Journal Club. Parkinsonismo iatrogeno

Transcription

1 PROGETTO UNIVA 2013 Journal Club Parkinsonismo iatrogeno Pietro Gareri, MD, PhD Geriatra ASP Catanzaro Lamezia Terme 3 Luglio 2013

2 Drug-induced parkinsonism (DIP) was recognized in the early 1950s as a common complication of antipsychotic therapy; initially considered to be present in 4-40% of patients treated with the first neuroleptics Reported as a complication of treatments with diverse compounds including new generation antipsychotics, CCB, gastrointestinal prokinetics, antiarrhythmics, antidepressants and others Reversible after drug suppression Persistency of the clinical deficits after culprit withdrawal may indicate a previous subclinical parkinsonism unmasked by the involved drugs Two groups of DIP patients: those with normal SPECT (suggesting normal density of dopamine terminals) and patients with reduced striatal uptake (suggestive of lesion of the presynaptic dopamine terminals) Some individuals, perhaps with genetic variants of genes involved in familial Parkinson s disease (PD), are especially susceptible to this complication

3 Key points Despite advances in ancillary tests, the clinical course of parkinsonism after drug discontinuation is paramount for a correct differential diagnosis. Management of DIP includes prevention, early recognition and withdrawal of the offending drug. Certain variables such as age, use of multiple drugs or previous vascular damage to the nigrostriatal pathway increase the risk of DIP. However, DIP susceptibility is highly variable and unpredictable among different subjects. DIP is the second cause of parkinsonism but is still perceived as a neglected pathology on the day-to-day clinics by most of the studies

4 Epidemiology Population studies have detected incidences of DIP among the years age group of per 100,000 person-years In the USA estimation of 20, ,000 incident cases of DIP per year Another study focused on an elderly population of 64 years or older patients estimated the prevalence of DIP to be 3.3%, representing a 37% of all cases of parkinsonism DIP as the second cause of parkinsonism after ipd with a prevalence of % Antipsychotics are the prototypical and most common compounds producing DIP

5 Clinical features Akinetic rigid syndrome Type of causative drug Age of the patient Length of exposure Dose

6 Clinical features Asymmetry is less characteristic of DIP although it may happen. In contrast with vascular parkinsonism, which severely involves the legs and produces frequent impairment of gait, DIP produces a less severe gait disorder and a relatively more pronounced masked facial expression. The first symptom is a decrease in arm swing when walking, rather than a difficulty to rise from a low seat. The presence of tremor is variable. It is uncommon with drugs that selectively involve the dopamine neurotransmission, such as dopamine D 2 blockers, and much more frequent with other compounds that act through a less selective mechanism, such as amiodarone or calcium channel blockers Patients not achieving full recovery after a long period of time should be excluded from the diagnosis of pure DIP. There is evidence supporting that certain drugs can induce a persistent and even progressive parkinsonism. Lack of reversibility can also be explained considering that at least some patients with DIP are individuals in the presymptomatic phase of PD

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9 D 2 2 Muscarinic Promazina Promazine 1 5HT H 1

10 D 2 receptor occupancy(%)

11 Pathogenetic mechanisms (1) Diminished D 2 receptor stimulation in the striatum The pharmacological effect of antipsychotics are achieved with a blockade of a % of the dopamine receptors and parkinsonism appears when the blockade reaches % (occupancy not equal to antagonism) Other compounds act by inhibiting uptake of dopamine into granular vesicles of presynaptic neurons. Monoamines are concentrated from the cytoplasm into vesicles by vesicular monoamine transporters (VMATs) (two isoforms). VMAT 1 is located predominantly in peripheral endocrine and paracrine cells while VMAT 2 is located in the brain and sympathetic neurons. TBZ and reserpine bind to the same site on the VAMT 2 but to different conformations. While reserpine binds irreversibly being potentially toxic, TBZ displays reversible binding.

12 Pathogenetic mechanisms (2) Certain calcium channel antagonists decrease neuronal activity, reduce monoamine neurotransmission and dopaminergic viability and reduce the levels of HVA in the CSF of healthy primates suggesting that, even without previous dopamine dysfunction, they can produce a calcium-dependent reduction of dopamine release. Other compounds responsible for DIP may produce not only a reversible pharmacological impairment of dopamine neurotransmission, but also neurotoxic effects on dopamine neurons. Short-term blockade of dopamine D 2 receptors inhibits the production of neurotrophic substances for dopamine neurons, such as BDNF and stimulates the firing of dopamine neurons increasing the metabolism of dopamine and production of free radicals.

13 Pathogenetic mechanisms (3) Treatment with haloperidol increases oxidative metabolism in the brain, reduces the phosphorylation of Akt and activates caspase-3 Pharmacokinetic has explained interindividual differences in susceptibility to DIP by haloperidol variability related to CYP34A and the polymorphic CYP3A5 isoenzyme systems, which metabolize haloperidol to its pyridinium ion. Compounds interacting with this system such as antidepressants may enhance toxicity related to the pyridinium ion in patients treated with haloperidol. Parkin knockout mice are more susceptible to the toxic effects of cinnarizine than wild-type controls. In parkin-deficient mice, cinnarizine produced changes in the metabolism of dopamine and increased the expression of proapoptotic proteins and reduced the proportion of astroglia and hyperactivated microglial cells, suggesting that in these genetically modified animals, cinnarizine selectively triggers the expression of neurotoxic factors that could produce an irreversible damage to the nigrostriatal dopamine system.

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15 Gareri et al.,

16 Management Prevention: many patients with cognitive impairment or communication disorders are given antipsychotics larga manu to cover lack of adequate behavioral stimulation, medical attention or to play a calming effect on medical problems such as pain, constipation or urinary retention, or for conditions unrelated to psychosis including insomnia, anxiety or depression The second management strategy is to substitute certain compounds by a related drug with a better side-effect profile (i.e. domperidone). Clozapine is a useful agent for the treatment of drug-induced psychosis in PD, but it can also improve the clinical symptoms of DIP induced by other D 2 antagonists. The third strategy would be to carefully monitor individuals with special risk factors for developing DIP. Senior individuals, those with family history of parkinsonism, dementia or tremor and those under treatment with multiple drugs are more prone to suffer DIP. The prognosis of complete recovery is uncertain and % of the patients will continue to have symptoms several months after the discontinuation of the causative drug. At least 10% of patients will develop a persistent and progressive parkinsonian syndrome.

17 Conclusions Certain variables such as age, previous vascular damage to the nigrostriatal pathway, treatment with multiple drugs and genetic variants have been identified as risk factors for the appearance of DIP, but we still lack the knowledge to determine why some people are so resistant to astonishingly high doses of dopamine blockers and others are incredibly sensible to lower doses of the same agents. Several mechanisms including a more antagonistic effect toward serotonin-2a receptors than toward dopamine receptors, and a faster dissociation from D 2 receptors explain the lower frequency of DIP with second- compared with firstgeneration antipsychotics The culprits have to be looked for and withdrawn if possible, second- and thirdgeneration are preferred to first-generation antipsychotics, there is no evidence supporting the use of levodopa, dopamine agonists or anticholinergics for the treatment of DIP and gastrointestinal motility drugs not crossing the blood--brain barrier (such as domperidone) are preferred to those with central effects. Second-generation antipsychotics such as quetiapine are associated with very low rates of DIP. Others, such as clozapine, have not been associated with DIP but entail a spectrum of undesirable side effects.

18 Grazie per la vostra attenzione