Medical Pharmacology Topics   

CNS Pharmacology: Movement Disorders

The brain regions involved in movement disorders are often referred to as the extrapyramidal system. Movement disorders are due to an imbalance among many neurotransmitters and pathways in the brain.

Dopamine deficiency in nigrostriatal (SN) and mesolimbic pathways seems to be the cause of Parkinson's disease. An excess of dopamine in those same pathways seem to be the underliying pathology in tardive dyskinesia and Huntington's disease.

An excess of acetylcholine in stratium interneurons is associated with Parkinson's disease, while a deficiency is associated with Huntington's disease. A deficiency of GABA in striatonigral pathway is associated with Huntington's disease.

Drugs used to treat movement disorders include anticholinergics, dopamine enhancers and dopamine agonists. The current treatment algorithm for Parkinson's disease calls for levodopa sparing, continuous dopaminergic stimulation and multidrug regimes.

Anticholinergics

Anticholinergic drugs compensate for the reduced inhibitory actions of dopaminergic neurons from the substantia nigra on the striatum, by decreasing acethylcholine activity in the striatum. Trihexylphenidyl and benztropine are particularly useful in young patiets with early Parkinson's disease already experiencing a prominent tremor.

Anticholinergics commonly cause dry mouth and blurred vision. More severe reaction that are worsen with older age include exacerbation of glaucoma, urinary retention, and impairment of cognitive function.

Dopamine Enhancers

Several drug types enhance dopamine action by different mechanisms: dopamine precursors, inhibitors of dopamine metabolism, inhibitors of its reuptake and/or promoters of its release.

Levodopa crosses the blood-brain barrier and is taken up by dopaminergic neurons to be converted to dopamine by levodopa decarboxylase. Levodopa is given in conjuction with carbidopa, a peripheral decarboxylase inhibitor, to prevents its depletion in the peripheral nerves. Levodopa is the most effective and rapid acting treatment for the symptoms of Parkinnson's disease. But less than 10% of the ingeste levodopa reaches the brain, even when combined with carbidopa. The absorption of levodopa in the intestine and at the blood-brain narrier is mediated by a saturable amino acid trasporter.

The half-life of carbidopa/levodopa is 1-1.5 hours. A controlled-release formulation take about 3 hours to dissolve in comparison to the 30 minutes for the regular formulation. Levodopa can cause GI istress, ortostatic hypotension, hallucinations, dyskinesias and motor fluctuations.

Selegiline is a MAO-B inhibitor used in the treatment of Parkinson's disease, preventing dopamine metabolism. It may cause insomnia and cofusion because of an amphetamiine-like metabolite. At the low doses used to treat Parkinson's disease, seregiline does not cause the potentially fatal "wine and cheese" reaction caused by MAO-A inhibitors.

Entacapone is a perypheral inhibitor of catecholamine-O-methyl transferase (COMT) used to increase the elimination hal-life of levedopa by approximately 50%. Entacapone can exacerbate the side effects of levodopa. A metabolite of etacapone may cause urine to turn orange, but there is no toxicity associated with this effect.

Amantadine is useful in early Parkinson's disease, may help treat dyskinesias in late disease and seems to have a neuroprotective effect. The effectiveness of amantadine in the treatment of Parkinson's disease is multifactorial: promotes dopamine release, inhibits dopamine reuptake, has anticholinergic effects and is a glutamate receptor antagonist.

Amantadine is excreted in the urine unmetabolized. Dosage should be adjusted in patients with impaired renal function. Amantadine canm cause anticholinergic sie effects and a rash (livedo reticularis) that is a rare but limitting adverse effects.

Dopamine Agonists

Dopamine agonists are now the first line tratment for symptomatic Parkinson's disease, in order to delay levodopa treatment as long as possible.

The ergot derivatives bromocriptine and pergolide are D2 agonists used to treat Parkinson's disease. Their half-life is between 6-27 hours. Adverse efects include GI distress, orthostatic hypotension, dyskinesias, hallucinations, "sleep attacks", pulmonary or retroperitoneal fibrosis, Raynaud's-like syndrome and erythromelalgia.

Pramipexole and ropinirole are non-ergot dopamine agonists with a half-life between 4-12 hours. They may also cause GI distress, orthostatic hypotension, dyskinesias, hallucinations and "sleep attacks".

Other Movement Disorders

Essential tremor is very common, with a prevlence around 6%. Approximatelly 50 of the patents with essential tremor have an autosomal dominant pattern of inheritance. It is treated with either propanolol, primidone (barbiturate), gabapenctin or alprazolam.

Tourette' syndrome and Huntington's disease are treated primarily with antipsychotics to control excessive movements. These medications can cause reversible parkinsonism tardive diskinesias and neuroleptic malignant syndrome.

Dystonia can be idiopatic (writers cramp), hereditary or secondary to numerous other conditions. It can be focal, multifocal or generalized. It is treated with trihexylphenidyl (anticholinergic), benzodiazepines, baclofen (GABA-B agonist) and botulinum toxin. Sedation is a dose-limiting adverse effect of baclofen. Rapid discontinuation of baclofen can elicit seizures ad acute psychosis. Botulinum toxin destroy the docking proteins of norepinephrine vesicles. Botulinum Injections approximately every 3 months are effective for focal dystonias. Adverse reactions include pain at the injection site and excessive weakness.

Wilson's disease is a rare autosomal recessive disease were disruption of copper homeostasis results in deposits in the liver, basal ganglia and iris. It is treated wth zinc, trietine and d-penicillamine. Zinc causes cooper to be bound to intestinal lumen cells. The copper is excreted with sloughing of the lumen cells each week. Trientine is a chelator that increases urinary excretion of copper, but can cause bone marrow suppression and autoimmune syndromes. D-penicillamine is another copper chelator, but has potentially severe adverse reaction including irreversible worsening of neurological symptoms in 25% of the patients.

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