2. Toxicity of Digitalis
The term digitalis is also used for drug preparations that contain cardiac glycosides,
particularly one called digoxin, and digotoxin that are extracted from various plants
genus hold the same name, digitalis “foxgloves”.
The most famous two species are D. purpurea and D. lutea
Digitalis glycosides have +ve inotropic (increase the force of cardiac contraction) , -ve
chronotropic and diuretic effects.
Increases myocardial contraction
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Increased cardiac output
Improved circulation
Improved tissue perfusion
Decreases conduction through AV node
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Decreased heart rate
They are excessively used in treatment of different cardiovascular disorders like
 Congestive heart failure.
 Cardiac arrhythmia (atrial fibrillation, atrial flutter, and tachyarhythmias)
Mechanism of action:
Digitalis aim to regulate the cytosolic Ca2+concentration
It inhibits Na+/K+-ATPase enzyme, which is associated with the sodium pump. Inhibition
of this enzyme leads to an increase in the intercellular Na+ which reduces the normal
transport of Ca++ out of the cell via the Na+/ Ca++ exchange mechanism. The increase in
the intercellular Ca++ level leads to increase the power of heart muscle.
Cardiac glycosides facilitate calcium entry into the cell through the voltage gated calcium
channels.
Cardiac glycosides increase the release of stored calcium from the sacroplasmic
reticulum
Digitalis Toxicity:
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Digitalis toxicity is a complication of digitalis therapy.
Digitalis has a very low therapeutic index and 60% of the toxic dose may be
required to produce a therapeutic effect.
Therapeutic serum digoxin levels is about 0.5-2ng/mL (6 hours after dose)
Toxicity level is >2.4ng/mL
1/3 of patients have toxic symptoms at <2.0ng/mL
Digitalis toxicity can occur from a single exposure large amount of the drug at
one time (acute toxicity) or from chronic overmedication (chronic toxicity)
Digitalis is a cumulative drug (slowly eliminated and highly bound to plasma
protein), thus successive doses will accumulate, leading to elevation of serum
drug concentration to toxic level (narrow therapeutic index).
Digitalis toxicity may also in patients with normal blood levels of digitalis if
other risk factor are present for example
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Diuretics therapy to decrease the blood volume, are usually used in some cases
of heart failure. Many diuretics can cause K+ loss. As myocardial function is
critically dependent on serum potassium level, low levels of K+ in the body
increase the risk of digitalis toxicity if concurrently administered. Digitalis itselve
in high toxic doses may be associated with hyperkalemia.
Risks include taking along with medications that interact with digitalis such as
quinidine, verapamil, amiodarone, and others.
Reduced kidney function will cause digitalis to build up in the body rather than be
removed normally through urine. Therefore, any disorders that disrupt kidney
functioning (including dehydration) make digitalis toxicity more likely.
Symptoms of Digitalis Toxicity:
Symptoms of digitalis toxicity areoften nonspecific, including:
1- GIT effect:
- Stimulation of (CTZ) in medulla thus induces vomiting.
- Local irritant action leading to diarrhea, abdominal cramps and vomiting.
- Digitalis toxicity is accompanied with anorexia.
2- Cardiac effects:
Digitalis has three cardiac altered functions
- Suppression of AV conduction
- Increased automaticity
- Decreased refractory period in ventricles
The most common ECG findings are
- Heart block
- Bradycardia.
- Cardiac arrhythmias (like AF).
- Hypotension
3-CNS effects:
- Headache, malaise, dizziness, fatigue, hallucination, delirium, disturbed color
perception and blurred yellow vision.
Mangement Digitalis Toxicity:
- Cessation of drug administration.
- Potassium chloride administration to prevent the recurrence of the arrhythmais as K+
competes with digitalis for Na+/K+- ATPase enzyme.
- Calcium ion chelating agents (disodium EDTA).
- Specific antiarrhythmic drugs, which include:
- β-adrenergic blockers.
- Diphenyl hydantion.
- Lidocaine.
- Atropine to control bradycardia or partial A.V. block.
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Antidote therapy is available for digoxin toxicity. Digibind, a digoxin-specific
antibody, rapidly binds to the pharmacologically active extracellular circulating
digoxin, forming complex molecules that is excreted in urine resulting in a
favorable concentration gradient for the efflux of digoxin out of cells
• Drug interactions:
1- Diuretic therapy (like thiazides ) as they produce hypokalemia. Cortisone also cause
Na+ retention and K+ loss
2- Drugs like Ibuprofen, Quinidine, Quinine, Amiodarone, verapamil that displace,
digoxin from tissue binding sites and/or depresses renal/bilary digoxin clearance
(increase serum levels of digoxin).
3- High Ca++ serum level as in case of hyperparathyrodism.
4 - Sympathomimetics especially β-agonist (e.g. Dobutamine and Isoproterenol) as they
increase Ca++ entery into the myocardium. β-blockers (e.g. Propranolol) also cause
additive bradycardia
5- Minor Food Interactions include administration of digoxin with a high-fiber meal has
been shown to decrease its bioavailability that fiber can sequester up to 45% of the
drug when given orally. Another food-drug interaction include grapefruit juice
increase the plasma concentrations of digoxin. The mechanism is increased
absorption of digoxin due to mild inhibition of intestinal P-glycoprotein.
Environmental Toxicity
1. Toxicity of Heavy Metals
Periodic table has 105 elements, 80 are considered metals that
they are charecterized by:
- luster, malleability, electric and thermal conductivity;
- Chemically form bases which can react with acids and
tendency to lose electrons and become positive ions (cations),
Examples of heavy metals and metalloid
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There are ~35 metals that concern us because of occupational
or residential exposure.
Depending on their physicochemical characteristics (e.g. sp.
gravity, atomic wt. , ….), some of them are classified as
heavy metals ( metal having an atomic weight greater than
sodium, sp. gravity >5 g/cm3)
Aluminum, antimony, arsenic, bismuth, cadmium,
chromium, cobalt, copper, gallium, gold, iron, lead,
manganese, mercury, nickel, platinum, selenium, silver,
thallium, tin, uranium, vanadium, and zinc
Small amounts of some of these elements are common in our
environment and diet and are actually necessary for good
health.
Large amounts of any of them may cause acute or chronic
toxicity (poisoning).
Indoor concentration of heavy metals is generally less than
their outdoor concentration
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Heavy metal environmental pollution is mainly produced
from industrial activities, and deposit slowly in the
surrounding water, air and soil
Heavy metals are found in everyday existence and are
frequently hard to avoid entirely. Most people can excrete
toxic heavy metals from the body successfully. However,
some people—especially those who suffer from chronic
conditions—cannot excrete them efficiently enough and
toxicity occurs
Heavy metal toxicity is an excessive build-up of metals in the
body. The most hazardous heavy metals that humans are
exposed to are arsenic (As), lead (Pb), mercury (Hg),
cadmium (Cd), aluminum (Al)and iron (Fe)
Examples of specific gravities of heavy metals: arsenic, 5.7;
cadmium, 8.65; iron, 7.9; lead, 11.34; and mercury, 13.546
Treatment of heavy metal toxicities
• Medicinal treatment for heavy metal poisoning is done by
chelation therapy by administering compounds known as
chelators or chelating agents. For example
1- Dimercaprol (British Anti-Lewisite ;BAL), It is a bidentate
chelator (i.e. it forms two bonds with the metal ion,
preventing it from binding to tissue proteins and permitting
its rapid excretion. It is a universal chelating agentthat is
used to treat toxicities with many heavy metals like Hg, AS,
and Pb. It is oily liquid given by parentral administration. Its
administration is associated with many side effects like
hypertension, tachycardia, headache, nausea, vomiting,
paresthesia, swelling, hematoma at the site of injection and
fever especially in children. Long-term use may associated
with thrombocytopenia andincrease prothrombin time.
2- Dimercaptosuccinic acid (DMSA, Succimer), another
bidentate chelating agent. It occurs in two diastereomers,
meso and the chiral dl forms. The meso isomer is used as a
chelating agent. It acts as conger of BAL with oral
bioavailability. It mainly used to treat arsenic and mercury
poisoning. It is also effective to treat lead toxicity in both
children and adults. It is less toxic than BAL but some GI
distress, skin rhashes,paresthesia and slight elevation in liver
enzymes may occur.
3-
2,3,-dimercaptopropane-1-sulfonate (Dimaval, Unithiol
; DMPS): It is a bidentate chelating agents that form
complexes with various heavy metals. It mainly used as
antidote for treatment of mercury poisoning. There are
indications that DMPS is also suitable for the increase of
heavy metal elimination in poisoning with arsenic (except
for poisoning with arsine), copper, lead, antimony,
chromium, cobalt.
4- D-Penicillamine (DPCN); It is a bidentate chelating agent.
It is a derivative of penicillin. It is used in treating of copper
poisoning and Wilson’s disease (presence of copper overload
causing hepatic and CNS symptoms).It also used as adjuvant
therapy in treatment of gold, arsenic, and lead intoxication. It
is given orally ,absorbed well from GIT and excreted
unchanged. Adverse effects could be severe like proteinurea,
pancytoprnia and hemolytic anemia.
5- Disodium calcium EDTA (ethylene diaminetetraacetic
acid); It is a polydentate chelating agent that is efficiently
used for polyvalent heavy metal detoxification like Lead
toxicity, Zinc toxicity, and acute cadmium poisoning. It is
administered parentrally. Side effects include nephrotoxicity
and ECG changes
6- Desferrioxamine (DFO); it has natural origin (a derivative
of the iron-bearing metabolite, ferrioxamine B, from
Streptomyces pilosus) . It is polydentate chelating agent used
mainly for Iron poisoning, and also in aluminum poisoning. It
is poorly compete with heme iron in hemoglobin and
cytochromes. Deferoxamine is also used in treatment of
Aceruloplasminemia (an autosomal recessive disorder of
iron
metabolism
characterized
by
progressive
neurodegeneration of the retina and basal ganglia and
development of diabetes mellitus). Side effects include skin
hypersenstivity, renal and hepatic toxicity and neurotoxicity.
Long-term use may cause blood coagulopathies.