Digoxin (Lanoxin/Lanoxicaps)

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

Digoxin (-) 2 + Ca + 3Na + 2K NaCaX ATPase + 3Na Ca2+ RyR ATP Ca2+ 2 + ATPase Ca 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 • ↑[Digoxin] by 70% • Verapamil • ↑[Digoxin] by 50-75% • Propafenone • ↑[Digoxin] by 30% • Quinidine • ↑[Digoxin] by 50-75% • Erythromycin • ↑[Digoxin]

PharmacokineticParameters • 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

Digoxin (Lanoxin/Lanoxicaps)