Dyskinesia levodopa

Dyskinesias are abnormal movements, usually caused by neurological diseases or by diugs used to treat neurological (e.g., levodopa) or psychiatric diseases (e.g., neuroleptics). 

Parkinson s disease (PD) 1. In a non-human primate model of PD endocannabinoid levels are elevated in the basal ganglia and may contribute to the generation of parkinsonian symptoms and/or to expression of levodopa-induced dyskinesia. The cerebrospinal fluid of untreated PD patients contains elevated levels of AEA 1. CB-) antagonists or biosynthesis inhibitors... 

Another indication of the importance of DA in motor control is the observation that in humans its precursor levodopa, and DA agonists like bromocriptine, not only overcome the akinesia of Parkinsonism but in excess will actually cause involuntary movements, or dyskinesia (Chapter 14). Also it is well known that DA antagonists like chlorpromazine and haloperidol produce Parkinsonian-like symptoms in humans (and catalepsy in animals) and, as indicated above, reduce the dyskinesia of Huntington s Chorea. Thus DA seems to sit on a knife edge in the control of motor function (Fig. 7.8). 

Figure 7.8 Dopamine and motor function. When nigrostriatal dopamine activity is normal so is motor function. Any reduction in this DA activity, as in Parkinson s disease, results in reduced motor activity, i.e. akinesia. By contrast, too much DA activity, as in Huntington s Chorea, produces abnormal motor function, i.e. dyskinesia. The latter may be controlled by neuroleptic drugs (DA antagonists) but they can swing the balance in DA activity sufficiently to produce akinesia (Parkinsonism). DA agonists (and levodopa) may overcome akinesia but can induce DA overactivity and dyskinesia (peak dose effect) (see Chapter 15)...

ExCDDIs certainly improve the efficacy and duration of action of levodopa so that it can be given in a smaller dose (e.g. 25%) and generally in a 4 1 ratio, levodopa ExCDDI. As might be expected, some DA side-effects such as dyskinesia and psychoses are worse, but hypotension is less (no peripheral effects of DA) and vomiting is actually much reduced or abolished. This is because the chemoreceptor trigger zone of the vomiting centre while in the brain is on the blood side of the blood-brain barrier and will not be stimulated since no DA is formed peripherally (Fig. 15.5). That an... 

Despite the fact that in quantitative studies of motor performance they often appear to produce more benefit than levodopa and are less likely to cause dyskinesia and ON-OFF fluctations, patients tend to prefer levodopa. Possibly unless DA function is... 

Since D2 (but not Di) receptors are expressed on neurons of the Ind Path, then D2 agonists will have the same effect on this pathway as levodopa and overcome the hypokinesia. Their inability to activate D] receptors could mean, however, that while they are less likely to cause dyskinesias, for the reasons given above, their ability to dampen the GPint may also not be sufficient to give the required facilitation of motor function. Conversely, the absence of Dj receptors on the Ind Path explains why their agonists carmot influence it and so appear unable to reduce hypokinesia. 

The first proper double blind trial of embryonic implants in 40 PD patients (20 undergoing just surgery without any implant), has shown no improvement in patients over 60 years but some clinical benefit (fewer symptoms between levodopa dosing) in those below that age. Unfortunately some of these responders eventually developed dyskinesias, a sign of too much dopamine, and further implants were halted until the technique has been re-evaluated, see Freed, CR et al. N EnglJ Med 2001, 344 710-719. 

Henry, B and Brotchie, JM (1996) Potential of opioid antagonists in the treatment of levodopa, induced dyskinesias in Parkinson s disease. Drugs and Ageing 9 149-158. 

Side effects include dyskinesias, orthostatic hypotension, dizziness, nausea, insomnia, sleep attacks, pathologic gambling, discoloration of urine/sweat, and psychiatric effects (confusion, hallucinations, nightmares, and altered behavior). Dyskinesias caused by adding other PD drugs to levodopa may be improved by decreasing the levodopa dose. Motor complications occur in about 40% of patients within 4 to 6 years of starting levodopa.1,8,24,25,37... 

Patients with severe dyskinesias and off periods may achieve more constant blood concentrations (lower peak and higher trough concentrations) by taking a liquid formulation of levodopa with carbidopa. Each day patients make a 1 mg/mL levodopa... 

Sinemet 10/100 Sinemet 25/100 Sinemet 25 0 Antiparkinsonian Tab Carbidopa 10 mg, levodopa 100 mg Tab Carbidopa 25 mg, levodopa 100 mg Tab Carbidopa 25 mg, levodopa 250 mg 1 tab tid-qid dyskinesia, nausea, mental status changes, paranoia, psychosis, depression. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxy-phenylalanine (levodopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed, likely causing undesirable effects (tachycardia, arrhythmias resulting from activation of Pi-adrenoceptors [p. 114], hypotension, and vomiting). Extracerebral production of dopamine can be prevented by inhibitors of DOPA-decarboxylase (car-bidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. Excessive elevation of brain dopamine levels may lead to undesirable reactions, such as involuntary movements (dyskinesias) and mental disturbances. 

Administration of levodopa plus carbidopa (or benserazide) remains the most effective treatment, but does not provide benefit beyond 3-5 y and is followed by gradual loss of symptom control, on-off fluctuations, and development of orobuccofacial and limb dyskinesias. These long-term drawbacks of levodopa therapy may be delayed by early monotherapy with dopamine receptor agonists. Treatment of advanced disease requires the combined administration of antiparkinsonian agents. 

CNS effects Certain adverse CNS effects (eg, dyskinesias) will occur at lower dosages and sooner during therapy with levodopa and carbidopa than with levodopa alone. 

In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been 800 mg or more, or if they had moderate or severe dyskinesias prior to treatment with entacapone. 

Hallucinations Dopaminergic therapy in Parkinson s disease patients has been associated with hallucinations. In clinical trials, hallucinations developed in approximately 4% of patients treated with 200 mg entacapone or placebo. Dyskinesia Entacapone may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate pre-existing dyskinesia. 

The use of pergolide in patients on levodopa may cause or exacerbate pre-existing states of confusion and hallucinations or preexisting dyskinesia. 

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