This document discusses pharmacokinetic considerations for amiodarone in cardiovascular disease patients. It provides guidelines on amiodarone use and dosing, including loading and maintenance doses. It discusses amiodarone's pharmacokinetic parameters such as its long half-life, extensive metabolism, and unpredictable oral bioavailability. It also covers dosing adjustments for special populations like children, pregnant women, and those with liver or kidney impairment. Research insights into amiodarone's concentration-effect relationship and electrophysiological effects in rats are presented. Understanding amiodarone's pharmacokinetics is essential for safe and effective use in arrhythmia patients.

1. PHARMACOKINETICS CONSIDERATION
IN CARDIOVASCULAR DISEASE
PATIENTS:
A PK INSIGHT ON AMIODARONE
Dalia A. Hamdy
BPSc, MSc, PhD, RP (ACP), MRSC
Assistant professor, Faculty of Pharmacy
Alexandria University, Alexandria, Egypt
Member in the Egyptian Young academy of Sciences
(EYAS)
dr.daliahamdy@gmail.com

2. SESSION OUTLINE
 Guidelines on Use
 Amiodarone PK parameters
 Amiodarone PD
 Dosing Considerations
 Drug interactions and side effects
 Research insights
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3. REFERENCES
 Goldshlager N, Epstein A.E., Nacarelli G. et al. Practical
Guideline for clinicians who treat patients with amiodarone.
ARCH INTERN MED.2000.160:1741-1748.
 Giardina E.G. and Passman R. Clinical Uses of Amiodarone.
Through Uptodate June 2016.
 Siddoway L.A. Amiodarone guidelines for use and monitoring.
Downloaded from the American Family Physician Web site at
www.aafp.org/afp. Copyright© 2003 American Academy of
Family Physicians.
 Schillinger, D. New Treatment Guidelines in Atrial
Fibrillationand updates on NOACs. University of California.
Through:
http://www.ucsfcme.com/2016/MDM16M02/slides/15.Schilling
er.AtrialFibrillation.pdf
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4. 2014 AHA/ACC/HRS Guideline for
the Management of Patients with
Atrial Fibrillation
1. Initial clinical evaluation
2. Preventing thromboembolism
3. Rate control
4. Rhythm control
Published in: Circulation. 2014; 129
http://www.ucsfcme.com/2016/MDM16M02/slides/15.Schillinger.AtrialFibrillation.pdf
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5. http://www.ucsfcme.com/2016/MDM16M02/slides/15.Schillinger.AtrialFibrillation.pdf
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6.  Should be used only if risks/side effects are
considered and other agents are not suitable
 Some knowledge of its PK, PD and
electropharmacologic characteristics is essential for
initiating therapy and dose adjustment
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7. AMIODARONE(AM) IS
 an iodinated class III
antiarrhythmic benzofuran
derivative drug.
 a potassium channel blocker
 a weak sodium channel
blocker
 non competitive α- and β-
adrenergic receptors inhibitor
 vagolytic and calcium-channel
blocker.
2-butylbenzofuran-3-yl)- [4-(2-
diethylaminoethoxy)- 3,5-diiodo-
phenyl]- methanone (as the
hydrochloride salt)
Podrid PJ. Ann Intern Med 1995;122:689—700. Connolly, S.J., 1999. Circulation 100, 2025–2034

8. AMIODARONE(AM)
 decreases heart rate
 prolongs PR and QTc intervals
 increases the duration of QRS complex in
electrocardiograms (ECG).
Human ECG
Mason JW et al. Circ Res. 1984 Sep;55(3):278-85

9. AMIODARONE(AM)
 Shows extensive metabolism in
hepatic and extrahepatic tissues
Grapefruit juice?!
 Major metabolite is the N-
desethylamiodarone (DEA),
which possesses some of AM
pharmacological and toxicological
properties.
DEA has longer t1/2
DEA
Shayeganpour et al , Drug Metab. Dispos. 34:43-50 (2006).

10. AM highly lipophilic nature
peculiar PK parameters
 large volume of distribution (Vd)~ 66 L/kg
 long terminal half life (t1/2) 60 and 142 days
 highly bound to plasma proteins (>95%)
 erratic absorption (30%-70%) leading to low and
unpredictable oral bioavailability . Effect of food?!
 little correlation between the AM plasma concentration
and drug efficacy or toxicity !!!!! Rats data?!
Wyss PA et al . J. Pharmacol. Exp. Ther. 254:502-507 (1990) & uptodate 2016

11.  An inhibitor to CYP3A4 enzyme Drug interactions?!
digoxin and warfarin
 The dose of digoxin empirically reduced by 50% at
the time of amiodarone initiation or the need for digoxin
reevaluated altogether.
Digoxin levels should be measured within three days after
amiodarone initiation.
 A reduction in warfarin dose to prevent an elevation in the INR
and potential bleeding complications. The INR level should be
checked more frequently in the one to two weeks after
amiodarone is initiated
Wyss PA et al . J. Pharmacol. Exp. Ther. 254:502-507 (1990) & uptodate 2016

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13.  Shifting from IV to oral dose:
The bioavailability 30-70%, Cmax ~5h
 Patients who have been on IV therapy for more than two weeks can be started on maintenance oral
amiodarone at a dose of 200 to 400 mg/day.
 Patients who have been on IV therapy for one to two weeks can be started on an intermediate
amiodarone dose of 400 to 800 mg/day. This should be continued until a total loading dose of 10 grams
has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400
mg/day.
 Patients who have been on IV therapy for one week or less should probably receive the usual oral
amiodarone loading dose of 400 to 1200 mg/day (typically in two divided doses). This should be
continued until a total loading dose of 10 grams has been received, then the dose should be reduced to
the usual maintenance dose of 200 to 400 mg/day.
 Both oral and IV therapy can be given concurrently for a few days if there is a concern about
gastrointestinal tract function.
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15. AMIODARONE DOSING IN SPECIAL POPULATION
Liver and Kidney Impairment
 Metabolized in the liver. (DEA, active metabolite)
Thus: Dose reduction is probably necessary in
patients with significant hepatic disease.
 In comparison, there is minimal elimination of both
amiodarone and desethylamiodarone by the
kidneys Why?
Dialysis?
Thus no dose adjustment of amiodarone in renal
disease or dialysis.
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16. AMIODARONE DOSING IN SPECIAL POPULATION
Pregnant and Nursing Mothers
Amiodarone complications during pregnancy include:
●Hypothyroidism or hyperthyroidism in the mother or fetus because of the
iodine in amiodarone
●Fetal bradycardia
●Fetal QT interval prolongation
●Premature labor
●Low birth weight
Amiodarone was found in fetal tissue and breast milk.
For these reasons,
1. Use of amiodarone in pregnancy should be reserved for maternal and
fetal arrhythmias not responding to agents with known safety.
2. Concomitant beta blocker therapy should be avoided.
3. Breast feeding is not recommended when the mother is taking
amiodarone
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17. AMIODARONE DOSING IN SPECIAL POPULATION
Children
 the overall safety and efficacy of amiodarone in
children has not been fully established.
 Optimal dosing is less well established in children
 For oral therapy, dosing is based upon body weight
or, in children less than one year of age, upon body
surface area.
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18. AMIODARONE DOSING IN SPECIAL POPULATION
Children
 The loading dose, which can be given in one or two
divided doses per day, is 10 to 15 mg/kg per day or
600 to 800 mg/1.73 m2 per day for 4 to 14 days or
until adequate control of the arrhythmia is attained
 The dose should then be reduced to 5 mg/kg per
day or 200 to 400 mg/1.73 m2 per day once daily
for several weeks. If the arrhythmia does not recur,
the lowest effective dose should be used for
maintenance. The usual minimal dose is 2.5 mg/kg
per day.
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19.  For IV therapy in critically ill children with
tachyarrhythmias who have not responded to standard
therapy, two dosing regimens have been reported:
1. A loading dose of 5 mg/kg divided into five 1 mg/kg
aliquots, with each aliquot given over five to 10 minutes.
If necessary, additional 1 to 5 mg/kg doses can be given 30
minutes later on a similar schedule.
The average loading dose is 6.3 mg/kg.
Among those requiring a continuous infusion, the
amiodarone infusion rate is typically 7 to 10 mcg/kg per min
(10 to 15 mg/kg per day).
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20.  For IV therapy in critically ill children with
tachyarrhythmias who have not responded to standard
therapy, two dosing regimens have been reported:
2. A loading dose of 5 mg/kg infused over one hour, then a
maintenance infusion rate starting at 5 mcg/kg per min.
The mean effective maintenance dose is 9.5 mcg/kg per
min (13.7 mg/kg per day).
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22. RESEARCH PK INSIGHTS
 A study in 2008 on rats
 Journal of Cardiovascular
Pharmacology
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23. EFFECT OF HL ON AM
HEART AND PLASMA
CONCENTRATIONS IN
RAT
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24. EFFECT OF HL ON EKG
Volts
0 0.04 0.08 0.12 0.16 0.2 0.24 sec
QT
QT
RR
RR
12h after
last
dose
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25. EFFECT OF HL ON EKG
QTC calculated using
Fridericia's formula (QTc=QT/ (RR) 1/3 )
Bazett’s formula (QTc=QT/RR1/2)
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26. AM CONCENTRATION EFFECT
RELATIONSHIP IN RAT
Hamdy DA and Brocks DR.J Cardiovasc. Pharmacol. 2009. 53(1):
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27. ??????
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