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Heart failure, results in low cardiac output, which decreases blood flow to eliminating organs Obesity, adds excessive adipose tissue to the body, which may change the way that drugs distribute in the body and alter the VD
Renal Disease
Glomerular filtration is the primary elimination route for many medications The most common method of estimating glomerular filtration for the purpose of drug dosing is to measure /estimate Creatinine Clearance (CrCl)
Equations:
U Cr xVurine CrCl(ml/min) ! SCr xT
UCr = the urine creatinine concentration (mg/dl) Vurine = the volume of urine collected (ml) SCr = the serum creatinine collected at the midpointof the urine collection (mg/dl) T = the time of urine collection (minute)
CrCl est = estimated creatinine clearance (ml/min) Age in years BW = body weight (kg) Scr = serum creatinine (mg/dl)
CrCl est(females)
42 x Height ! S cr
Problem
OI is a 65 yo, 170 kg (55) female with Class III heart failure. Her current serum creatinine is 4.7 mg/dl and is stable. A digoxin dose of 125 Qg/d given as tablets was prescribed and expected to achieve Css equal to 1 ng/ml. After 3 weeks of therapy, the Css was measured and equalled 2.5 ng/ml. Calculate a new digoxin dose that will provide a Css of 1.2 ng/ml
Solution
1. Estimate CrCl. This patient has a stable Scr and is obese [IBWfemales (kg) = 45 + 2.3 (Ht 60) = 45 + 2.3 (65 60) = 57 kg]. The Salazar and Corcoran eq. can be used to estimate CrCl (Ht is converted from inches to meters(65 in x 2.54 m/in)/(100cm/m) = 1.65 m
Cl est(females) Cl est(females)
Cl est(females) ! 22 ml/min
This patient has poor renal function, but can be expected to be at Css with regard to digoxin serum conc after 3 weeks of treatment. 2. Compute drug clearance (digoxin conc in ng/ml = Qg/L)
60 Qg/d or 120 Qg every other day. This would be rounded to digoxin tablets 125 Qg every other day. The new suggested dose is 125 Qg every other day given as digoxin tablets, to be started at the next scheduled dosing time. Since the dosing interval is being changed, a day should be skipped before the next dose is given.
Renal dysfunction
Urinary excretion of drugs decreased due to a decrease in renal function (exp: cephalosporine) drug accumulation (exp: amikacin in patient with 17% renal function) Drug accumulation depends on frequency of adm and t elimination. If t increase tss increase, then dosage must be reduced
CL Cr (d) RF ! CL Cr (t)
CLCr (d) = creatinine clearance in the patient with renal dysfunction CLCr (t) = creatinine clearance in the typical 55 year-old and 70 kg patient RF = renal function
MD
(d)
! RF MD
(*)
(t)
Adjusment may be made by reducing the frequency of administration, or reducing the MD or both.
Confirmation by TDM
t amikacin in typical patient = 2 hr t amikacin in (d) patient = 12 hr TDM results in:
Regimen with 72 hrs interval showed >>> fluctuations Changing MD reduced fluctuation but inconvenience of frequent im injection Change interval & MD, reduced fluctuation and inconvenience : the most appropriate Loading dose: same usual LD for amikacin suggested
Hepatic Disorders
Most lipid soluble drugs are metabolized to some degree by the liver, the mechanism: 1. Phase I : oxidation, hydrolysis and reduction; mediated by the cytochrome P-450 enzyme system, occur in hepatocytes 2. Phase II: conjugation to form glucuronides, acetates, or sulfates; mediated by cytosolic enzymes in hepatocytes
Absent None
Slight Moderate
Moderate Severe
Each of the symptom is given a score of 1 (normal) to 3 (severely abnormal), and the scores for the five areas are summed. The Child-Pugh score for a patient with normal liver function is 5, whereas for abnormal (hepatic damage) is 15
Dosage adjusment
A Child-Pugh score of 8 9 : a moderate decrease (+ 25%) in initial daily drug dose for agents that are primarily (> 60%) metabolized hepatically A Child-Pugh score of > 10 : a significant decrease in initial daily dose (+ 50%) is required for drugs that are mostly liver metabolized It is possible to decrease the dose while retaining the normal dosage interval, retain the usual dose and prolong the dosage interval, or modify both the dose and dosage interval
Heart Failure
Is accompanied by a decrease in cardiac output results in lower liver and renal blood flow Decreased drug bioavailability has been reported, due to collection of edema fluid in the GI tract difficult absorption and decreased blood flow to GI tract VD of some drugs decreases, the alteration in t is difficult to predict in patients with heart failure