Therapeutic Drug Monitoring of

AMIODARONEE

PD505 Prachi Bansode

PD506 Liza Basumatary
PD507 Vaishnavi Berad
Therapeutic Drug Monitoring
Introduction-
Therapeutic drug monitoring (TDM) is a powerful tool for dose individualization. Broadly, the term
refers to measuring plasma drug concentrations and using this information to make dose adjustments.

It refers to the individualization of drug dosage by maintaining plasma or blood drug concentrations
within a targeted therapeutic range or window.

TDM involves measuring drug concentrations in various biological fluids and interpreting these
concentrations in terms of relevant clinical parameters.

Clinical pharmacists and pharmacologists use pharmacokinetic principles to assess these

interpretations

The goal of this process is to individualize therapeutic regimens for optimal patient benefit.
Amiodarone-

Category - Antiarrhythmic drugs

It is a class-3 antiarrhythmic drugs.
Amiodarone affects the rhythm of heartbeats. It is used to help keep the heart beating
normally in people with life-threatening heart rhythm disorders of the ventricles (the lower
chambers of the heart that allow blood to flow out of the heart).
Amiodarone is used to treat ventricular tachycardia or ventricular fibrillation.
It is used only in treating life-threatening heart rhythm disorders.
Indications -
It is primarily indicated for -
Atrial fibrillation and flutter.
Effective in maintaining sinus rhythm.
Not useful in patient with risk of sudden cardiac death after MI
It is indicated when other treatments are ineffective or have not been tolerated esp. In
recurrent life threatening ventricular Arrhythmias.
Useful in hemodynamically unstable patients and patients with congestive heart failure
Mechanism of Action-
● Blocks K+ channels,thus increasing
the effective refractory period.
● Effective blocker of Na+ channels
with high affinity for inactivated
channels.
● Anti adrenergic effects by non
competitively blocking α and β
receptors.
● Weak calcium channel blocker.
● Slows sinus rate and AV
conduction,slightly prolongs the
QT interval.
Route Of Administration-
Oral- 200 mg 3 times daily for 1 week reduced to 200 mg twice daily for a further week; maintenance ,
usually 200 mg daily or the minimum required to control the arrhythmia

IV infusion- initially 5 mg/kg over 20–120 minutes with ECG monitoring

Dosage and administration-

- loading dosage varies from 600 to 400 mg /day for 2 to 21 days.

- usual maintenance dose varies from 200 to 600 mg /day.

- plasma concentration of AMIODARONE are usually between 1 to 2 mcg/ml during effective therapy.

- level of drug >3-4mcg/ml, for prolonged periods of time are associated with adverse effect.
Drug Interaction-

Amiodarone influences the activity of many CYP enzymes and can lead to multiple drug
interactions. It inhibits CYP1A2, CYP2C9, CYP2D6, CYP3A4 and also P- glycoprotein
resulting mainly in increased concentrations of other drugs metabolized via these
pathways.

Amiodarone increases the plasma concentration of digoxin

Amiodarone can result in increased plasma concentration of Phenytoin

Amiodarone increase anticoagulant effect by inhibiting metabolism of Warfarin.

Pharmacokinetic Parameters-

Absorption-

The oral absorption of amiodarone is unpredictable.

The time to peak concentration in plasma is usually 3-6, but may be delayed up to 12
hrs.
Distribution-

Amiodarone is distributed in decreasing order in lung, liver, thyroid gland, kidney, heart,
adipose tissue, muscle tissue and brain.

The metabolite desethylamiodarone Exihibited a distribution pattern comparable to the

parent drug.
Metabolism-

Amiodarone is extensively metabolized in the liver by cytochrome P450 3A4 and can
effects the metabolism of numerous other drugs.

It interacts with digoxin, warfarin, Phenytoin.

The major metabolite of amiodarone is desethylamiodarone, which also has antiarrhythmic

properties.

The metabolism of amiodarone is inhibited by grapefruit juice, leading to elevated

serum levels of amiodarone.
Excretion-

Excretion is primarily via the liver and the bile duct with almost no elimination via the
kidney and it is not dialyzable.

Elimination half-life average of 58 days.

There is 10-50% transfer of amiodarone and desethylamiodarone in the placenta as well as

a presence in breast milk.
Pregnancy Category-

Category D

There is positive evidence of human foetal risk, but the benefits from use in pregnant
women may be acceptable despite the risk
 CONTRAINDICATIONS
➔ Cardiogenic shock
➔ Severe sinus-node dysfunction, causing marked sinus bradycardia
➔ Second or third-degree atrioventricular block
➔ Bradycardia
➔ Known hypersensitivity to the drug or to any of its components, including iodine
DOSAGE
 MONITORING PARAMETERS

➔ pulmonary function assessment (including chest X-ray)

➔ ECG and serum potassium levels
➔ liver function tests
➔ thyroid function tests
➔ ophthalmological examination if there is pre-existing visual impairment.
BRAND NAME
Cordarone

Aratac

Atlansil

Tachyra
 Why TDM is required for Amiodarone?
Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there
is negligible excretion of Amiodarone or DEA (desethylamiodarone) in urine. Hence
abnormal concentrations of amiodarone or its metabolite DEA in hepatic circulation can
lead to hepatic damage resulting in the fatal ADR of amiodarone such as Cirrhosis,
hepatitis, hepatic failure, cholestasis. This makes it important to keep the target range
between 0.5-2.5mg/mL. Thus amiodarone requires TDM.
 Amiodarone Toxicity

NZ reports include serious adverse reactions associated with amiodarone

The Centre for Adverse Reactions Monitoring has received 340 adverse reaction reports associated
with amiodarone therapy, up to the end of December 2004. These reports include the following
serious adverse reactions (number of reported cases is given in brackets):
Visual Disturbances

Eye problems including keratitis (13), corneal ulceration (1), eye pain (1), corneal oedema (1),
optic neuritis (1), retinal disorder (1) and scotoma (1). There have also been 19 reports of corneal
deposits and 10 reports of abnormal vision.

Pulmonary Toxicity

Serious pulmonary reactions include pulmonary fibrosis (10), pneumonitis (8), pneumonia (5),
alveolitis (3), pleural effusion (2), interstitial lung disease (2), pulmonary oedema (1) and
respiratory failure (1).
Hepatotoxicity
Cases of serious liver toxicity including cirrhosis (2), necrosis (2), hepatitis (3) and hepatocelluar
damage (6). There have been 15 reports of liver enzyme disturbance.
Cardiac Toxicity
There have been a number of adverse reactions affecting the cardiovascular system including
arrhythmias (10), hypotension (10), hypertension (4), torsades de pointes (2), cardiac arrest (1),
cardiac failure (2), pulmonary embolism (1), sudden death (2), and several reports of aggravation of
chest pain.
Thyroid Toxicity
Thyroid disturbances include reports of hypothyroidism (12), thyrotoxicosis (1) and thyroid disorder
(4).
 Checklist for Adult Patients Taking Amiodarone (Cordarone)

Checklist for the monitoring of adult patients taking amiodarone. (H&P = history and physical examination; HF = heart failure; PT = prothrombin time;
INR = International Normalized Ratio; PFT = pulmonary function test; Dlco = diffusing capacity of lung for carbon monoxide).
 ASSAY
High performance liquid chromatography (HPLC)

PRINCIPLE: The separation of a substance depends on the relative distribution of mixture

constituents between 2 phases, a mobile phase and a stationary phase.
VOLUME USED: 0.5-1 ml
ADVANTAGES: speed, efficiency, accuracy.
DISADVANTAGE: costly, complex.
 REFERENCE
https://biomed.papers.upol.cz/artkey/bio-201702-
0003_Therapeutic_monitoring_of_amiodarone_pharmacokinetics_and_evaluation_of_the_relationship_between_eff
ect_and_do.php
https://www.sciencedirect.com/science/article/abs/pii/002822439290174W
https://www.clinicaltherapeutics.com/article/S0149-2918(17)30552-0/fulltext
https://pubmed.ncbi.nlm.nih.gov/28414390/

https://www.medsafe.govt.nz/profs/puarticles/amiod.htm
https://www.drugs.com/monograph/amiodarone.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689516/
https://www.aafp.org/pubs/afp/issues/2003/1201/p2189.html
THANK YOU