Dopamine replacement therapy

These symptoms are alleviated by administering levodopa (L-dopa), a precursor for dopamine. L-dopa is taken up by the axon terminals of dopaminergic neurons and used to form dopamine. Interestingly, in some patients, a side effect of dopamine replacement therapy is the development of symptoms characteristic of schizophrenia. (Recall that this mental disorder is caused by overactive dopaminergic neurons.) On the other hand, drugs used to treat schizophrenia — dopamine receptor antagonists — may elicit symptoms of Parkinson s disease. 

Since Parkinson s disease arises from a deficiency of DA in the brain, the logical treatment is to replace the DA. Unfortunately, dopamine replacement therapy cannot be done with DA because it does not cross the blood-brain barrier. However, high doses (3-8 g/day, orally) of L(-)-DOPA (levodopa), a prodrug of DA, have a remarkable effect on the akinesia and rigidity. The side effects of such enormous doses are numerous and unpleasant, consisting initially of nausea and vomiting and later of uncontrolled movements (limb dyskinesias). The simultaneous administration of carbidopa (4.75) or benserazide (4.76)—peripheral DOPA decarboxylase inhibitors—allows the administration of smaller doses, and also prevents the metabolic formation of peripheral DA, which can act as an emetic at the vomiting center in the brainstem where the blood-brain barrier is not very effective and can be penetrated by peripheral DA. 

Giovannoni G, O Sullivan JD, Turner K, Manson AJ, Lees AJ. Hedonistic homeostatic dysregulation in patients with Parkinson s disease on dopamine replacement therapies. J Neurol Neurosurg Psychiatry 2000 68(4) 423-8. 

The potential benefits of alleviating dopamine deficiency in the brains of Parkinson s patients by tissue implantation have been widely discussed from both clinical and ethical perspectives. Conventional dopamine replacement therapy suffers from well known and serious limitations. The most recent data indicate that fetal-tissue transplants into patients with idiopathic or MPTP-induced Parkinson s disease are clinically encouraging and may be highly beneficial for at least some patients (6,7). 

Nicotine is most often used in replacement therapy for tobacco addiction, but also has some potential uses to treat other conditions. It has been helpful in stopping bleeding in ulcerative colitis. Nicotine gum is being tested in conjunction with Tourette syndrome where it has been seen to lessen the severity and frequency of tics. Nicotine may reduce tremors in Parkinson s patients because it increases dopamine levels, which are reduced in these patients. It also improves attention in Alzheimer s patients. Nicotine is being studied for its effect on dystonias (movement disorders), chronic pain syndrome, sleep apnea, ulcers, attention deficit disorder, obesity, and chronic inflammatory skin disorders as well. 

Avoidance of salt depletion and a salt load (500-1000 ml of 0.9% saline) reduce the renal toxicity of DAMB (120-126). Also the maintenance of adequate serum potassium concentrations by replacement therapy may be important and may contribute to kidney sparing (127). Other preventive measures, including dopamine infusion, are of no value (128). 

The major clinical feature of patients with deficiency of dopamine p-hydroxylase is orthostatic hypotension caused by reduced synthesis and release of norepinephrine by sympathetic nerves. The deficiency is characterized neuro-chemically by decreased levels of norepinephruie and norepinephrine metabolites and increased levels of dopamine and dopamine metabolites. Diagnosis is best achieved from an increased ratio of plasma dopamine to norepinephrine. Copper deficiency in Menkes disease is due to defects in the gene coding for a copper-transporting adenosine triphosphatase. Because dopamine p-hydroxylase is a copper-dependent enzyme, the deficiency is associated with decreased activity of the enzyme and reduced production of norepinephrine from dopamine. Prompt diagnosis at childbirth is essential for copper-replacement therapy, and... 

Supportive care goals for the critically ill patient with ARF include aggressive fluid management. Cardiac output and blood pressure must be supported to allow for adequate tissue perfusion. However, a fine balance must be struck in this regard. For example, fluids must be typically restricted in anuric and ohguric patients unless the patient is hypovolemic or is able to achieve fluid balance via renal replacement therapy. If fluid intake is not minimized, edema rapidly occurs, especially in hypoalbuminemic patients. In contrast, vasopressors like dopamine >2 mcg/kg per minute or norepinephrine are used to maintain adequate tissue perfusion, but may also induce kidney hypoxia via a reduction in renal blood flow. Consequently, S wan-Ganz monitoring is essential for critically ill patients. 

Levodopa, (laevo-dihydroxyphenylalanine) is the principle drug in this group. Replacement therapy with dopamine itself is not possible because it does not pass the blood-brain barrier. Levodopa is the precursor of dopamine and it does penetrate the brain where it is converted in the neurons to dopamine by decarboxylation. 

Replacement therapy with dopamine itself is not possible in Parkinson s disease because dopamine does not pass Ihe blood-brain harrier. Kowever, its precursor. levod >pa (i. dupa). does penetrate the... 

Levodopa is the immediate precursor of dopamine and is able to penetrate the brain, where it is converted to dopamine. The site of this decarboxylation in the parkinsonian brain is uncertain, but a.s dopa decarboxylase is not rate limiting, there may be. sufficient enzyme in the remaining dopaminergic nerve terminals. Another possibility is that the conversion occurs in noradrenergic or serotonergic terminals, because the decarboxylase activity in these neurotics is not specific. In any event, the release of dopamine replaced in the brain by Icvodopa therapy must be very abnormal, and it is remarkable that most patients with Parkinson s disease benefit, often dramatically, from its administration. 

Replacement therapy with L-dopa and 5-hydroxytryptophan has been suggested as the means to circumvent the block in synthesis of dopamine and serotonin (Steinfeld et al., 2002). 

---