DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

NH H NH 2 3 C
2
1607
O
AMANTADINE
O
HN
COOC 2 H 5
HO
RIMANTADINE
HO
NH NH 2 2
HN
H
N
O
HN
OH
O
COOH
CHAPTER 58
ANTIVIRAL AGENTS (NONRETROVIRAL)
OSELTAMIVIR
Figure 58–4. Chemical Structures of the Anti-Influenza Drugs.
ZANAMIVIR
rimantadine is metabolized extensively by hydroxylation, conjugation,
and glucuronidation prior to renal excretion. Following oral
administration, the elimination t 1/2
of rimantadine averages 24-36
hours, and 60-90% is excreted in the urine as metabolites. Renal
clearance of unchanged rimantadine is similar to creatinine clearance.
Untoward Effects. The most common side effects related to amantadine
and rimantadine are minor dose-related CNS and gastrointestinal
(Schmidt, 2004). These include nervousness, light-headedness, difficulty
concentrating, insomnia, and loss of appetite or nausea. CNS
side effects occur in 5-33% of patients treated with amantadine at
doses of 200 mg/day but are significantly less frequent with rimantadine.
The neurotoxic effects of amantadine appear to be increased by
concomitant ingestion of antihistamines and psychotropic or anticholinergic
drugs, especially in the elderly. Amantadine dose reductions
are required in older adults (100 mg/day) because of decreased
renal function, but 20-40% of infirm elderly will experience side
effects even at this lower dose. At comparable doses of 100 mg/day,
rimantadine is significantly better tolerated in nursing home residents
than amantadine (Keyser et al., 2000).
High amantadine plasma concentrations (1.0-5.0 μg/mL)
have been associated with serious neurotoxic reactions, including
delirium, hallucinosis, seizures, and coma, and cardiac arrhythmias.
Exacerbations of preexisting seizure disorders and psychiatric symptoms
may occur with amantadine and possibly with rimantadine.
Amantadine is teratogenic in animals. Both drugs are considered
pregnancy Category C because safety has not been established in
pregnancy.
Therapeutic Uses. Seasonal prophylaxis with either amantadine or
rimantadine (a total of 200 mg/day in one or two divided doses in
young adults) is ~70-90% protective against influenza A illness.
Efficacy has been shown during pandemic influenza, in preventing
nosocomial influenza, and in curtailing nosocomial outbreaks.
Doses of 100 mg/day are better tolerated and still appear to
be protective against influenzal illness. Postexposure prophylaxis
with either drug provides protection of exposed family contacts if
ill young children are not concurrently treated (Schmidt, 2004).
Seasonal prophylaxis is an alternative in high-risk patients if
the influenza vaccine cannot be administered or may be ineffective
(i.e., in immunocompromised patients). Prophylaxis should be started
as soon as influenza is identified in a community or region and should
be continued throughout the period of risk (usually 4-8 weeks)
because any protective effects are lost several days after cessation of
therapy. Alternatively, the drugs can be started in conjunction with
immunization and continued for 2 weeks until protective immune
responses develop.
The amantadines are effective against influenza A H1N1 in
adults and children if treatment is initiated within 2 days of the onset
of symptoms (Schmidt, 2004). Therapy reduces duration of viral
excretion, fever, and other systemic complaints, but resistance has
become more widespread with use. Duration of illness is shortened
by ~1 day. In uncomplicated influenza A illness of adults, early