is responsible for maintenance of resting membrane
potential (RMP) in most excitable cells

Relative reduction of Ca+ expulsion from the cell by

Na+/Ca+ exchanger caused by the increase of
intracellular Na+.
Toxicodynamics
 Toxicodynamics
More intracellular Ca Intracellular Na

Release of Ca
from
sarcoplasmic
reticulum
 Toxicodynamics
2-They exert negative chronotropic effect through
vagal and extravagal stimulation.
-ve dromotropic
effect +ve bathmotropic
effect

3-They decrease AV conduction through direct

action on the myocardium and vagal stimulation.

4-They increase heart automaticity in overdose as when

conduction and the normal pacemaker are both
depressed, ectopic pacemakers may take over,
producing atrial and ventricular tachycardia .
 Signs & symptoms
A) Cardiac
Dysrrhythmia
- Decrease AV conduction leading to bradycardia and heart
block : First
Second Conduct all pulses but slowly
one or more (but not all) of the
atrial impulses fail to conduct
to the ventricles due to
impaired conduction.
Third Complete heart block
-Increase automaticity leading to several types of
tachyarrhythmias.
Signs & symptoms
 Signs & symptoms

B) Non cardiac
GIT manifestations

Nausea, vomiting, abdominal pain, anorexia

Nausea and vomiting

Digitalis preparation where the preparation
and leaves increases vagal
stimulation and activate
(CTZ)
Leaves Local irritation
 Signs & symptoms

B) Non cardiac
CNS manifestation

Psychic disturbance Hallucination, confusion and

(personality changes) disorientation, amnesia

Nightmares Convulsions
 Signs & symptoms

B) Non cardiac
Visual disturbance
Colored vision (yellow and green patches)

Scotomata (Isolated areas of Diplopia

varing size and shape in which the
vision is absent)
 Signs & symptoms

B) Non cardiac

Endocrine disturbance

Due to steroidal nature

Gynaecomastia Menstrual disturbance

 Signs & symptoms

B) Non cardiac
Electrolyte disturbance
Hyperkalemia in acute toxicity

Hypokalemia in chronic toxicity

 Signs & symptoms

B) Non cardiac
Electrolyte disturbance
Both hypokalmeia and hyperkalemia increase digitalis
toxicity WHY??

Hypokaleima allows Hyperkalemia decreases

digitalis to act on the Na/K AV conduction so
ATP ase pump without enhances digitalis toxicity
competition
 Toxicokinetics

-There are two types of digitalis glycosides: digoxin and

digitoxin.

-They differ in their kinetics where as the number of OH

groups on steroidal nucleus decreases, the polarity
decreases, the lipophillicity increases, and the absorption
increases.

-Digitoxin is metabolized by the liver to both active and

inactive products because of enterohepatic circulation
 Toxicokinetics
Item Digoxin Digitoxin

GIT absorption More OH gp on

steroidal nucleus
less lipid solubility
less absorption
60-85% 90-100%
Onset of action 15-30 mins 0.5-2 hrs

Plasma albumin 25% 97%

binding Vd Vd
(tissue bound)
 Toxicokinetics
Item Digoxin Digitoxin

Toxic levels 2.4 34

ng/ml
Half life 36 hrs 5-7 days
(enterohepatic
recirculation)
Excretory Renal Hepatic
pathway
 Risk factors
Renal diseases
Digoxin is mainly eliminated via kidney thus renal
injury will decrease its excetion

Aging
Elderly are more likely to have decreased renal
function

Fluid status
Fluid loss or poor fluid intake can lead to electrolyte
imbalance
 Risk factors
Electrolyte imbalance

Hypokalemia Hypercalcemia Hypomagnesemia

Increased Sensitize heart to
digoxin binding
Ca overload digoxin effects as
to the Na/K enhancing can cause
ATPase pump digoxin hypokalemia via
due to impairing
inotropic Na/KATPase,
decreased
completion effect decreasing
with potassium cellular uptake of
K
 Risk factors
Drug interactions
A) Drugs decreasing AV conduction
Beta blockers, Verapamil, Deltiazem,
Amiodarone, Qunidine

B) Drugs decreasing digoxin clearance

Verapamil, Deltiazem, Amiodarone, Qunidine
 Risk factors
Drug interactions
C) Drugs causing hypokalemia
Loop (furosemide) & thiazide (hypochlorothiazide)
diuretics, licorice (Na water retention)

D) Drugs decreasing decreased gut flora

Broad spectrum Abs; Erythromycin, Ciprofloxacin,
Tetracyclines
N.B: gut flora that degrades digoxin
 Management
1- ABCD
2- Prevent any further absorption
Gastric lavage (Atropine??)

Activated charcoal (Repeated dosing)

Cholestyramine ( binds acidic drugs)

 Induced emesis with ipecac syrup - Not
recommended, because of the increased vagal
effect
 Management
3-Enhance elimination

Hemodialysis and hemoperfusion

Digitalis is bound to tissues

 Management

3-Symptomatic and supportive treatment

*Tachycardia lidocaine or phenytoin

*Bradycardia Atropine
Insulin + glucose to shift K+
*Hyperkalemia
intracellularly, Avoid Ca gluconate
?????
*Hypokalemia K+ supplement

* EDTA & To shift extra intracellular calcium

extracellularly give EDTA
 Management
4) Specific antidote Digibind
1
2
Inject digoxin
Take antiserum
in sheep

Autogenicity
Abs formed & elimination
against digoxin
4
Remove Fc
& take FAB
Inject FAB FAB portion
portion in
human 3
Fc
 Management
Digibind
Fab binds to digoxin extracellularly

Forming a complex excreted in the urine

Digoxin moves from inside to the outside of the cell

N.B: (Less effective in case of chronic toxicity).

 Management
Digibind
Contraindications
- Patients with known hypersensitivity to ovine (sheep)
products
- Patients previously treated with these antibodies as Fab
fragments are themselves immunogenic, patients treated
more than once may experience an acute hypersensitivity
reaction
Side effects
Re-intoxication, due to complex degradation in patients
with impaired renal clearance due to impaired elimination
of digoxin-Fab complex