Trihexifenidilo: droga con dificultades en su prescripción, mal usada y poco conocida / Trihexyphenidyl: a drug with difficulties in its prescription, poorly used and little known

Se realizó una amplia revisión de lo descrito en la literatura sobre el trihexifenidilo, droga anticolinérgica empleada básicamente en enfermedades psiquiátricas y neurológicas, con el fin de contribuir desde el punto de vista educativo a la información del personal de salud sobre las potencialidades farmacológicas de este medicamento en cuanto a su consumo. Se valoró el binomio riesgo-beneficio, se particularizó en los detalles de sus indicaciones, dosificaciones y posibles alternativas de sustitución del fármaco, así como implicaciones de su consumo de riesgo y su poder adictivo. Se hacen recomendaciones para ejecutar buenas prácticas en medicina y la valoración de sus aspectos médico-legales. Finalmente, se hacen referencias de la función del personal de la salud como divulgador de la temática y su responsabilidad en la consecución de estilos de vida saludables y mayor calidad de vida de nuestra población(AU)

Treatment with subthreshold doses of caffeine plus trihexyphenidyl fully restores locomotion and exploratory activity in reserpinized rats.

Trihexyphenidyl (THP) is a drug commonly used to reduce parkinsonian symptoms. An important side effect of this agent is memory impairment. Since caffeine enhances the potency of THP to inhibit haloperidol-induced catalepsy, caffeine may be used as an adjuvant of lower doses of THP, in order to improve its antiparkinsonian effects without causing memory disruption. To further assess the synergism between caffeine and THP, both drugs were tested in reserpinized rats, another preclinical model of Parkinson's disease. Four groups of rats (n = 7) were treated with reserpine (5 mg/kg, i.p.). A control group (n = 7) was treated only with the vehicle for reserpine (dimethylsulphoxide). The spontaneous locomotor behavior was tested 24 h later in a box with infrared sensors, 30 min after receiving one of the following treatments: distilled water (1 ml/kg), caffeine (1 mg/kg), THP (0.1 mg/kg) or caffeine plus THP. The levels of horizontal locomotion (14 +/- 5%) and vertical exploration (15 +/- 10%) were significantly lower in reserpinized rats treated with distilled water, compared with the mean activity values (100%) recorded in animals pretreated only with the vehicle for reserpine. The reserpine-induced hypokinesia was neither reversed by caffeine alone nor by THP alone. However, the combination of caffeine plus THP restored locomotion (141 +/- 19%) and vertical exploration (82 +/- 17%) to levels not significantly different to those of non-reserpinized rats. Moreover, the time-course of locomotion and exploration displayed the characteristic habituation over time, in which short-term memory processes are involved. Also, the thigmotaxis index indicated that the combined treatment did not induce anxiety-like behavior. Hence, these results support the proposal that low, subthreshold doses of caffeine plus THP have the potential to alleviate the motor disabilities in parkinsonian patients, with a low risk of causing anxiety or memory impairment.

Fármacos antiparkinsonianos / Anti-Parkinson drugs

La enfermedad de Parkinson requiere la administración de diversos fármacos. En el siguiente artículo se describen las diferentes drogas utilizadas, -agentes dopaminérgicos, anticolinérgicos y neuroprotectores- sus modos de acción, efectos adversos y precauciones y advertencias (AU)

Selective A2A, but not A1 adenosine antagonists enhance the anticataleptic action of trihexyphenidyl in rats.

In rats made cataleptic with haloperidol (5.32 micromol/kg), the bar test was used to assess the possible synergism between the muscarinic antagonist trihexyphenidyl (THP) and selective adenosine A(1) and A(2A) receptor antagonists. Neither catalepsy intensity nor latency were affected by a subthreshold dose of THP (0.33 micromol/kg). The selective adenosine A(1) antagonist 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) (5.15 micromol/kg) caused a small, but significant reduction of catalepsy intensity that remained unchanged when combined with THP. DPCPX had no effect on catalepsy latency, either alone or combined with THP. In contrast, an equimolar dose of the selective adenosine A(2A) antagonist 4-(2-[7-amino-2-(2-furyl)1,2,4-triazolo[2,3-a]-[1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) (5.15 micromol/kg) produced a significant reduction of catalepsy intensity and increased catalepsy latency. Both effects were potentiated when ZM 241385 was combined with THP. The synergism was more evident when rats were pretreated with a subthreshold dose of ZM 241385 (1.55 micromol/kg) that was unable to modify catalepsy parameters when applied alone, but produced a significant reduction in catalepsy intensity and an increase in catalepsy latency when administered with THP. Catalepsy was unaffected by a combination of equimolar, subthreshold doses of DPCPX (1.55 micromol/kg) and ZM 241385 (1.55 micromol/kg). These findings indicate that the anticataleptic effect of anticholinergics is enhanced only by the selective blockade of adenosine A(2A) receptors.

Selective M1 muscarinic receptor antagonists disrupt memory consolidation of inhibitory avoidance in rats.

The effect of three different M1 muscarinic antagonists, pirenzepine, biperiden, and trihexyphenidyl on memory consolidation was investigated. Rats were trained in a one-trial step-through inhibitory avoidance task and injected intraperitoneally immediately afterwards, either with pirenzepine, biperiden, or trihexyphenidyl (dose range from 0 to 16 mg/kg). The non-selective antimuscarinic compound scopolamine, was also administered for comparison. One day later, rats were tested for retention. Results show that biperiden, trihexyphenidyl and scopolamine produced a dose-dependent impairment of inhibitory avoidance consolidation, while pirenzepine had no effect. The amnestic state produced by biperiden and trihexyphenidyl was comparable to that observed after the administration of scopolamine. These results indicate that the selective blockade of the central M1 muscarinic receptors interfere with memory consolidation of inhibitory avoidance and suggest that this receptor subtype is critically involved in mnemonic functions.

Evidence that the M1 muscarinic receptor subtype mediates the effects of oxotremorine on masculine sexual behavior.

The cholinergic system participates in the regulation of masculine sexual behavior, mainly through the muscarinic system. Recently, muscarinic receptors have been subdivided into at least two subtypes, M1 and M2, according to their differential affinity for pirenzepine. In this study, we analyzed the possible participation of the M1 muscarinic receptor subtype on masculine sexual behavior regulation. In the first experiment, trihexyphenidyl, a specific M1 antagonist, was administered to experienced adult male rats in a wide range of doses (from 0.1 to 6.4 mg/kg). No modification was observed in any of the male sexual behavior parameters recorded, with the exception of the highest dose at which an increase of the intromission frequency and a decrease of the ejaculation frequency were observed. In the second experiment, trihexyphenidyl was administered in several doses (from 0.2 to 1.6 mg/kg), before the administration of oxotremorine, a muscarinic agonist, at a dose that readily facilitates masculine sexual behavior. Trihexyphenidyl completely prevented the facilitatory effects of oxotremorine even at the smallest dose used. These results strongly suggest that the M1 muscarinic receptor subtype participates in the cholinergic facilitation of masculine sexual behavior.