RESUMEN
BACKGROUND AND OBJECTIVES: Accumulating evidence indicates that amitriptyline decreases pain sensation when administered orally, intraperitoneally, or for sciatic nerve block. Previous reports of intrathecal administration of amitriptyline have yielded inconsistent results. The failure of amitriptyline to provide antinociception may partly be related to its high logP (octanol-water partition coefficient) and consequent poor spread within the cerebrospinal fluid. We evaluated spinal block after various concentrations of amitriptyline administered intrathecally in a fixed high volume. METHODS: We administered 100 microL of 5, 10, 15.9 (0.5%), 25, 50, or 100 mmol/L amitriptyline hydrochloride solution or 100 microL of 15.4 mmol/L (0.5%) bupivacaine hydrochloride solution intrathecally to rats. The neurologic deficit was evaluated by antinociceptive, motor, and proprioceptive responses, and the spinal cord was examined for histopathologic changes. RESULTS: Doses of 100 microL amitriptyline at 15.9 mmol/L (0.5%) and 25 mmol/L produced longer complete nerve block than did bupivacaine at 15.4 mmol/L (0.5%); 5 and 10 mmol/L amitriptyline produced only partial nerve block. However, with 100 microL intrathecal amitriptyline at 50 and 100 mmol/L, many rats did not fully recover from spinal block. Severe axonal degeneration, myelin breakdown, and replacement of neuronal structures by vacuoles were seen in the spinal root section of animals injected with concentrations higher than 25 mmol/L amitriptyline. CONCLUSIONS: At lower doses, intrathecal injection of high volumes of amitriptyline results in long-acting spinal block. At higher doses, intrathecal amitriptyline results in irreversible neurologic deficit. Therefore, we do not recommend the use of intrathecal amitriptyline because of a very low therapeutic index.
Asunto(s)
Amitriptilina/farmacología , Analgésicos no Narcóticos/farmacología , Enfermedades del Sistema Nervioso/inducido químicamente , Amitriptilina/administración & dosificación , Amitriptilina/efectos adversos , Analgésicos no Narcóticos/administración & dosificación , Analgésicos no Narcóticos/efectos adversos , Análisis de Varianza , Anestésicos Locales/administración & dosificación , Animales , Bupivacaína/administración & dosificación , Relación Dosis-Respuesta a Droga , Inyecciones Espinales/métodos , Masculino , Actividad Motora/efectos de los fármacos , Bloqueo Nervioso/métodos , Propiocepción/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Médula Espinal/efectos de los fármacos , Médula Espinal/ultraestructura , Factores de TiempoRESUMEN
UNLABELLED: Among various tricyclic antidepressants, doxepin and amitriptyline are also long-acting local anesthetics. We synthesized a new compound, N-methyl doxepin, and investigated whether this derivative possesses local anesthetic properties. N-methyl doxepin and doxepin were tested in a rat sciatic nerve model at 2.5, 5.0, and 10 mM. Proprioceptive, motor, and nociceptive blockade were evaluated and compared with those induced by 0.5% bupivacaine. Block of Na(+) channels by N-methyl doxepin and doxepin was assessed in cultured pituitary tumor cells under voltage clamp conditions. N-methyl doxepin elicited complete nociceptive blockade that generally lasted longer than that caused by doxepin (e.g., approximately 7.4 h versus 5.3 h at 10 mM). Significant differences were observed for full recovery of function at all concentrations and for the duration of complete blockade except at 2.5 mM. Bupivacaine at 0.5% (15.4 mM) was less effective in producing complete blockade (approximately 1.5 h) than N-methyl doxepin and doxepin. Both doxepin and N-methyl doxepin were potent Na(+) channel blockers, although N-methyl doxepin displayed a slower wash-in rate. No morphological alterations were detected in cross-sectioned sciatic nerve specimens with these three drugs. We conclude that N-methyl doxepin is a potent Na(+) channel blocker and a long-acting local anesthetic for rat sciatic nerve blockade. IMPLICATIONS: N-methyl doxepin and doxepin are both potent Na(+) channel blockers; they elicit rat sciatic nerve block lasting longer than that induced by bupivacaine and seem to be nontoxic to peripheral nerves at concentrations up to 10 mM.
Asunto(s)
Anestésicos Locales/farmacología , Bupivacaína/farmacología , Doxepina/análogos & derivados , Doxepina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Línea Celular Tumoral , Masculino , Nociceptores/efectos de los fármacos , Neoplasias Hipofisarias/patología , Propiocepción/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/patología , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacosRESUMEN
BACKGROUND: Increasing the duration of local anesthesia and/or creating greater differential blockade (i.e., selective block of pain-transmitting nerve fibers) has been attempted by modifying currently available agents. Most drugs show a different profile depending on the model or species studied. This study was designed to investigate the differential nerve-blocking properties of amitriptyline and its quaternary ammonium derivative in rats and sheep. METHODS: The Na+ channel-blocking properties of N-methyl amitriptyline were determined with the patch clamp technique in cultured GH(3) cells. Various functions (motor, nociception, proprioception-ataxia) were compared in rats (spinal and sciatic nerve blockade) and sheep (spinal blockade) with amitriptyline, N-methyl amitriptyline, lidocaine, and bupivacaine (partially from historical data). RESULTS: In vitro testing revealed N-methyl amitriptyline to be a potent Na+ channel blocker similar to amitriptyline but with a much longer duration of action. All drug concentrations tested in both the sciatic nerve model and the spinal block model produced no significant differential blockade in rats. Three of six rats in the 20-mM N-methyl amitriptyline group showed residual blockade 4 days after sciatic nerve injection. However, in the sheep spinal model, amitriptyline and in particular N-methyl amitriptyline displayed significant differential blockade at most time points. Sheep data for lidocaine and bupivacaine seemed to be more comparable to the clinical experience in humans than did rat data. CONCLUSIONS: Amitriptyline and N-methyl amitriptyline are potent Na+ channel blockers and show greater differential blockade in sheep than in rats. This differential blockade in sheep is greater than that produced by lidocaine or bupivacaine.
Asunto(s)
Amitriptilina/análogos & derivados , Amitriptilina/farmacología , Antidepresivos Tricíclicos/farmacología , Bloqueo Nervioso , Anestesia Raquidea , Anestésicos Locales/farmacología , Animales , Conducta Animal/efectos de los fármacos , Células Cultivadas , Electrofisiología , Femenino , Lidocaína/farmacología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiología , Ovinos , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacos , Especificidad de la EspecieRESUMEN
Amitriptyline, nortriptyline, imipramine, doxepin, desipramine, protriptyline, trimipramine, and maprotiline are tricyclic antidepressants (TCAs) used orally in treating major depressive disorders. Recent studies showed that amitriptyline is more potent in blocking the sciatic nerve functions in vivo by local injection than bupivacaine, a long-acting local anesthetic. We therefore tested whether various TCAs could likewise act as local anesthetics in vivo after single injection via the rat sciatic notch. The duration of complete sciatic nerve blockade by TCAs and the time to reach full recovery were measured with neurobehavioral assays and compared with results from bupivacaine. Amitriptyline, doxepin, and imipramine at 5mM elicited a longer complete sciatic nerve blockade than did bupivacaine at 15.4mM (0.5%), whereas trimipramine and desipramine at 5mM produced a shorter blockade. In contrast, nortriptyline, protriptyline, and maprotiline failed to elicit complete sciatic nerve blockade. Thus, TCAs have very different efficacy as local anesthetics in vivo. The duration of rat sciatic nerve blockade in vivo by TCAs is not well correlated with the 50% inhibitory concentration (IC(50)) of TCAs in blocking human cardiac Nav1.5 Na(+) channels expressed in human embryonic kidney cells. With this in vitro expression system, TCAs appear more potent than bupivacaine as Na(+) channel blockers in Nav1.5 Na(+) channels. We suggest that the ability of TCAs to pass through various membrane barriers within peripheral nerve trunks is crucial to their local anesthetic efficacy in vivo. TCAs with a tertiary amine appear more effective in penetrating these membrane barriers than TCAs with a secondary amine.
Asunto(s)
Anestésicos Locales/farmacología , Antidepresivos Tricíclicos/farmacología , Nervio Ciático/efectos de los fármacos , Aminas/química , Aminas/clasificación , Anestésicos Locales/uso terapéutico , Animales , Antidepresivos Tricíclicos/uso terapéutico , Línea Celular , Relación Dosis-Respuesta a Droga , Doxepina/farmacología , Doxepina/uso terapéutico , Impedancia Eléctrica , Embrión de Mamíferos , Humanos , Riñón/efectos de los fármacos , Masculino , Potenciales de la Membrana/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Examen Neurológico/efectos de los fármacos , Nortriptilina/farmacología , Nortriptilina/uso terapéutico , Dolor/tratamiento farmacológico , Dimensión del Dolor/métodos , Técnicas de Placa-Clamp , Propiocepción/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Trastornos Relacionados con Sustancias , Factores de Tiempo , Transfección/métodosRESUMEN
BACKGROUND: The antidepressant amitriptyline is commonly used orally for the treatment of chronic pain, particularly neuropathic pain, which is thought to be caused by high-frequency ectopic discharge. Among its many properties, amitriptyline is a potent Na(+) channel blocker in vitro, has local anesthetic properties in vivo, and confers additional blockade at high stimulus-discharge rates (use-dependent blockade). As with other drug modifications, adding a phenylethyl group to obtain a permanently charged quaternary ammonium derivative may improve these advantageous properties. METHODS: The electrophysiologic properties of N-phenylethyl amitriptyline were assessed in cultured neuronal GH(3) cells with the whole cell mode of the patch clamp technique, and the therapeutic range and toxicity were evaluated in the rat sciatic nerve model. RESULTS: In vitro, N-phenylethyl amitriptyline at 10 microm elicits a greater block of Na(+) channels than amitriptyline (resting block of approximately 90% vs. approximately 15%). This derivative also retains the attribute of amitriptyline in evoking high-degree use-dependent blockade during repetitive pulses. In vivo, duration to full recovery of nociception in the sciatic nerve model was 1,932 +/- 72 min for N-phenylethyl amitriptyline at 2.5 mm (n = 7) versus 72 +/- 3 min for lidocaine at 37 mm (n = 4; mean +/- SEM). However, there was evidence of neurotoxicity at 5 mm. CONCLUSION: N-phenylethyl amitriptyline appears to have a narrow therapeutic range but is much more potent than lidocaine, providing a block duration several times longer than any clinically used local anesthetic. Further work in animal models of neuropathic pain will assess the potential use of this drug.
Asunto(s)
Amitriptilina/farmacología , Anestésicos Locales/farmacología , Bloqueo Nervioso/métodos , Nervio Ciático/efectos de los fármacos , Amitriptilina/análogos & derivados , Animales , Células Cultivadas , Lidocaína/farmacología , Ratas , Factores de TiempoRESUMEN
BACKGROUND AND OBJECTIVES: We tested the hypothesis that the duration of cutaneous anesthesia elicited by the permanently charged compound N-phenylethyl lidocaine (tonicaine) would be longer than that elicited by its parent structure, lidocaine, and that it would be less affected by epinephrine (epi), after subcutaneous injection in rats, as a model for infiltration anesthesia. METHODS: Subcutaneous injections were performed on the shaved dorsal skin of rats with either tonicaine or lidocaine (0.1% or 0.5%, n = 8 in each group) with and without epi (1:200,000). Inhibition of the cutaneous trunci muscle reflex was quantitatively evaluated by a blinded observer by the number of times pinpricks failed to elicit the nocifensive motor response out of a total of 6 pinpricks applied to the injected area. RESULTS: Duration of complete nociceptive blockade in the 0.5% tonicaine and lidocaine groups was 619 +/- 47 and 58 +/- 2 minutes, respectively; duration of full recovery in these groups was 1,106 +/- 19 and 86 +/- 3 minutes, respectively. Epi increased the duration of complete block in the 0.5% tonicaine and lidocaine groups to 750 +/- 13 and 97 +/- 11 minutes, respectively, and the duration of full recovery to 1,185 +/- 13 and 172 +/- 6 minutes, respectively. Skin toxicity was seen only in the 0.5% tonicaine with epi group (3 of 8 rats). CONCLUSIONS: Tonicaine is a substantially longer lasting local anesthetic with a delayed onset of action compared with lidocaine and may be useful in situations where long duration of infiltration block is desirable.