DIGOXIN.docx

DIGOXIN Describe the two main clinical indications for digoxin. Indication of Digoxin Mechanism of Action of Digoxin Congestive heart failure (positive inotrope) Atrial fibrillation (negative chronotrope) Positive Inotropic Effect Binds to Na+/K+ ATPase in myocytes ↑ Na+ intracellularly...

DIGOXIN Describe the two main clinical indications for digoxin. Indication of Digoxin Mechanism of Action of Digoxin Congestive heart failure (positive inotrope) Atrial fibrillation (negative chronotrope) Positive Inotropic Effect Binds to Na+/K+ ATPase in myocytes ↑ Na+ intracellularly activates Na+/Ca2+ ion exchange ↑ Ca2+ intracellularly to enhance myocardial contractility Has direct effect on cardiac cells Negative Chronotropic Effect ↑ parasympathetic activity and vagal tone slow conduction and ↓ ventricular HR Effects rhythm Pharmacokinetics Two compartment model – do not measure concentration until distribution phase complete Explain the absorption, distribution, and elimination characteristics of digoxin. Absorption Absorbed primarily in small intestine E. lentum is an anerobic bacteria in the gut that inactivates digoxin Inhibition of p-glycoprotein (ex: by erythromycin and clarithromycin) ↑ bioavailability of digoxin Distribution VD = 5-9 L/kg (average = 7 L/kg) large VD Protein binding: 25% concentrates in heart and kidneys with largest storage in skeletal muscle PK not affected by obesity due to its large binding to skeletal muscle dose based on IBW in obese patients Muscle mass not affected by obesity Metabolism E. lentum in gut is variable between patients and may contribute to minor differences in absorption between patients Metabolism is minimal, making it a useful probe p-gp substrate Elimination 75% eliminated unchanged by GFR and active tubular secretion (by p-gp) 15-25% removed by biliary excretion (by p-gp) Clearance proportional to CrCl T1/2 = ~36 hours (24-48 hours) for ClCr > 80 mL/min Non-renal clearance is ↓ for patients with moderate/severe heart failure HF ↓ CO ↓ delivery of digoxin to liver does not reduce total digoxin clearance as much as decline in renal function because only 25% eliminated non-renally ↓ renal function = ↓ digoxin VD, not digoxin clearance In renal failure, unknown substance displaces digoxin from binding site on skeletal muscle and goes back into blood stream ↓ VD Know and explain common digoxin toxicities. Renal Failure Moderate/Severe HF Hyperthyroidism Electrolyte Disturbances ↓ Cl, ↑ T1/2, ↓ VD In poor renal function (CrCl<30), non-renal clearance is primary ↓ CO ↓ liver perfusion ↓ hepatic Cl ↑ renal and non-renal clearance ↑ pharmacologic responses with hypokalemia, hypomagnesemia, hypercalcemia For patients with CHF on loop diuretic, monitor K+ Toxicity: GI, CNS, Cardiac GI: anorexia, nausea, vomiting, diarrhea, abdominal pain, constipation CNS: headache, fatigue, nausea, confusion, vertigo, visual disturbances* Cardiac: second or third degree AV block, premature ventricular contractions (PVCs), bradycardia and dysrhythmias Visual disturbances Blurred vision, changes in color vision, colored halos around objects often involving the yellow-green spectrum. Describe what to monitor for digoxin efficacy and toxicity. Digoxin Efficacy Digoxin Toxicity For CHF: Dyspnea EKG For atrial fibrillation: ↓ ventricular rate to <100 beats/min A-fib characterized by atrial rate of 400-600 beats/min CCss > 2 ng/mL ↑ incidence of AE For concentrations ≥ 2.5 ng/mL, 50% of patients experience digoxin toxicity. Symptoms: GI: anorexia, NVD, abdominal pain, constipation CNS: HD, fatigue, nausea, confusion, vertigo, visual disturbances Cardiac: 2º or 3º AV block, premature ventricular contractions, bradycardia, dysrhythmias Hypokalemia is the greatest cause of digoxin toxicity Recommend appropriate treatment for digoxin overdose. Digoxin immune Fab (DigiFab): digoxin antibody fragments that bind and neutralize digoxin. It is derived from antidigoxin antibodies formed in sheep. Each vial contains 40 mg of DigiFab. Improvements are seen within 30 minutes of administration. Measuring plasma concentrations of digoxin after DigiFab administration will be inaccurate due to digoxin being bound to DigiFab. Some adverse reactions are hypersensitivity and anaphylactic shock. If serum concentration or estimation of amount ingested is not available, 20 vials are used for life-threatening acute overdoses. For chronic digoxin overdoses, 6 vials (480 mg) are required. Re-administration may be required due to the drug leaving tissue and re-distributing into the bloodstream. Identify the therapeutic range of digoxin concentrations for both ionotropic and chronotropic effects. Atrial Fibrillation (negative chronotrope) Heart Failure (positive ionotropic) Loading dose: PO: 500 mcg x1, 250 mcg 6 hours later, 250 mg 6 hours later total 1 mg Maintenance dose: 0.125 – 0.25 mg/daily Therapeutic range: 0.8-1.5 ng/mL No loading doses Maintenance dose: 0.125 – 0.25 mg/daily 0.125 mg daily every other day for patients >70 years old, impaired renal function, low lean body mass Therapeutic range: 0.5-1 ng/mL Calculate a new digoxin dose given the appropriate information. Assumptions: steady-state concentrations obtained after 3-5 half-lives, linear PK and dosage ratios $\frac{Dose\ (New)}{Css\ (New)}$ = $\frac{Dose\ (old)}{Css\ (old)}$ Recognize drugs that are likely to interact with digoxin and explain the mechanism of action. Amiodarone Amiodarone inhibits p-gp ↑ digoxin concentration by 70% ↓ digoxin clearance Aystole (no electrical activity from heart) and torsades de pointes reported ↓ digoxin dose by 50% and monitor levels Calcium Channel Blockers Verapamil is most potent inhibitor of digoxin clearance among the CCB Inhibits renal/extrarenal digoxin clearance ↑ digoxin concentration by 50-75% ↓ dose by 50% and monitor digoxin level