Fandi Harmiki

111012003
Digoxin is used for the treatment of congestive heart
failure (CHF) because of its inotropic effects on the
myocardium and for the treatment of atrial
fibrillation because of its chronotropic effects on the
electrophysiological system of the heart.
Digoxin is used for the control of ventricular rate in
patients with atrial fibrilation with no accessory
pathway and can be an excellent choice if the patient
is sedentary or has heart failure or left ventricular
dysfunction.
DIGOXIN
In oral or intravenous dose, the serum digoxin
concentration-time curve follows a two-
compartement model and exhibits a long and large
distribution phase of 8-12 hours
During the distribution phase, digoxin in the serum is
not in equilibrium with digoxin in the tissues, so
digoxin serum concentrations should not be
measured until the distribution phase is finished
THERAPEUTIC AND TOXIC CONCENTRATIONS
When digoxin serum concentration is very high but the
patient is not signs or symptoms of digitalis overdose,
clinicians should consider the possibility that the blood
sample for the determination of a digoxin serum
concentration was obtained during the distribution phase,
is too high because digoxin has not had the opportunity to
diffuse out of the bloodstream into the myocardium, and is
not reflective of myocardial tissue concentrations
Clinically beneficial inotropic effects of digoxin are generally
achieved at steady-state serum concentrations of 0.51
ng/mL.
Increasing steady-state serum concentrations to 1.21.5
ng/mL may provide some minor, additional inotropiceffect
Chronotropic effects usually require higher
digoxin steady-state serum concentrations of
0.81.5 ng/mL
At digoxin concentrations of 2.5 ng/mL or
above ~50% of all patients will exhibit some
form of digoxin toxicity. Most digoxin side
effects involve the gastointestinal tract,
central nervous system, or cardiovascular
system

In patients receiving digoxin for heart failure, the common
signs and symptoms of CHF should be routinuely
monitored; left-sided failure-dyspnea on exertion,
paroxymal nocturnal dyspnea, orthopnea, tachypnea,
cough, hemoptysis, pulmonary rales/edema, s3 gallop,
pleural effusion, cheyne-strokes respiration; right-sided
failure-abdominal pain, anorexia, nausea, bloating,
constipation, ascites, peripheral edema, jugular venous
Distention, hepatojugular reflux, hepatomegaly, general
symptoms-fatigue, weakness, nocturia, CNS symptoms,
tachycardia, paloor, digital ctanosis, cardiomegaly.

Clinical Monitoring Parameters

When used for the treatment of atrial
fibrilation, digoxin will not stop the atrial
arrhytmia but is used to decrease or contol
the ventricular rate should be monitored and
an electrocardiogram can also be useful to
clinician able to interpret the output
The patients pulse or ventricular rate should
be monitored, and an electrocardiogram can
also be useful to clinicians able to interpret
the output.
Atrial fibrillation is characterized by 400600
nonuniform atrial beats/min.
Patients with severe heart disease such as
cornary artery disease can have increased
pharmacodynamic sensitivity to cardiac
glycosides and patients receiving these drugs
should be monitored closely for adverse drug
effects
Augmented pharmacologic responses to
digitalis derivates occur with serum electrolyte
disturbances such as hypokalemia,
hypomagnesemia, and hypercalcemia even
tough steady state digoxin serum
concentrations are in the therapeutic range
As an adjunct to the patients clinical
response, postdistribution (8-12 hours
postdose) staedy-state digoxin serum
concentrations can be measured 3-5 half-lives
after a stable dose is initiated. Digoxin is
primarily eliminated unchanged by the kidney
(75%) so its clearance is predominately
influenced by renal function.
The primary route of digoxin elimination from the body
is by the kidney via glomerular filtration and active
tubular secretion of unchanged drug (~75%).
The remainder of a digoxin dose (~25%) is removed by
hepatic metabolism or biliary excretion.
The primary transporter involved in active tubular
secretion and biliary excretion is p-glycoprotein (PGP)
Enterohepatic recirculaton (reabsorption of drug from
the gastrointestinal tract after elimination in the bile) of
digoxin occurs
BASIC CLINICAL PHARMACOKINETIC PARAMETERS
Digoxin is given as an intravenous injection or orally as a
tablet, capsule, or elixir. When given intravenously, doses
should be infused over at least 510 minutes. Average
bioavailability constants (F) for the tablet, capsule, and
elixir are 0.7, 0.9, and 0.8.
Digoxin is not usually administered intramuscularly due to
erratic absorption and severe pain at the injection site.
Plasma protein binding is ~25% for digoxin.
Usual digoxin doses for adults are 250 g/d (range: 125
500 g/d) in patients with good renal function (creatinine
clearance 80 mL/min) and 125 g every 23 days in
patients with renal dysfunction (creatinine clearnace 15
mL/min)
Adults with normal renal function (creatinine
clearance 80 mL/min, Table 6-2) have an
average digoxin half-life of 36 hours (range:
2448 hours) and volume of distribution of 7
L/kg (range: 59 L/kg).
Effect of Disease States and Conditions on Digoxin
Pharmacokinetics and Dosing


Because digoxin is principally eliminated by
the kidney, renal dysfunction is the most
important disease state that effects digoxin
pharmacokinetics. The digoxin clearance rate
decreases in proportion to creatinine
clearance, and this relationship will be utilized
to aid in the computation of initial doses later.
The equation that estimates digoxin clearance
from creatinine clearance is:
Cl= 1,303(CrCl)+Cl
NR
Cl= digoxin clearance (mL/min)
ClNR= digoxin clearance by nonreal routes of elimination
CrCl= creatinine clearance (mL/min)
Unbound digoxin molecules displaced from
tissue binding sites move into the blood
causing the decreased volume of distribution
*V = Vb + (fb / ft) Vt,
where V is digoxin volume of distribution, Vb
is blood volume, Vt is tissue volume, fb is the
unbound fraction of digoxin in the blood, and
ft is the unbound fraction of digoxin in the
tissues.
The equation that estimates digoxin volume of
distribution using creatinine clearance is:

V=(226 + ((298 x CrCl) : 29,1 + CrCl))) (Wt/70)
V= volume distribution (L/70 kg)
Wt=body weight (kg)
CrCl=creatinine clearance (mL/min)

Digoxin is not significantly eliminated by
hemodialysis or peritoneal dialysis.28,29
Hemofiltration does remove digoxin with a
typical sieving coefficient of 0.7
Heart failure decreases cardiac output which
in turn decreases liver blood flow. Liver blood
flow is an important factor in the
determination of hepatic clearance for drugs
because it is the vehicle that delivers drug
molecules to the liver for possible elimination.
Moderate-severe heart failure decreases the
hepatic clearance of digoxin by this mechanism.
hepatic clearance of digoxin by this mechanism.
When estimating digoxin clearance for the
purpose of computing initial drug doses, it is
necessary to decrease the nonrenal clearance
(ClNR) factor to 20 mL/min in the equation to
compansate for decreased hepatic clearance: Cl =
1.303 (CrCl) + 20, where Cl is digoxin clearance in
mL/min, CrCl is creatinine clearance in mL/min,
and 20 is digoxin nonrenal clearance ClNR in
mL/min.
digoxin clearance is lower in neonates and
premature infants because renal and hepatic
function are not completely developed.
Premature infants and neonates have average
digoxin half-lives equal to 60 hours and 45
hours, respectively.
In older babies and young children (6 months
to 8 years old) renal and hepatic function are
fully developed and half-lives can be as short
as 18 hours.
Older children (12 years old) have mean digoxin
half-lives (t1/2 = 36 hours) that are similar to
those found in adults. Also, volume of
distribution is larger in infants and children
compared to adults as is found with many other
drugs.
Malabsorption of oral digoxin has been reported
in patients with severe diarrhea, radiation
treatments to the abdomen and gastrointestinal
hypermotility. In these cases, steady-state digoxin
serum concentrations decrease due to poor
bioavailability of the drug.
INITIAL DOSAGE DETERMINATION METHODS
The pharmacokinetic dosing method
The Jelliffe method
Nomograms that use the dosing concepts in the Jelliffe
dosing method are available. But, in order to make
calculations easier, they make simplifying assumptions. The
nomograms are for adults only, and separate versions are
needed for intravenous injection (Table 6-4A), tablet (Table
6-4B), and capsule (Table 6-4C) because of bioavailability
differences among dosage forms. All three nomograms
assume that digoxin total body stores of 10 g/kg are
adequate, so are limited to heart failure patients requiring
this dose. Recommended initial doses for pediatric patients
are given in Table 6-3.


Pharmacokinetic Dosing Method
The goal of initial dosing of digoxin is to compute
the best dose possible for the patient given their
set of disease and condition that influence
digoxin pharmacokinetic paramenters for the
patient will be estimated using averange
parameters measured in order patients with
similiar disease and condition profiles.
- Jusko-Koup method
- Jelliffe Method
THERAPEUTIC AND TOXIC CONCENTRATIONS
When given intravenously, the serum lidocaine
concentration/time curve follows a two
compartment model.
This is especially apparent when initial loading
doses of lidocaine are given as rapid
intravenous injections over 15 minutes
(maximum rate: 2550 mg/min) and a
distribution phase of 3040 minutes is
observed after drug administration (Figure 7-1).
The generally accepted therapeutic range for
lidocaine is 1.55 g/mL. In the upper end of
the therapeutic range (>3 g/mL), some
patients will experience minor side effects
including drowsiness, dizziness, paresthesias,
or euphoria.
Lidocaine serum concentrations above the
therapeutic range can cause muscle twitching,
confusion, agitation, dysarthria, psychosis,
seizures, or coma.
Cardiovascular adverse effects such as
atrioventricular block, hypotension, and
circulatory collapse have been reported at
lidocaine concentrations above 6 g/mL, but
are not strongly correlated with specific serum
levels.
Clinicians should understand that all patients
with toxic lidocaine serum concentrations in
the listed ranges will not exhibit signs or
symptoms of lidocaine toxicity. Rather,
lidocaine concentrations in the given ranges
increase the likelihood that an adverse effect
will occur
For dose adjustment purposes, lidocaine
serum concentrations are best measured at
steady state after the patient has received a
consistent dosage regimen for 35 drug
halflives. Lidocaine half-life varies from 11.5
hours in normal adults to 5 hours or more in
adult patients with liver failure.
If lidocaine is given as a continuous
intravenous infusion, it can take a
considerable amount of time (35 half-lives or
7.525 hours) for patients to achieve effective
concentrations so an intravenous loading dose
is commonly administered to patients
Pharmacology of Lidocaine
Steady State - Bolus 1-1.5 mg/kg plus
- Infusion >1.0 mg/kg/hr

Lightheadedness -5 mcg/ml serum levels
Unconsciousness -10 mcg/ml
Seizures -(12-18)mcg/ml
Respiratory and Cardiac Depression
-(20-24)mcg/ml

CD100 HUMANS -(5-7)mg/kg rapid bolus
CD 50 - HUMANS -(2-4)mg/kg rapid bolus

Dose and Toxicity
Evidence for intravenous lidocaine use

Use in chronic neuropathic pain

Major abdominal surgery

Radical prostatectomy


Clinical Monitoring Parameters
The electrocardiogram (ECG or EKG) should be
monitored to determine the response to
lidocaine in patients with ventricular
tachycardia or fibrilation.
The goal of therapy is suppression of
ventricular arrhytmias and avoidance of
adverse drug reactions
Lidocaine therapy is often discontinued after
6-42hr of treatment so the need for long term
antiarrhytmic drug use can be reassessd,
although longer infusion may be used in
patients with presistent tachyarrhytmias
Lidocaine usually given for short duration (<24hr),
its often not necessary to obtain serum lidocaine
concentrations in patients receiving appropriate
dose who curretly have no ventricular arrhytmia
or adverse drug effects
Lidocaine serum concentration should be
obtained in patients who have a recurrence of
ventricular tachyarrhytmias, are experiencing
possible lidocaine side effects, or are receiving
lidocaine does not consistent with disease states
and conditions known to alter lidocaine
pharmacokinetics
Initial Dosage Determination Methods
The pharmacokinetic dosing method is the
most flexible of the techniques.
Literaturebased recommended dosing is a
very commonly used method to prescribe
initial doses of lidocaine.
Linear Pharmacokinetics Method
Because lidocaine follows linear, dose-proportional
pharmacokinetics in most patients during short-term infusions
(<24 hours), steady-state serum concentrations change in
proportion to dose according to the following equation: Dnew /
Css,new = Dold / Css,old or Dnew =(Css,new / Css,old)Dold,
where D is the dose, Css is the steady-state concentration, old
indicates the dose that produced the steady-state concentration
that the patient is currently receiving, and new denotes the dose
necessary to produce the desired steady-state concentration.
The advantages of this method are that it is quick and simple.
The disadvantages are steady-state concentrations are required,
and accumulation of serum lidocaine concentrations can occur
with long-term (>24 hours) infusions.
Pharmacokinetic Parameter Method
The pharmacokinetic parameter method of adjusting
drug doses was among the first techniques available to
change doses using serum concentrations. It allows the
computation of an individuals own, unique
pharmacokinetic constants and uses those to calculate a
dose that achieves desired lidocaine concentrations. The
pharmacokinetic parameter method requires that steady
state has been achieved and uses only a steady-state
lidocaine concentration (Css in mg/L or g/mL). During a
continuous intravenous infusion, the following equation
is used to compute lidocaine clearance (Cl in L/min): Cl =
k0/Css, where k0 is the dose of lidocaine in mg/min.
The clearance measured using this technique is
the patients own, unique lidocaine
pharmacokinetic constant and can be used in the
intravenouscontinuous infusion equation to
compute the required dose (k0 in mg/min) to
achieve any desired steady-state serum
concentration (Css in mg/L or g/mL): k0 = CssCl,
where Cl is lidocaine clearance in L/min. Because
this method also assumes linear
pharmacokinetics, lidocaine doses computed
using the pharmacokinetic parameter method
and the linear pharmacokinetic method should
be identical
Summary
Digoxin and Lidocain have narrow therapeutic
window so the range between MIC and MTC is
very little so the dose must be given correctly
For the patients with renal failure and liver
disease the elimination and metabolism of
drug is abnormal so we mush calculate the
appropriate dose.