10. Digoxin.✅.pdf

Ionotropic agent congestive heart failure (CHF) Primarily used to treat - atrial fibrillation. Intro: Given once daily (Long elimination half life for adults) 1mg/70kg(0.01-0.02 mg/kg) Loading dose: 0.125 to 0.25 mg/day. Maintenance dose: Who are being converted from parenteral to oral thera...

Ionotropic agent congestive heart failure (CHF) Primarily used to treat - atrial fibrillation. Intro: Given once daily (Long elimination half life for adults) 1mg/70kg(0.01-0.02 mg/kg) Loading dose: 0.125 to 0.25 mg/day. Maintenance dose: Who are being converted from parenteral to oral therapy or vice versa, closely correlated with glomerular filtration rate. Renal excretion Main route of elimination : With renal impairment, Dosage adjustments important for patients: CHF, tubular secretion Thyroid abnormalities or In addition, some: perhaps tubular reabsorption occurs. Who take amiodarone concurrently. (Along with digoxin) Nearly all of the digoxin in urine is excreted unchanged, Small part as active metabolites. Considerable variation between patients, ~ Plasma digoxin concentrations of: ~ Elimination : 1-2 mcg /L (ng/mL) considered to be within the therapeutic range. THERAPEUTIC PLASMA CONCENTRATIONS: Clinical significance of dihydrodigoxin as a metabolite remains to be resolved. 0.5 to 1 mcg/L for patients with CHF recognized by many clinicians Therapeutic range of: About 25 to 28% of digoxin eliminated by nonrenal routes. Due to variation what’s needed? Biliary excretion may rise up to 30% of a given dose. Monitoring About 70 to 80% of an oral dose of digoxin is absorbed, mainly in the proximal part of the small intestine. Enterohepatic cycle seems to be of minor importance Varies considerably In calculating question use any number In between/ use 0.7 Digoxin tablets : 0.5 to greater than 0.9. Should be estimated for each patient. metabolic (Clm) Elixir : 0.8. Total digoxin clearance (Clt) : sum of: renal (Clr) clearances Soft gelatin capsules : completely absorbed Clt = Clm + Clr Metabolic clearance of digoxin : 0.57 to 0.86 mL/kg/min Bioavailability: ~ In healthy individuals Intravenous route of administration : 100% Decrease in bioavailability of 25 % by St. John’s wart Interaction with p-glycoprotein and other mechanisms of induction of hepatic metabolism. = higher bioavailability CLEARANCE (Cl) : Renal clearance is equal to or a little less than creatinine clearance. In most cases increase bioavailability Various antibiotics reported to alter bioavailability Reduces metabolic clearance of digoxin to about one-half its usual value. Suppress bacteria in the gastrointestinal tract that metabolize digoxin. CHF: May reduce the renal clearance slightly (0.8 mL/kg/min)(Weight in kg) + (Cl cr in mL/min) Most common class of antibiotics reported to increase digoxin concentrations Macrolides. Non –CHF patients Azithromycin - unique, does not inhibit CYP3A4 (0.33 ml/min)(Weight in kg) +(0.9) (Cl cr in mL/min) (140-Age)(Weight in kg)/(72)(SCrss) Patients with CHF Total digoxin clearance in ml/ kg/min: Cl cr for males (ml/min)= Creatinine clearance estimated from patients serum creatinine Clarithromycin O Dirithromycin US FDA-approved : Equations : Cl cr for females (ml/min)= Erythromycin ~ Equation: Roxithromycin Antibiotic macrolides: Telithromycin Patients with normal renal function: 2 days Spiramycin - approved in Europe and other countries - Anephric patients : 4 to 6 days. Increase less than might be expected NotUSFDA-approved : HALF-LIFE (t1/2) : Troleandomycin - used in Italy and Turkey Tylosin/tylocine - used in animals Reduction in clearance Degree of binding to serum albumin : Decrease in volume of distribution in patients with diminished renal function. 7 to 14 days after maintenance regimen is initiated or changed. Plasma samples for routine digoxin level monitoring ~ 20 to 30% = so 70-80% free in blood Extensively distributed in the tissues Notes : Ensures that steady state has been attained on the current dosing regimen. Reflected by large volume of distribution If have a low VD? Then only present in blood Delay in obtaining digoxin samples High concentrations found in heart and kidneys 15 to 20 days to achieve steady state because of the prolonged half life. Patients with end stage renal disease Skeletal muscles form the largest digoxin storage Confirm relationship between digoxin plasma concentration and pharmacological response or establish the apparent volume of distribution. ~ Plasma samples obtained within 24 hours of an initial loading dose 7.3L/kg. Average volume of distribution : ~ Digoxin X 70 = 500 L of distribution Time of sampling : Early samples not used for evaluation of maintenance regimen. With renal disease .i.e at least 4 hours following intravenous dose or 6 hours following an oral dose acceptable Routine plasma samples for digoxin monitoring just before the next dose V decreased in patients: Once steady state has been achieved, ~ Require digoxin plasma level monitoring To determine the extent of alteration of pharmacokinetics Hypothyroid patients. Patients taking digoxin who are to be given amiodarone or quinidine 2 Taking quinidine. Volume of distribution: V digoxin (L/70 KG) = 226 + (298) (Clcr in ml/min) / 29 + Clcr in ml/min V digoxin (L) Whether drug interaction alters digoxin volume of distribution or clearance or both. Time course for expected change in digoxin concentration depends on: ⛔ when creatinine clearance is in ml/min and Correlation of Pharmacodynamic effects including toxic symptoms ~ weight is in kilogram, the Pharmacodynamic points : uptake of digoxin in the heart after a single dose = (3.8 L/KG) $ (Weight in kg) + (3.1) (Clcr in ml/min) Calculated volume of distribution units are L/70kg and L Key parameters: Digoxin with: Therapeutic Range = 0.8 - 2 μg/L Tablets = 0.7 and with steady state serum digoxin concentration during maintenance therapy Elixir = 0.8 Bioavailability (F) Impairedkidneyfunction -- Biovailability of digoxin formulation used Chemical form (S) (administered as active form) = 1 Values & equations: Volume of distribution Amount of extrarenal clearance Soft gelatin capsule = 1 Factors which may modify serum level of digoxin: Body weight Serum albumin concentration Certain drug interactions during the absorptive phase Digoxin is given once daily.(Long elimination half life for adults) Dosage adjustments important for patients who are being converted from parenteral to oral therapy or vice versa. ~ Equations: Conclusion : Various antibiotics have also been reported to alter bioavailability of digoxin. Creatinine clearance ~ Distribution of digoxin follows a two- compartment model Factors that alter Volume of distribution: Obesity Quinidine Hypothyroid Hyperthyroid Creatinine clearance, : Obesity, Quinidine, Factors that alter Digoxin Clearance: Hypothyroid, Hyperthyroid, Congestive heart failure, Q:1 Problems: Amiodarone Verapamil Two- compartment model. First distributes into Vi, Then into Vt. Initial volume of distribution Tissue volume of distribution VT (total) = Vi + Vt Plasma samples obtained from Vi, Q:2 Plasma digoxin level do not accurately reflect the drug’s pharmacological effect Heart behaves as though it were in tissue compartment , Distribution of digoxin: Initial high serum concentrations not reflective of either therapeutic or toxic potential of digoxin. Plasma concentrations meaningful when obtained after equilibration is complete. (At least 4 hours after an intravenous dose or 6 hours after an oral dose). Visuals : until it is completely distributed into both compartments. ⛔ ♦