Putri Ramadhani

1111012012
Class :C
Digoxin is the primary cardiac glycoside in
clinical use.Digoxin is used for the
treatment of congestive heart failure (CHF)
because of its inotropic effects on the
myocardium.
The positive inotropic effect of digoxin is
caused by binding to sodium and
potassium-activated adenosine
triphosphatase.

When given as oral or intravenous
doses,the serum digoxin
concentration/time curve follows a two-
compartment model.
Exhibits a long and large distribution phase
of 8-12 hours.
When a digoxin serum concentration is
very high but the patient is not exhibiting
signs or symptoms of digitalis overdose.

Clinically beneficial inotropic effects of
digoxin are generally achieved at steady-
state serum concentrations of 0,5-1 ng/ml.
Increasing steady-state serum
concentrations to 1,2-1,5 ng/ml may
provide some minor, additional inotropic
effect.
Chronotropic effects usually require higher
digoxin steady-state serum concentrations
of 0,8-1,5 ng/ml.

Steady state digoxin serum
concentrations above 2 ng/ml are
associated with an increased incidence of
adverse drug reactions.
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
gastrointestinal tract, central nervous
system, or cardiovascular system.

Plasma protein binding is ~25% for
digoxin.
The primary route of digoxin elimination
from the body is by the kidney via
glomerular filtration and active tubular
secretion as unchanged drug (~75%).
The remainder of a digoxin dose (~25%) is
removed by hepatic metabolism or biliary
excretion.
Usual digoxin doses for adults are 250
g/d (range 125-500 g/d)
In patient with good renal function
(creatinine clearance 80 ml/min
And 125 g every 2-3 days in patients with
renal dysfunction (creatinine clearance
15 ml/min).

Quinidine decreases both the renal and
non- renal clearance of digoxin and also
decreases the volume of distriboution of
digoxin.
Verapamil, diltiazem, and bepridil inhibit
digoxin clearance and increase mean
digoxin steady-state concentrations by
various degrees.
Amiodarone decreases digoxin clearance.
Lidocaine is a local anesthetic agent that
also has antiarrhythmic effects.
It is classified as a type IB antiarrhythmic
agent.
Used for the treatment of ventricular
tachycardia or ventricular fibrilation.

When lidocaine is given intravenously, the
serum lidocaine concentration/time curve
follow a two-compartment model.
When initial loading doses of lidocaine are
given as rapid intravenous injections over
1-5 minutes (maximum rate 25-50 mg/min)
Distributions phase of 30-40 minutes is
observed after drug administration.
The generally accepted therapeutic range for
lidocaine is 1,5-5 g/min
In the upper end of the therapeutic range
(>3g/ml)
Lidocaine half-life varies from 1-1,5 hours in
normal adults.
5 hours or more in adult patients with liver
failure
If lidocaine is given a continuous intravenous
infusion, it can take a considerable amount of
time (3-5 half-lives or 7,5-25 hours).

Lidocaine is almost completely eliminated
by hepatic metabolism (>95%)
Oral absorption of lidocaine is nearly 100%
Plasma protein binding in normal
individuals is about 70%.
Propanolol, metoprolol, and nadolol have
been reported to reduce lidocaine
clearance due to the decrease in cardiac
output caused by -blocker agents.
Cimetidine also decreases lidocaine
clearance.
Lidocaine clearance may be accelerated
by contamitant use of phenobarbital or
phenytoin.
Procainamide is an antiarrhythmic agent that is used
intravenously and orally.
It is classified as a type IA antiarrhythmic agent and
can be used for the treatment of supraventricular or
ventricular arrhythmias
It is a drug of choice for the treatment of stable
sustained monomorphic ventricular tachycardia with
coronary heart disease
Procainamide can be used as an antiarrhythmic for
patients that are not converted using electrical shock
and intravenous epinephrine or vasopressin.

The generally accepted therapeutic range for
procainamide is 410 g/mL.
Serum concentrations in the upper end of the
therapeutic range (8 g/mL) may result in minor
side effects such as gastrointestinal disturbances
(anorexia, nausea, vomiting, diarrhea),
weakness, malaise, decreased mean arterial
pressure (less than 20%), and a 1030%
prolongation of electrocardiogram intervals (PR
and QT intervals, QRS complex)

Procainamide serum concentrations initially drop
rapidly after an intravenous bolus as drug
distributes from blood into the tissues during the
distribution phase. During the distribution phase,
drug leaves the blood due to tissue distribution
and elimination. After 2030 minutes, an
equilibrium is established between the blood and
tissues, and serum concentrations drop more
slowly since elimination is the primary process
removing drug from the blood. This type of
serum concentration/time profile is described by
a two-compartment model.

To maintain therapeutic procainamide
concentrations, an intravenous loading dose
(over 2530 minutes) of procainamide is
followed by a continuous intravenous infusion of
the drug. A distribution phase is still seen due to
the administration of the loading dose. Note that
the administration of a loading dose may not
establish steady-state conditions immediately,
and the infusion needs to run 35 half-lives until
steady-state concentrations are attained.

Serum concentration/time profile for rapid-
release procainamide (solid line, given
every 3 hours) or sustained-release
procainamide (dashed line, given every 6
hours) oral dosage Forms after multiple
doses until steady state is achieved. The
curves shown would be typical for an adult
with normal renal and hepatic function.
Because many procainamide therapeutic and
side effects are not correlated with its serum
concentration, it is often not necessary to obtain
serum procainamide concentrations in patients
receiving appropriate doses who currently have
no arrhythmia or adverse drug effects.
Procainamide serum concentrations should be
obtained in patients who have a recurrence of
tachyarrhythmias, are experiencing possible
procainamide side effects, or are receiving
procainamide doses not consistent with disease
states and conditions known to alter
procainamide pharmacokinetics

Procainamide is eliminated by both hepatic
metabolism (~50%) and renal elimination
of unchanged drug (~50%).
Hepatic metabolism is mainly via N-
acetyltransferase II (NAT-II)
N-acetyl procainamide is the primary
active metabolite resulting from
procainamide metabolism by N-
acetyltransferase II

Normal adults without the disease states and
conditions given later in this section and with
normal liver and renal function have an average
procainamide half-life of 3.3 hours (range: 2.5
4.6 hours) and a volume of distribution for the
entire body of 2.7 L/kg (V =23.8 L/kg)
Because about 50% of a procainamide dose is
eliminated unchanged by the kidney, renal
dysfunction is the most important disease state
that effects procainamide pharmacokinetics

Uncompensated heart failure reduces
procainamide clearance because of decreased
hepatic blood flow secondary to compromised
cardiac output.
Volume of distribution (V = 1.6 L/kg) is
decreased in uncompensated heart failure
patients as well
The majority of N-acetyltransferase II
responsible for the conversion of procainamide
to NAPA is thought to reside in the liver. Because
of this, most clinicians recommend a decrease in
initial doses for procainamide in patients with
liver disease

Cimetidine, trimethoprim, ofloxacin,
levofloxacin, and ciprofloxacin are all drugs
that compete for tubular secretion with
procainamide and NAPA
Amiodarone increases the steady-state
concentrations of procainamide and NAPA
by 57% and 32%, respectively

Quinidine was one of the rst agents used for
its antiarrhythmic effects. It is classied as a
type IA antiarrhythmic agent and can be used
for the treatment of supraventricular or
ventricular arrhythmias.
Because of its side effect prole, quinidine is
considered by many clinicians to be a
second-line antiarrhythmic choice. Quinidine
inhibits transmembrane sodium inux into the
conduction system of the heart thereby
decreasing conduction velocity.
When given intravenously, the serum
quinidine concentration/time curve follows a
two-compartment model.
When oral quinidine is given as a rapidly
absorbed dosage form such as quinidine
sulfate tablets, a similar distribution phase is
also observed with a duration of 2030
minutes. If extended-release oral dosage
forms are given, absorption occurs more
slowly than distribution so a distribution phase
is not seen.

The generally accepted therapeutic range
for quinidine is 26 g/mL. Quinidine
serum concentrations above the
therapeutic range can cause increased QT
interval or QRS complex widening (>35
50%) on the electrocardiogram,
cinchonism, hypotension, high-degree
atrioventricular block, and ventricular
arrhythmias.
For dose adjustment purposes, quinidine
serum concentrations are best measured as a
predose or trough level at steady state after
the patient has received a consistent dosage
regimen for 35 drug half-lives.
Quinidine half-life varies from 68 hours in
normal adults to 910 hours or more in adult
patients with liver failure. If quinidine is given
orally or intravenously on a stable schedule,
steady-state serum concentrations will
beachieved in about 2 days (5 8 h = 40 h)
Quinidine is almost completely eliminated by
hepatic metabolism (~80%). Hepatic
metabolism is mainly via the CYP3A enzyme
system. 3-Hydroxyquinidine is the primary
active metabolite resulting from quinidine
metabolism while dihydroquinidine is an a
ctive compound that is found as an impurity in
most quinidine dosage forms. The hepatic
extraction ratio of quinidine is about 30%, so
quinidine is typically classied asan
intermediate extraction ratio drug.
Plasma protein binding of quinidine in normal
individuals is about 8090%. The drug binds to
both albumin and 1-acid glycoprotein (AGP). AGP
is classied as an acute phase reactant protein
that is present in lower amounts in all individuals
but is secreted in large amounts in response to
certain stresses and disease states such as
trauma, heart failure, and myocardial infarction.
The recommended dose of quinidine is based on
the concurrent disease states and conditions
present in the patient that can inuence quinidine
pharmacokinetics.
Normal adults without the disease states and
conditions given later in this section and with
normal liver function have an average
quinidine half-life of 7 hours (range: 68
hours) and a volume of distribution for the
entire body of 2.4 L/kg (V = 23 L/kg).
Patients with liver cirrhosis have increased
quinidine clearance and volume of distribution
which results in a prolonged average
quinidine half-life of 9 hours.
Clearance and volume of distribution are
larger in patients with liver disease because
albumin and AGP concentrations are lower in
these patients and result in reduced quinidine
plasma protein binding (average V = 3.8
L/kg).
The increased unbo raction in the plasma
allows more quinidine to enter the liver
parenchyma where hepatic drug metabolizing
enzymes are present and leads to increased
drug clearance. Decreased plasma protein
binding also leads to higher unbound levels
for a given total quinidine serum
concentration.
Heart failure reduces quinidine clearance
because of decreased hepatic blood ow
secondary to compromised cardiac output.
After a myocardial infarction, serum AAG
concentrations increase up to 50% over a
1272 hour time period. As AAG serum
concentrations increase, plasma protein
binding of quinidine increases and the
unbound fraction of quinidine decreases.
Patient age has an effect on quinidine clearance
and half-life. For elderly patients over the age of
65, studies indicate that quinidine clearance is
reduced, the volume of distribution is unchanged,
and half-life is longer (average half-life = 10 hours)
compared to younger subjects. A confounding
factor found in quinidine pharmacokinetic studies
conducted in older adults is the possible accidental
inclusion of subjects that have subclinical or mild
cases of the disease states associated with
reduced quinidine clearance (heart failure, liver
disease, etc.).
Quinidine has serious drug interactions with
other drugs that are capable of inhibiting the
CYP3A enzyme system.
Because this isozyme is present in the
intestinal wall and liver,quinidine serum
concentrations may increase due to
decreased clearance, decreased rstpass
metabolism, or a combination of both.
P-glycoprotein is also inhibited by quinidine
so drug transport may be decreased and
cause drug interactions.
Erythromycin, ketoconazole, and verapamil
have been reported to increase quinidine
serum concentrations or area under the
concentration/time curve (AUC) by >3050%.
Drugs that induce CYP3A (phenytoin,
phenobarbital, rifampin, rifabutin) decrease
quinidine serum concentrations by increasing
quinidine clearance and rst-pass
metabolism.
Propranolol, metoprolol, and timolol have
decreased clearance due to quinidine
coadministration.
When quinidine is given concomitantly with
codeine, the conversion from codeine to
morphine does not take place, and patients
do not experience analgesia.
Quinidine increases digoxin serum
concentrations 3050% by decreasing
digoxin renal and nonrenal clearance as well
as digoxin volume of distribution.
Antacids can increase urinary pH leading to
increased renal tubular reabsorption of
unionized quinidine and decreased quinidine
renal clearance.