AMANTADINE & RIMANTADINE

INTRODUCTION: Amantadine and its α-methyl derivative, rimantadine, are tricyclic amines of the adamantane family that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication. They are active against influenza A only.

PHARMACOKINETICS: Rimantadine is four to ten times more active than amantadine in vitro. Amantadine is well absorbed and 67% protein bound. Its plasma half-life is 12–18 hours and varies by creatinine clearance. Rimantadine is about 40% protein-bound and has a half-life of 24–36 hours. Nasal secretion and salivary levels approximate those in the serum, and cerebrospinal fluid levels are 52–96% of those in the serum; nasal mucus concentrations of rimantadine average 50% higher than those in plasma. Amantadine is excreted unchanged in the urine, whereas rimantadine undergoes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly and in patients with renal insufficiency, and for rimantadine in patients with marked hepatic insufficiency.

CLINICAL SIGNIFICANCY: In the absence of resistance, both amantadine and rimantadine, at 100 mg twice daily or 200 mg once daily, are 70–90% protective in the prevention of clinical illness when initiated before exposure. When begun within 1–2 days after the onset of illness, the duration of fever and systemic symptoms is reduced by 1–2 days. The primary target for both agents is the M2 protein within the viral membrane, incurring both influenza A specificity and a mutation-prone site that results in the rapid development of resistance in up to 50% of treated individuals. 

ANTIMICROBIAL RESISTANCE: Resistant isolates with single-point mutations are genetically stable, retain pathogenicity, can be transmitted to close contacts, and may be shed chronically by immunocompromised patients. The marked increase in the prevalence of resistance to both agents in clinical isolates over the last decade, in influenza A H1N1 as well as H3N2, has limited the usefulness of these agents for either the treatment or the prevention of influenza. Cross-resistance to zanamivir and oseltamivir does not occur.

ADVERSE EFFECTA: The most common adverse effects are gastrointestinal (nausea, anorexia) and central nervous system (nervousness, difficulty in concentrating, insomnia, light-headedness); side effects are dose related and may diminish or disappear after the first week of treatment despite continued drug ingestion. More serious side effects (eg, marked behavioral changes, delirium, hallucinations, agitation, and seizures) may be due to alteration of dopamine neurotransmission; are less frequent with rimantadine than with amantadine; are associated with high plasma concentrations; may occur more frequently in patients with renal insufficiency, seizure disorders, or advanced age; and may increase with concomitant antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole.

Clinical manifestations of anticholinergic activity tend to be present in acute amantadine overdose. Both agents are teratogenic and embryotoxic in rodents, and birth defects have been reported after exposure during pregnancy.

RELATED;

1. ANTIVIRAL DRUGS  

2. DOPAMINE  

3. DRUG RESISTANCE

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