Amantadine

Debasis Mondal Tulane Univ. Health Sciences Center, New Orleans, USA
ã 2007 Elsevier Inc. All rights reserved.

Introduction

Amantadine is a water-soluble tricyclic amine, introduced as an antiviral agent for the

prophylactic treatment A2 influenza. It appears to block a late stage in the assembly of
influenza Avirus Couch and Six (1986). While vaccine is the preferred method of
prophylaxis, during an influenza A epidemic amantadine is recommended for unimmu-
nized patients at risk of developing complications from influenza such as those with
cardiovascular disease, those who are immunocompromised, such as AIDS patients, and
in contact personnel. Amantadin also causes symptomatic improvement in Parkinson’s
Disease. This action is due to its ability to inhibit the reuptake of dopamine and to its
anticholinergic effects.

Nomenclature
Name of the Clinical Amantidine hydrochloride or 1-adamantanamine hydrochloride
Form
Related Names adamantadine; adamantamine hydrochloride; adamantan;
Source: EMTREE adamantanamin; 1 adamantanamine; adamantanamine; 1
adamantanamine hcl; 1adamantanamine hydrochloride;
adamantanamine hydrochloride; 1adamantaneamine;
adamantaneamine; adamantine; amandatine; amantadin;
amantadine acid; amantadine chloride; amantadine hcl;
amantadinehydrochloride; amantan; amanten; amantidine
hydrochloride; 1 aminoadamantane; 1 aminoadamantane;
aminoadamantane; 1 aminoadamantine; aminoadamantine;
1 aminodiamantane; levo amantadine; levo
aminoadamantane; mantadan; mantadix; midantane; nsc
83653; Symmetrel (trade); Symadine; symetrel; symmetrel;
viregyt; virofral; Amantadine; 1 adamantanamine
hydrochloride; 1 adamantaneamine; 1 amino adamantane; 1
aminotricyclo[3.3.1.1 3,7]decane; amantadine
hydrochloride; c adamantanamine; contenton; exp 105; exp
105 1; exp 1051; exp105; exp105 1; exp1051; l
adamantanamine; l amantadine; symadine
Chemical Names 1-aminotriclo-[3.3.1.13,7] decane
CAS Number 768-94-5

1
2 Amantadine

Basic Chemistry
Chemical Structure
Structure

Comments SYMMETREL is available in a syrup form containing 50 mg/5 ml

and SYMADINE is available as 100-mg capsules.
Chemical Formula C10 H17 N
Properties
Physical Properties Amantidine is a stable, white or nearly white, crystalline powder.
Crystals are obtained from absolute ethanol and anhydrous
ether, by sublimation. Its melting point is 160-190oC.
Molecular Weight 151.251
Solubility Amantidine hydrochloride is freely soluble in water (at least 1:20),
alcohol and chloroform; practically insoluble in ether.
Ionization Constant
Value Salt Conditions Reference Comments
pKa 9.0 Williams (2002)

Human Pharmacokinetics

Amantadine is excreted primarily in the urine. Along with the parent compound, eight
amantadine metabolites have been identified in human urine. Its use is not recommended
in nursing mothers because amantadine is excreted in breast milk.

Pharmacokinetic Properties

Prep. and
Route of
Value Units Admin. Reference Comments

Absorption
Bioavailability >80 % p.o. Physician’s Desk
Reference (2000)
Distribution
Volume of Distribution 3-8 l/kg Physician’s Desk
Reference (2000)
Plasma Protein Binding 67 % Physician’s Desk
Reference (2000)
Metabolism
Plasma Half-Life 20-41 hrs Physician’s Desk Mean is 29 hours.
Reference (2000)
Bio Half-Life
 Amantadine 3

Clearance 0.2- l/hrs/ Physician’s Desk Significantly higher in

0.3 kg Reference (2000) males compared to
females and is
reduced in patients
with renal
insufficiency.
Routes of Elimination Glomerular filtration and tubular secretion of amantadine is the primary
means of elimination. Five to fifteen percent of an administered dose is
excreted in urine as the N-acetylated derivative.

Targets-Pharmacodynamics

Amantadine appears to prevent the release of viral nucleic acids into the host cells by
interfering with the function of the transmembrane domain of the viral M2 protein. Its
effectiveness in the treatment of Parkinson’s disease is mainly due to its ability to inhibit
neuronal dopamine re-uptake, thereby increasing the extracellular concentrations of this
transmitter in brain.

Target Name(s):
Influenza virus M2 protein
Dopamine transporter

Therapeutics

Amantadione is effective in preventing infection by the influenza A virus, including

subtypes H1N1, H2N2 and H3N2. It is also indicated in the treatment of Parkinson’s
disease.

Indications

Prep. and
Route of
Value Units Admin. Reference Comments

Flu
Dosage 4-8 mg/kg/day syrup Drug Facts and For ages 1-9 years;
(Symmetrel),; Comparisons treatment is continued
p.o. (2001) for 90 days in case of
repeated exposure.
Flu
Dosage 200 mg/day syrup/tablet,; p. Drug Facts and For ages 10-64 years;
o. Comparisons dosage is dependent on
(2001) patient age and renal
function.
Parkinson’s disease
Dosage 100 mg/day syrup/tablet,; p. Drug Facts and Dose is dependent on
o. Comparisons patient age and renal
(2001) function. Initial dose is
gradually increased up to
400 mg/day after one to
two weeks.
4 Amantadine

Contraindications
Amantadine is contraindicated in those who are hypersensitive to it.

Adverse Effects
Adverse events associated with the use of amantadine include nausea, headache, consti-
pation, ataxia, insomnia, dizziness, and depression

Agent-Agent Interactions

Agent Name Mode of Interaction

Anticholinergic agents Will display enhanced anticholinergic actions
when given in combination with amantadine.

Pre-Clinical Research
Pharmacokinetics

Potency

Organ/ Prep. and Cell Line/ Exp. End

Value Units Tissue Route of Admin. Type Effects Point Reference Comments

Mice
LD50 700 mg/kg p.o. O’Neil (1989)
Rats
LD50 1275 mg/kg p.o. O’Neil (1989)

Journal Citations

Couch, R.B., Six, H.R., 1986. The antiviral spectrum and mechanism of action of amantadine and
rimantadine. Antiviral Chemotherapy: New Directions for Clinical Applications and Research50–57.

Book Citations

Drug Facts and Comparisons 2001 Antiviral Agents. Cada, D.J. (Ed.), Drug Facts and Comparisons, Edition
5, pp. 846–848, A Wolters Kluwer Company, St. Louis, Missouri.
Physician’s Desk Reference 2000 Sifton, D.W. (Ed.), Physician’s Desk Reference, Edition 54. , Medical
Economics company, Montvale, New Jersey.
O’Neil, M.J., 1989. O’Neil, M.J. (Ed.), Merck Index, Edition 11. , Merck and Co. Inc., New Jersey.
Williams, D., 2002. pKa Values for some drugs and Miscellaneous Organic Acids and Bases. Willams, D.,
Lemke, T.L. (Ed.), Foye’s Principles of Medicinal Chemistry, pp. 1070–1080, Lippincott Williams and
Wilkins, Philadelphia.