Digoxin (Lanoxin/Lanoxicaps)

foxglove digitalis

Seth Adams

Duy Cao

Scott Davis

Cheryl Hanslovan

Bryan Ing

Kristin McKay

Vic Patel

Dan Rackham

Darren Smith

Phong Vuong

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.

SR

ATP

ADP

Ca2+

Ca2+

3Na+

Contraction

NaCaX

ATPase

3Na+

ATPase

2K+

RyR

Digoxin

(-)

Ca2+

Ca2+

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.

• 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

Main Clinical Indications

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]

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