Levodopa toxicity

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  1. Dopamine, a catecholamine, is synthesized in the terminal of dopaminergic neurons from tyrosine; the rate limiting step in the synthesis of dopamine is the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA a.k.a. levodopa) by the enzyme tyrosine hydroxylase which is present within the neuron; levodopa is converted rapidly to dopamine by aromatic L-amino acid decarboxylase; this process is blocked by reserpine (which also blocks synthesis and storage of norepinepherine) and leads to the depletion of dopamine; dopamine is metabolized my monoamine oxidase and is broken down to homovanillic acid
  2. Levodopa is the most effective agent in the treatment of Parkinson's disease; dopamine is not effective when given orally or IV because it cannot cross the blood-brain barrier; Levodopa is taken up by nigral cells which convert it to dopamine
  3. Adverse effects are due to the decarboxylation of levodopa to dopamine (half life is 1-3 hours); levodopa is usually administered with an inhibitor of aromatic L-amino acid decarboxylase such as carbidopa or benserazide (carbidopa + levodopa = sinamet); aromatic amino acid decarboxylase inhibitors decrease the peripheral metabolism of L-Dopa, reduce the amount of L-dopa needed, and increase the transport of L-dopa in the brain
  4. Levodopa can improve tremor, rigidity and bradykinesia
  5. On-off phenomenon in Parkinson disease refers to the random symptomatic fluctuations that patients have
  6. Adverse effects of dopamine include nausea and dyskinesias which are most common, also causes hallucinations and confusion in the elderly
  7. L-DOPA has been found to be toxic for dopaminergic and non-dopaminergic mesencephalic neurons in vitro; catechol-O-methyltransferase (COMT)attenuates toxicity.
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