Pharmacology and

Pharmacokinetics of
Amiodarone
Group 6
Members
Họ và tên Mã sinh viên

Nguyễn Thị Na 21100243

Nguyễn Bảo Ngọc 21100255

Trịnh Tiến Đạt 21100192

Nông Thị Nhàn 21100515

Trịnh Thị Quỳnh Trang 21100299

Phương Thành Nam 21100245

Nguyễn Thị Mai Vân 21100311

Trần Phương Thảo 21100284

Nguyễn Phương Nga 21100248

 Content
01 Introduction
02
Assessment of the response to Pharmacokinetics
amiodarone administration & metabolism
03
Initiation of therapy and
04 maintenance dosing

05 Conclusions
 01
Introduction
- Amiodarone is a unique
antiarrhythmic agent originally
developed as a vasadil.

Amiodarone HCl

- It is a di-iodinated benzofuran
derivative, containing a diethylated
tertiary amine chain.
 Drug actions
● As a Type III antiarrhythmic, it
also has both nonspecific
antisympathetic and direct, fast
channel-membrane effects.
● Hemadynamic effects of orally
administered amiodarone are
usually negligible, and are
usually compensated for by
induced vasodilatian.
● Effects an thyroid and hepatic
function.
Characteristics
● Bioavailable = 20-80% and
undergoes extensive
enterohepatic circulation
before entry into a central
compartment.
● The principal metabolite,
mono-n-desethyl amiadarone is
also an antiarrhythmic.
● t1/2 ~ 4 hours.
● tg = 9-77 days.
Dosage forms
● The oral preparation
(200 mg/tablet): has been
approved by the Food and
Drug Administration for use in
the U.S, insoluble in aqueous
solutions, it is miscible in
polysorbate-800 and either
ethanol or benzyl alcohol.
● An intravenous form
(40 mg/mL): This article
focuses on the orally available
form.
 Pharmacokinetics
02 and metabolism
 Bioavailability, Tissue distribution and Metabolism
Bioavailability:
● Oral bioavailability is ranging
from 20% to 80%.
● After absorption, undergoes
extensive enterohepatic circulation
before distribution.
● High first-pass effect through the
liver and portal vein.
● Peak serum levels reached in 3-7
hours after oral dosing.
● Highly protein bound (96-99%),
mainly to albumin and beta-
lipoprotein.

Tissue distribution:
● Highest concentrations found in adipose tissue, lung, liver, and lymph nodes.
● Lowest concentrations found in brain, thyroid, and muscles.
● Highly lipophilic with a log(Poct) of 6.66.
Metabolism:
● Primarily metabolized by P-450 cytochrome oxidase in the liver via oxidative de-ethylation.
● Phenobarbital and 3-methylcholanthrene induce this metabolic pathway.
● Mono-N-desethyl amiodarone is the primary de-ethylated metabolite.
● Further dealkylation can occur, leading to the formation of the primary amine.
● Other metabolic pathways include deiodinations, O-dealkylation, and hydroxylation.
● Glucuronidation is the major mechanism of amiodarone clearance.
● Renal clearance is negligible, and dose adjustment is not needed for patients with renal failure or on
dialysis.
 Initial Drug Distribution
Because of the differing solubilities of the drug within many tissues (characterized by the differing
partition coefficients), amiodarone pharmacokinet- ics are usually described using multi-
compartmental models (Figure 1).
● Amiodarone pharmacokinetics are complex due to its different solubilities in various tissues.
● Multi-compartmental models are used to describe its distribution, with compartments categorized as central, deep,
or peripheral based on the drug's solubility.
● The central compartment has limited volume and restricted solubility, leading to rapid rise in serum levels after
absorption.
● Drug levels in deep and peripheral compartments with larger volumes and lower perfusion rise slower.
● Total tissue load also decreases slower in these compartments due to slower rate constants and prolonged half-life.

● Studies show varying apparent half-lives (18.7-

35.9 hours) after single doses, reflecting the Has a beautiful Planet Saturn is
distribution phase. name, but it’s the ringed one. It
● These half-lives represent the time it takes for terribly hot is a gas giant
amiodarone to be sequestered in tissue
compartments, in which amiodarone is
sequestered.( Table III)
 Elimination Kinetics
The (terminal) elimination pharma- cokinetics of amiodarone appear to be first order, with a linear relationship
between the amount of drug administered and the steady-state plasma level (Table IV)

● A study with 6 volunteers receiving 400mg amiodarone

intravenously found a multi-compartmental distribution
with a rapid initial distribution half-life of 4 minutes and a
prolonged elimination half-life of 24.8 ± 11.7 days.
● The total body clearance was 8.6 ± 1.9mL/min and the total
body volume of distribution at steady-state was 4936 ± 3920
L.
● In patients who discontinued chronic oral amiodarone
therapy, the elimination half-life was significantly longer for
both amiodarone (52.6 ± 23.7 days) and mono-N-desethyl
amiodarone (61.2 ± 31.1 days).
 03
Assessment of
the response to
amiodarone
administration
 ● Assessing the response to amiodarone treatment requires a rapid evaluation of its impact on the heart's
conduction system.
● While initial hypotheses suggested monitoring amiodarone levels wasn't necessary, it's now recognized as
valuable during the initial stages of therapy.

● Although plasma levels don't directly predict

● Plasma levels help determine:
- Under-dosage: Levels below 1.0mg/L indicate
insufficient medication.
- Potential toxicity: Levels exceeding 2.5mg/L
raise concerns about adverse effects.
antiarrhythmic efficacy, studies suggest:
- Levels between 1.0-1.5mg/L are associated with
reduced ventricular ectopy.
- Doses exceeding 2.5mg/L offer no additional
antiarrhythmic benefit.

● Other methods like programmed electrical stimulation for predicting efficacy are unreliable.
● Notably, even patients who respond to amiodarone may remain inducible, and inducibility doesn't
necessarily predict a negative outcome.
Overall, monitoring amiodarone levels during the initial stages helps define a therapeutic window,
maximizing the benefit-to-risk ratio by identifying under-dosage and potential toxicity.
 04
Initiation of
therapy and
maintenance
dosing
● Loading doses used when chronic therapy is contemplated, have largely been developed empirically.

- One(more) rational oral dosing schedule (based on pharmacokinetic modeling) for the treatment
of ventricular arrhythmias has been proposed by Siddoway et al.

Day 1 2.000 mg

3 days 1.400 mg/day

7 days 1.000 mg/day

1 to 2 weeks 800 mg/day

Maintenance doses 400 mg/day

A total loading dose of 6.200 mg is delivered.

- In the case of treatment of supraventricular arrhythmias, some authors have suggested the
aforementioned regimen be reduced 25 to 50% because of the increased sensitivity of supraventricular
arrhythmias to amiodarone.
- Alternatively, a loading dose schedule developed by Ward et al allows a total loading dose as low as
1,200 mg.

Using either regimen antiarrhythmic

7 days 600 mg/day effect is extremely variable. After
loading, it is only necessary to
administer the chronic therapy of 200 to
7 days 400 mg/day 400 mg per day to achieve therapeutic
efficacy.
 05
Conclusions
 05
● The riddle of amiodarone pharmacokinetics is slowly being
elucidated. They are in fact enigmatic of a
pharmacokinetically unique drug. One with multiple
Conclusions
metabolic fates, each of which probably has multiple modes
of action.

● A firm understanding of pharmacokinetics becomes

essential since the useful-ness of amiodarone is limited by
its time-effect and adverse reaction profiles (both of which
are probably related).
● Future questions include the
determination of the role of following
tissue as well as plasma levels of
amiodarone, the role of following
plasma levels to possibly deter
adverse reactions and utilization of
the unique kinetic profile of
amiodarone to allow for alternatives
inNo
dosing that would lead to greater
Secondary Effects
patient compliance without loss of
efficacy.
Thank you!
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