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By K K Jain MD

Pramipexole is an amino-benzothiazole–type dopamine agonist. It binds to presynaptic and postsynaptic dopamine D2 and D3 receptors, but does not have affinity for the dopamine D1 receptor site.

Pharmacodynamics. Pramipexole stimulates presynaptic and postsynaptic dopamine D2 receptors in a dose-dependent manner and reduces extracellular concentrations of dopamine by inhibiting dopamine synthesis and release. Although not proven, the motor benefits of pramipexole in Parkinson disease are likely due to dopamine D2 stimulation, whereas its effects on mood and apathy may be related to its D3 agonist properties. Pramipexole has a relatively high affinity for a2 adrenoreceptors but has little effect on other neurotransmitter systems. In addition to an antiparkinsonian effect, it is considered to have a neuroprotective effect demonstrated by prevention of levodopa-induced toxicity in vitro. The possible mechanisms are as follows:

  • Site-directed antioxidant effect on dopamine neurons and receptors, which is an action that it does not share with bromocriptine and pergolide. Pramipexole reduces neuronal damage in gerbil ischemia models and reduces amphetamine-induced neuronal damage.
  • Like other dopamine agonists, pramipexole reduces dopamine synthesis turnover in mice during repeated injections of amphetamine and, thus, reduces the free radical formation during this process. This is considered to contribute to the neuroprotective effect of pramipexole.
  • Pramipexole attenuates intracellular processes such as the mitochondrial transition pore opening that is associated with programmed cell death.
  • It stimulates a mesencephalic-derived neurotrophic activity.
  • Pramipexole has biological regulatory effects on dopaminergic neuron-associated genes, which may explain both the slower decline of imaged dopamine transporter and the neuroprotective effect (Pan et al 2005).
  • A study in cell model system showed that pramipexole prevented cell death, but the protective effect was not prevented by dopamine receptor blockade, and protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity (Gu et al 2004). This indicates that nondopaminergic mechanisms are involved in the neuroprotective effect of pramipexole, which require further investigation for their clinical relevance.
  • Pramipexole has a neuroprotective effect and protects dopaminergic neurons from glutamate neurotoxicity by the reduction of intracellular dopamine content, independently of dopamine D(2)-like receptor activation (Izumi et al 2007).

A review of various studies shows that neuroprotection requires treatment prior to neurologic insult and high concentrations of pramipexole are required (Albrecht and Buerger 2009).

Pharmacokinetics. Pramipexole exhibits linear pharmacokinetics over the dose range of 0.125 to 1.5 mg administered every 8 hours in healthy volunteers. Plasma concentrations of pramipexole are proportional to dose. The plasma elimination half-life is approximately 7 to 9 hours, sufficiently long to make it a practical drug for oral administration in Parkinson disease patients with short-duration levodopa responses. Pramipexole is excreted by the renal organic transport system and renal clearance accounts for about 80% of the total clearance of an oral dose.

Formulations. An extended-release formulation of pramipexole is available for use as a once-daily oral treatment for Parkinson disease, and the effects are equal to that of 3-times-daily immediate release pramipexole (Chwieduk and Curran 2010).

Pharmacogenetics. DRD3 Ser9Gly gene polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with Parkinson disease (Liu et al 2009).