Digoxin

therapeutic drug montoring of the cardiac glycoside

1. THERAPEUTIC DRUG MONITORING DIGOXIN Blessy Rachel Thomas V th Pharm D

2. INTRODUCTION Digoxin is the primary cardiac glycoside . It is used in the -treatment of CHF because of its inotropic effects on the myocardium. - treatment of atrial fibrillation because of its chronotropic effects . -treatment of atrial flutter because of its positive inotropic effects -treatment paroxysmal atrial tachycardia because of its positive inotropic effects

3. PHARMACOLOGICAL ACTIVTY The positive inotropic effects is caused by the binding to Na+ K+ ATPase activated adenosine phosphate → inhibition of Na pump → decreased transport of Na+ out of myocardial cells ( increased intracellular conc ) → calcium entry and decrease calcium elimination → enhanced myocardial contractility.

4. THERAPEUTIC RANGE 0.8-2 ng /ml

5. CLINICAL PHARMACOKINETICS/ PHARMACODYNAMICSCONSIDERATIONS Pharmacodynamic considerations for tachyarrhythmias and systolic heart failure as follows: Tachyarrhthmias N arrow therapeutic range . Used to control the ventricular response rate , particular in CHF. Ventricular rate control usually achieved over 24 hours. A loading dose given in divided doses because of a long distribution half-life. Possible to use higher doses to control rate in the acute setting.

6. S ystolic heart failure Decreases frequency of hospitalization for exacerbation of heart failure. No improvement in cardiovascular mortality . Serum concentration achieved in mortality trial at the lower end of therapeutic range. Necessary to maintain serum conc in the mid to low therapeutic range ( < 1.5 ng /ml ). Edema and cardiac output changes with severity of heart failure may alter pharmacoknetic parameters.

7. PHARMACOKINETIC CONSIDERATION: ABSORPTION Completely absorbed from the gut. In some patients, absorption may be decreased due to digoxin inactivation by gut bacteria ( Eubacterium lenium ). Also by some drugs like antacids, cholestyramine , tetracycline, neomycin and kaolin. For patients with normal absorption: Digoxin tablets: 50-90% Digoxin elixir: 80% Digoxin liquid filled capsules: 100%

8. DISTRIBUTION Digoxin distributes into lean body tissue but not appreciably into adipose or fatty tissues. For this reason ideal body weight should be used to dose digoxin . 20-30% bound to albumin. Vd : 6- 7 l/kg Distributive phase is 6 to 8 hour. Two clinical implications: -loading doses of digoxin need to be administered in divided doses 6 hour apart. -serum digoxin levels should be determined at least 8 hr after administration.

9. METABOLISM Takes place in stomach and intestine. Involves : Deglycosylation Reduction of the lactone ring Oxidation Epimerization Conjugation to polar metabolites

10. CONTINUE... In Stomach, Gastric acid removes digitoxose sugars of digoxin formation of deglycosylated congeners In intestine, I ntestinal flora results in metabolism of digoxin to its reduced form, dihydrodigoxin

11. Continue….. Digoxin overdose decreased sodium pump activity Hyperkalemia

12. ELIMINATION Excreted largely unchanged in the urine. Small proportion is cleared by nonrenal routes, biliary excretion and intestinal clearence . Vd decreases with decrease in renal function . In patients with severe renal dysfunction , 18% of digoxin is only bound to protein. Displacement of digoxin by endogenous substances that are not cleared efficiently in renal patients Reduces protein binding by digoxin

13. Systemic clearance ( Cl t ): Cl t = (1.01 × Cl r ) + Cl m Cl r = renal clearence = 0.927 × C r Cl ( ml/min/1.73 m 2 ) Cl m = metabolic clearence = 36 ml /min ÷ 1.73 m 2 (in resolved or no history of heart disease) = 20 ml /min ÷ 1.73 m 2 ( with severe heart disease)

14. Available dosage forms Dosage form Tablet (conventional) Capsules ( lanoxicaps ) Elixir Parenteral injection 125 ,250, 500 mcg 50,100,200 mcg 50mcg/ml 100, 250 mcg /ml Biovailalability 60-80% 90-100% 60-80% 100% T max There is a significant distribution phase after administration , even after IV administraton .Therefore , there is a time lag before maximum effect.

15. THERAPEUTIC DRUG MONITORING

16. INDICATIONS Confirmation of toxicity Assessing the effect of factors altering pharmacokinetics Therapeutic failure Medication compliance

17. Confirmation of toxicity Need to measure digoxin conc for Confirmation of toxicity due to the low therapeutic index. Therapeutic range : 1.0-2.5 nmol /l Risk of toxicity : Over 2.6 nmol /l

18. Assessing the effect of factors altering pharmacokinetics No. of factors influence the pharmacokinetics. Renal function is the major contributor . Cockroft gault equation will result in an appropriate dose. P-glycoprotein is involved in the transport of digoxin into the body and out of the body i n the renal tubules . Mutation within this gene → alter bioavailability and renal clearence . drug interaction → affect serum conc of digoxin by competitive inhibition of P-glycoprotein.

19. Therapeutic failure TDM is useful to detect patients with -low digoxin conc -who may benefit from increased dose -who develop toxicity symptoms from an increased dose Results from the “PROVED” and “ RADIANCE ” trials, suggest that digoxin concentrations between 0.6 & 1.2 nmol /l may be efficacious and less pro- arrythmic ,than conc with heart failure.

20. APPROPRIATE SAMPLING TIME Digoxin is well absorbed , with peak serum conc occurring within one hour . Because of large Vd , digoxin concentrates in the tissues , with the active site within myocardial and other cells. Redistribution from serum to tissue takes at least 8 hours.

21. Samples taken within 8 hours falsely shows elevated conc results in inappropriate dose reduction thus, measure digoxin conc after 8 hours (when conc have steady state) shows linear

22. Digoxin elimination is predominantly renal in nature (fraction excreted: 0.6-0.9) Depends on glomerular filtration and p-glycoprotein mediated active tubular secretion. A long t 1/2 of atleast 30 hour results in steady state conc taking at least 5 days to be achieved (in normal renal function patient). In the elderly and patients with renal impairment, elimination is diminished and t 1/2 prolonged . In this case , steady state may take several weeks to achieve.

23. DOSE ADJUSTMENT When the conc is above the therapeutic range , the dose should be reduced even in the absence of obvious toxicity →patient is at risk of arrhythmias. Also, toxicity can occur with conc within the therapeutic range → result from several known factors that change tissue sensitivity to digoxin and alter the therapeutic index.

24. Increased sensitivity Decreased sensitivityy Hypokalemia Hypercalcaemia Hypothyroidism Hypoxia/acidosis Hyperkalemia Hypocalcaemia Hyperthyroidism Neonates

25. DOSING Jeliffe method is a simple method for calculating loading and maintenance dose. Produce dosing regimens that will provide a serum digoxin level of approx 2.0 ng /ml. it is important to adjust the dose empirically if significant drug-disease or drug-drug interactions are present.

26. LOADING DOSE ( TOTAL BODY STORES) LD ( TBS) = (10 mcg/kg)×IBW(kg) F Half of this loading dose is administered intravenously or orally. The remaining dose is divided equa lly and administered at 6-h interval (1/2 dose , ¼ dose, ¼ al 6 h intervals). This is necessary to account for the slow distribution , half life of the drug.

27. MAINTENANCE DOSE it can be calculated based on the amount of the loading dose ( TBS) that is eliminated each day. % TBS lost daily = 14 + Cl Cr ( ml/min) 5 MD =TBS (% TBS lost each day)

28. Example: JL is a 68 year old male who is admitted to the hospital for atrial fibrillation. During his hospitalization he is converted to normal sinus rhythm b quinidine. His past medical history includes CHF . His thyroid function is normal. His weight is 84 kg (IBW = 73 kg) and his estimated creatinine clearance is 68 ml/min. what would be an appropriate oral loading and maintenance dose?

29. LD = 10 × 73 =TBS = 1043 mcg(1.4 mg) 0.7 Administer 0.5 mg orally, then 0.25 mg in 6 h, then 0.25 mg in 6 h. MD= TBS (%TBS LOST EACH DAY) % TBS LOST EACH DAY =14 + 68 ml/min = 27.6% 5 MD = 1.04 mg (27.6%) = 0.29 mg Because JL is also on quinidine the MD would be decreased by 50%. MD = 0.15 or 0.125 mg/day

30. ANALYTICAL METHODS Enzyme Immunoassay ( EIA) Cloned Enzyme Donor Immunoassay (CEDIA) Enzyme M ultiplied Immunoassay (EMIT) Fluorescence Polarisation Immunoassay (FPIA)

31. Enzyme Immunoassay ( EIA) In this method, the label on the tracer is an enzyme . The catalytic properties of enzymes allows the detection and quantitation of small quantities of the drug.

32. Cloned Enzyme Donor Immunoassay (CEDIA) The method uses an antibody to detect the drug to be measured. A label is used to measure the binding reaction . It uses genetically engineered fragment of the enzyme β - galactosidase as the label.

33. Enzyme Multiplied Immunoassay (EMIT) The method uses activity as an enzyme glucose 6-phosphate dehydrogenases chemically coupled to a drug molecule. Activity of the enzyme is inhibited when the drug is bound to a specific antibody. The extent of enzyme activity reflects the proportion of enzyme-labelled drug which is not bound to antibody, which in turn reflects the no. of binding sites occupied by unlabelled drug and hence the drug conc in the sample.

34. Fluorescence Polarisation Immunoassay (FPIA) The method uses specific antibodies to isolate the desired analyte . Small fluorescent molecule , excited with polarised vertical light , rotates rapidly and emits polarised light in comparison to molecules. The intensity of polarised light is a measure of conc of the analyte .

35. ANALYTICAL ISSUES Specimens from patients treated with digoxin antidote give misleading values for digoxin conc by most immunoassays. Biological activities of some metabolites of digoxin are low relative to the parent compound. One method for measuring the unbound digoxin →to use ultrafiltration before immunoassay.

36. Pharmacokinetic parameter and TDM information PARAMETER VALUE Elimination half life 36 hrs(adults) 18-37 hrs(children) Total body clearance(ml/min/kg) 2.7 Volume of distribution ‘V’ 6-7L/kg(total body weight) Plasma protein binding 20-30% Therapeutic range 0.9-2 ng /ml for atrial fibrillation (0.5-1.2 for CHF) Time to steady state concentration 6-10 days Loading dose Two 0.5mg oral tablet doses or Two 0.375mg IV doses, separated by 6 hrs ( pts.with creatinine clearance>20ml/min) 0.2 mg/day( creatinine clearance>20 ml/min) Maintenance dose 0.125 mg/day(clearance <20ml/min or body weight < 40kg ) Clinically important metabolite Bis and mono- digitoxosides As cardioactive as digoxin