Digoxin- GLYCOSIDE

1. DIGOXIN
DR ZIKRULLAH

2.  The term DIGITALIS is a general term used for all
plant derived cardiac glycosides.
 Digitalis is widely used in the treatment of various
heart conditions, namely atrial fibrillation, atrial flutter
and congestive heart failure that cannot be controlled
by other medication.
 DIGOXIN is a purified cardiac glycoside .
 Digitalis glycosides found in
– Foxglove, oleander, lily of the valley

3. Name the Plant
http://biology.clc.uc.edu/graphics/steincarter/florida/
http://www.huntingtonbotanical.org/Shakespeare/photogallery.htm
http://www.dososos.com/availability_photos/lily_valley.html
Lilly of the
Valley
Oleander Foxglove

4. DIGOXIN PREPARATIONS
 DIGOXIN can be used orally, I.V and I.M
injection.
 It is available as a
– 0.25 mg tabs & capsules
– 0.05 mg/mL oral solution and
– 0.25 mg/mL( 2 ml) or 0.5 mg/mL (1 ml)
injectible solution.

5.  The vehicle is 40% propylene glycol and 10%
alcohol.
 The injection is buffered to a pH of 6.8 to 7.2
with 0.17% sodium phosphate and 0.08%
anhydrous citric acid.
 Dilution is not required.

6.  Digoxin exists as odorless white crystals that
melt with decomposition above 230°C.
 The drug is practically insoluble in water and in
ether; slightly soluble in diluted (50%) alcohol
and in chloroform; and freely soluble in
pyridine.
 Temp range = 15 to 30°C (59 to 86°F) and
protect from light.

7. CHEMICAL STRUCTURE
 Basic structure of all cardiac glycosides consists of a
cyclopenteno-phenantherene nucleus which consists
of a GLYCONE and a AGLYCONE portion.
 GLYCONE portion in usually glucose or digitoxose –
pharmacologically inactive but necessary for fixation.
 AGLYCONE portion is responsible for
pharmacological action.

9. MECHANISM OF ACTION
 The beneficial effects of digoxin result from:
– direct actions on cardiac muscle, as well as
– indirect actions on the cardiovascular system
mediated by effects on the autonomic nervous
system.

10. Inhibits sodium-potassium ATPase of myocardial
fibres ↓
Progressive accumulation of Na+ intracellularly
↓
Indirect increase of Ca++ intracellularly
↓
Ca++ transients are augmented in myocardium
↓
↑ force of myocardial contraction

12. CHANGES IN CARDIAC ACTION POTENTIAL
AFTER DIGITALIZATION
 Increased automaticity – decreasing resting
membrane potential and increase in slope of
Phase 4 depolarization.
 Inhibition of outward sodium decreases slope
of Phase 0
 Decrease in duration of action potential mainly
due to shortened duration of Phase 2
0
1 2
3
4

13. ECG CHANGES DUE TO DIGITALIZATION
(therapeutic)
 Prolonged PR interval – due to delay of
conduction at AV node
 Shortened QTc interval because of more rapid
ventricular repolarization.
 ST depression(scaphoid or scooped out) due to
decreased slope of Phase 3
 Flattened or inverted T wave

14. Digitalis Effect
http://www.emedu.org/ecg/voz.php

15.  The autonomic (indirect) effects include:
– a vagomimetic action,
– Arterial baro-receptor (carotid sinus)
sensitization
– Activation of Nodose Ganglion in the CNS
 These lead to increase parasympathetic tone and
subsequent decrease activity of the SA and AV
node resulting in suppression of ectopic activity

16.  The pharmacologic consequences of these direct
and indirect effects are:
– an increase in the force and velocity of myocardial
systolic contractions (positive ionotropic action);
– a decrease in the degree of activation of the
sympathetic nervous system and renin-angiotensin
system (neurohormonal deactivating effect);
– slowing of the heart rate and decreased
conduction velocity through the AV node
(vagomimetic effect).

17. PHARMACOKINETICS
ABSORPTION
 Oral – 75% in First hour with peak plasma
concentration occurring at 1-2 hrs
 IM – not preferred as is painful, unpredictable
absorption.
 IV – peak effect at ~ 5-30 min

18.  DISTRIBUTION:
– Following drug administration, a 6- to 8-hour tissue
distribution phase is observed.
– Principal reservoir in body are skeletal muscles
– This is followed by a much more gradual decline in the
serum concentration of the drug, which is dependent
on the elimination of digoxin from the body.

19. – Digoxin has a large apparent volume of
distribution.
– Digoxin crosses both the blood-brain barrier
and the placenta.
– Approximately 25% of digoxin in the plasma
is bound to protein.

20.  METABOLISM
– Only 25 % of a dose of digoxin is metabolized
via hydrolysis, oxidation, and conjugation.
– The end metabolites: 3 β-digoxigenin, 3-keto-
digoxigenin, and their glucuronide and sulfate
conjugates.
– The metabolism of digoxin is not dependent
upon the cytochrome P-450 system
– digoxin is not known to induce or inhibit the
cytochrome P-450 system.

21.  EXCRETION:
– Elimination of digoxin follows FIRST-
ORDER KINETICS .
– 50% to 70% of a digoxin dose is excreted
unchanged in the urine. Renal excretion of
digoxin is proportional to GFR.

22. – In Pt with normal renal function, digoxin has a
half-life of 1.5 to 2.0 days.
– In anuric patients is prolonged to 3.5 to 5 days.
– Not effectively removed from the body by
dialysis, exchange transfusion, or during
cardiopulmonary bypass .

23. CLINICAL USES
 Used in patients with heart failure and atrial
fibrillation
 Only about 50% of patients with normal sinus
rhythm (usually those with systolic dysfunction)
will have documentable relief of heart failure
from digitalis.

24.  Digitalis is useful in the management of ATRIAL
ARRHYTHMIAS because of its cardio selective
parasympathomimetic effects.
 In ATRIAL FLUTTER, the depressant effect of the drug
on atrioventricular conduction will help control an
excessively high ventricular rate.
 The effects of the drug on the atrial musculature may
convert flutter to fibrillation, with a further decrease in
ventricular rate.

25.  In ATRIAL FIBRILLATION, the same
vagomimetic action helps control ventricular rate,
thereby improving ventricular filling and increasing
cardiac output.
 Digitalis has also been used in the control of
paroxysmal-atrial and atrio-ventricular nodal
tachycardia but not WPW syndrome associated
atrial fibrillation.

26. DOSAGE
 The dose of digoxin, the following factors must be
considered:
– The body weight of the patient - lean body weight.
– Renal function - on the basis of creatinine clearance.
 Serum Digoxin Concentrations

27.  Heart Failure:
– Rapid digitalization- achieved by administering a single
initial intravenous dose (0.5 to 1 mg) or oral (0.75 to 1.5
mg ) based upon projected peak digoxin body stores.
– Maintenance Dose = Loading Dose x % Daily
Loss/100
(Where: % Daily Loss = 14 + C.cr/5)
[C.cr is creatinine clearance, corrected to 70 kg body
weight or 1.73 m2 body surface area.]

28. Gradual digitalization
 may be obtained by beginning an appropriate
maintenance dose, thus allowing digoxin body stores
to accumulate slowly.
 Therapy is generally initiated
– at a dose of 250 mcg (0.25 mg) once daily in
patients under age 70 with good renal function,
– at a dose of 125 mcg (0.125 mg) once daily in
patients over age 70 or with impaired renal function
– at a dose of 62.5 mcg (0.0625 mg) in patients with
marked renal impairment.
 Doses may be increased every 2 weeks according to
clinical response.

30. INTERACTIONS
 Risk for developing serious digitalis-induced cardiac
arrhythmias if hypokalemia develops, as in diuretic
therapy, diarrhea or oral antacids.
 Patients at risk if given quinidine, which displaces
digoxin from tissue binding sites (a minor effect) and
depresses renal digoxin clearance (a major effect).
 Antibiotics that alter gastrointestinal flora may
increase digoxin bioavailability in about 10% of
patients.

31.  Succinylcholine can abruptly increase parasympathetic
nervous system activity can have a additive effect but
not significant clinically.
 IV calcium can cause dysarrythmias.
 Fentanyl, enflurane and to a lesser extent isoflurane
protect against digitalis induced cardiac automaticity.
 Sympathomimetics with β activity like Pancuronium
may sensitize the myocardium to digitalis induced
arrhythmias.

32. Digitalis toxicity

33. Clinical Features
 Nonspecific cardiac dysrhythmias
– May be life threatening
– Any dysrhythmia or junctional escape rhythm with
an AV block consider digoxin toxicity
– PVC’s
Frequent PVC’s are the most common dysrhythmia
– Bi-directional V-tach
Rare, but relatively specific for digitalis toxicity

34. Digoxin Toxic Dysrhythmias
 Bradycardia with AV block

35.  Second degree AV block, Type I –
Wenckebach
 Atrial tachycardia with AV block

36.  A. Fib with a regular ventricular rate
 PVC’s
http://www.tchpeducation.com/General%20Interest/Digoxin%20Toxicity/dig

37.  Ventricular Tachycardia
 Bifascicular Ventricular Tachycardia

38. Clinical Features
 Other symptoms:
– Gastrointestinal
distress
– Dizziness
– Headache
– Weakness
– Syncope
– Seizure
– Confusion
– Disorientation
– Delirium
– Hallucinations
– Visual changes
(yellow-green
halos)

39. Laboratory Evaluation
 Potassium
– Acute poisoning of the Na+K+ATPase pump
causes elevated potassium levels
– Potassium level may be a better prognostic
indicator in acute poisoning than the digoxin level
– Potassium less elevated in chronically poisoned
patients

40.  Digoxin level
– Therapeutic levels 0.5 – 1.5( or 2.5) ng/ml
With signs of toxicity therapeutic level does not exclude
toxicity
– Acute exposures
Digoxin absorbed into the plasma then redistributed to
the tissues
Serum levels most reliable at 6 hours
 Renal and hepatic function, and electrolytes
must also be evaluated.

41. Acute vs. Chronic
 Acute
– Asymptomatic for
several hours
– GI symptoms often
occur first
– Bradydysrhythmias
or supraventricular
with AV block
– Severity correlates
with K+ not with
digoxin level
– High digoxin level
 Chronic
– Elderly on digoxin
and diuretics
– May mimic influenza
or gastroenteritis
– Mental status change
– Many dysrhythmias,
but ventricular more
common than in
acute
– K+ often low and
digoxin is a poor
predictor

42. Factors Enhancing Toxicity
 Electrolyte abnormalities
– Hypokalemia, hypomagnesemia, and
hypercalcemia
– Cardiac hypersensitivity with myocardial disease
or ischemia
– Decreased renal, hepatic, or thyroid function
– Drugs
Antidysrhythmic, spironolactone, indomethacin,
clarithromycin, erythromycin

43. Dysrhythmia Treatment
 ABC’s
 Initiate
– Continuous cardiac monitoring, IV’s, frequent
reevaluations
 Extended observation at least 12 hours
 Correct hypoxia, hypoglycemia, and electrolytes
 Atropine and cardiac pacing

44.  Antidysrhythmias
– Lidocaine and phenytoin
Both decrease ventricular automaticity
Phenytoin increases conduction through AV
node therefore often considered the DOC for
bradydysrhythmias
– Bretylium shown clinical use but animal studies do
not support it.
– Class IA antidysrhythmics are contraindicated as
they slow AV nodal conduction

45.  Electrocardioversion
– May induce ventricular fibrillation so only as last
resort
 Digoxin specific Fab fragment is the treatment of
choice for life-threatening dysrhythmias that do not
respond to conventional therapy
 Hyperkalemia
– Glucose, insulin, and sodium bicarbonate
– Potassium-binding resins
– Avoid Calcium
Calcium may promote cardiac toxicity

46. Digoxin-Specific Fab Antibody
 Sheep IgG antibody to digoxin
 Remove digoxin from plasma and tissue
 Clinical improvement within 1 hour in 90% of
patients
 Indications
1. Ventricular dysrhythmias
2. Unresponsive hemodynamically significant
bradydysrhythmias
3. Hyperkalemia > 5.5 mEq/L with suspected
digoxin toxicity

48.  Adverse effects
– Cardiogenic shock reported in patients dependent
on digoxin for inotropic support
– Increased ventricular response to A. Fib
– Hypokalemia from rapid digoxin removal
– Rare hypersensitivity reactions

49.  Dosage
– Calculate total body load
Based on amount ingested
–Total body load = amount ingested x 0.8
Based on digoxin concentration
–[Digoxin level (ng/mL) x 5.6 x weight (kg)]
/ 1000
– Calculate number of vials
Digibind vials (40mg) required = total body
load/0.6

50. PRECAUTIONS
 Use in thyroid disorders and hypermetabolic states
 Use in patients with acute myocardial infarction
 Use during electrical cardioversion
 Pregnancy
 Nursing mothers
 Pediatric use
 Geriatric use

51. Thank you……