CARDIOVASCULAR

AGENTS
PUTRI HASANAH RAHMIN
0811012051
FACULTY OF PHARMACY
ANDALAS UNIVERSITY
DIGOXIN
Digoxin is used for the treatment of
congestive heart failure (CHF) because
of its inotropic effects on the
myocardium
Digoxin is used too for the treatment of
atrial fibrillation because of its
chronotropic effects on the
electrophysiological system of the heart
 Thepositive inotropic effect of digoxin is caused by
binding to sodium- and potassiumactivated
adenosine triphosphatase, also known as Na,K-
ATPase or the sodium pump.

 Digoxin-induced inhibition of Na,K-ATPase leads to

decreased transport of sodium out
of myocardial cells and increased intracellular
sodium concentrations that aid calcium
entry and decrease calcium elimination via the
sodium-calcium exchanger.
THERAPEUTIC AND TOXIC
CONCENTRATIONS

 When given as oral or intravenous doses, the

serum digoxin concentration–time curve
follows a two-compartment model and exhibits
a long and large distribution phase of
8–12 hours
Digoxin serum concentrations after 250-μg doses given intravenously (circles and
solid line) and orally as a tablet (squares with dashed line)
 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.
 When drug distribution is complete, digoxin
serum and tissue concentrations will be
proportional to each other so that digoxin
serum concentrations reflect concentrations at
the site of action
 Clinicallybeneficial 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.
 Additional chronotropic effects may be observed at
digoxin steady-state serum concentrations as high as 2
ng/mL.
SIDE EFFECT
Most digoxin side effects involve
 gastointestinal tract
 central nervous system
 cardiovascular system
GASTOINTESTINAL TRACT SIDE
EFFECT
anorexia
 nausea
 vomiting
diarrhea
abdominal pain
 constipation.
CENTRAL NERVOUS
SYSTEM SIDE EFFECT
Headache
 fatigue
Insomnia
 confusion
 vertigo
CARDIAC SIDE EFFECT
 second or third degree atrioventricular block
 atrioventricular dissociation
 bradycardia
 premature ventricular contractions
 ventricular tachycardia
CLINICAL MONITORING PARAMETERS

 In patients receving digoxin for heart failure, the

common signs and symptoms of CHF should be
routinuely monitored
 When used for the treatment of atrial fibrillation,
digoxin is used to decrease, or control, the ventricular
rate. The patient’s pulse or ventricular rate should be
monitored,
and an electrocardiogram can also be useful to
clinicians able to interpret the output.
 Patients
with severe heart disease such as
cornary artery can have increased
pharmacodynamic sensitivity to cardiac
glycosides, and patients receiving these
drugs should be monitored closely for
adverse drug effects.
 BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
 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 adigoxin 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).
 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 5–10 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 μg/d (range: 125–500
μg/d) in patients with good renal function (creatinine clearance
≥80 mL/min) and 125 μg every 2–3 days in patients with renal
dysfunction (creatinine clearnace ≤15 mL/min).
EFFECTS OF DISEASE STATES AND
CONDITIONS ON DIGOXIN
PHARMACOKINETICS AND DOSING

 Adults with normal renal function have an

average digoxin half-life of 36 hours
(range: 24–48 hours) and volume of
distribution of 7 L/kg (range: 5–9 L/kg)
 The volume of distribution is large due to
the extensive tissue binding of digoxin in
the body.
 The digoxin clearance rate decreases in proportion to
creatinine clearance.
 The equation that estimates digoxin clearance from
creatinine clearance is:

Cl = 1.303 (CrCl) + ClNR

where
Cl : digoxin clearance in mL/min,
CrCl :creatinine clearance in mL/min
ClNR : digoxin clearance by nonrenal routes of
elimination which equals 40 mL/min
inpatients with no or mild heart failure
Digoxin clearance is proportional to creatinine clearance for patients with [circles
with
solid line: Cl = 1.303(CrCl) + 20] and without [squares with dashed line: Cl =
1.303(CrCl) + 40] moderate-severe (NYHA class III or IV) heart failure
 The equation that estimates digoxin volume of distribution
using creatinine clearance is:

298.CrCl
V= 226 + (Wt/70)
29.1+CrCl

 V is digoxin volume of distribution in L/70 kg, Wt is body

weight in kilogram (use ideal body weight if >30%
overweight) and CrCl is creatinine clearance in mL/min
digoxin clearance is lower in neonates
and premature infants because renal and
hepatic function are not completely
developed
Malabsorption of oral digoxin has been
reported in patients with severe diarrhea,
radiation treatments to the abdomen and
gastrointestinal hypermotility
DRUG INTERACTIONS
 Inhibition of P-glycoprotein, a drug efflux
pump which is found in the kidney, liver, and
intestine, appears to be involved in the majority
of digoxin interactions
 Quinidine decreases both the renal and
nonrenal clearance of digoxin and also
decreases the volume of distribution of digoxin
Verapamil, diltiazem, and bepridil inhibit
digoxin clearance and increase mean
digoxin steady-state concentrations by
various degrees
Amiodarone and propafenone are
antiarrhythmic agents that decrease
digoxin clearance
Cyclosporine therapy has been reported to
increase average steady-state digoxin
concentrations up to 50%
INITIAL DOSAGE DETERMINATION
METHODS

pharmacokinetic dosing method

Jelliffe method
LIDOCAINE
 Lidocaine is a local anesthetic agent that also
has antiarrhythmic effects. It is classified as a
type IB antiarrhythmic agent and is a treatment
for ventricular tachycardia or ventricular
fibrillation

 Forepisodes of sustained ventricular

tachycardia with signs or symptoms of
hemodynamic instability ,electrical
cardioversion is the treatment of choice.
 Lidocaine inhibits transmembrane sodium
influx into the His-Purkinje fiber conduction
system thereby decreasing conduction velocity
 It also decreases the duration of the action
potential and as a result decreases the duration
of the absolute refractory period in Purkinje
fibers and bundle of His.
THERAPEUTIC AND TOXIC
CONCENTRATIONS
 When given intravenously, the serum lidocaine
concentration/time curve follows a
twocompartment model
 This is especially apparent when initial loading
doses of lidocaineare given as rapid
intravenous injections over 1–5 minutes
(maximum rate: 25–50 mg/min) and a
distribution phase of 30–40 minutes is
observed after drug administration
Lidocaine serum concentrations initially drop rapidly after an intravenous
bolus as drug distributes from blood into the tissues during the distribution
phase
 accepted therapeutic range for lidocaine is 1.5–
5 μg/mL. In the upper end of the therapeutic
range (>3 μg/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.
 CLINICAL MONITORING
PARAMETERS
 The electrocardiogram (ECG or EKG) should be
monitored to determine the response to lidocaine in
patients with ventricular tachycardia or fibrillation.
 The goal of therapy is suppression of ventricular
arrhythmias and avoidance of adverse drug reactions.
 Lidocaine therapy is often discontinued after 6–24 hours
of treatment so the need for longterm antiarrhythmic drug
use can be reassessed, although longer infusions may be
used in patients with persistent tachyarrhythmias.
 Patientsreceiving lidocaine infusions for longer
than 24 hours are prone to unexpected
accumulation of lidocaine concentrations in the
serum and should be closely monitored for
lidocaine side effects
 While receiving lidocaine, patients should be
monitored for the following adverse drug effects:
drowsiness, dizziness, paresthesias, euphoria,
muscle twitching, confusion, agitation, dysarthria,
psychosis, seizures, coma, atrioventricular block,
or hypotension.
 BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
 Lidocaine is almost completely eliminated by hepatic metabolism
(>95%).
 Hepatic metabolism is mainly via the CYP3A enzyme system.

 Monoethylglycinexylidide (MEGX) is the primary metabolite

resulting from lidocaine metabolism
 Intramuscular administration of medications can increase creatine
kinase (CK) concentrations due to minor skeletal muscle trauma
inflicted by the injection, and this enzyme is monitored in patients
who may have had a myocardial infarction
 Plasma protein binding in normal individuals is
about 70%.
 Of this value, approximately 30% is due to
drug binding to albumin while 70% is due to
lidocaine bound to α1-acid glycoprotein (AGP)
 The recommended dose of lidocaine is based
on the concurrent disease states and conditions
present in the patient that can influence
lidocaine concentrations.
EFFECTS OF DISEASE STATES AND
CONDITIONS ON LIDOCAINE
PHARMACOKINETICS AND DOSING

 Normal adults without the disease states and

conditions given later in this section with
normal liver function have an average
lidocaine half-life of 1.5 hours (range: 1–2
hours), a central volume of distribution of 0.5
L/kg (Vc = 0.4–0.6 L/kg) and the volume of
distribution for the entire body of 1.5 L/kg
(Varea = 1–2 L/kg
 Patients with liver cirrhosis or acute hepatitis
have reduced lidocaine clearance which results
in a prolonged average lidocaine half-life of 5
hours
 Heart failure causes reduced lidocaine
clearance because of decreased hepatic blood
flow secondary to compromised cardiac output.
 Patients with cardiogenic shock experience
extreme declines in lidocaine clearance due to
severe decreases in cardiac output and liver
blood flow
Patient age has an effect on lidocaine
volumes of distribution and half-life
Lidocaine serum concentrations
accumulate in patients receiving long-
term (>24 hours) infusions even if the
patient did not have a myocardial
infarction
DRUG INTERACTIONS
 Lidocaine has serious drug interactions with β-adrenergic receptor
blockers and cimetidine that decrease lidocaine clearance 30% or
more.
 Propranolol, metoprolol, and nadolol have been reported to reduce
lidocaine clearance due to the decrease in cardiac output caused by
β-blocker agents.
 Decreased cardiac output results in reduced liver blood flow which
explains the decline in lidocaine clearance caused by these drugs.
 Cimetidine also decreases lidocaine clearance, but the mechanism
of the interaction is different. B
 ecause cimetidine does not change liver blood flow, it is believed
that cimetidine decreases lidocaine clearance by inhibiting hepatic
microsomal enzymes
INITIAL DOSAGE DETERMINATION
METHODS

pharmacokinetic dosing
method
Literature based
recommended dosing
PROCAINAMIDE/N-
ACETYLPROCAINAMI
DE
 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.
 Procainamide is a useful agent in the treatment
of idiopathic repetitive polymorphic ventricular
tachycardia in patients with coronary heart
disease.
 Procainamide can be administered for the long-
term prevention of chronic supraventricular
arrhythmias such as supraventricular
tachycardia, atrial flutter, and atrial fibrillation.
 N-acetyl procainamide is an active metabolite
of procainamide that has type III
antiarrhythmic effects.
THERAPEUTIC AND TOXIC
CONCENTRATIONS
 When given intravenously, the serum procainamide
concentration/time curve follows a two-compartment
mode
 The generally accepted therapeutic range for
procainamide is 4–10 μg/mL.
 Serum concentrations in the upper end of the therapeutic
range (≥8 μg/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 10–30% prolongation of
electrocardiogram intervals
Procainamide serum concentrations initially drop rapidly after an
intravenous bolus
as drug distributes from blood into the tissues during the
distribution phase.
 Nondose or concentration related side effects to
procainamide include rash, agranulocytosis, and a
systemic lupus-like syndrome.
 An active procainamide metabolite, known as N-
acetyl procainamide (NAPA) or acecainide, also
possesses antiarrhythmic effects.
 For dose adjustment purposes, procainamide serum
concentrations during oral administration are best
measured as a predose or trough level at steady state
after the patient has received a consistent dosage
regimen for 3–5 drug half-lives.
CLINICAL MONITORING
PARAMETERS
 The electrocardiogram (ECG or EKG) should be
monitored to determine the response to procainamide.
 The goal of therapy is suppression of arrhythmias and
avoidance of adverse drug reactions.
 if a possible concentration-related procainamide adverse
drug reaction is noted in a patient and the procainamide
serum concentration is <4 μg/mL, it is possible that the
observed problem may not be due to procainamide
treatment and other sources can be investigated.
BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
 Procainamide is eliminated by both hepatic metabolism (~50%) and
renal elimination of unchanged drug (~50%).1
 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.
 N-acetyltransferase II exhibits a bimodal genetic polymorphism that
results in “slow acetylator” and “rapid acetylator” phenotypes.
 If the patient has normal renal function, acetylator status can be
estimated using the ratio of NAPA and procainamide (PA) steady-
state concentrations: acetylator ratio = NAPA/PA.
 If this ratio is 1.2 or greater, it is likely the patient is a rapid
acetylator.
 If the ratio is 0.8 or less, it is likely the patient is a slow
acetylator.
 The ratio of procainamide renal clearance and creatinine
clearance is 2–3 implying that net renal tubular secretion is
taking place in the kidney.
 The average oral bioavailability of procainamide for both
immediate-release and sustained-release dosage forms is 83%.
 Plasma protein binding of procainamide in normal individuals
is only about 15%.
EFFECTS OF DISEASE STATES AND
CONDITIONS ON
PROCAINAMIDE PHARMACOKINETICS AND
DOSING

 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 = 2–3.8 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
 Studies investigating the impact of obesity (30% over ideal
body weight) on procainamide pharmacokinetics have found
that volume of distribution correlates best with ideal body
weight, but clearance correlates best with total body weigh
DRUG INTERACTIONS

 Procainamide has serious drug interactions

with other drugs that are capable of inhibiting
its renal tubular secretion.
 Cimetidine, trimethoprim, ofloxacin,
levofloxacin, and ciprofloxacin are all drugs
that compete for tubular secretion with
procainamide and NAPA.
INITIAL DOSAGE DETERMINATION
METHODS

The pharmacokinetic dosing

method
Literature based
recommended dosing
QUINIDINE
 Quinidine was one of the first agents used for its
antiarrhythmic effects. It is classified as a type IA
antiarrhythmic agent and can be used for the treatment
of supraventricular or ventricular arrhythmias
 quinidine therapy can be used to chemically convert
atrial fibrillation to normal sinus rhythm for a patient.
 Quinidine inhibits transmembrane sodium influx into
the conduction system of the heart thereby decreasing
conduction velocity
THERAPEUTIC AND TOXIC
CONCENTRATIONS
 When given intravenously, the serum quinidine
concentration/time curve follows a
twocompartment 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 20–30 minutes
 The generally accepted therapeutic range for quinidine
is 2–6 μg/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 symptoms that includes tinnitus, blurred
vision, lightheadedness, tremor, giddiness, and altered
hearing which decreases in severity with lower
quinidine concentrations
 Quinidine metabolites (3-hydroxyquinidine, 2′-
quinidinone, quinidine-N-oxide, O-
desmethylquinidine) all have antiarrhythmic effects in
animal models
 Of these compounds, 3-hydroxyquinidine is the most
potent (60–80% compared to the parent drug) and
achieves high enough serum concentrations in humans
that its antiarrhythmic effects probably contribute to
the clinical effects observed during quinidine
treatment
CLINICAL MONITORING
PARAMETERS
 The electrocardiogram (ECG or EKG)
should be monitored to determine the
response to quinidine.
 The goal of therapy is suppression of
arrhythmias and avoidance of adverse
drug reactions.
 Serum concentration monitoring can aid in
the decision to increase or decrease the
quinidine dose.
 While receiving quinidine, patients should be
monitored for the following adverse drug effects:
anorexia, nausea, vomiting, diarrhea, cinchonism,
syncope, increased QT interval or QRS complex
widening (>35–50%) on the electrocardiogram,
hypotension, high-degree atrioventricular block,
ventricular arrhythmias, and hypersensitivity reactions
(rash, drug fever, thrombocytopenia, hemolytic
anemia, asthma, respiratory depression, a lupus-like
syndrome, hepatitis, anaphylactic shock).
BASIC CLINICAL PHARMACOKINETIC
PARAMETERS
 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 active compound
that is found as an impurity in most quinidine
dosage forms.
 After oral administration, quinidine is subject to
moderate first-pass metabolism by CYP3A contained in
the liver and intestinal wall.
 Quinidine is also a substrate for P-glycoprotein.

 Approximately 20% of a quinidine dose is eliminated

unchanged in the urine
 Three different salt forms of quinidine are available.
Quinidine sulfate contains 83% quinidine base,
quinidine gluconate contains 62% quinidine base, and
quinidine polygalacturonate contains 60% quinidine
base.
 Plasma protein binding of quinidine in normal
individuals is about 80–90%.
 The drug binds to both albumin and α1-acid
glycoprotein (AGP).
 AGP is classified 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.
 In patients with these disease states, quinidine binding
to AGP can be even larger resulting in an unbound
fraction as low as 8%.
 DRUG INTERACTIONS
 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 firstpass 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 >30–50%.
 Other macrolide antibiotics (such as clarithromycin) or azole
antifungals (such as fluconazole, miconazole, and itraconazole)
that inhibit CYP3A probably cause similar drug interactions with
quinidine Quinidine increases digoxin serum concentrations 30–
50% by decreasing digoxin renal and nonrenal clearance as well
as digoxin volume of distribution.
 The probable mechanisms of this drug interaction are inhibition
of digoxin renal and hepatic P-glycoprotein (PGP) elimination
and tissue binding displacement of digoxin by quinidine.
 Antacids can increase urinary pH leading to increased renal
tubular reabsorption of unionized quinidine and decreased
quinidine renal clearance.
INITIAL DOSAGE DETERMINATION
METHODS

pharmacokinetic dosing method

Literature based recommended dosing
THANK YOU