Amantadine Parkinsonism

Low affinity use-dependent NMDA recqrtor antagonists meet the criteria for safe administration into patients. Drugs like amantadine and memantine have modest effects on Parkinson s disease and are used as initial therapy or as adjunct to l-DOPA. Their adverse effects include dizziness, lethargy and sleep disturbance. 

AMANTADINE The nurse administers this drug for the prevention or treatment of respiratory tract illness caused by influenza A virus. Some patients are prescribed this drug to manage extrapyramidal effects caused by drugp used to treat Parkinsonism (See Chaps. 29 and 32). The nurse should protect the capsules from moisture to prevent deterioration. When the drug is administered for symptoms of influenza, it is important to start therapy within 24 to 48 hours after symptoms begin. 

The mechanism of action of amantadine (Symmetrel) and selegiline (Eldepryl) in die treatment of parkinsonism is not fully understood. 

Ms. Dennis, age 89 years, has Parkinson s disease and is taking amantadine daily. In discussing her care with the family, determine what information you would include in the teaching plan and what information would be most important for the family to understand. Explain your answer. 

In pharmacology, two adamantane derivatives. Amantadine (1-adamanta-neamine hydrochloride) and Rimantadine (a-methyl-1-adamantane methyla-mine hydrochloride) (see Fig. 24), have been well known because of their antiviral activity [129]. The main application of these drugs is prophylaxis (treatment to prevent the onset of a particular disease) and treatment of influenza-A viral infections. They are also used in the treatment of parkinsonism and inhibition of hepatitis-C virus. Memantine (1-amino-3,5-dimethyladaman-tane) (see Fig. 24) has been reported effective in slowing the progression of Alzheimer s disease [130]. 

Chlorpromazine is an aliphatic phenothiazine antipsychotic used in schizophrenia and which may exacerbate parkinsonism. Co-careldopa is a combination of levodopa and the peripheral dopa-decarboxylase inhibitor, carbidopa. Co-careldopa, amantadine, entacapone and bromocriptine are all indicated in the management of parkinsonism. 

Parkinson s disease 100 mg twice/day when used alone. Onset of action is usually within 48 h. Initial dose is 100 mg/day for patients with serious associated medical illnesses or those receiving high doses of other antiparkinson drugs. After one to several weeks at 100 mg once/day, increase to 100 mg twice/day, if necessary. Patients whose responses are not optimal at 200 mg/day may occasionally benefit from an increase up to 400 mg/day in divided doses supervise closely. Patients initially benefiting from amantadine often experience decreased efficacy after a few months. Benefit may be regained by increasing to 300 mg/day, or by temporary discontinuation for several weeks. Other antiparkinson drugs may be necessary. 

Pharmacology The exact mechanism of action is unknown, but amantadine is thought to release dopamine from intact dopaminergic terminals that remain in the substantia nigra of parkinson patients. 

Parkinsonism and drug-induced extrapyramidal reactions See amantadine in the... 

Abrupt withdrawal Do not discontinue amantadine abruptly in patients with Parkinson s disease. A few patients have experienced a parkinsonian crisis (a sudden marked clinical deterioration) when this medication was suddenly stopped. Abrupt P.1045... 

Amantadine is an old drug with several pharmacological properties warranting its (empirical) use in Parkinson s disease facilitation of dopamine release, blockade of dopamine re-uptake, anticholinergic effect, blockade of NMDA receptors. Amantadine is usually employed early in the disease process (monotherapy, 100 mg b.i.d.) and most often in combination with levodopa in more advanced stage disease (anti-dyskinesia effect ). 

Amantadine has a long history in the symptomatic treatment of Parkinson s disease. Several recent double-blind, placebo-controlled studies have confirmed the impressive acute antidyskinetic effects of amantadine (Rajput et al. 1998 Verhagen Metman et al. 1998 Luginger et al. 2000 Del Dotto et al. 2001 Shoghi-Jadid et al. 2002). One study also indicates that amantadine s antidyskinetic benefit is maintained for at least 1 year (Metman et al. 1999). The related compound memantine was found, as in the MPTP monkey, to have no effect on dyskinesia in a double-blind study but it did improve parkinsonian symptoms (Merello et al. 1999). This indicates that the antidyskinetic effects of amantadine may be unrelated to NMDA receptor antagonism (Danysz et al. 1997). 

Luginger E, Wenning GK, BOsch S, Poewe W (2000) Beneficial effects of amantadine on L-dopa-induced dyskinesias in Parkinson s disease. Mov Disord 15 873-878 Ly CD, Roche KW, Lee HK, Wenthold RJ (2002) Identification of rat EMAP, a delta-glutamate receptor binding protein. Biochem Biophys Res Commun 291 85-90 Madden DR (2002) The structure and function of glutamate receptor ion channels. Nat Rev Neurosci 3 91-101... 

Amantadine was originally introduced as an antiviral compound (see Chapter 50), but it is modestly effective in treating symptoms of parkinsonism. It is useful in the early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake. Additional sites of action may include antagonism at muscarinic and A-methyl-D-aspartate (NMDA) receptors. Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis. Amantadine and the anticholinergics may exert additive effects on mental functioning. 

D. Although not widely used, amantadine may be useful in the early stages of Parkinson s disease or as an adjunct to other agents. Livedo reticularis is a characteristic purple mottling of the skin associated with amantadine. 

The Centers for Disease Control s (CDC) Immunization Practices Advisory Committee recommends annual vaccination as the method of choice in the prevention of influenza infection. However, when vaccination is contraindicated or early vaccination is not possible, amantadine and rimantadine are effective prophylactic agents that have been shown to protect approximately 70 to 90% of patients from influenza A infection. Since these drugs do not prevent the host immune response to influenza A, they may be used to prevent infection during the 2- to 4-week period required to develop immunity following vaccination. An additional use of amantadine, unrelated to its antiviral activity, is in the therapy of Parkinson s disease (see Chapter 31). 

The storage and release of DA can be modified irreversibly by reserpine (3.1), just as in vesicles containing other catecholamines and serotonin. Dopamine release can be blocked specifically by y-hydroxybutyrate (4.78) or its precursor, butyrolactone, which can cross the blood-brain barrier. High doses of amphetamines do deplete the storage vesicles, but this is not their principal mode of action. Apparently, amantadine (4.79), an antiviral drug that is likewise beneficial in parkinsonism (and also perhaps to relieve fatigue in multiple sclerosis), may also act by releasing DA. 

Amantadine, an antiviral agent, was by chance found to have antiparkinsonism properties. Its mode of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. It has been reported to antagonize the effects of adenosine at adenosine 2 receptors, which are receptors that may inhibit D2 receptor function. Release of catecholamines from peripheral stores has also been documented. 

Amantadine is less efficacious than levodopa, and its benefits may be short-lived, often disappearing after only a few weeks of treatment. Nevertheless, during that time it may favorably influence the bradykinesia, rigidity, and tremor of parkinsonism. The standard dosage is 100 mg orally two or three times daily. Amantadine may also help in reducing iatrogenic dyskinesias in patients with advanced disease. 

An overview of the drugs used to treat Parkinson disease is shown in Table 10-1. The primary drug used is levodopa. Other agents such as amantadine, anticholinergic drugs, catechol-O-methyltransferase... 

Amantadine appears to work by blocking the N-methyl-D-aspartate (NMDA) receptor in the brain, thereby inhibiting the effects of excitatory amino acids such as glutamate.18,47 This suggests that excitatory neurotransmitters play a role in motor complications associated with advanced Parkinson disease.23,65 Future research may discover other ways of controlling these excitatory neurotransmitters, thus providing additional treatments for people with advanced Parkinson disease. 

The primary adverse effects associated with amantadine are orthostatic hypotension, CNS disturbance (e.g., depression, confusion, hallucinations), and patches of skin discoloration on the lower extremities (livedo reticularis). However, these side effects are relatively mild compared to those of other anti-Parkinson drugs and are usually reversed by altering the drug dosage. 

Crosby NJ, Deane KH, Clarke CE. Amantadine for dyskinesia in Parkinson s disease. Cochrane Database SystRev. 2003 CD003467. 

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