Cardiac glycoside toxicity By Dr. Shorouk El-Sayyad

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

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

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 5 - 7 days as compared to digoxin which has shorter half-life; 1-2 days) so Digoxin is most widely prescribed more than digitoxin

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

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

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 0.9-2 ng/ml *digoxin toxicity is accelerated by hypokalemia *presence of hyperkalemia (>5mmol/l) a bad prognostic sign -if K+ <5………..mortality 0 % -if K+ 5-5.5……………mortality 50% -if K+ > 5.5…………….mortality 100%

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 50 -75 %) in this setting

Function of Na+/K+ ATPase

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

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

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

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

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,

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

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

Atrial fibrillation with accelerated Junctional Rhythms

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

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

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

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

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+] 5.0-5.5 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

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

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

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

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

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

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 •

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

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 0.001 (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: 120-240 mg (adults), 40-80 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.

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 10-15 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

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. . .

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

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