Digitalisintoxication T46.0

Synonyms

Digitalis poisoning;

First describer

The cardiac efficacy of Digitalis was mentioned in the Papyrus Ebers as early as 1500 BCE. In the course of the Middle Ages, however, traces of a specific therapeutic use are lost.

In Ireland, the first references to the medicinal plant can be found around 400 to 500 CE, where it was used by herbalists for various indications. From there it reached mainland Europe, where it was first given its present name "digitalis" (foxglove) by the botanist Leonhard Fuchs in 1542.

At the end of the 18th century, the Scottish physician William Withering made a name for himself with his exact characterizations regarding the effects of digitalis, thus opening the era of scientific treatment with digitalis (Rietbrock 2013). He successfully treated patients with "cardiac dropsy" with a tea made from digitalis leaves (Hein 2020).

Homolle, a French physician and chemist, isolated three different substances from digitalis leaves in1864. The crystallized digitalin was first named "digitoxin" by the Strasbourg pharmacologist Schmiedeberg in 1874.The other two pure substances were later given the names "digoxin" and "gitoxin." Digoxin later gave rise to the albsynthetic derivatives acetyldigoxin and methyldigoxin (Rietbrock 2013).

Digitalis (glycosides), also called cardiac glycosides, can be obtained from many different plants, the best known being the red foxglove (Digitalis purpurea) and the woolly foxglove (Digitalis lanata).

(Böhm 2000)

The most commonly used preparations in medicine are digoxin and digitoxin.

Digoxin:

- Enteral absorption: 50 - 80 %,

- Plasma protein binding: 30 - 40 %.

- Half-life: 36 - 48 h

- renal excretion: 70 %

- oral maintenance dose: 0,1 - 0,25 mg / d (Böhm 2000)

Digitoxin:

Digitoxin is obtained from the leaves of Digitalis purpurea and Digitalis lanata. It is available as a pure glycoside in tablet, oral solution and solution for injection (Hänsel 1999).

- Enteral absorption: 99 %,

- Plasma protein binding: 97 %.

- Half-life: 5 - 7 d

- renal excretion: 25 %

- oral maintenance dose: 0.07 - 0.1 mg / d (Böhm 2000).

Since digitoxin is more lipophilic than digoxin, there is a slower onset of action, which cannot be achieved more rapidly even by i. v. injection (Karow 2021).

Beta-acetyldigoxin:

- Enteral absorption: 80 %,

- Protein binding: 25 %.

- Elimination half-life in serum: 1.5 - 2 d

- renal elimination: 70 - 80 %

- oral maintenance dose: 0,2 - 0,4 mg / d (Karow 2021)

Beta- methyldigoxin:

- Enteral absorption: 90 %,

- protein binding: 25

- elimination half-life in serum: 2.0 - 2.3 d

- renal elimination: 70 - 80

- oral maintenance dose: 0.15 - 0.2 mg / d (Karow 2021).

Cardiac glycosides have only a narrow therapeutic range, ranging from 1.5 to 3 times the therapeutic dose (Karow 2021).

Digitalis intoxication can be acute or chronic. The acute form is always life-threatening (Gertsch 2007).

The incidence of chronic digitalis intoxication in digitized patients varies between 6 - 23 %. It occurs particularly frequently in elderly patients with reduced body weight and in patients with renal insufficiency. Women are affected more frequently than men - possibly due to relative overdose (Gertsch 2007).

Digitalis intoxication can occur due to:

• Errors in dosage
• presence of a contraindication to digitalis
• with criminal or suicidal intent (Herold 2022): The lethal dose of digoxin, for example, is about 15 mg (Gertsch 2007).
• increased sensitivity to digitalis due to e.g:
  • Diarrhea
  • Vomiting
  • Diuretics
  • Laxatives
  • Hypokalemia
  • Hypercalcemia
  • Hypomagnesemia
  • Hypothyroidism
  • Renal insufficiency
  • Amyloidosis
  • Acidosis (e.g. in cor pulmonale)
  • Drugs such as:
    • Amiodarone
    • Diltiazem
    • Erythromycin
    • Quinidine
    • Spironolactone
    • Tetracyclines
    • Verapamil (Böhm 2000)
    • Quinidine
• acute ischemia (Gertsch 2007)

• Cardiac arrhythmias occur in approximately 97% of patients with digitalis intoxication (Disam 2002) in the form of:
  • AV nodal tachycardia
  • AV blockage
    • AV block I in approx. 29.3% of cases
    • AV- Block II type Wenckebach at approx. 3,4 %
    • AV- Block II Type Mobitz at approx. 1,7 %
    • AV block III at approx. 6.9 % (Erdmann 1983)
  • sinus bradycardia (found in about 17.2 % [Erdmann 1983])
  • Extrasystoles:
    • ventricular extrasystoles in about 39.7 %, supraventricular in about 13.8 % [Erdmann 1983])
    • supraventricular extrasystoles in approx. 13.8 % (Erdmann 1983)
  • paroxysmal atrial tachycardia not uncommon with 2: 1 AV block (in about 8.6% [Erdmann 1983]) (Herold 2022)
  • Bigeminal block (ventricular bigeminal block is found in approximately 17.2% [Erdmann 1983])
  • Ventricular bradycardia in atrial fibrillation in approximately 10.3 %
  • sinus tachycardia in about 6.9
  • Ventricular tachycardia in approx. 1.7%.
  • Ventricular fibrillation at approx. 1.7 % (Erdmann 1983)
• Visual and central nervous disturbances (found in 45% of patients [Disam 2002])such as color vision (yellow or green cast, halos, etc. [Gertsch 2007])
• Gastrointestinal disturbances (occur in about 90% [Disam 2002]) in the form of diarrhea, nausea, nausea (Herold 2022)
• Intestinal ischemia, also known as NOMI (nonocclusive mesenteric ischemis) occurs only in rare cases (Susen 2007)
• Hyperkalemia: This is found in the early phase of intoxication and may progress to refractory hyperkalemia (Erdmann 1983).

Diagnosis of digitalis intoxication includes history, clinical symptoms, and determination of serum glycoside levels (Herold 2022).

There is no strict correlation between digitalis serum levels and ECG changes. In patients without previous cardiac disease, disturbances of AV conduction are frequently found in digitalis intoxication, in patients with previous cardiac disease, VES is more frequent (Gertsch 2007).

- Arrhythmias:

Digitalis intoxication can cause almost all forms of arrhythmias - up to tachycardic atrial fibrillation.

- ST depressions:

These occur with both normal and pathological digitalis levels.

- QT time significantly shortened:

Shortening of QT- time is found exclusively in elevated digitalis levels, but not in normal ones.

- Atrial tachycardia with AV block (as opposed to atrial flutter with AV block) should always be suspicious for digitalis intoxication (Gertsch 2007).

• Determination of serum glycoside level.
  • Therapeutic serum level for:
    • Digoxin: generally 0.8 - 2.0 ng / ml, in heart failure 0.5 - 0.8 ng / ml
    • Digitoxin: generally 9 - 30 ng / ml, in heart failure no data (Karow 2021).

In patients with acute digitalisin intoxication, serum levels do not indicate reliable levels until about 8 h after ingestion (Gertsch 2007).

• Potassium (Herold 2022):

In acute digitalis intoxication, potassium levels are (initially) elevated or in the upper range of normal values. In chronic intoxication, potassium levels are usually in the normal range, except in renal insufficiency (Gertsch 2007).

Potassium levels should be in the upper normal range because potassium inhibits the action of digitalis (Karow 2021).

• Calcium:

Calcium level should be as low as possible because calcium potentiates the effect of digitalis (Karow 2021).

- ECG changes possible with therapeutic dose of digitalis in the form of:

- frequency-corrected shortening of QT duration

- Trough-shaped ST depression V 5/6

- PQ prolongation

- T- negation

- T- flattening (Herold 2022)

- Tissue necrosis due to digitalis-induced vasospasm (Böhm 2000).

• Immediate cessation of digitalis intake
• Promotion of elimination of digitalis by:
  • Antidote treatment with Fab antibody fragments such as DigiFab (Böhm 2000). Dosage:
    • if the amount of digitalis is known: 80 mg of antidigoxin Fab binds 1 mg of digoxin, so that the digoxin level drops by 1ng / ml and by 10 ng / ml for digitoxin (Flake 2021)
    • If the amount of digitalis is unknown: bolus of 160 mg as a short infusion in 5% glucose for 20 min, then 20 mg / h for 12 h (Flake 2021)
  • Detoxification measures in the form of:
    • Gastric lavage at a time interval < 1 h
    • administration of activated charcoal
    • in case of intoxication with digitoxin:
      • additional use of exchange resins such as colestipol or colestyramine
      • Hemoperfusion
        • however, not effective in case of intoxication with digoxin
        • hemodialysis and peritoneal dialysis are not suitable for glycoside elimination (Böhm 2000)
• Symptomatic therapy in the form of:
  • temporary pacemaker
  • Atropine for bradycardia (Herold 2022) Dosage: 1mg atropine i. v. (Böhm 2000)
  • In ventricular extrasystoles, tachycardias, and ventricular flutter Use of:
    • Magnesium 20 mval i. v. (2 mval = 1 mmol / l (Hartig 2004)
    • Phenytoin 100 mg i. v.
    • Lidocaine 100 mg i. v.
    • Defibrillation
    • Cardioversion (Böhm 2000)
• Potassium:

Hyperkalemia increases the risk of AV block (Lemmer 2007). Therefore, in case of hyperkalemiaimmediate antidote treatment with Fab- antibody fragments (see above) should be given (Mori 2012). If no antidote is available, the shift of potassium into the intracellular space can be treated with glucose, insulin, and bicarbonate (Gertsch 2007).

However, potassium is always contraindicated in pre-existing conduction disorders (Lemmer 2007). In case of hypokalemia, potassium should be substituted except in case of pre-existing conduction disorders (Mori 2012).

• Calcium:

Ca2+ enhances the effect of digitalis and thus promotes toxicity. From there, calcium supplements are contraindicated in digitalis intoxication. Existing hypercalcemia should be corrected promptly (Karow 2021).

In older studies, the lethality of digitalis poisoning is between 3 - 11 %. In later studies, 5 of a total of 6,612 subjects died (Rietbrock 1983).

The lethal dose for digoxin is approximately 15 mg (Gertsch 2007).

Antmann et al. (1990) showed in multicenter studies that

- 80% of 150 patients recovered completely

- 54 % of the 56 patients with cardiac arrest survived it (Gertsch 2007).

Very high digitalis levels of > 6.0 mmol / l correlate with increased mortality, which can be as high as 50%(Gertsch 2007).

Digoxin mortality is increased in women with heart failure and reduced left ventricular function, but not in men with the same constellation. It is therefore recommended by Eichhorn and Gheorghiade, especially in women, a serum concentration of < 1.0 mmol / l (Gertsch 2007),

General Info:

Pharmacodynamics

Cardiac glycosides have a positive inotropic effect, leading to an increase in intracellular Na + - ion concentration by inhibition of Na + / K + - ATPase and to an increase in Ca 2+ - ion concentration by activation of sarcolemmal Na + / Ca 2+ - ATPase exchangers.

In digitalis intoxication, inhibition of Na + / K + - ATPase results in massive hyperkalemia with concomitant intracellular potassium depletion (Böhm 2000).

The other main effects of cardiac glycosides are a positive inotropic effect (this is exclusively detectable in patients with heart failure ), negative chronotropic and negative dromotropic effect (Böhm 2000).

Indication

The value for the evaluation of digitization for the purpose of frequency control in tachyarrhythmias and in heart failure is meanwhile discussed very contradictorily - especially because of the small therapeutic breadth. According to Erdmann (2016), tachyarrhythmia absoluta in atrial fibrillation can now be treated more effectively by calcium antagonists and beta blockers, and digitalis is no longer needed for evidence-based heart failure.

The indication for digitalis has therefore been severely restricted by (Krakow 2021) and now includes:

- rare cases of heart failure

- Atrial fibrillation (Pautas 2012).

Digitoxin should be preferred over digoxin for treatment with digitalis, as the latter can also be used in the elderly and renal insufficients due to its more stable and renal-independent elimination (Erdmann 2016).

Dosage and route of administration

Digoxin:

The effect after i. v. administration occurs after 10 - 20 minutes (Böhm 2000).

Digitoxin:

The effect after i.v. administration occurs after 30 - 40 minutes (Böhm 2000).

There are so far - despite the medical use of digitalis for more than 200 years - no dosage recommendations that have been backed up by clinical studies (Erdmann 2016).

Preparations

- Digoxin: e.g. Lanicor, Novodigal

- Digitoxin: e.g. Digimerck, Digimed (Endres 2021).

- Beta-acetyldigoxin: e.g. Novodigal

- Beta- methyldigoxin: e.g. Lanitop (Karow 2021)

In patients treated with digoxin, digitalis levels should be checked regularly - especially in the elderly and patients with renal insufficiency (Bundesärztekammer 2021).

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