2. Introduction
• One of top toxins in the world because of the wide
availability of digoxin 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.
• Digoxin-specific fragment antigen-binding (Fab)
antibody has contributed significantly to the
improved morbidity and mortality of toxic patients
4. -Normal depolarization of the cardiac myocyte begins
with the opening of the fast sodium channels. The
resulting increase in intracellular sodium, and
subsequent change in the resting membrane
potential, opens voltage-gated calcium channels. The
initial influx of calcium induces further release of
calcium from the sarcoplasmic reticulum, which
results in muscle contraction.
- Sodium is then removed from the cell by, among
several mechanisms, the sodium-potassium ATPase.
Some calcium is removed from the cell by the sodium-
calcium antiporter.
5. Mechanism Of Action
The positive inotropic effect of digitalis has the following
component:
Direct inhibition of membrane-bound Na+/K+ -ATPase,
which normally 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.
6. • 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 of the heart (inotropic effect).
7. - They exert negative chronotropic effect
through vagal and extravagal stimulation.
- They decrease AV conduction through
direct action on the myocardium and vagal
stimulation.
- They increase heart automaticity in by
shortening the refractory period of atria and
venticles
8.
9. Pathophysiology
1. Cardiac: arrhythmia
• Alterations in cardiac rate and rhythm occurring in
digitalis toxicity may simulate almost every known
type of arrhythmia.
- Decrease AV conduction leading to bradycardia and
heart block (first, second, third).
Indeed, AV junctional block of varying degrees, alone or
with increased ventricular automaticity, are the most
common manifestations of digoxin toxicity, occurring
in 30-40% of patients with recognized digoxin
toxicity.
10. - Increase automaticity leading to several types of
tachyarrhythmias.
When conduction and the normal pacemaker are both
depressed, ectopic pacemakers may take over,
producing atrial and ventricular tachycardia.
2- Arrhythmias can cause inadequate tissue perfusion,
with resultant central nervous system (CNS) and renal
mplications such as the following:
• Hypoxic seizures
• Acute tubular necrosis
11.
12. 3- Hyperkalemia is the major electrolytic complication in
acute, massive digoxin poisoning. In addition
hyperkalmemia slows AV conduction adding to digoxin
toxicity.
Hypokalemia is seen with chronic toxicity.
13. 4- GIT manifestations:
nausea, vomiting, abdominal pain, anorexia
vagal stimulation>>
Chemoreceptor trigger zone
5- Visual disturbance:
colored vision (yellow and green
patches), Scotomata, diplopia.
14. Digoxin pharmacokinetics
• The onset of action by oral administration occurs in
30-120 minutes
• the onset of action with intravenous administration
occurs in 5-30 minutes.
• its bioavailability is 95%.
• Only 1% of the total amount of digoxin in the body is
in the serum; of that amount about 30 % bound to
plasma proteins.
• Large volume of distribution about 8L.
15. • The kidney excretes 60-80% of the digoxin dose
unchanged.
• A dose less than 5 mg is rarely to cause toxicity,
however a dose higher than 11 mg may be fatal
• In pediatrics a dose higher than 4 mg can cause
toxicity.
• Because of digoxin's large volume of distribution and
molecular weight, extracorporeal removal is not
beneficial. Neither hemoperfusion nor hemodialysis
have been shown to be helpful in the management of
digoxin toxicity.
16. CLINICAL FEATURES AND DIAGNOSIS of toxicity:
History:
-Determine the agent, amount taken, time of
ingestion, and any coingestants whenever possible.
- Determine also if the patient normally takes digitalis
or if it was someone else's prescription.
- Ask about symptoms suggesting an acute illness.
- Inquire carefully about gastrointestinal, cardiac, and
neurologic manifestations, including visual
disturbances.
- Inquire also about symptoms that suggest
hypoperfusion, such as confusion and abdominal
pain, which may stem from mesenteric ischemia.
17.
18. Circumstances of toxicity
• Deteriorating renal function, dehydration, electrolyte
disturbances, or drug interactions usually precipitate
chronic toxicity.
• Acute overdose or accidental exposure to plants containing
cardiac glycosides may cause acute toxicity.
• Acute, non therapeutic overdose—unintentional, suicidal,
or homicidal—can cause toxicity
19. LABORATORY AND ECG EVALUATION:
(1) Serum digoxin concentration:
With acute toxicity, ideally, blood samples should be
collected four hours after an intravenous dose or six
hours after an oral dose in order to account for drug
distribution and obtain an accurate measurement.
20. (2) Serum potassium concentration:
-Hyperkalemia is correlated with mortality in acute intoxication.
- All patients with an initial potassium level greater than 5.5 have poor
prognosis.
-As regards chronic toxicity, the most common precipitating cause of
digitalis intoxication is hypokalemia which occurs often in patients with
heart failure as a result of diuretic therapy.
(3) Creatinine and BUN to assess renal function:
Renal dysfunction is also commonly encountered in the setting of
chronic digoxin toxicity and is often what precipitates the rise in the
digoxin level.
(4) Serial electrocardiograms:
24. Managment
• A- B - C
• hydration with IV fluids, oxygenation and support of
ventilatory function, discontinuation of the drug,
and, sometimes, the correction of electrolyte
imbalances.
• Fab antibody fragments are extremely effective in
the treatment of severe, acute digitalis toxicity
25. GI Decontamination and Enhanced
Elimination
• The administration of activated charcoal (AC)
or cholestyramine for gastrointestinal decontamination
should be viewed as adjunctive and not primary therapy in
patients with digitalis poisoning.
• Patients suspected of having an acute digitalis intoxication
who present to the emergency department within one to
two hours of ingestion may benefit from the administration
of AC.
• Cardiac glycosides undergo some degree of enterohepatic
or enteroenteric recirculation and are adsorbed
to activated charcoal . AC or multi-dose AC (MDAC) are
recommended for digitalis toxicity .
26. • Management of arrhythmia:
- In case of tachycardia: give lidocaine or phenytoin
(No effect on AV conduction).
- Life-threatening ventricular arrhythmias are treated
according to the algorithms of advanced cardiac life
support (ACLS).
- In case of bradycardia: give atropine.
- Correct electrolyte disturbances
- In case of hyperkalemia: give EDTA and give insulin +
glucose to shift K+ intracellularly But Ca gluconate is
contraindicated
• However, hyperkalemia itself does not cause death, and
treatment with potassium-lowering agents
does not reduce mortality.
27.
28. Indications of Antidotal therapy with antibody (Fab) fragments
- Fab fragments should be given in all cases of severe
digitalis poisoning.
- Life-threatening arrhythmia (eg, ventricular tachycardia;
ventricular fibrillation; asystole; complete heart block;
Mobitz II heart block; symptomatic bradycardia)
-Evidence of end-organ dysfunction (eg, renal failure,
altered mental status)
-Hyperkalemia (serum potassium >5 to 5.5 meq/L)
-serum digoxin concentration is greater than
10 ng/mL at steady state in acute ingestions, or greater
than 4 ng/mL in chronic ingestions
- an adult ingests more than 10 mg or a child more than 4
mg acutely.
