62 ischemic heart disease heart failure B } B } !Aspirin(80) 1*1 pc } !Digoxin(0.25) 1*1 pc } !Furosemide (40) 1*2 pc (-)B } !

} !Isordil (10) 1*3 ac } !Enalapril(5) 1*1 pc } !Simvastatin (20) 1*1 hsB

}

B } 6-7 4 B } B } 34 B } 100/60 mmHg EKGB

}

Potassium 2.8 mEq/L (diarrhea+vomiting +furosemide) } Digitalis level 3.5 ng/mL (0.8 - 2 ng/mL)
}

Impress; Digitalis Intoxication } (precipitating factor : Hypokalemia)B

Paramat thimachai,MD Resident2 toxicology unit

} } }

Digoxin foxglove (Scrophulariaceae) phylogenetic (Plantaginaceae) Other names Digitalis, Lanoxin Inotropic and AV node blocking agent. Used in the treatment of congestive heart failure, atrial fibrillation, atrial flutter, and tachyarhythmias.

} } } } } }

60-85% absorbed after oral administration of tablets 75-80% absorbed after administration of elixir 90-100% absorbed from liquid filled capsules 80% absorbed from intramuscular injection (not recommended) 100% absorbed from intravenous dose 40% degraded by intestinal bacteria1 in 10

}
} } } }

} } } } }

25% protein bound. 6-8 hour tissue distribution phase Widely distributed Vd 5.6 L/kg Correlates well with lean body tissue .Early high levels of serum concentration do not reflect action at desired site Increase Vd in hypothyroid Heart/blood level = 70/1 Hypokalemia increase distritbution to heart and muscle. Receptor binding is the rate limiting step. Crosses the placenta and enters breast milk Pregnancy category C

Initial loading dose required.

Fig. 2. Representative fit of the slow binding model to digoxin disposition data by Kramer et al. (1974) (subject TF, Div = 1 mg). The inset shows the shape of the model curve within the first 2 min after injection.

Time to peak effect: 1-4 hours (IV) and 2-6 hours (PO) } Half life elimination ; Parent drug 38 hrs Metabolite -digoxigenin 4 hrs -monodigitoxoside 3-12 hrs Therapeutic serum digoxin levels : 0.5-2ng/mL (6 hours after dose) Now is narrow 0.5-0.9 ng/mL Inhibits Na-K ATPase Increases myocardial contraction

Decreases conduction through AV node

Decreased heart rate

Increased cardiac output Improved circulation Improved tissue perfusion

16% is metabolized by liver Metabolism ;Substrate of CYP 3A4 [minor] 50-70% is excreted almost entirely unchanged by the kidneys Excretion proportional to GFR Half life: 36-48 hours, increased in renal impairment Not effectively removed by dialysis

} } }

Toxicity level: >2.4ng/mL 1/3 of patients have toxic symptoms at <2.0ng/mL First signs of toxicity: Abdominal pain Anorexia Nausea Vomiting Visual disturbances Bradycardia Arrhythmias Confusion Delirium Infants: arrhythmias

Serious adverse reaction } May result in 1st, 2nd or 3rd degree block } Ventricular dysrhythmias } Three cardiac altered functions
}

Dilantin and Lidocaine effective treatment

Suppression of AV conduction Increased automaticity Decreased refractory period in ventricles

The combination of SVT and AV block, for example, is highly suggestive of digitalis toxicity . Although hypokalemia predisposes to digitalis toxicity, massive overdose can lead to hyperkalemia as inhibition of the Na-K-ATPase pump impairs potassium entry into cells. 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. Several factors (importantly hypokalemia) can predispose to toxicity at levels below 2 ng/mL, which is considered the upper limit of normal. On the other hand, clearly elevated levels (above 3 ng/mL) can be seen in asymptomatic patients.

Drug Interactions

} } } } } } }

A number of drugs can raise digitalis levels by interfering with its metabolism or renal excretion CYP 450 = CYP 3A4 Colchicine,donedarone,midodrine - increase level. Antiarrhythmics increase serum levels of digoxin Spironolactone increases half life of digoxin Beta blockers additive bradycardia Thiazide and Loop diuretics cause hypokalemia Cortisone Na retention and K loss All of these increase the risk of toxicity

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 percent) and in the maintenance dose (by 50 to 75 percent) in this setting.

Finally, there are a number of factors that can increase the sensitivity to digoxin and predispose to toxicity at plasma levels at the upper limits of normal

1. Old age 2. Certain cardiac diseases - active ischemia, myocarditis, cardiomyopathy, cardiac amyloidosis, cor pulmonale. 3. Metabolic factors - hypokalemia, hypomagnesemia, hypoxemia, hypernatremia, hypercalcemia, and acid-base disturbances.

Monitor pulse prior to administration } Monitor blood pressure throughout therapy } Monitor ECG throughout IV administration and periodically during therapy, as new arrhythmias and bradycardia may develop } Kidney and thyroid dysfunction alters dosage required } Increased age increases risk of toxicity
}

} }

Discontinuation of digitalis may be enough Hypokalemia and adequate renal function Arrhythmias
Potassium salts Medications or ventricular pacing Digibind

Life threatening arrhythmias Digibind

Digoxin immune Fab Binds with digoxin, forming complex molecules Excreted in urine

Digoxin-specific antibody Fab fragments (Digibind), purified from sheep IgG, rapidly bind to circulating digoxin and are indicated in
1. Ingestion of more than 10 mg of digoxin in adults or 4 mg in children. 2. Plasma digoxin concentration above 10 ng/mL . 3. 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.

The proposed sequence of events that occurs after infusion of Fab fragments begins with rapid binding of intravascular digoxin and is followed by diffusion of the fragments into the interstitial space to bind free digoxin at that site.

The affinity of the fragments for digoxin is greater than the affinity of digoxin for Na-K ATPase. } The Fab fragments are relatively small (mol wt 50,000) which allows them and bound digoxin to be rapidly excreted by glomerular filtration in patients with nearnormal renal function. } The elimination half-life of the fragments is 15 to 20 hours in this setting.
}

Digibind can also be successfully in patients with renal insufficiency, including those on maintenance dialysis . } In the largest study, 18 patients had a pretreatment plasma creatinine concentration of more than 5 mg/dL, including five who were on dialysis. } These patients responded to Digibind in a manner similar to patients with normal renal function.
}

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 } Of the patients who experienced cardiac arrest, 54 percent survived hospitalization
}

Several factors which contribute to partial responses.B

1. underlying heart disease that was the true cause of some of the presumed manifestations of digitalis toxicity. 2. too low a dose of Fab . 3. treatment of patients who were already moribund A dramatic fall in the plasma potassium concentration can occur after digibind therapy . The decline in the plasma potassium concentration begins within one hour and is complete within 4 hrs. Thus, monitoring of the plasma potassium concentration should be performed in all patients receiving this therapy

Despite the improvement induced by digibind, potentially important side effects can occur 1. Exacerbation of congestive heart failure, 2. Increased ventricular response in patients with A-fib. 3. Hypokalemia . Idiosyncratic allergic manifestations are very rare, occurring in less than one percent of cases. Plasma digoxin measurements are unreliable for one to two weeks after fragment therapy.

Total body load of digitalis (TBL, in mg) = SDC (serum digitalis concentration) x volume of distribution 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
} }

One vial of digibind contains 40 mg, which neutralizes approximately 0.6 mg of digoxin

TBL = (SDC x 5.6 x weight) 1000

} Number

of vials = TBL 0.6

Or

Number of vials = (SDC x weight) 100

If the amount ingested is known, then the TBL can be calculated directly: } TBL = Dose ingested (mg) x 0.8 for digoxin which has 80 percent bioavailability } If the SDC and the amount ingested are not known, then digibind is given empirically according to the following regimen } For an acute overdose in adults:
} }

With chronic toxicity:

Give 10 vials; repeat with another 10 vials if indicated Give 6 vials to an adult, one vial to a child

Hemodialysis or hemoperfusion can help control hyperkalemia or volume overload in patients with concurrent renal failure } They are, however, of limited utility in removal of digoxin because of its extensive tissue binding and very large volume of distribution (5.6 L/kg)
}

} }

Deglin, J.H. & Vallerand, A. H.. (2001). Davis s Drug Guide for Nurses (7th Ed.). E.A. Davis Company:Philadelphia. Deska-Pagana, K. & Pagana, T.J.. (2002). Mosby s Manual of Diagnostic and Laboratory Tests (2nd Ed.). Mosby: St Louis. GlaxoKlineSmith. (2006). Lanoxin. [Online]. Available at http://us.gsk.com/products/assets/ us_lanoxin_tablets.pdf. LeFever-Kee, J. & Hayes, E.R.. (2000). Pharmacology: A Nursing Process Approach. W.B. Saunders: Philadelphia. Muira, T., Kojima, R., Suguira, Y., Mizutani, M., Takatsu, F., & Suzuki, Y.. (2000). Effect of aging on the incidence of digoxin toxicity. The Annals of Pharmacotherapy 34(4), 427-432. Weiss, M. (2007). Mechanistic modeling of digoxin distribution kinetics incorporating slow tissue binding. European Journal of Pharmaceutical Sciences 30(3-4), 256-263. Wikipedia. (2008). Digoxin. [Online]. Available at http://en.wikipedia.org/wiki/Digoxin. Wikipedia. (2008). Na-K-ATPase. [Online]. Available at http://en.wikipedia.org/wiki/Na%2B,K %2B-ATPase. Williamson, K., Thrasher, K., Fulton, K., Lapointe, N., Dunham, G., Cooper, A., Barrett, P., & Patterson, J.. (1998). Digoxin toxicity. Archives of Internal Medicine 158(22), 2444-2449.