Digitalis Glycosides 45

Digitalis Glycosides
Michael Wahl
& 2005 Elsevier Inc. All rights reserved.
This article is a revision on the previous print edition article
by Daniel J Cobaugh, volume 1, pp. 479–481, & 1998,
Elsevier Inc.
* REPRESENTATIVE CHEMICALS: Digoxin; Digitoxin
* CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBERS:
CAS 20830-75-5 (Lanoxicaps); CAS 71-63-6
(Crystodigin)
* SYNONYMS: Lanoxin; Foxglove
* CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Digoxin
is a cardiac glycoside congener of digitalis with a
hydroxyl group at the C12 position. Digitoxin is a
cardiac glycoside congener of digitalis that does
not contain a C12 hydroxyl group
* CHEMICAL STRUCTURES:
Digoxin is also available for parenteral administra-
tion and parenteral toxic exposures can occur.
Toxicokinetics
Digoxin
Oral administration of digoxin tablets and liquid
results in 60–85% absorption from the small intes-
tine. Liquid-filled digoxin capsules are 90–100%
absorbed. The presence of food or other medications
may delay oral absorption. Approximately 80% of
digoxin is absorbed following intramuscular admini-
stration. Minimal metabolism occurs. Cleavage of
the sugar moieties occurs in the liver and via bacteria
in the large intestine. Protein binding is 20–30%.
Volume of distribution approximates 4l kg
1 in
adults. Digoxin is excreted in the urine primarily as

O O

O O

OH
CH3 CH3
H H

CH3 H CH3 H

H OH H OH
H H

O O
CH3 H CH3 H

O O

O O
OH 3 OH 3
H H

Uses unchanged drug. In healthy patients, the half-life

Digitalis glycosides are positive inotropic agents used ranges from 34 to 44 h. The half-life can be pro-
in the management of patients with congestive heart longed in renal failure.
failure. They control ventricular rate in supravent-
ricular arrhythmias including atrial fibrillation and
atrial flutter.
Digitoxin

Oral absorption of digitoxin is rapid and complete. It

Exposure Routes and Pathways
is extensively metabolized in the liver to several
Ingestion is the most common exposure pathway active metabolites including digoxin. Protein binding
following accidental and intentional ingestions. is 97%. The volume of distribution approximates
46 Digitalis Glycosides
0.47–0.76 l kg
1. Renal, biliary, and fecal elimina-
tion occur. The half-life can range from 4 to 14 days.
Mechanism of Toxicity
The digitalis glycosides interfere with the Na þ ,K þ -
ATPase pump with a resultant intracellular loss of
potassium and intracellular increases in sodium and
calcium. The net effects of this are increased myocar-
dial contractility and decreased cardiac conduction.
Acute and Short-Term Toxicity
(or Exposure)
Animal
Animals manifest toxic effects similar to those seen in
humans. Cases of cows ingesting large quantities of
plants that contain cardiac glycosides demonstrated
anorexia, weakness, diarrhea, and arrhythmias.
Human
Nausea and vomiting are frequently seen. Changes in
level of consciousness may be observed. Rhythm dis-
turbances are common signs of toxicity. The most
common arrhythmias include bradycardia, heart
block, and paroxysmal atrial tachycardia. Premature
ventricular contractions and ventricular tachycardia
are less common. Severe hyperkalemia can also occur
following acute ingestion of a digitalis glycoside.
Serum potassium levels as high as 13.5 mEq l
1 have
been reported after acute digitalis ingestion. Digoxin
serum concentrations can be extremely high imme-
diately following an acute ingestion. Normal digoxin
serum concentration is 0.5–2 ng ml
1. Normal
digitoxin serum concentrations are 18–22 ng ml
1.
These may decrease over 8–12 h as distribution of the
drug occurs.
Chronic Toxicity (or Exposure)
Animal
Digoxin has been used in animals to treat congestive
heart failure as in humans. Some concern has been
raised about potential effects of drugs like digoxin
causing toxicity in aquatic animals from sewer efflu-
ent or landfill leachate. In a study using a Hydra
vulgaris model, digoxin at concentrations of 1 mg l
1
for 17 days and did not demonstrate adverse effects in
feeding or bud formation.
Human
Anorexia, nausea, vomiting, and diarrhea occur after
chronic exposure. Decreases in level of consciousness
and delirium may be observed. Visual changes inclu-
ding color changes and snowy vision have been des-
cribed frequently. Common arrhythmias that occur
during chronic toxicity include premature ventricular
contractions, ventricular tachycardia, and ventricular
fibrillation. Hypokalemia is often present in chronic
toxicity and actually precipitates toxicity. Serum
digoxin/digitoxin concentrations will be elevated
but not as high as those seen in acute toxic exposures.
In Vitro Toxicity Data
Studies have demonstrated that Tween 80, a common
nonionic surfactant, increases permeability of digox-
in in Caco-2 cells.
Clinical Management
Basic and advanced life-support measures should be
utilized as necessary. A baseline 12-lead electro-
cardiogram should be obtained and continuous car-
diac monitoring should be utilized. A digoxin/
digitoxin serum concentration should be obtained
as well as a serum potassium level. Gastrointestinal
decontamination procedures should be used as nec-
essary based on the patient’s level of consciousness
and history of ingestion. Activated charcoal can be
used for substantial recent ingestions. In patients
with severe dysrhythmias, serum potassium concen-
trations 45 mEq l
1, and elevated digoxin/digitoxin
serum concentrations, digoxin immune Fab should
be given. This sheep antibody, which binds digitalis
glycosides, is effective in reversing both acute and
chronic toxicities. Each 40 mg vial binds 0.6 mg
of digoxin/digitoxin. Dosage should be based on
serum concentration of digoxin/digitoxin or amount
ingested. If these are unavailable, 10 vials can be
administered.
Digoxin immune Fab can be administered over
30 min or it can be administered intravenous push to
patients in cardiac arrest. Since it will pull digoxin/
digitoxin out of tissue sites, serum concentrations of
digoxin/digitoxin will rise. These will represent
bound digitalis and should not be reacted to clini-
cally. Adverse reactions to digoxin immune Fab in-
clude exacerbation of heart failure and atrial
arrhythmias as well as hypokalemia. Allergic reac-
tions have not been commonly reported. The anti-
gen/antibody complex should be eliminated within 5
days of administration. This may be delayed beyond
7 days in patients with renal failure. In chronic toxi-
city, hypokalemia should be treated cautiously
with potassium replacement since rapid increases in
serum potassium can exacerbate conduction distur-
bances. Ventricular arrhythmias can he treated with

phenytoin or lidocaine. Overdrive pacing should also
be considered. Class IA antiarrhythmics such as
quinidine should be avoided since they can cause
conduction disturbances. Conduction disturbances
should be managed with a transvenous pacemaker.
See also: Cardiovascular System; Foxglove.
Dimethoate
Nikita Mirajkar and Carey N Pope
& 2005 Elsevier Inc. All rights reserved.
* CHEMICAL NAME: O,O-Dimethyl-S-2-(methylami-
no)-2-oxoethyl phosphorodithioate
* CHEMICAL ABSTRACTS SERVICE REGISTRY NUMBER:
CAS 60-51-5
* SYNONYMS: Phosphamide; Cygon; De-fend; Rogor;
Rogodial; Roxion; Dimetate; Devigon; Dicap; Di-
met; Rogodan
* CHEMICAL/PHARMACEUTICAL/OTHER CLASS: Synthetic
organophosphorus pesticide of the phosphoroth-
ionate class
* CHEMICAL STRUCTURE:
S O
(CH3O)2P S CH2 C N CH3
H potent in inhibiting acetylcholinesterase than the
Uses
Dimethoate is a systemic and contact insecticide–
acaricide used on a range of insects including mites,
flies, aphids, and planthoppers. Dimethoate is used
very commonly in livestock for the control of botflies
and mites. Formulations include aerosols, dusts,
granules, and emulsifiable concentrates.
Exposure Routes and Pathways
Dimethoate can be absorbed by the oral, dermal, or
inhalation route.
Toxicokinetics
Dimethoate is rapidly absorbed after any route of
administration in mammals. It is rapidly metabolized
in the liver. Like other phosphorothionate pesticides,
the parent compound is activated by cyp450 to
Dimethoate 47
Further Reading
Shumaik GM, Wu AW, and Ping AC (1988) Oleander poi-
soning: treatment with digoxin-specific Fab antibody
fragments. Annals of Emergency Medicine 17: 732–735.
Smolarz A, Roesch E, Lenz E, et al. (1985) Digoxin specific
antibody (Fab) fragments in 34 cases of severe digitalis
intoxication. Journal of Toxicology. Clinical Toxicology
23: 327–340.
the active metabolite, omethoate. A major route of
detoxification of the parent compound is hydrolysis
of the C–N bond. Pretreatment with phenobarbital
increases sensitivity to dimethoate in mice. In male
rats, B60–80% of an orally administered dose of
dimethoate is eliminated via the kidneys within 24 h
of exposure. Elimination was almost complete within
48 h of exposure. Female rats appear to eliminate
dimethoate at a slower rate. The rate of metabolism
and elimination of dimethoate varies in different
species. Dimethoate produces less toxicity in animals
with high rates of dimethoate metabolism and ani-
mals with high liver-to-body weight ratios.
Mechanism of Toxicity
Dimethoate exerts toxicity through inhibition of
acetylcholinesterase. The oxidative metabolite (i.e.,
omethoate) is two to three orders of magnitude more
parent compound. The N-demethylated omethoate
may be the most potent inhibitor of cholinesterases.
The enzyme in red blood cells may be more sensitive
to inhibition than plasma enzyme following dime-
thoate exposure.
Acute and Short-Term Toxicity
(or Exposure)
Animal
The acute oral LD50 for pure dimethoate in rodents is
around 500 mg kg
1, but reported values using tech-
nical products range from 28 to 400 mg kg
1. Early
formulations contained the solvent methyl Cello-
solve, which appears to have participated in chemical
changes upon storage that increased mammalian
toxicity. In studies comparing dermal and oral expo-
sures, the dermal LD50 values were generally report-
ed to be about twice as high. In a reproductive
toxicity test, dimethoate exposure in the drinking
water (B10 mg kg
1 day
1) was associated with