1. Cardiac glycoside toxicityBy
Dr. Shorouk El-Sayyad

2. Cardiac glycosides are used to treat Congestive Heart Failure
CHF: a condition in which the heart is unable to provide adequate perfusion of peripheral organs to meet their metabolic requirements

3. What is digoxin?
Digoxin (Lanoxin) is a cardiac glycoside, obtained from the leaves of the foxglove (Digitalis purpurea), Digitalis lanata. Both species are used as sources of the C. glycosides viz.,
Digoxin and digitoxin
They have similar actions on the heart but have different levels of toxicity in the body
In medicinal doses, cardiac glycosides increase the force of contractions of the heart beat  cardiac output Improved circulation, decreases edema, and increases kidney output
So improve CHF symptoms

4. Differences in pharmacokinetics
Digitoxin is more absorbed from the gastrointestinal tract
Serum concentration not altered significantly by other medications or changes in renal or hepatic function
Digitoxin has a much longer elimination time (half life days as
compared to digoxin which has shorter half-life; 1-2 days) so Digoxin is most widely prescribed more than digitoxin

5. digoxin Digitoxin Highly lipophilic highly bound to plasma proteins
Mainly eliminated in urine and feces 4-Does not accumulate during kidney dysfunction
Less lipophilic
Show lower protein binding 3-Shorter half-life
4-Mainly eliminated by kidney Accumulated quite rapidly in cases of renal insufficiency

6. Differences in toxicity
Prospective studies show
-Digoxin toxicity rates 15 to 27%
-Digitoxin toxicity rates 3 to 5.8%
toxicity three times greater for patients taking digoxin as compared to digitoxin

7. Digoxin toxicity causes -50% of pts are on chronic therapy
-10% took accidental
-40% as suicide attempts
-rarely due to ingestion of certain plants
*normal blood digoxin level is ng/ml
*digoxin toxicity is accelerated by hypokalemia
*presence of hyperkalemia (>5mmol/l) a bad prognostic sign
-if K+ <5………..mortality 0 %
-if K ……………mortality 50%
-if K+ > 5.5…………….mortality 100%

8. Predisposing factors to digoxin toxicity
-Drug interactions………increase digoxin level
Verapamil, Diltiazem, amiodarone, itraconazole…... Decreased renal clearance
Erythromycin, clarithromycin, tetracycline………. decreased gut flora metabolism
Toxicity can be increased by any medication decreasing serum K e.g. diuretics ??
-Metabolic disturbance (hypokalemia, hypercalcemia)
-cardiac diseases (myocarditis, active cardiac ischemia,…)
-Renal insufficiency
-End-stage renal disease, prolongs the half-life of digoxin and reduces its volume of distribution
-There must be reductions both in the loading dose (by about 40 %) and in the maintenance dose (by %) in this setting

9. Function of Na+/K+ ATPase

10. Digitalis Na+/K+ ATPase Na+/Ca2+ Exchange + + + + Na Ca2 CONTRACTILITY
Outside cell (blood)
Digitalis
Na+/K+ ATPase Na
+ + +
Na+/Ca2+ Exchange +
Myofilaments
Ca2
Inside cell
CONTRACTILITY

11. Digitalis Na+/K+ ATPase Na+/Ca2+ Exchange + + + + + + + + 2 Na Ca2
Outside cell (blood)
What would happen if K+ was low?
Digitalis
Na+/K+ ATPase Na
Na+/Ca2+ Exchange
+ + + + + +
+ +
Myofilaments
Ca2 2
Ca CONTRACTILIT+Y
Inside cell

12. Digoxin Properties of digoxin
Increases inotropy (contractility) of the heart
Decreases chronotropy (heart rate)
Natriuresis (sodium loss)  minor effect
Neurohormonal effects
Plasma Norepinephrine
Peripheral nervous system activity
RAAS activity
Vagal tone

13. Symptoms of digitalis poisoning
Cardiac dysrhythmias
Nausea Vomiting Abdominal Pain
Change in visual acuity hallucination
Headache
Shortness of the breath , dyspnoea , hypotension Sweating
Confusion
Fever and/or Chills Anxiety
In acute toxicity hyperkalaemia is common but chronic toxicity is often accompanied by hypokalaemia and hypomagnesaemia

14. chromatopsia Vision Effects yellow-tinted vision or
yellow corona-like spots
chromatopsia
Abnormal condition in which objects appear falsely Coloured. Depending upon the colour seen, the chromatopsia is called xanthopsia (yellow vision),
erythropsia chloropsia
(red vision), (green vision) or
cyanopsia (blue vision). This condition may appear due to some damage to the areas of the visual cortex involved in the processing of colour perception,

15. Conduction Defects in Digoxin Toxicity
Slows nodal conduction while increasing automaticity
More likely in patients with CAD, particularly active ischemia and are potentiated by low Mg, K
Downward slurring of ST Heart block VT
-Bidirectional VT
Dali’s Mustache

16. First Degree AV block PR prolongation i.e. PR interval > 200 msec

17. Atrial fibrillation with accelerated Junctional Rhythms

18. Bidirectional Ventricular Tachycardia (BVT)
QRS axis shift 180 degree with each alternate beat

19. General principles of therapy of digoxin poisoning
Gastrointestinal decontamination
ipecac-induced emesis or lavage is carried out with care to avoid vagal stimulation which may worsen existing conduction block
activated charcoal effectively adsorbs digitalis, if ingestion has occurred within 6-8 hours
repeated doses can be given to adsorb active metabolites as they are excreted by the biliary tract
cholestyramine is an alternative to activated charcoal

20. 2-Correction of electrolyte imbalances
Hypokalemia (the toxicity), hypomagnesemia, and other electrolyte disorders should be corrected
Potassium replacement should be given carefully, since raising the plasma potassium concentration can increase AV block
Some acutely intoxicated patients present with severe hyperkalemia, requiring therapy with glucose and insulin and sodium bicarbonate (if the pt is acidotic)
3-Management of cardiac arrhythmias
Severe bradyarrhythmias are treated with atropine, electrical pacing is used in unresponsive patients

21. Potassium will affect affinity for Na/K pump
Treatment
If early after intentional overdose, can give activated charcoal Bradycardia
-If asymptomatic keep serum K at least 4 mmol/L (or higher)
Potassium will affect affinity for Na/K pump
-Symptomatic- Atropine, pacing
Digibind (Humanized sheep Mab)
-Symptomatic bradycardia not responsive to Atropine
-Malignant arrhythmia (particularly in the setting of hyperkalemia)
-Hyperkalemia
-Important to give adequate dose initially as digoxin levels will be affected for
up to 2 weeks

23. Potassium effects
Hyperkalaemia is a feature of poisoning, due to inhibition of the Na+/K+ ATPase. Causes hyperpolarisation of cardiac tissue, enhancing AV block.
Study of 91 acutely digitoxin poisoned patients before use of anti- digoxin Fab (Bismuth, Paris):
All with [K+] >5.5 mmol/L died
50% of those with [K+] mmol/L died
None of those with [K+] < 5.0 mmol/L died
Plasma digoxin levels are markedly elevated in these patients, usually being above 10 ng/mL Other signs of toxicity can occur at lower levels of 3 to 5 ng/mL

24. DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS
Digoxin-specific antibody Fab fragments (Digibind®), purified from sheep IgG, rapidly bind to circulating digoxin and are indicated in
Ingestion of more than 10 mg of digoxin in adults or 4 mg in children
Plasma digoxin concentration above 10 ng/mL
A plasma potassium concentration above 5 meq/L in the presence of life- threatening arrhythmia – ventricular tachycardia or fibrillation, progressive bradycardia, or high degree AV nodal block
Mechanism of action
Fab fragments rapid binding of intravascular digoxin
The affinity of the fragments for digoxin is greater than the affinity of digoxin for Na-K ATPase

25. Efficacy of Digibind
In the largest series of 150 patients with life-threatening digitalis toxicity,
80 percent had resolution of all signs and symptoms,
10 percent improved, and
10 percent showed no response
The median time to initial response was 19 minutes and the time to complete response was 88 minutes

26. When to Use Digibind Hemodynamic instability
Life-threatening arrhythmias
Severe Bradycardia-even if atropine works
Plasma K above 5
Plasma Digoxin above 10
Presence of digoxin toxicity rhythm combined with dig toxic level

27. Dosing regimen for digoxin- specific antibody fragments
Total body load of digitalis (TBL, in mg) =
SDC (serum digitalis concentration) x Vd x weight (kg)
The serum digitalis concentration is measured in ng/mL and for digoxin, the volume of distribution is 5.6 L/kg, therefore
TBL = (SDC x 5.6 x weight) ÷ 1000
One vial of digibind contains 40 mg, which neutralizes approximately 0.6 mg of digoxin

28. Dosing regimen for digoxin- specific antibody fragments
Number of vials required
= TBL ÷ 0.6 Or
Number of vials =
(SDC x weight) ÷ 100

29. Side effects of digibind therapy
Dosing Digibind
Give over 30min
Vials of digibind= [digoxin level(ng/ml) X mass (kg)/100.
If digitalis toxic due to herbs give 5-10 vials
Side effects of digibind therapy
important side effects can occur
exacerbation of congestive heart failure,
increased ventricular response in patients with A-fib. hypokalemia
Idiosyncratic allergic manifestations
Plasma digoxin measurements are unreliable for one to two weeks after fragment therapy •

30. Known amount of digoxin ingested:
80 mg of digoxin-specific Fab for each 1 mg of digoxin absorbed. The 38 mg vial can be considered equivalent to a dose of 40 mg.
The approximate dose absorbed is an estimate of the total body load of digoxin.
Dose of antidote recommended =dose ingested (in mg) x 0.8 x 80

31. If steady-state digoxin level is known:
Approx. total body load of digoxin (mg)
= serum conc. (in ng/mL) x 5 x body weight (in kg) x (Assume Vd= 5 L/kg)
Refer to the table for dose of antidote required
(i.e. 80 mg of antidote for each 1 mg of digoxin) Unknown amount of digoxin absorbed:
Acute poisoning: 400 mg of digoxin-specific Fab (children, use lower dose
if < 20 kg body weight) Chronic toxicity: mg (adults), mg (children: use lower dose
if < 20 kg body weight) Repeat dose if symptoms do not resolve in 1 hour, or if they recur.
Reconstitute as recommended in package insert.
Administer as slow IV infusion over 30 minutes. Longer infusion times (1-7 hours) have been used.
May be given as a rapid IV bolus for life-threatening arrhythmias.

32. Sampling time of digoxin
Drug levels should be drawn during the 8 to 24 hour interval following the previous dose.
It is better the samples to be taken at approximately the same time.
Physical activity increase binding of Digoxin to skeletal muscle. So 2 hr rest is required before sample time
Loading Dose
Adults: Load mcg/kg in divided doses
(50%, then 25%, then 25%), load based on ideal body weight, with a normal Vd.
Children:
20 mcg/kg
30 mcg/kg
premature infants
full term neonates (< 2 months of age)
infants (< 2 years of age) children (> 2 years of age)
40-50 mcg/kg
30-40 mcg/kg

33. Monitoring parameters
The following patient parameters should be monitored during digoxin therapy:
Digoxin serum level
Obtain level within 24 hours of digitalization, weekly until stable, and at steady state.
BUN and serum Creatinine
Measure every two days, or every day in unstable renal function.
Weigh patient daily.
Measure and monitor urine output daily
Monitor apical pulse daily.
Therapeutic serum concentrations
The usual Digoxin therapeutic range is 0.8 to 2 ng/ml. . .

34. DRUG INTERACTIONS Drugs that increase Digoxin concentration:
diuretics: spironolactone, amiloride, triamterene
antiarrhythmics: quinidine, amiodarone
calcium antagonists: verapamil, minimal effect with nifedipine and diltiazem
atorvastatin in high dose (80 mg daily)
macrolide antibiotics: erythromycin, clarithromycin, roxithromycin
benzodiazepines: alprazolam
Drugs that decrease Digoxin concentration:
rifampicin: induces p-glycoprotein-mediated tubular secretion
liquid antacids: reduce digoxin absorption
Drugs that increase Digoxin effect:
diuretics: via hypokalaemia

35. DRUG INTERACTIONS Propantheline may increase bioavailability
The absorption of oral Digoxin from the gastrointestinal tract is influenced by many different compounds.
Aluminum-containing antacids and kaolin-pectin physically adsorb digoxin rending it unabsorbable.
Sulfasalazine and neomycin each decrease digoxin oral bioavailability by unknown mechanisms.
metoclopramide and cisapride decreases oral digoxin bioavailability by decreasing gastrointestinal transit time.
Propantheline may increase bioavailability