INTRODUCTION

1. INTRODUCTION Digoxin , also known as digitalis, is a purified cardiacglycoside extracted from the foxglove plant, Digitalis lanata .Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin. Digoxin is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and sometimes heart failure that cannot be controlled by other medication. Digoxin preparations are commonly marketed under the trade names Lanoxin, Digitek, and Lanoxicaps.

2. Basics of kinetics: Bioavailability • 60 to 80% (Oral) • Protein binding capability • Hepatic (16%) • Half-life: 36 to 48 hours(patients with normal renal function)3.5 to 5 days(patients with impaired renal function) • Excretion:Renal • Routes:Oral, Intravenous

3. MECHANISM OF ACTION: • Digoxin binds to a site on the extracellular aspect of the α-subunit of the Na+/K+ATPase pump in the membranes of heart cells (myocytes) and decreases its function. This causes an increase in the level of sodium ions in the myocytes, which leads to a rise in the level of intracellular calcium ions. This occurs because of a sodium/calcium exchanger on the plasma membrane, which depends on a constant inward sodium gradient to pump out calcium. Digoxin decreases sodium concentration gradient and the subsequent calcium outflow, thus raising the calcium concentration in myocardiocytes and pacemaker cells. • Increased intracellular calcium lengthens Phase 4 and Phase 0 of the cardiac action potential, which leads to a decrease in heart rate. Increased amounts of Ca2+ also leads to increased storage of calcium in the sarcoplasmic reticulum, causing a corresponding increase in the release of calcium during each action potential. This leads to increased contractility, the force of contraction, of the heart. • There is also evidence that digoxin increases vagal activity, thereby decreasing heart rate by slowing depolarization of pacemaker cells in the AV node. . This negative chronotropic effect would therefore be synergistic with the direct effect on cardiac pacemaker cells. Digoxin is used widely in the treatment of various arrhythmias

4. INDICATIONS: • Today, the most common indications for digoxin are probably atrial fibrillation and atrial flutter with rapid ventricular response, but beta- or calcium channel- blockers should be the first choice.High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves owing to improved filling. • The use of digoxin in heart problems during sinus rhythm . In theory the increased force of contraction should lead to improved pumping function of the heart. Digoxin is no longer the first choice for congestive heart failure, but can still be useful in patients who remain symptomatic despite proper diuretic and ACE inhibitor treatment. It has fallen out of favor because it was proven to be ineffective at decreasing morbidity and mortality in congestive heart failure

5. USE OF DIGOXIN IN HEART FAILURE: Patients with more severe heart failure, a third heart sound gallop, left ventricular enlargement and a depressed left ventricular ejection fraction are more likely to respond to digoxin therapy. • Many compensatory mechanisms, including the sympathetic nervous system and salt- and water-retaining systems, become activated in the setting of a depressed cardiac output. The compensatory systems can maintain left ventricular function for days to months. However, when patients become overtly symptomatic, they begin to experience a striking increase in morbidity and mortality. The transition to symptomatic heart failure is accompanied by further activation of the neurohormonal system, including the sympathetic nervous system and a series of adaptive changes in the myocardium. • Digoxin-Induced Neurohormonal Modulation • In the past, digoxin was considered to be solely a positive inotropic agent. In patients with heart failure, digoxin exerts its positive inotropic effect by inhibiting sodium-potassium adenosine triphosphatase (ATPase). Inhibition of this enzyme in cardiac cells results in an increase in the contractile state of the heart. it has been shown that digoxin exerts a positive inotropic effect at higher dosages (0.25 mg or more per day); however, at lower dosages (less than 0.25 mg per day), this drug exerts a mainly neurohormonal effect and has little inotropic activity.21 • The neurohormonal effect of digoxin showed that digoxin reduced plasma norepinephrine levels; these results were validated in other studies.The explanation for this effect was that digoxin improves impaired baroreceptor reflexes in heart failure. • Digoxin may also lower plasma renin levels, either because of a direct renal effect or secondary to inhibition of sympathetic activity. By inhibiting sodium-potassium ATPase in the kidney, digoxin decreases renal tubular reabsorption of sodium, thereby increasing delivery of sodium to the distal tubules and suppressing renin secretion.

6. DIGOXIN THERAPY IN CONGESTIVE HEART FAILURE: • Digoxin has been shown to improve morbidity without any benefit on mortality. • Digoxin may act by decreasing sympathetic activity. • Digoxin may not be effective in patients who have normal left ventricular systolic function. • The benefits of digoxin therapy are greatest in patients with severe heart failure, an enlarged heart and a third heart sound gallop. • Digoxin may be used in patients with mild to moderate heart failure if they do not respond to an angiotensin-converting enzyme inhibitor or a beta blocker. • Low dosages of digoxin can be effective. • Renal function and possible drug interactions must be considered in deciding on an appropriate dosage of digoxin. • In general, digoxin therapy should be avoided in the acute phase after myocardial infarction.

7. ECG OF CHF

8. ATRIAL FIBRILLATION: • Atrial fibrillation (AF) is the most common type of heart arrhythmia. An arrhythmia is a problem with the rate or rhythm of the heartbeat. • Atrial fibrillation occurs when rapid, disorganized electrical signals cause the atria to fibrillate (contract very fast and irregularly). When this happens, the heart's upper and lower chambers don't work together as they should.

9. If a clot (thrombus) forms in the left atrium of the heart, a piece of it can dislodge and travel to an artery in the brain, blocking blood flow through the artery. The lack of blood flow to the portion of the brain fed by the artery causes a stroke.

10. ATRIAL FLUTTER: Atrial flutter refers to rapid and regular contractions (usually in the range of 120 to 350 times each minute) that is characterised on the ECG by a saw-tooth appearance. Not all atrial contractions are necessarily conducted to the ventricles due to a variable block within the atrioventricularnode. When conduction to the ventricles does occur, the QRScomplex morphology is regular but RR intervals may be random or follow a specific pattern.

11. The ECG trace shows regular flutter waves (arrowed) at a rate of five per second. Ventricular conduction is occurring after every two (shaded RR intervals) or three (unshaded RR intervals) atrial contractions.

12. DOSING AND TDM of Digoxin:

13. DOSAGE FORM OF DIGOXIN:

14. BIOAVALABILITY FACTOR (F)OF DOSAGE:

15. CRCL-BASED MAINTANCE DOSAGE AND INTERVAL ADJUSTMENT:

16. DOSING : • Digoxin may be taken with or without food. Digoxin is primarily eliminated by the kidneys; therefore, the dose of digoxin should be reduced in patients with kidney dysfunction. Digoxin blood levels are used for adjusting doses in order to avoid toxicity. The usual starting dose is 0.0625-0.25 mg daily depending on age and kidney function. The dose may be increased every two weeks to achieve the desired response.

17. HEART FAILURE:

18. ATRIAL FIBRILLATION:

19. Usual pediatric dose in atrial fibrillation:

20. Usual pediatric dose in atrial fibrillation:(cont.)

21. DOSE ADJUSTMENTS: • If patients are switched from intravenous to oral formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages. When changing from oral formulations to IM or IV therapy, dosage should be reduced by 20% to 25%.  • Divided dosage of the capsule formulation is preferred in patients that require a daily dose greater than 300 mcg, those with a previous history of digitalis toxicity, and in patients who may be more likely to become toxic.

22. GENERAL ADVICE: • Calculate doses based upon lean (ideal) body weight. • Consider the differences in bioavailability between digoxin injection, tablets, and oral solution when changing patients from one dosage form to another. • For IV administration, digoxin injection may be diluted (4-fold or more) with normal saline, dextrose 5% in water, or sterile water for injection. Infuse slowly, 5 min or longer. • IM injection can lead to severe pain at the injection site. If the drug must be administered IM, inject it deeply into the muscle and follow with massage. Do not inject more than 2 mL (500mcg) into a single site.

23. THERAPEUTIC DRUG MONITORING OF DIGOXIN: • Digoxin is one of the most commonly used drugs in medicine. Despite this widespread use and a history of over 200 years of clinical use and research, much controversy continues concerning its efficacy and safety. Two of the most prominent features of the clinical use of digoxin are : • 1.Its narrow therapeutic index • 2.An endpoint of therapy which is difficult to define and measure. Digitalis toxicity is one of the most frequently encountered drug-related causes of hospitalization. Conversely, the effect of serum digoxin concentrations below 0.8 ng/ml is clinically unimportant in most patients.

24. Calculation of individual patient doses: • The great variability in serum digoxin concentrations in patients given the same dose has led to the development of nomograms and equations designed to estimate the optimal digoxin dosage. These methods include factors such as age, weight, sex, renal function, disease state, and concurrent drug therapy to calculate the dose and corresponding serum concentration. An accurate method could decrease the potential for drug toxicity, which can be life-threatening, and decrease the time period required to optimize therapy, which is otherwise done by trial and error.

25. WHY DO WE NEED A LOADING DOSE? • An adequate loading dose is necessary for rapid attainment of therapeutic serum levels. Choosing to initiate therapy with out a loading dose means that, because of digoxin's long half-life, therapeutic serum levels may not be achieved for weeks.

26. Monitoring parameters: • The following patient parameters should be monitored during digoxin therapy: • Digoxin serum levelObtain level within 24 hours of digitalization, weekly until stable, and at steady state. • BUN and serum creatinineMeasure every two days, or every day in unstable renal function. • Weigh patient daily. • Measure and monitor urine output daily Monitor apical pulse daily

27. PRECAUTIONS & PREDISPOSING FACTORS: • Proper timing of serum sampling is critical.Serum samples should be drawn just prior to the daily dose and no sooner than six hours after administration of the drug. • Factors affecting digoxin pharmacokinetics • Factors which predispose to digoxin toxicity:Hypokalemia, uncorrected hypothyroidism, renal dysfunction, and interacting drugs which decrease digoxin clearance (e.g: verapamil). • Factors which predispose to suboptimal clinical response:Hyperkalemia, uncorrected hyperthyroidism, interacting drugs which delay or prevent oral absorption (e.g antacids,).

28. HOW TO DESIGN A REGIMEN? • Before calculating an initial dose or adjusting the maintenance dose one must know the target digoxin serum level, whether the patient is in acute congestive failure and whether any interacting drugs are being concurrently administered. • Initial dosing(using a TDM software) The program first calculates an ideal loading dose, enter a practical dose and the desired dosage form of the loading dose. Enter 0 if no loading dose is desired. The program calculates an ideal maintenance dose, the user enters a practical maintenance dose and interval. The program then displays an estimated steady-state serum level.

29. Dosage adjustment based on serum levels: • First enter the measured serum digoxin concentration, the dosage form, digoxin dose and interval. The program then requires the date and time the current dosage regimen was initiated, this is used to determine whether the patient’s digoxin level is at a steady-state. The program then calculates an incremental loading dose or temporary interruption, depending upon whether the serum level is below or above the target level. The user enters a practical loading dose or temporary interruption. The program calculates an ideal maintenance dose and the user enters a practical maintenance dose and interval. The program then displays an estimated steady-state serum level.

30. DIGOXIN DOSING FLOW CHART:

31. DIGITALIZING A PATIENT: • Initial dosing: • Estimation volume of distribution (jusko equation) • Calculate loading dose • Estimate clearance(koda –kimble) • Calculate maintance dose • Estimate steady -state trough level

32. ESTIMATE VOLUME OF DISTRIBUTION (JUSKO EQUATION): Vd = 226 + [(298 x CrCl) / (29.1 + CrCl)] x (BSA / 1.73)where CrCl = normalized creatinine clearance (ml/min)BSA = Body surface area (square meters)

33. CALCULATE LOADING DOSE: LD = Vd x Cp/F where Vd = Volume of distribution (liters)Cp = target serum level (mcg/l)F = bioavailability factor • IV push = 1 • capsules= 0.95 • elixir = 0.8 • tablets = 0.75

34. ESTIMATE CLEARANCE (KODA KIMBLE): Cl =[(A x CrCl) +B] x C Where; A =0.88 for aute CHF ,otherwise =1 B=23 for acute CHF ,otherwise=40 C=corrective factor for interacting drugs: Quinidine =0.65 Spirolatone =0.75 Verapamil=0.7 Other =0.71

35. CALCULATE MAINTENANCE DOSE: • MD = (Cl x Cp x tau) / F • where Cl = Clearance (liters/hour)Cp = target serum level (mcg/l)tau = dosing interval (hours)F = bioavailability factor

36. Estimate steady-state trough level: Cpss = (MD x F) / (Cl x tau)where MD = Maintenance dose (mcg)F = bioavailability factorCl = Clearance (liters/hour)tau = dosing interval (hours)

37. ADJUST MAINTENANCE DOSE: • Estimate Volume of Distribution (Jusko Equation) • Calculate digoxin clearanceCl = [(MD x F) / Cp] / tauwhere MD = Maintenance dose (mcg)F = Bioavailability factorCp = Steady-state serum digoxin concentration (mcg/l)tau = Dosing interval (hours) • Calculate Maintenance Dose MD = (Cl x Cp x tau) / Fwhere Cl = Digoxin clearance (l/hr)Cp = target serum level (mcg/l)tau = dosing interval (hours)F = bioavailability factor

38. Estimate steady-state trough level: • Cpss = (MD x F) / (Kel x Vd x tau)where MD = Maintenance dose (mcg)F = bioavailability factorKel = Elimination rate (1/hours)Vd = Volume of distribution (liters)tau = dosing interval (hours)

39. SIGNIFICANCE OF TDM: • Therapeutic drug monitoring (TDM) is only of value for a limited number of drugs. For such measurements to be clinically worthwhile, the following criteria should be fulfilled: • 1. Established relationship between plasma drug concentration and therapeutic response and/or toxicity; • 2. Poor relationship between plasma concentration and drug dosage; • 3. A good clinical indication for the test such as : no response to treatment; suspected non-compliance; signs of toxicity; • 4. The collection of an appropriately timed and dated specimen with proper patient information; • 5. Adequate clinical information to allow the interpretation of results.

40. CONTRAINDICATIONS:

41. CONTRAINDICATIONS TO DIGOXIN ARE MANY: • 1.Hypertrophic obstructive cardiomyopathy (hypertrophic subaorticstenosis, asymmetrical septal hypertrophy) is a contraindication (unless there is atrial fibrillation and severe myocardial failure), because the inotropic effect can worsen outflow obstruction,hypokalemia,ventricular tachycardia.

42. 2.In some cases of Wolff-Parkinson-White syndrome with atrial fibrillation, digitalization may accelerate anterograde conduction over the bypass tract to precipitate ventricular tachycardia or ventricular fibrillation. 3.Significant AV nodal heart block. Intermittent complete heart block or second-degree AV block or sick sinus syndrome may be worsened by digitalis, especially if there is a history of Stokes-Adams attacks or when conduction is likely to be unstable, as in AMI or acute.

43. HYPERTROPHIC CARDIOMYOPATHY: • Hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle becomes thick. The thickening makes it harder for blood to leave the heart, forcing the heart to work harder to pump blood. • Hypertrophic cardiomyopathy is often asymmetrical, meaning one part of the heart is thicker than the other parts. The condition is usually passed down through families (inherited). It is believed to be a result of several problems (defects) with the genes that control heart muscle growth.

44. Why digoxin is contraindicated in hypertrophic obstructive cardiomyopathy? • Because the inotropic effect can worsen outflow obstruction.

45. WOLFF-PARKINSON-WHITE SYNDROME (WPW): • Wolff-Parkinson-White (WPW) syndrome, digoxin and verapamil may result in extremely fast heart rates that can lead to lightheadedness, fainting (syncope), and even death. These drugs are only dangerous when given in an emergency when someone with Wolff-Parkinson-White syndrome is having atrial fibrillation.Treatment of WPW frequently requires antiarrhythmic medicines, such as propafenone (Rythmol) or flecainide (Tambocor), that slow electrical conduction over the extra connection.

46. VENTRICULAR FIBRILLATION AND OTHER HEART DISEASES: • Digoxin is contraindicated in patients with ventricular fibrillation. Ventricular fibrillation is a condition in which the heart beats rapidly causing the ventricles to stop pumping blood. This causes the blood pressure to fall and the supply of blood to the other parts of the body gets cut off. • Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased.

47. SECOND-DEGREE ARTIOVENTICULAR BLOCK: • Second-degree AV block is a disease of the electrical conduction system of the heart. It refers to a conduction block between the atria and ventricles.

48. WHY DIGOXIN IS CONTRAINDICATED IN AV BLOCK: • Digoxin inhibits the sodium/potassium ATPase pump resulting in increased intracellular sodium leading to impaired sodium/calcium exchange in increased intracellular calcium. This increased intracellular calcium is stored in the sarcoplasmic reticulum of the cardiac muscle , resulting in increased calcium reserve stronger muscle contraction. Digoxin also potentiates the vagally mediated slowing of AV conduction and increased atrial ventricular block. • Patients with hypokalemia, second-degree AV block, third-degree AV block, and patients with atrial fibrillation , who also have Wolfe-Parkinson-White syndrome should not be given digoxin.

49. SICK SINUS SYNDROME: • Sick sinus syndrome is a collection of conditions in which the ECG indicates sinus node dysfunction. It is characterised by sinus node dysfunction with an atrial rate inappropriate for normal requirements. Sick sinus syndrome is usually caused by idiopathic fibrosis of the sinus node.

50. CAUSES: • Hyperkalaemia, hypoxia, hypothermia, hypothyroidism, hyperthyroidism • Drugs, e.g. digoxin, calcium-channel blockers, betablockers, sympatholytic agents, antiarrhythmic drugs • Toxins, e.g. result of sepsis • In some cases of sinoatrial disorder (i.e. Sick Sinus Syndrome) digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block.