Digoxin (Lanoxin/Lanoxicaps) Seth Adams Duy Cao Scott Davis Cheryl Hanslovan Bryan Ing Kristin McKay Vic Patel Dan Rackham Darren Smith Phong Vuong foxglove digitalis

General Structure

Mechanism of Action Digoxin inhibits membrane bound sodium-potassium ATPase resulting in an increased intracellular [Na+] and thus an increase in the intracellular [Ca2+] by stimulation of Na+ and Ca2+ exchange. Digoxin has an indirect effect on the sinoatrial and atrioventricular nodes (vagomimetic actions). Baroreceptor sensitization also results from digoxin. This leads to increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system.

Ca Digoxin (-) SR 2 + Ca2+ Ca2+ 3Na 2K 3Na Contraction Ca RyR ATP ADP NaCaX ATPase 3Na + Ca2+ RyR ATP Ca2+ Ca 2 + ATPase SR ADP Contraction

Net Effect Positive inotropic action (an increase in the force and velocity of myocardial systolic contraction). A decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system. Slowing of the heart rate and decreased conduction velocity through the AV node.

Main Clinical Indications Heart Failure Increases cardiac output by positive inotropic actions Therapeutic level of 0.5-1 mcg/L Atrial Fibrillation Rate control by vagomimetic actions Therapeutic level of 0.5-2 mcg/L

Available Dosage Forms Tablets ( F = 0.6 - 0.7) 125 mcg ( yellow, # Y3B ) or 250 mcg ( white, # X3A ) Capsules (Lanoxicaps) ( F = 0.9 – 0.95) 50 mcg ( red, # A2C ) , 100 mcg ( yellow, # B2C ), and 200 mcg ( green, # C2C) Pediatric Elixer ( F = 0.75 – 0.85) 50 mcg per 1 ml (10% alcohol) Injection ( F = 1.0 ) 250 mcg per 1 ml (1 ml ampule) Pediatric Injection ( F = 1.0 ) 100 mcg per 1 ml (1 ml ampule)

Side Effects & Toxicities Yellow/green visual changes, halos around light N&V and diarrhea (50-75% of patients) Bradycardia (75-90% of patients) Fatigue, malaise, confusion, headache, etc. Anorexia

Drug Interactions Amiodarone Verapamil Propafenone Quinidine ↑[Digoxin] by 70% Verapamil ↑[Digoxin] by 50-75% Propafenone ↑[Digoxin] by 30% Quinidine Erythromycin ↑[Digoxin]

Pharmacokinetic Parameters Absorption After oral dosing: Onset of action in 0.5 – 2 hours Peak effect reached in 2 – 6 hours Distribution Skeletal and heart muscle, but not into adipose tissue Up to 25-30% is bound to plasma proteins Metabolism Follows first-order kinetics Limited metabolism via sugar hydrolysis and lactone ring reduction Half-life = 1-2 days Excretion 60-80% excreted unchanged in urine Undergoes ACTIVE tubular secretion in the kidneys

Clinical Considerations Doses must be individualized and depends on the type & severity of the disease, age & weight of the patient, renal function, and concomitant disease states Normal dosage range is 125 – 500 mcg (50 – 200 mcg capsules) a day in a single dose Contraindications: Patients w/ ventricular fibrillation, renal impairment, hypokalemia, hypomagnesemia, hypercalcemia, and pulmonary disease Patient must be advised not to take nonprescription cough or cold medications, antacids, laxatives, or antidiarrheals without consulting the pharmacist or physician Pregnancy category C

Digoxin Equations IBW = 50 (or 45.5) + 2.3 x (inches over 60) CrCl = ((140 - Age) x IBW) / (72 x SCr) ( x 0.85 for females) Clearance Digoxin: Cldig = (0.8 ml/min/kg x IBW) + CrCl w/ CHF: Cl = (0.33 ml/min/kg x IBW) + (0.9 x CrCl) (these values were multiplied by 0.06 to convert them from mL/min to L/hr) w/ co-administration of amiodarone: Cl = 0.5 x Cl (without amiodarone) Vd = 7.3 L/kg x IBW w/ renal dysfunction: Vd = (3.8 L/kg x IBW) + (3.1 x CrCl) LD = (Cp (desired level) x Vd) / (F) MD = (Cp (desired level) x Cldig x Xo) / (F)

Sample Problems WB is a 75-year-old female with PMH including atrial fibrillation, type II diabetes, hypertension, and renal insufficiency. She is 5’4” and weighs 75 kg. Her SCr is 3.4 mg/dL. Calculate a loading and maintenance dose for Lanoxin tablets for Mrs. B. Target Cpss = 1.0 mcg/L for atrial fibrillation AS is a 78-year-old male with CHF. He is 5’10” and weighs 73kg. His SCr is 1.1 mg/dL. Calculate a dosing regimen using Lanoxicaps. Target Cpss = 0.7 mcg/L for CHF

Problem Solutions - 1 WB w/ Renal Dysfunction: IBW = 45.5 kg + 2.3 (4 in) = 54.7 kg CrCl = ((140-75) x 54.7 kg (.85)) / (3.4 x 72) = 12.35 mL/min Vd = (3.8 L/kg x 54.7 kg) + 3.1 (12.35 mL/min) = 246.15 L Cldig= (0.8 mL/min/kg x 54.7 kg) + 12.35 mL/min = 56.11 mL/min = 3.37 L/hr LD = (246.15 L x 1 mcg) / (0.7) = 351.64 mcg  Use 375 mcg tabs once MD = Cpss = 1 mcg/L = (Xo(0.7)) / (3.37 L/hr x 24 hr)  0.7Xo = 80.88 mcg  Xo = 115.54 mcg  Use 125 mcg tabs qday

Problem Solutions - 2 AS w/ Congestive Heart Failure: IBW = 50.0 kg + 2.3 (10 in) = 73 kg CrCl = ((140-78) x 73 kg) / (1.1 x 72) = 57.15 mL/min Vd = (7.3 L/kg x 73 kg) = 532.9 L Cldig= (0.33 mL/min/kg x 73 kg) + 0.9 (57.15 mL/min) = 75.52 mL/min = 4.53 L/hr LD = (532.9 L x 0.7 mcg) / (0.95) = 392.66 mcg  Use 400 mcg caps once MD = Cpss = 0.7 mcg/L = (Xo(0.95)) / (4.53 L/hr x 24 hr)  0.95Xo = 76.1 mcg  Xo = 80.11 mcg  Use 100 mcg caps qday

References 20th edition top 200 pharmacy drug cards. SFI Medical Publishing. 2004. Class lecture. Pharmacy 750. 11/3/2005. Connie Covington Tharp, R. (2006) Digoxin Dosing. Retrieved March 9, 2006 from the world wide web: http://www.rxkinetics.com/dig.html Medicinal Plants. (2006) Digoxin Image. Updated Aug 12, 2005. Retrieved March 8, 2006 from world wide web: http://www.science.siu.edu/plant-biology/PLB117/Nickrent.Lecs/Medicine.html Rx-List. (2006) Digoxin. Updated March 12, 2006. Retrieved March 8, 2006 from world wide web: http://www.rxlist.com/cgi/rxlist.cgi?drug=digoxin Digoxin Structure. Retrieved March 8, 2006 from world wide web: http://medpharm.chunma.ac.kr/Aldja/CVS/cardiac_glycoside/img/digoxin_structure.GIF