Case Scenario for Clinical pharmacokinetics• A 64 yrs old male had heart failure was put on digoxin therapy in tablet form, formulated by XY pharmaceutical. Initially he was given 0.5 mg 8 hourly for three days followed by 0.125 mg/day. Simultaneously he was suffering from severe cough, fever and malaise, the physician after thorough investigations diagnosed as a case of lower respiratory tract infection and prescribed 100mg/d doxycycline initially for one week which was further extended to 10 days. The patient suffered from diarrhea, doxycycline was discontinued, a course of metronidazole was given and patient got cured.• After few days patient complaint of fatigue, palpitations and dyspnea. The dose of digoxin was increased to 0.25mg/ day and he felt better.• After several years he was diagnosed for chronic renal failure, blood urea and creatinine is raised. He developed heart sinking and palpitation. ECG showed pulses bigeminy. Serum digoxin was 2.8ng/ml. Digoxin therapy was stopped for three days. KCl was administered for few days The plasma level was now 1ng/ml and the dose of digoxin was adjusted to 0.125mg digoxin/day.
Case Scenario for Clinical pharmacokinetics1. What is form?2. Why patient was asked to take the digoxin formulated by XY pharmaceutical only?3. Why he suffered from diarrhea?4. Why he was given high doses of digoxin initially?5. Why the patient complaint of fatigue, palpitations and dyspnea.6. Why the physician had to increase the dose of digoxin?7. Therapeutic blood monitoring is required, at which time you will take blood sample?8. Plasma concentration is found to be 0.35 ng/ml. How will you calculate the new dose?
8. What is the first symptom of digoxin toxicity leading to diagnosis?9. Why patient developed cardiac toxicity?10. Enumerate the formulas applied for Estimation of GFR & Creatinin clearance11.What is the normal range of serum digoxin level?12. After increasing the dose to 0.25 mg/day how long it took to improve the patients condition and was stabilized?13. What is the mechanism of development of pulses bigeminy?14. What will be effect of chronic renal failure on plasma half life of digoxin?15. Later, on reducing the dose from 0.25 to 0.125 mg, how long will it take to reach Css?
Clinical EvidencesDoxycycline• Antibiotics might increase digoxin absorption by inactivating intestinal bacteria• John R Horn, Pharmacy times 2004Azole Derivatives• Antifungal Agents (Azole Derivatives, Systemic): May increase the serum concentration of Cardiac Glycosides. (UpToDate)
Doxycycline• Unlike many tetracyclines, doxycycline does not appear to accumulate in patients with impaired renal function, and aggravation of impairment may be less likely. Similarly, there is also no evidence that doxycycline causes severe hepatitis (BMJ)
Metronidazole• DOSING: RENAL IMPAIRMENT• To reduce possible accumulation in patients receiving multiple doses, consider reduction to 50% of dose or every 12 hours; Note: Dosage reduction is unnecessary in short courses of therapy. Some references do not recommend reduction at any level of renal impairment (Lamp, 1999).• DOSING: HEPATIC IMPAIRMENT — Unchanged in mild liver disease; reduce dosage in severe liver disease.
4-variable MDRD," (Modification of Diet in RenalDisease Study Group) serum creatinine, age race, & Gender.CKD-EPI including urinary albumin