Digoxin- GLYCOSIDE

Digoxin- GLYCOSIDE

1. DIGOXIN DR ZIKRULLAH

2. The term DIGITALIS is a general term used for all plant derived cardiac glycosides. Digitalis is widely used in the treatment of various heart conditions, namely atrial fibrillation, atrial flutter and congestive heart failure that cannot be controlled by other medication. DIGOXIN is a purified cardiac glycoside . Digitalis glycosides found in Foxglove, oleander, lily of the valley

3. Name the Plant http://biology.clc.uc.edu/graphics/steincarter/florida/ http://www.huntingtonbotanical.org/Shakespeare/photogallery.htm http://www.dososos.com/availability_photos/lily_valley.html Lilly of the Valley Oleander Foxglove

4. DIGOXIN PREPARATIONS DIGOXIN can be used orally, I.V and I.M injection. It is available as a 0.25 mg tabs & capsules 0.05 mg/ mL oral solution and 0.25 mg/ mL ( 2 ml) or 0.5 mg/ mL (1 ml) injectible solution.

5. The vehicle is 40% propylene glycol and 10% alcohol. The injection is buffered to a pH of 6.8 to 7.2 with 0.17% sodium phosphate and 0.08% anhydrous citric acid. Dilution is not required.

6. Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. Temp range = 15 to 30°C (59 to 86°F) and protect from light .

7. CHEMICAL STRUCTURE Basic structure of all cardiac glycosides consists of a cyclopenteno-phenantherene nucleus which consists of a GLYCONE and a AGLYCONE portion. GLYCONE portion in usually glucose or digitoxose – pharmacologically inactive but necessary for fixation. AGLYCONE portion is responsible for pharmacological action.

8. MECHANISM OF ACTION The beneficial effects of digoxin result from: direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system.

9. Inhibits sodium-potassium ATPase of myocardial fibres ↓ Progressive accumulation of Na + intracellularly ↓ Indirect increase of Ca++ intracellularly ↓ Ca++ transients are augmented in myocardium ↓ ↑ force of myocardial contraction

10. CHANGES IN CARDIAC ACTION POTENTIAL AFTER DIGITALIZATION Increased automaticity – decreasing resting membrane potential and increase in slope of Phase 4 depolarization. Inhibition of outward sodium decreases slope of Phase 0 Decrease in duration of action potential mainly due to shortened duration of Phase 2 1 2 3 4

11. ECG CHANGES DUE TO DIGITALIZATION (therapeutic) Prolonged PR interval – due to delay of conduction at AV node Shortened QTc interval because of more rapid ventricular repolarization . ST depression( scaphoid or scooped out) due to decreased slope of Phase 3 Flattened or inverted T wave

12. Digitalis Effect http://www.emedu.org/ecg/voz.php

13. The autonomic (indirect) effects include: a vagomimetic action, Arterial baro -receptor (carotid sinus) sensitization Activation of Nodose Ganglion in the CNS These lead to increase parasympathetic tone and subsequent decrease activity of the SA and AV node resulting in suppression of ectopic activity

14. The pharmacologic consequences of these direct and indirect effects are: an increase in the force and velocity of myocardial systolic contractions (positive ionotropic action); a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system ( neurohormonal deactivating effect); slowing of the heart rate and decreased conduction velocity through the AV node ( vagomimetic effect).

15. PHARMACOKINETICS ABSORPTION Oral – 75% in First hour with peak plasma concentration occurring at 1-2 hrs IM – not preferred as is painful, unpredictable absorption. IV – peak effect at ~ 5-30 min

16. DISTRIBUTION: Following drug administration, a 6- to 8-hour tissue distribution phase is observed. Principal reservoir in body are skeletal muscles This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body.

17. Digoxin has a large apparent volume of distribution. Digoxin crosses both the blood-brain barrier and the placenta. Approximately 25% of digoxin in the plasma is bound to protein.

18. METABOLISM Only 25 % of a dose of digoxin is metabolized via hydrolysis, oxidation, and conjugation. The end metabolites: 3 β- digoxigenin , 3-keto-digoxigenin, and their glucuronide and sulfate conjugates . The metabolism of digoxin is not dependent upon the cytochrome P-450 system digoxin is not known to induce or inhibit the cytochrome P-450 system.

19. EXCRETION: Elimination of digoxin follows FIRST-ORDER KINETICS . 50% to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to GFR.

20. In Pt with normal renal function, digoxin has a half-life of 1.5 to 2.0 days. In anuric patients is prolonged to 3.5 to 5 days. Not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass .

21. CLINICAL USES Used in patients with heart failure and atrial fibrillation Only about 50% of patients with normal sinus rhythm (usually those with systolic dysfunction) will have documentable relief of heart failure from digitalis.

22. Digitalis is useful in the management of ATRIAL ARRHYTHMIAS because of its cardio selective parasympathomimetic effects. In ATRIAL FLUTTER , the depressant effect of the drug on atrioventricular conduction will help control an excessively high ventricular rate. The effects of the drug on the atrial musculature may convert flutter to fibrillation, with a further decrease in ventricular rate.

23. In ATRIAL FIBRILLATION , the same vagomimetic action helps control ventricular rate, thereby improving ventricular filling and increasing cardiac output. Digitalis has also been used in the control of paroxysmal- atrial and atrio -ventricular nodal tachycardia but not WPW syndrome associated atrial fibrillation.

24. DOSAGE The dose of digoxin , the following factors must be considered: The body weight of the patient - lean body weight. Renal function - on the basis of creatinine clearance. Serum Digoxin Concentrations

25. Heart Failure : Rapid digitalization - achieved by administering a single initial intravenous dose (0.5 to 1 mg) or oral (0.75 to 1.5 mg ) based upon projected peak digoxin body stores. Maintenance Dose = Loading Dose x % Daily Loss/100 (Where: % Daily Loss = 14 + C.cr/5) [C.cr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area.]

26. Gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly . Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70 with good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients over age 70 or with impaired renal function at a dose of 62.5 mcg (0.0625 mg) in patients with marked renal impairment. Doses may be increased every 2 weeks according to clinical response.

27. INTERACTIONS Risk for developing serious digitalis-induced cardiac arrhythmias if hypokalemia develops, as in diuretic therapy, diarrhea or oral antacids. Patients at risk if given quinidine , which displaces digoxin from tissue binding sites (a minor effect) and depresses renal digoxin clearance (a major effect). Antibiotics that alter gastrointestinal flora may increase digoxin bioavailability in about 10% of patients.

28. Succinylcholine can abruptly increase parasympathetic nervous system activity can have a additive effect but not significant clinically. IV calcium can cause dysarrythmias . Fentanyl , enflurane and to a lesser extent isoflurane protect against digitalis induced cardiac automaticity. Sympathomimetics with β activity like Pancuronium may sensitize the myocardium to digitalis induced arrhythmias.

29. Digitalis toxicity

30. Clinical Features Nonspecific cardiac dysrhythmias May be life threatening Any dysrhythmia or junctional escape rhythm with an AV block consider digoxin toxicity PVC’s Frequent PVC’s are the most common dysrhythmia Bi-directional V- tach Rare, but relatively specific for digitalis toxicity

31. Digoxin Toxic Dysrhythmias Bradycardia with AV block

32. Second degree AV block, Type I – Wenckebach Atrial tachycardia with AV block

33. A. Fib with a regular ventricular rate PVC’s http://www.tchpeducation.com/General%20Interest/Digoxin%20Toxicity/digoxin_toxicity.htm

34. Ventricular Tachycardia Bifascicular Ventricular Tachycardia

35. Clinical Features Other symptoms: Gastrointestinal distress Dizziness Headache Weakness Syncope Seizure Confusion Disorientation Delirium Hallucinations Visual changes (yellow-green halos)

36. Laboratory Evaluation Potassium Acute poisoning of the Na + K + ATPase pump causes elevated potassium levels Potassium level may be a better prognostic indicator in acute poisoning than the digoxin level Potassium less elevated in chronically poisoned patients

37. Digoxin level Therapeutic levels 0.5 – 1.5( or 2.5) ng /ml With signs of toxicity therapeutic level does not exclude toxicity Acute exposures Digoxin absorbed into the plasma then redistributed to the tissues Serum levels most reliable at 6 hours Renal and hepatic function, and electrolytes must also be evaluated.

38. Acute vs. Chronic Acute Asymptomatic for several hours GI symptoms often occur first Bradydysrhythmias or supraventricular with AV block Severity correlates with K + not with digoxin level High digoxin leve l Chronic Elderly on digoxin and diuretics May mimic influenza or gastroenteritis Mental status change Many dysrhythmias , but ventricular more common than in acute K + often low and digoxin is a poor predictor

39. Factors Enhancing Toxicity Electrolyte abnormalities Hypokalemia , hypomagnesemia , and hypercalcemia Cardiac hypersensitivity with myocardial disease or ischemia Decreased renal, hepatic, or thyroid function Drugs Antidysrhythmic , spironolactone , indomethacin , clarithromycin , erythromycin

40. Dysrhythmia Treatment ABC’s Initiate Continuous cardiac monitoring, IV’s, frequent reevaluations Extended observation at least 12 hours Correct hypoxia, hypoglycemia, and electrolytes Atropine and cardiac pacing

41. Antidysrhythmias Lidocaine and phenytoin Both decrease ventricular automaticity Phenytoin increases conduction through AV node therefore often considered the DOC for bradydysrhythmias Bretylium shown clinical use but animal studies do not support it. Class IA antidysrhythmics are contraindicated as they slow AV nodal conduction

42. Electrocardioversion May induce ventricular fibrillation so only as last resort Digoxin specific Fab fragment is the treatment of choice for life-threatening dysrhythmias that do not respond to conventional therapy Hyperkalemia Glucose, insulin, and sodium bicarbonate Potassium-binding resins Avoid Calcium Calcium may promote cardiac toxicity

43. Digoxin -Specific Fab Antibody Sheep IgG antibody to digoxin Remove digoxin from plasma and tissue Clinical improvement within 1 hour in 90% of patients Indications Ventricular dysrhythmias Unresponsive hemodynamically significant bradydysrhythmias Hyperkalemia > 5.5 mEq /L with suspected digoxin toxicity

44. Adverse effects Cardiogenic shock reported in patients dependent on digoxin for inotropic support Increased ventricular response to A. Fib Hypokalemia from rapid digoxin removal Rare hypersensitivity reactions

45. Dosage Calculate total body load Based on amount ingested Total body load = amount ingested x 0.8 Based on digoxin concentration [ Digoxin level ( ng / mL ) x 5.6 x weight (kg)] / 1000 Calculate number of vials Digibind vials (40mg) required = total body load/0.6

46. PRECAUTIONS Use in thyroid disorders and hypermetabolic states Use in patients with acute myocardial infarction Use during electrical cardioversion Pregnancy Nursing mothers Pediatric use Geriatric use

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