Management of Parkinson’s disease – Wikipedia, the free encyclopedia

Treatment for Parkinson's Disease (PD), due to its chronic nature, requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.

While many medications treat Parkinson's, none actually reverse the effects of the disease or cure it. Furthermore, the gold standard treatment varies with the disease state. People with Parkinson's therefore often must take a variety of medications to manage the disease's symptoms.[1] Several medications currently in development seek to better address motor fluctuations and nonmotor symptoms of PD. However, none are yet on the market with specific approval to treat Parkinson's.[2]

The main families of drugs useful for treating motor symptoms are Levodopa, dopamine agonists and MAO-B inhibitors.[3] The most commonly used treatment approach varies depending on the disease stage. Two phases are usually distinguished: an initial phase in which the individual with PD has already developed some disability for which he needs pharmacological treatment, and a second stage in which the patient develops motor complications related to levodopa usage.[3] Treatment in the initial state aims to attain an optimal tradeoff between good management of symptoms and side-effects resulting from enhancement of dopaminergic function. The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of causing the onset of dyskinesias to be retarded.[3] In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication, and overuse by some patients, also have to be controlled.[3] When medications are not enough to control symptoms, surgical techniques such as deep brain stimulation can relieve the associated movement disorders.[4]

Levodopa (or L-DOPA) has been the most widely used treatment for over 30 years.[3] L-DOPA is transformed into dopamine in the dopaminergic neurons by dopa-decarboxylase.[3] Since motor symptoms are produced by a lack of dopamine in the substantia nigra the administration of L-DOPA temporarily diminishes the motor symptomatology.[3]

Only 5-10% of L-DOPA crosses the bloodbrain barrier. The remaining is often metabolised to dopamine elsewhere, causing a wide variety of side effects including nausea, dyskinesias and stiffness.[3]Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors.[3] They inhibit the metabolism of L-DOPA in the periphery thereby increasing levodopa delivery to the central nervous system. They are generally given as combination preparations with levodopa.[3] Existing preparations are carbidopa/levodopa (co-careldopa, trade names Sinemet, Parcopa, Atamet) and benserazide/levodopa (co-beneldopa, trade name Madopar). Levodopa has also been related to a dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and punding.[5]

There are controlled release versions of Sinemet and Madopar that spread out the effect of the levodopa. Duodopa is a combination of levodopa and carbidopa. Slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.[3]

Tolcapone inhibits the catechol-O-methyltransferase COMT enzyme, which degrades dopamine and levadopa, thereby prolonging the therapeutic effects of levodopa.[3] It, alongside inhibitors of peripheral dopa decarboxylase, have been used to complement levodopa. However, due to its possible side effects such as liver failure, it's limited in its availability.[3] A similar drug, entacapone has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time.[3] Entacapone is available for treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo).[3]

Levodopa results in a reduction in the endogenous formation of L-DOPA, and eventually becomes counterproductive. Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication.[3] When this occurs PD patients change rapidly from stages with good response to medication and few symptoms ("on" state) to phases with no response to medication and important motor symptoms ("off" state).[3] For this reason levodopa doses are kept as low as possible while maintaining functionality.[3] Delaying the initiation of dopatherapy, using instead alternatives for some time, is also common practice.[3] A former strategy to reduce motor complications was to withdraw patients from L-DOPA for some time. It is discouraged now since it can bring dangerous side effects such as neuroleptic malignant syndrome.[3] Most people will eventually need levodopa and later develop motor complications.[3]

The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.

Dopamine agonists in the brain have a similar effect to levodopa since they bind to dopaminergic post-synaptic receptors.[3] Dopamine agonists were initially used for patients experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa but they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications.[3][6] When used in late PD they are useful at reducing the off periods.[3] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride.

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Management of Parkinson's disease - Wikipedia, the free encyclopedia