Chemical structure and structural chemical functions related to PK parameters Amiodarones chemical name is 2-n-butyl-3-[4-(2diethylaminoethoxy)-3, 5-diiodobenzoyl] benzofuran hydrochloride

and encompasses a molecular formula of C25H29I2NO3.HCl in a commercial product. Aesthetics comprise of a translucent, white power that is finely-grained. Amiodarone is insignificantly soluble in water but soluble in alcohol/methyl alcohol. Storage of Amiodarone should be kept between 20 25 C and must be protected from any light due to decomposition. Amiodarone is classified as a class III antiarrhythmic drug that is used in the management of ventricular as well as supraventricular arrhythmias. Amiodarones pharmacological effect is based upon a decrease in SA node automaticity, which also decreases AV node conduction and bypass tract conduction. Amiodarone prolongs the refractory period of the heart tissue. Furthermore amiodarone encompasses limited -blocker activity.

Pure Drug Nomenclature (Last modified: 07-Feb-2011 Martindale: the complete drug reference) y y y y y y y y y y Synonyms: 51087-N; Amiodaron; Amiodaroni; Amiodaronum; L-3428; SKF-33134-A BAN: Amiodarone USAN: Amiodarone INN: Amiodarone [rINN (en)] Chemical name: 2-Butylbenzofuran-3-yl 4-(2-diethylaminoethoxy)-3,5-di-iodophenyl ketone Molecular formula: C25H29I2NO3 =645.3 CAS: 1951-25-3 ATC code: C01BD01 ATC code (veterinary): QC01BD01 UNII code: N3RQ532IUT

Describe the 4 PK parameters of the drug and their meaning in regards of the ADME for the selected drug The Pharmacokinetic data of Amiodarone are incomplete. The 4 Pharmacokinetic PARAMETERS are: y y y y Volume of Distribution Half-life Clearance Elimination rate The 4 Pharmacokinetic PROCESSES are: y y y y Absorption Distribution Metabolism Excretion

Abs Amiodarone in the Gastrointestinal Tract is fractional and fragmentary s bseq ent to oral administration. Bioavailability is diverse and may range between 22% to 86% however it encompass an average of 50%. Maximum plasma level concentrations are achieved approximately 3 7 hours following a single dose. Pharmacological effects are seen consistently between 1-3 wee s after administration, even when an initial loading does is utilised. Pre-systemic metabolism plays a vital role in the bioavailability of Amiodarone. Also the rate and extent of absorption into the systemic circulation are amplified by ingestion of food. Bioavailability tests have been performed in 30 patients who received a single dose of 600 milligrams of amiodarone following food consumption as well as an overnight fast. Consequently, the area under the curve of the amiodarone concentration/time function (A C) as well as the Cmax increased by 2.3 and 3.8 respectively. The presence of food also increased the absorption rate ka. Following an oral drug administration of Amiodarone of 200-400 milligrams, the apparent Vd is 6.31 Litres per Kilogram with a freedom margin of +/ - 4.93 Litres per Kilogram. Evidently, distribution is excessive as it aggregates well in both adipose and muscle tissue. It is highly bound to plasma proteins with an average of 96% binding. The Half-life of Amiodarone is extensive and lengthy. Although the half-life is consistently between the 14-59 days range, it may vary between 14-110 days if the patient has been using the drug for a chronic condition. This substantial half-life is due to an extensive volume of distribution. As amiodarone utilisation is terminated, it is evident to recognise its metabolite formation, a substance called Desethylamiodarone. Desethylamiodarone carries a longer half-life than the principle drug; however the pharmacological action of it is unknown in humans. In relation to animals, this metabolite has some anti-arrhythmic as well as electro-physiologic properties that are comparable to the parent drug amiodarones pharmacological actions in humans. Metabolism of amiodarone occurs by the CYP-450 group of enzymes in particular the CYP-3A4 and CYP-2C8. Moreover, every amiodarone 200-milligram tablet encompasses 75 milligrams of iodide, which in practice liberates approximately 6 milligrams of iodide throughout metabolism; this is significant to patients with thyroid problems as this excess in iodide may cause hypo/hyper thyroidism. Its major route of excretion takes place through the hepatic metabolism as well as well as biliary excretion. There may also be some enterohepatic cycling involved. Renal excretion is small and insignificant. In a clinical study involving clearance of amiodarone following intravenous administration in patients with differentiated tachycardia and ventricular fibrillation, the clearance ranged from 220 to 440 mL/h/kg after 2-7 days of utilisation. In another clinical study, a single dose administration of amiodarone was administered to 12 patients and illustrated a multi-compartmental approach to pharmacokinetics. The viewed mean half-life was discovered to be 58 days for the parent drug and 36 days for the metabolite.

Disc ss which of these 4 PK parameters would change and how (increase or decrease) if the patient receiving the drug is :

Hepatically impaired In a healthy patient, amiodarone utilisation may cause elevation of hepatic enzymes levels, in which most circumstances the increase is asymptomatic and hence threatening. Dose reduction is offered as an option to patients who exhibit a 3 X normal level of hepatic enzymes with the prospects of discontinuation of therapy. Doctors who have performed liver biopsies have discovered that the histology of patients with elevated hepatic enzymes have been comparable in make-up to livers of patients suffering from cirrhosis and alcoholic hepatitis. In a patient that exhibits hepatic impairment, the dosing regimen may need to be reduced to a safe level. The elimination rate and hence clearance of amiodarone will be significantly decreased in a patient exhibiting hepatic impairment as a reduction in metabolism and a risk of accumulation of the drug will occur and consequently hepatotoxicity will form.
y y y y

Renally impaired Amiodarone as mentioned earlier is majorly excreted through hepatic and biliary metabolism, therefore very minimally renally excreted. As the renal function does not play a vital role in the pharmacokinetics of amiodarone, none of the 4 pharmacokinetic parameters will need to be changed. A patient exhibiting renal impairment does not require any alteration or adjustment of the dosing regimen, as their plasma concentration of amiodarone is not elevated.
y

An Adult Over 120Kg An adult over 120kg is an adult who illustrates either high adipose tissue or high muscle content in their body. Amiodarone accumulates rapidly in both types of tissues and this can result in toxicity. After oral administration amiodarone travels through the gastrointestinal tract and is absorbed into the human tissue. Due to its high affinity to adipose and muscle tissue, its transit time inside these tissues will increase and hence consequently become accumulated if the 120kg patient is consistently taking his or her medication. This build-up of amiodarone is not being cleared from the body in a timely manner and hence will cause toxicity in the patient s body.
y y y

Volume of distribution is unchanged Half-life will increase Elimination rate will decrease Clearance will decrease

Pharmacokinetics of amiodarone are not influenced by the renal system and hence parameters are consistent without taking the kidney excretion into account.

Volume of distribution will dramatically increase Half-life will increase Clearance will decrease

A Child nder 5 Years Old The safety of amiodarone as well as its efficacy in infants and children has yet to be concluded. Although this is the case, amiodarone has been used in the past both orally and intravenously in both infants and humans. If utilised for the management of differentiated arrhythmias, amiodarone is given orally with an initial loading dose daily for a certain time period followed by the minimal therapeutic maintenance dose (which may range according to body weight )daily. Children and infant doses are significantly reduced due to the developing nature of their hepatic system. A child s hepatic capabilities are considerably inferior to that of an adult, hence hepatic metabolism of amiodarone will be hindered which will result in an accumulation of the parent drug in the liver and cause hepatotoxicity, which may be fatal to the child or infant.
y y y y

Volume of distribution is unaffected Half life will increase if dose is unadjusted to paediatric dose Elimination rate will decrease if dose is unadjusted to paediatric dose Clearance will decrease if dose is unadjusted to paediatric dose