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PK & dose alterations in selected drugs in cardiac patients, , , -…
PK & dose alterations in selected drugs in cardiac patients
Theophylline
significant
reduction in clearance
in HF patients
Two studies also reported a significantly
longer elimination half life
of the drug in HF
By contrast, the volume of distribution was similar to that of controls
Theophylline undergoes significant
metabolism in the liver
and only a minimal fraction of the
unchanged
drug is eliminated in
the urine
Notably, significant
liver and renal dysfunction
were reported in only
one
study investigating theophylline pharmacokinetics
Digoxin
Digoxin clearance was mildly, albeit
significantly, lower
(between 6 % and 32 %) in HF patients vs . controls in
four
studies.
Clearance of digoxin is
unlikely
to be significantly affected in HF patients with
preserved renal function.
However,
no significan
t between group differences in digoxin clearance were reported in
two
other studies
Prazocin
The alpha 1 blocker prazosin, with significant
reductions ( 54 %) in clearance
The mechanisms responsible for these alterations are unknown given that prazosin is extensively metabolized in
the liver
and its metabolites are almost completely
excreted in the bile
. Furthermore,
liver function
was preserved in one study but unknown in another
a marked
prolongation in elimination half life
(between + 153 % and 160 %)
greater area under the curve
(between + 111 % and 127) in HF patients
Renin -Angiotensin system inhibitors[,
Enalapril, Fosinopril ,Lisinopril, Perindopril and Irbesartan)
Enalapril
(In HF Patients)
An
increase in the time
to reach peak concentrations (+67 %)
Elimination half life
(+130 %)
reduced clearance
(%75)
Lisinopril
(in HF patients with preserved renal function)
increase
in
the area under the curve
It is
excreted
unchanged
almost entirely in the
urine
A significant
reduction
in
clearance
However, no statistical analyses between HF patients and controls were reported in this study
Perindopril
significantly longer time to reach peak concentrations
elimination half life
had similar peak concentrations
a significantly greater area under the curve
When compared to controls,changes in liver and/or renal function might have influenced the results as the relevant information was not provided in this study
Furosemide
The alteration in absorption
was directly related to
the severity of congestive HF
Other authors have obtained
similar
results in patients with
congestive HF and reduced creatinine clearance
while
no chang
e in
half life
and
clearance was found in patients with congestive HF and normal renal function
The altered absorption
is a factor that could
explain the resistance (decreased response to orally administered furosemide
commonly observed in clinical practice in patients with congestive HF
Reduction in renal function
, in turn, resulted in
decreased total and renal clearance of furosemide
less drug excreted into the urine after both the IV and oral routes and a
prolonged half life
these changes were correlated with the decrease in renal function
A prompt diuretic response requires intravenous therapy
A decrease in clearance (1.40 vs 1.84 ml/min/kg in normal subjects) and a
prolongation
of furosemide half life 122 vs 91 min) were found in patients with a broad spectrum of severity of congestive HF
Otherwise a gradual response can most likely be obtained with sufficiently high oral doses
IV is more potent than the oral route:
Severe or unstable heart failure require initial IV therapy due to:
Reduced intestinal motility
Perhaps mucosal edema
Interstitial edema of the GIT
Decrease intestinal perfusion
It may slow the rate of drug absorption & rate of drug delivery to the kidney.
It may be necessary to give the drug intravenously if a prompt response is desired