PD is a progressive neurodegenerative illness characterized by tremor, muscular rigidity, bradykinesia (slowness of movement), and postural imbalance.8 The incidence of PD is estimated to be about 1% in the general population older than 60 years of age.9 Although characterized as a neuro-muscular disorder, dementia also occurs at a much greater rate in PD patients over the normal age-matched population.10 Although the etiology of PD remains unknown, several factors appear to play a role, including the aging process, environmental chemicals, oxidative stress, and genetic aspects.9 The discovery that drug addicts exposed to the pyridine derivative 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP), a byproduct of "synthetic heroin," developed a profound parkinsonian state led to intense study of the pathogenesis of PD.11,12 On the basis of investigations in the treatment of MPTP-treated primates, a working
Figure 13.3 • Metabolic pathway of DA.
understanding of neurochemical basis of PD has developed. The primary motor control-related symptoms have shown to be the result of dysregulation of the motor cortex via the nigrostriatal pathway. The dysregulation is caused by the depletion of DA-producing neurons within the pars compacta region of the substantia nigra that project to the striatum. This is often accompanied by Lewy bodies, which are abnormal aggregates of protein that develop inside nerve cells. In healthy individuals, stimulation of D1 receptors within the striatum results in an increased excitatory outflow from the thalamus to the motor cortex and is known as the "direct pathway"; whereas stimulation of the D2 receptors within the striatum results in a decreased excitatory outflow from the thalamus to the motor cortex and is known as the "indirect pathway." However, under conditions of PD, the loss of dopaminergic input to the striatum leads to a decreased activity in the direct pathway and an increased activity in the indirect pathway (via D1 and D2 receptors, respectively). Both of these changes lead to
Nucleus accumbens Striatum
Nucleus accumbens Striatum
decreased excitatory input to the motor cortex and the hypokinetic symptomology associated with PD. Nevertheless, the symptoms of PD are not seen until about 80% of the dopaminergic neurons in the striatum have been destroyed. Thus, significant disease progression must occur before there is an observable reduction of motor movement and control.
Although DA loss within the striatum is the primary neurological factor associated with PD, other DA pathways and receptors have also been implicated. It has been postulated that dysregulation of mesolimbic and mesocor-tical dopaminergic pathways directly contributes to the depression states common with PD.13 Dementia with PD has been shown to correlate with a loss of response to dopaminergic drugs, which has been correlated with reduced D3 receptors.14 DA D3 receptors have also been postulated to play a role in motor control deficits associated with PD because they are often found colocalized with D1 and D2 and have shown to have a reduced expression in the basal ganglia of postmortem PD brains.14-16 However, the recognition of dopaminergic pathway and receptor changes has not led to any more effective treatment than levodopa, which remains the gold standard. Clinical trials on the D1/D2/D3 agonist rotigotine have shown promise in alleviating symptoms of early PD.17 Yet, simply obtaining an optimal ratio of drug activity at these receptors will not slow the degeneration of dopamineric neurons. Nevertheless, current PD pharmacotherapy is centered on replacement of dopaminergic activity within the striatum. Whether this is to enhance DA release from remaining neurons, increase DA synthesis, provide exogenous DA agonists, or reduce DA metabolism, none of these approaches or combinations therein have shown to provide successful long-term treatment of symptoms.
The first significant breakthrough in the treatment of PD came about with the introduction of high-dose levodopa. Fahn18 referred to this as a revolutionary development in treating parkinsonian patients. The rationale for the use of levodopa for the treatment of PD was established in the early 1960s. Parkinsonian patients were shown to have decreased striatal levels of DA and reduced urinary excretion of DA. Since then, levodopa has shown to be remarkably effective for treating the symptoms of PD.19 Because of enzymatic action of MAO-A in the gastrointestinal (GI) tract and AADC in the periphery, only a small percentage (1%-2%) of levodopa is delivered into the CNS. Coadministration of levodopa with the AADC inhibitor, carbidopa, prevents decarboxylation of levodopa outside of the CNS. The combination of levodopa and carbidopa results in a substantial increase in DA delivery to the CNS with a decrease in peripheral side effects. Long-term therapy with levodopa leads to predictable motor complications. These include loss of efficacy before the next dose ("wearing off"), motor response fluctuations ("on/off"), and unwanted movements (dyskinesias).20,21 These effects are thought to be caused by the inability of levodopa therapy to restore normal DA levels in the CNS.22 As a result, the use of longer-acting DA agonists may benefit parkinsonian patients.
Levodopa, United States Pharmacopeia (USP).
Levodopa, (S)-2-amino-3-(3,4-dihydroxyphenyl) propanoic acid, is a white or almost white crystalline powder, slightly soluble in water, soluble in acidic and basic solutions, and practically insoluble in alcohol, chloroform, and ether. Aqueous solutions are neutral to slightly acidic (pKa's = 9.9 and 11.8).23 Levodopa is rapidly absorbed from the small intestine by an active transport system for aromatic amino acids. It is widely distributed to most body tissues, but less to the CNS, and is bound to plasma proteins only to a minor extent (10%-30%). Levodopa is extensively decarboxylated by first-pass metabolism in the liver. A small amount is methylated to 3-O-methyldopa (3OMD), which accumulates in the CNS because of its long half-life. Most of levo-dopa is converted to DA, small amounts of which in turn are metabolized to norepinephrine and epinephrine. At least 30 metabolites of levodopa have been identified. Metabolites of DA are rapidly excreted in the urine. The principal metabolites DOPAC and HVA (Fig. 13.3) account for up to 50% of the administered dose. After prolonged therapy with levodopa, the ratio of DOPAC and HVA excreted may increase, probably reflecting a depletion of methyl donors necessary for metabolism by COMT. Antipsychotic drugs, such as phenothiazines, butyrophenones, and reserpine interfere with the therapeutic effects of levodopa, and nonspecific MAO inhibitors interfere with inactivation of DA. Anticholinergic drugs (e.g., trihexyphenidyl, benztropine, and procyclidine) act synergistically with levodopa to improve certain symptoms of PD, especially tremor. However, large doses of anticholinergic drugs can slow gastric emptying sufficiently to cause a delay in reabsorption of levodopa by the small intestine. Sympathomimetic agents such as epinephrine or isoproterenol may also enhance the cardiac side effects of levodopa. In some patients, the coadministration of antacids may enhance the GI absorption of levodopa. Levodopa is essentially a prodrug; that is itself inactive, but after penetrating, the BBB is metabolized to DA. Levodopa is indicated for the treatment of idiopathic, postencephalitic, and symptomatic parkinsonism.
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