Adjuvantes Francisco José de la Prada Alvarez. Servicio de Nefrología. Hospital Universitario Son Dureta

AdjuvantesAdjuvantes

Francisco José de la Prada Alvarez.Francisco José de la Prada Alvarez.Servicio de Nefrología.Servicio de Nefrología.

Hospital Universitario Son DuretaHospital Universitario Son Dureta

Programa InformedPrograma Informed 22




2.2 Según la causa subyacente se reconocen 2.2 Según la causa subyacente se reconocen tres tipos generales de dolor:tres tipos generales de dolor:

1) nociceptivo somático 1) nociceptivo somático 2) nociceptivo visceral 2) nociceptivo visceral 3) neuropático.3) neuropático.

2.2.1 El dolor nociceptivo somático proviene de 2.2.1 El dolor nociceptivo somático proviene de la estimulación de nociceptores específicos en la estimulación de nociceptores específicos en los tejidos cutáneo y conjuntivo profundo los tejidos cutáneo y conjuntivo profundo (músculos, tendones, huesos, etc.), y se suele (músculos, tendones, huesos, etc.), y se suele asociar a lesión o enfermedad. El dolor somático asociar a lesión o enfermedad. El dolor somático se describe a menudo como “sordo” o “agudo” y se describe a menudo como “sordo” o “agudo” y como “algia”. El dolor somático suele ser como “algia”. El dolor somático suele ser constante y por lo general se controla al eliminar constante y por lo general se controla al eliminar la causa o al tratar la patología subyacente. la causa o al tratar la patología subyacente.


2.2 Según la causa subyacente se reconocen 2.2 Según la causa subyacente se reconocen tres tipos generales de dolor:tres tipos generales de dolor:–


2.2.2 El dolor nociceptivo visceral es un dolor 2.2.2 El dolor nociceptivo visceral es un dolor que se origina por la lesión, distensión, que se origina por la lesión, distensión, obstrucción o inflamación de los órganos obstrucción o inflamación de los órganos torácicos, abdominales o pélvicos. Por ejemplo, torácicos, abdominales o pélvicos. Por ejemplo, el dolor visceral puede provenir de la el dolor visceral puede provenir de la obstrucción de una víscera hueca (p. ej., el obstrucción de una víscera hueca (p. ej., el intestino), la distensión o la isquemia de los intestino), la distensión o la isquemia de los componentes del intestino o por el rápido componentes del intestino o por el rápido estiramiento de la cápsula de un órgano sólido estiramiento de la cápsula de un órgano sólido (hígado).(hígado).


2.2 Según la causa subyacente se reconocen tres tipos 2.2 Según la causa subyacente se reconocen tres tipos generales de dolor:generales de dolor:–


2.2.3 2.2.3 El dolor neuropático está causado por la El dolor neuropático está causado por la lesión o la destrucción de los nervios localizados lesión o la destrucción de los nervios localizados en la periferia o en el sistema nervioso centralen la periferia o en el sistema nervioso central . . Esto provoca una función anormal del nervio, que se Esto provoca una función anormal del nervio, que se manifiesta como un dolor que se califica de manifiesta como un dolor que se califica de “quemazón”, “latigazo” u “hormigueo”.“quemazón”, “latigazo” u “hormigueo”. El dolor El dolor neuropático puede ser constante y sostenido, pudiendo neuropático puede ser constante y sostenido, pudiendo existir un dolor intermitente, sobreimpuesto, similar a un existir un dolor intermitente, sobreimpuesto, similar a un choque, que se describe como eléctrico o en choque, que se describe como eléctrico o en escopetazo. Además, escopetazo. Además, pueden aparecer pueden aparecer sensaciones anormales como alodinia, sensaciones anormales como alodinia, parestesia y disestesia.parestesia y disestesia.




Los analgésicos adyuvantes tricíclicos son la amitriptilina, la doxepina, la Los analgésicos adyuvantes tricíclicos son la amitriptilina, la doxepina, la imipramina, la desipramina y la nortriptilina. Son especialmente útiles en los imipramina, la desipramina y la nortriptilina. Son especialmente útiles en los síndromes de dolor neuropático.síndromes de dolor neuropático.

Los analgésicos adyuvantes anticonvulsivantes son la carbamazepina, la Los analgésicos adyuvantes anticonvulsivantes son la carbamazepina, la difenilhidantoína, el ácido valproico, el divalproato sódico y gabapentina. difenilhidantoína, el ácido valproico, el divalproato sódico y gabapentina. Son especialmente útiles en el dolor neuropático lancinante.Son especialmente útiles en el dolor neuropático lancinante.

La dexametasona y la prednisona son los corticoides utilizados con mayor La dexametasona y la prednisona son los corticoides utilizados con mayor frecuencia en el tratamiento del dolor. Una serie de alteraciones dolorosas frecuencia en el tratamiento del dolor. Una serie de alteraciones dolorosas responden a su empleo, entre ellas el dolor óseo metastásico, el aumento responden a su empleo, entre ellas el dolor óseo metastásico, el aumento de la presión intracraneal, la compresión aguda de la médula espinal y el de la presión intracraneal, la compresión aguda de la médula espinal y el dolor neuropático debido a la infiltración o la compresión por el tumor.dolor neuropático debido a la infiltración o la compresión por el tumor.

La metotrimeprazina es un analgésico neuroléptico de probada utilidad en La metotrimeprazina es un analgésico neuroléptico de probada utilidad en los pacientes con cáncer avanzado que tienen dolor con ansiedad, los pacientes con cáncer avanzado que tienen dolor con ansiedad, agitación o náuseas. agitación o náuseas.

El clonazepam es una benzodiazepina ampliamente aceptada en el El clonazepam es una benzodiazepina ampliamente aceptada en el tratamiento del dolor neuropático.tratamiento del dolor neuropático.


AnticonvulsivantesAnticonvulsivantes

Los anticonvulsivantes utilizados en el manejo del dolor Los anticonvulsivantes utilizados en el manejo del dolor incluyen la incluyen la carbamazepina, la difenilhidantoína y los carbamazepina, la difenilhidantoína y los fármacos relacionados con el ácido valproico y fármacos relacionados con el ácido valproico y gabapentina.gabapentina. Todos se han mostrado útiles en el Todos se han mostrado útiles en el tratamiento del dolor neuropáticotratamiento del dolor neuropático. .

Los anticonvulsivantes se han utilizado para el Los anticonvulsivantes se han utilizado para el tratamiento del dolor desde hace más de 50 años.tratamiento del dolor desde hace más de 50 años.

Fenitoina, Carbamacepina, ácido valproico, gabapentina, Fenitoina, Carbamacepina, ácido valproico, gabapentina, topiramate, vigabatrina, tiagabina, levetiracetam, topiramate, vigabatrina, tiagabina, levetiracetam, zonisamida y oxcarbacepina.zonisamida y oxcarbacepina.



Limitaciones de uso.Limitaciones de uso.– Los más antiguos (fenitoina, Los más antiguos (fenitoina,

carbamacepina y acido valproico) carbamacepina y acido valproico) requieren monitorizacion sanguínea y de requieren monitorizacion sanguínea y de la función hepática.la función hepática.

– Efectos secundarios en un alto porcentaje Efectos secundarios en un alto porcentaje de pacientes.de pacientes.


Drug Systemic side effects Neurotoxic side effects

Carbamazepine Nausea, vomiting, diarrhea, hyponatremia, rash, pruritus

Drowsiness, dizziness, blurred or double vision, lethargy, headache

Ethosuximide Nausea, vomiting Sleep disturbance, drowsiness, hyperactivity

Felbamate Nausea, vomiting, anorexia, weight loss Insomnia, dizziness, headache, ataxia

Gabapentin None known Somnolence, dizziness, ataxia

Lamotrigine Rash, nausea Dizziness, somnolence

Levetiracetam Infection Fatigue, somnolence, dizziness, agitation, anxiety

Oxcarbazepine Nausea, rash, hyponatremia Sedation, headache, dizziness, vertigo, ataxia, diplopia

Phenytoin Gingival hypertrophy, body hair increase, rash, lymphadenopathy

Confusion, slurred speech, double vision, ataxia, neuropathy (with long-term use)

Pregabalin Weight gain Dizziness, somnolence, ataxia

Primidone, phenobarbital

Nausea, rash Alteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, tolerance, dependence

Tiagabine None known Dizziness, lack of energy, somnolence, nausea, nervousness, tremor, difficulty concentrating, abdominal pain

Topiramate Weight loss, renal stones, paresthesias Fatigue, nervousness, difficulty concentrating, confusion, depression, anorexia, language problems, anxiety, mood problems, tremor

Valproate Weight gain, nausea, vomiting, hair loss, easy bruising

Tremor

Zonisamide Nausea, anorexia Somnolence, dizziness, ataxia, confusion, difficulty concentrating




GabapentinaGabapentina: el más efectivo; debe : el más efectivo; debe considerarse de primera elección en el considerarse de primera elección en el tratamieto del dolor neuropático.tratamieto del dolor neuropático.Neuralgia del trigémino: carbamacepinaNeuralgia del trigémino: carbamacepina y luego y luego lamotrignina, toppiromato, o gabapentina, solos lamotrignina, toppiromato, o gabapentina, solos o en combinación.o en combinación.Neuropatía diabética: carbamazepine, Neuropatía diabética: carbamazepine, gabapentina y oxcarbacepina.gabapentina y oxcarbacepina.Fenitoina:Fenitoina: barato, disponible por vía oral y barato, disponible por vía oral y parenteral.parenteral.


N03AA-Barbitúricos

NOMBRE GENÉRICO

PRESENTACIÓN VÍA NOMBRE COMERCIAL

Fenobarbital Amp 200 mg/1 mlComp 15 mgComp 100 mg

IMOROR

Luminal Luminaletas Luminal 0,1


N03AB-Hidantoinas

NOMBRE GENÉRICO


Fenitoína sódica Comp 100 mgCaps 100 mgJbe 125 mg/5 mlVial 250 mg/5 ml

ORORORIV, IM

NeosindantoínaEpanutinFenitoína Rubió


N03AD-Carboxamidas

NOMBRE GENÉRICO


Carbamazepina Comp 200 mg OR Tegretol


N03AG-Acidos grasos

NOMBRE GENÉRICO


Valproico Acido Comp 200 mgComp 500 mgSol 200 mg/mlVial 400 mg

ORORORIV

DepakineDepakine iny

Vigabatrina Comp 500 mgSobres 500 mg

OROR

Sabrilex


N03AX-Otros antiepilépticos

NOMBRE GENÉRICO


Gabapentina Cap 300 mgCap 400 mg

OROR

Neurontin

Lamotrigina Comp 100 mgComp 200 mg

OROR

Lamictal

GabapentinaGabapentina



Molécula estructuralmente relacionada con Molécula estructuralmente relacionada con GABA.GABA.No se une a los receptores GABA, ni influye No se une a los receptores GABA, ni influye en su síntesis ni recaptación.en su síntesis ni recaptación.Parece que se une a receptores de calcio Parece que se une a receptores de calcio voltaje dependientes, localizados voltaje dependientes, localizados presinapticamente, que modulan la presinapticamente, que modulan la liberación de neurotransmisores excitatorios liberación de neurotransmisores excitatorios relacionados con la nociocepcion y la relacionados con la nociocepcion y la genesis de epilepsia.genesis de epilepsia.



DOSING: ADULTSDOSING: ADULTS Anticonvulsant: Oral:Anticonvulsant: Oral: Initial: 300 mg 3 times/day, if necessary the dose may be Initial: 300 mg 3 times/day, if necessary the dose may be increased up to 1800 mg/dayincreased up to 1800 mg/day Maintenance: 900-1800 mg/day administered in 3 divided doses; Maintenance: 900-1800 mg/day administered in 3 divided doses; doses of up to 2400 mg/day have been tolerated in long-term doses of up to 2400 mg/day have been tolerated in long-term clinical studies; up to 3600 mg/day has been tolerated in short-term clinical studies; up to 3600 mg/day has been tolerated in short-term studiesstudies Note: If gabapentin is discontinued or if another anticonvulsant is Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 added to therapy, it should be done slowly over a minimum of 1 week.week.Chronic painChronic pain (unlabeled use): Oral: (unlabeled use): Oral: 300-1800 mg/day given in 3 300-1800 mg/day given in 3 divided dosesdivided doses has been the most common dosage range has been the most common dosage rangePostoperative painPostoperative pain (unlabeled use): (unlabeled use): 300-1200 mg 1-2 hours 300-1200 mg 1-2 hours before surgerybefore surgeryPostherpetic neuralgiaPostherpetic neuralgia: Day 1: 300 mg, Day 2: 300 mg twice : Day 1: 300 mg, Day 2: 300 mg twice daily, Day 3: 300 mg 3 times/day; dose may be titrated as daily, Day 3: 300 mg 3 times/day; dose may be titrated as needed for pain relief (range: 1800-3600 mg/day, daily doses needed for pain relief (range: 1800-3600 mg/day, daily doses >1800 mg do not generally show greater benefit)>1800 mg do not generally show greater benefit)



DOSING: PEDIATRICDOSING: PEDIATRIC Anticonvulsant: OralAnticonvulsant: Oral Children 3-12 years: Initial: 10-15 mg/kg/day in 3 Children 3-12 years: Initial: 10-15 mg/kg/day in 3 divided doses; titrate to effective dose over ~3 days; divided doses; titrate to effective dose over ~3 days; dosages of up to 50 mg/kg/day have been tolerated in dosages of up to 50 mg/kg/day have been tolerated in clinical studiesclinical studies Children 3-4 years: Effective dose: 40 mg/kg/day in 3 Children 3-4 years: Effective dose: 40 mg/kg/day in 3 divided dosesdivided doses Children 5-12 years: Effective dose: 25-35 mg/kg/day Children 5-12 years: Effective dose: 25-35 mg/kg/day in 3 divided dosesin 3 divided doses Children >12 years: Refer to adult dosing. Children >12 years: Refer to adult dosing.Note: If gabapentin is discontinued or if another Note: If gabapentin is discontinued or if another anticonvulsant is added to therapy, it should be done anticonvulsant is added to therapy, it should be done slowly over a minimum of 1 weekslowly over a minimum of 1 week



DOSING: ELDERLYDOSING: ELDERLY — —

Studies in elderly patients have shown a Studies in elderly patients have shown a decrease in clearance as age increasesdecrease in clearance as age increases. . This is most likely due to age-related This is most likely due to age-related decreases in renal function; dose decreases in renal function; dose reductions may be needed.reductions may be needed.


GabapentinaGabapentinaDOSING: RENAL IMPAIRMENTDOSING: RENAL IMPAIRMENT — — Hemodialysis: DialyzableHemodialysis: DialyzableGabapentin Dosage Adjustments in Renal ImpairmentGabapentin Dosage Adjustments in Renal Impairment– Clcr 60 mL/minute): 300-1200 mg 3 times/day Clcr 60 mL/minute): 300-1200 mg 3 times/day – Clcr >30-59 mL/minute: 200-700 mg twice/day Clcr >30-59 mL/minute: 200-700 mg twice/day – Clcr >15-29 mL/minute: 200-700 mg/day Clcr >15-29 mL/minute: 200-700 mg/day – Clcr 15 mL/minute: 100-300 mg/day Clcr 15 mL/minute: 100-300 mg/day – Clcr <15 mL/minute: Reduce daily dose in proportion to creatinine clearance. Clcr <15 mL/minute: Reduce daily dose in proportion to creatinine clearance.

Hemodialysis single supplemental dose: 125-350 mg (given after each 4 Hemodialysis single supplemental dose: 125-350 mg (given after each 4 hours of hemodialysis).hours of hemodialysis).

FG > 50 ml/min

FG 10-50 ml/min

FG < 10 ml/min

Dosis suplemtaria tras HD

DPCA TSCR

Gabapentina 400 mg/8 h400 mg/8 h 300 mg/12-300 mg/12-24 h24 h

300 mg/dia300 mg/dia 200-300 mg200-300 mg DesconocidaDesconocida 300 mg/12-300 mg/12-24 h24 h



ADVERSE REACTIONS SIGNIFICANTADVERSE REACTIONS SIGNIFICANT — As — As reported in patients >12 years of age, unless reported in patients >12 years of age, unless otherwise noted in children (3-12 years)otherwise noted in children (3-12 years)

>10%:>10%: Central nervous system: Central nervous system: SomnolenceSomnolence (20%; (20%; children 8%), children 8%), dizziness dizziness (17% to 28%; children (17% to 28%; children 3%), 3%), ataxiaataxia (13%), fatigue (11%) (13%), fatigue (11%) Miscellaneous: Viral infection (children 11%) Miscellaneous: Viral infection (children 11%)


GabapentinaGabapentinaADVERSE REACTIONS SIGNIFICANTADVERSE REACTIONS SIGNIFICANT — As reported in patients >12 years of age, — As reported in patients >12 years of age, unless otherwise noted in children (3-12 years)unless otherwise noted in children (3-12 years)1% to 10%:1% to 10%: Cardiovascular: Peripheral edema (2% to 8%), vasodilatation (1%) Cardiovascular: Peripheral edema (2% to 8%), vasodilatation (1%) Central nervous system: Fever (children 10%), hostility (children 8%), emotional Central nervous system: Fever (children 10%), hostility (children 8%), emotional lability (children 4%), fatigue (children 3%), headache (3%), ataxia (3%), abnormal lability (children 4%), fatigue (children 3%), headache (3%), ataxia (3%), abnormal thinking (2% to 3%; children 2%), amnesia (2%), depression (2%), dysarthria (2%), thinking (2% to 3%; children 2%), amnesia (2%), depression (2%), dysarthria (2%), nervousness (2%), abnormal coordination (1% to 2%), twitching (1%), hyperesthesia nervousness (2%), abnormal coordination (1% to 2%), twitching (1%), hyperesthesia (1%)(1%) Dermatologic: Pruritus (1%), rash (1%) Dermatologic: Pruritus (1%), rash (1%) Endocrine & metabolic: Hyperglycemia (1%) Endocrine & metabolic: Hyperglycemia (1%) Gastrointestinal: Diarrhea (6%), nausea/vomiting (3% to 4%; children 8%), Gastrointestinal: Diarrhea (6%), nausea/vomiting (3% to 4%; children 8%), abdominal pain (3%), weight gain (adults and children 2% to 3%), dyspepsia (2%), abdominal pain (3%), weight gain (adults and children 2% to 3%), dyspepsia (2%), flatulence (2%), dry throat (2%), xerostomia (2% to 5%), constipation (2% to 4%), flatulence (2%), dry throat (2%), xerostomia (2% to 5%), constipation (2% to 4%), dental abnormalities (2%), appetite stimulation (1%)dental abnormalities (2%), appetite stimulation (1%) Genitourinary: Impotence (2%) Genitourinary: Impotence (2%) Hematologic: Leukopenia (1%), decreased WBC (1%) Hematologic: Leukopenia (1%), decreased WBC (1%) Neuromuscular & skeletal: Tremor (7%), weakness (6%), hyperkinesia (children Neuromuscular & skeletal: Tremor (7%), weakness (6%), hyperkinesia (children 3%), abnormal gait (2%), back pain (2%), myalgia (2%), fracture (1%)3%), abnormal gait (2%), back pain (2%), myalgia (2%), fracture (1%) Ocular: Nystagmus (8%), diplopia (1% to 6%), blurred vision (3% to 4%), Ocular: Nystagmus (8%), diplopia (1% to 6%), blurred vision (3% to 4%), conjunctivitis (1%)conjunctivitis (1%) Otic: Otitis media (1%) Otic: Otitis media (1%) Respiratory: Rhinitis (4%), bronchitis (children 3%), respiratory infection (children Respiratory: Rhinitis (4%), bronchitis (children 3%), respiratory infection (children 3%), pharyngitis (1% to 3%), cough (2%)3%), pharyngitis (1% to 3%), cough (2%) Miscellaneous: Infection (5%) Miscellaneous: Infection (5%)



CONTRAINDICATIONSCONTRAINDICATIONS — Hypersensitivity to — Hypersensitivity to gabapentin or any component of the formulationgabapentin or any component of the formulation

DRUG INTERACTIONSDRUG INTERACTIONS — — CNS depressantsCNS depressants: : Sedative effects may be additive with CNS Sedative effects may be additive with CNS depressants; includes ethanol, barbiturates, depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents. narcotic analgesics, and other sedative agents. Monitor for increased effect.Monitor for increased effect.



EMABARAZOEMABARAZO — — – Efectos teratogénicos en animales de Efectos teratogénicos en animales de

experimentación.experimentación.

LACTANCIALACTANCIA — —– Pasa a la leche materna. Los recien nacidos Pasa a la leche materna. Los recien nacidos

pueden estar expuestos a 1 mg/kg/dia de pueden estar expuestos a 1 mg/kg/dia de gabapentinagabapentina



TOXICOLOGY / OVERDOSE TOXICOLOGY / OVERDOSE COMPREHENSIVECOMPREHENSIVE — — Acute oral overdoses up to 49 g have been Acute oral overdoses up to 49 g have been reported; double vision, slurred speech, reported; double vision, slurred speech, drowsiness, lethargy, and diarrhea were drowsiness, lethargy, and diarrhea were observed. observed. Tratamiento: Tratamiento: – De soporte.De soporte.– Lavado gastrico, carbón activado, catárticos.Lavado gastrico, carbón activado, catárticos.– Hemodialisis.Hemodialisis.



PHARMACODYNAMICS / KINETICSPHARMACODYNAMICS / KINETICS Absorption: 50% to 60% from proximal small bowel by L-amino Absorption: 50% to 60% from proximal small bowel by L-amino transport systemtransport systemDistribution: Vd: 0.6-0.8 L/kgDistribution: Vd: 0.6-0.8 L/kgProtein binding: Protein binding: <3%<3%Bioavailability: Inversely proportional to dose due to saturable Bioavailability: Inversely proportional to dose due to saturable absorption:absorption: 900 mg/day: 60% 900 mg/day: 60% 1200 mg/day: 47% 1200 mg/day: 47% 2400 mg/day: 34% 2400 mg/day: 34% 3600 mg/day: 33% 3600 mg/day: 33% 4800 mg/day: 27% 4800 mg/day: 27%Half-life elimination: 5-7 hours; Half-life elimination: 5-7 hours; anuria 132 hours; during dialysis anuria 132 hours; during dialysis 3.8 hours3.8 hoursExcretion: Proportional to renal function; Excretion: Proportional to renal function; urine (as unchanged urine (as unchanged drug)drug)



AntidepresivosAntidepresivos

Los tricíclicos se han mostrado efectivos en el Los tricíclicos se han mostrado efectivos en el tratamiento del dolor neuropático, especialmente las tratamiento del dolor neuropático, especialmente las disestesias continuas y el dolor lancinante.disestesias continuas y el dolor lancinante.También son útiles en el dolor con depresión e insomnio También son útiles en el dolor con depresión e insomnio (Cherny, 1995, 254–255). (Cherny, 1995, 254–255). Sus mecanismos de acción analgésica consisten en un Sus mecanismos de acción analgésica consisten en un efecto bloqueador del dolor a la altura de la médula, una efecto bloqueador del dolor a la altura de la médula, una mejoría del humor y una potenciación o favorecimiento mejoría del humor y una potenciación o favorecimiento de la analgesia opioide. de la analgesia opioide. Efectos adversos: sedación, síntomas colinérgicos y de Efectos adversos: sedación, síntomas colinérgicos y de la conducción cardíaca como la sequedad de boca, la la conducción cardíaca como la sequedad de boca, la visión borrosa, la retención urinaria y anomalías de la visión borrosa, la retención urinaria y anomalías de la conducción cardíaca.conducción cardíaca.


AntidepresivosAntidepresivosNinguno de los ADT tienen la indicación para el tratamiento del Ninguno de los ADT tienen la indicación para el tratamiento del dolor.dolor.

La Amitriptilina es el más estudiado, La Amitriptilina es el más estudiado, pero también se han pero también se han utilizado utilizado doxepin, imipramine, nortriptyline, y desipraminedoxepin, imipramine, nortriptyline, y desipramine

Tienen efectos analgésicos independientes y capacidad para Tienen efectos analgésicos independientes y capacidad para controlar los sintoma depresivos asociados con el dolor crónico.controlar los sintoma depresivos asociados con el dolor crónico.

Mecanismo analgésico desconocido. Mecanismo analgésico desconocido. – Inhibición de la recaptación de seroronina y norpeinefrina.Inhibición de la recaptación de seroronina y norpeinefrina.– Potenciación del sistema opioide endógeno.Potenciación del sistema opioide endógeno.

En el dolor crónico En el dolor crónico se usan a dosis inferiores a las usdas en la se usan a dosis inferiores a las usdas en la depresión.depresión.


AntidepresivosAntidepresivos

El efecto analgésico puede ocurrir tras días de El efecto analgésico puede ocurrir tras días de tratamiento, y a veces son necesarias semanas tratamiento, y a veces son necesarias semanas de tratamiento antes de obtener un efecto de tratamiento antes de obtener un efecto beneficioso.beneficioso.

A veces es necesario cambiar a otro ADT si no A veces es necesario cambiar a otro ADT si no se obtiene tratamiento.se obtiene tratamiento.

Estan contraindicados en pacientes con Estan contraindicados en pacientes con alteracion del ritmo cardíaco y alteraciones alteracion del ritmo cardíaco y alteraciones gastrointestinales.gastrointestinales.


N06AA-Antidepresivos inhibidores no selectivos de monoaminas

NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL

Amitriptilina Comp 10 mgComp 25 mgComp 75 mg

OROROR

Tryptizol

Clomipramina(Clorimipramina)

Amp 25 mg/2 mlComp 10 mgComp 25 mgComp 75 mg

IMOROROR

Anafranil

Imipramina comp. 10 mgComp 25 mgCaps 75 mg

OROROR

Tofranil

Maprotilina Comp 10 mgComp 25 mgComp 75 mg

OROROR

Ludiomil


N06AB-Antidepresivos inhibidores selectivos de la recaptación de serotonina

NOMBRE GENÉRICO


Fluoxetina (1) (2) Caps 20 mgSol 20mg/5ml

OROR

Prozac

Nota 1: Otros antidepresivos Inhibidores Selectivos de la Recaptación de Serotonina (ISRS) como los fármacos: Fluvoxamina (Dumirox) Paroxetina (Seroxat), Sertralina (Besitran) y Citalopram (Seropram) no están incluidos en la Guía. Cuando un paciente ingresa con un tratamiento de origen ambulatorio se considera adecuado seguir con el mismo tratamiento mientras el paciente permanezca ingresado. Consultar programa de intercambio terapéutico. Nota 2: Escitalopram (Cipralex, Entact, Esertia) y programa de intercambio terapéutico. Se acuerda no incluir Escitalopram en la Guía Farmacoterapéutica (Reunión CFT 09-02-2005) Dentro del programa de intercambio terapéutico (PIT) del hospital, los pacientes que ingresen en tratamiento con escitalopram se pasarán a citalopram, siendo la equivalencia de dosis: Escitalopram 10 mg equivale a citalopram 20 mg. Escitalopram 20 mg equivale a citalopram 40 mg. El escitalopram es el S(+)-enantiómero del antidepresivo citalopram


NOMBRE GENÉRICO


Fenelzina Comp 15 mg OR Nardelzine

N06AF-Antidepresivos Inhibidores no selectivos de la MAO


N06AX-Otros antidepresivos

NOMBRE GENÉRICO


Mianserina Comp 30 mg OR Lantanon

Mirtazapina Comp 15 mgComp 30 mg

OROR

Rexer flas

Trazodone Comp 100 mgAmp 50 mg/5 ml

ORIV

Deprax

Venlafaxina Comp 37,5 mg OR Dobupal, Vandral


AmitriptilinaAmitriptilina

Mecanismo de acción:Mecanismo de acción:– Aumenta la concentración sináptica de Aumenta la concentración sináptica de

serotonina y/o norepinefrina en el SNC por serotonina y/o norepinefrina en el SNC por inhibición de su recaptación por la membrana inhibición de su recaptación por la membrana presinaptica de la neurona.presinaptica de la neurona.


N06AA-Antidepresivos inhibidores no selectivos de monoaminas

NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL

Amitriptilina Comp 10 mgComp 25 mgComp 75 mg

OROROR

Tryptizol

Clomipramina(Clorimipramina)

Amp 25 mg/2 mlComp 10 mgComp 25 mgComp 75 mg

IMOROROR

Anafranil

Imipramina comp. 10 mgComp 25 mgCaps 75 mg

OROROR

Tofranil

Maprotilina Comp 10 mgComp 25 mgComp 75 mg

OROROR

Ludiomil



DOSING: ADULTSDOSING: ADULTS Depression: Oral: 50-150 mg/day single dose at Depression: Oral: 50-150 mg/day single dose at bedtime or in divided doses; dose may be bedtime or in divided doses; dose may be gradually increased up to 300 mg/day.gradually increased up to 300 mg/day.Chronic pain management (unlabeled use): Chronic pain management (unlabeled use): Oral: Initial: 25 mg at bedtime; may increase Oral: Initial: 25 mg at bedtime; may increase as tolerated to 100 mg/day.as tolerated to 100 mg/day.Migraine prophylaxis (unlabeled use): Oral: Migraine prophylaxis (unlabeled use): Oral: Initial: 10-25 mg at bedtime; usual dose: 150 mg; Initial: 10-25 mg at bedtime; usual dose: 150 mg; reported dosing ranges: 10-400 mg/dayreported dosing ranges: 10-400 mg/day



DOSING: PEDIATRICDOSING: PEDIATRIC Chronic pain management (unlabeled use): Oral: Initial: 0.1 mg/kg Chronic pain management (unlabeled use): Oral: Initial: 0.1 mg/kg at bedtime, may advance as tolerated over 2-3 weeks to 0.5-2 at bedtime, may advance as tolerated over 2-3 weeks to 0.5-2 mg/kg at bedtimemg/kg at bedtimeDepressive disorders:Depressive disorders: Children (unlabeled use): Oral: Initial doses of 1 mg/kg/day given Children (unlabeled use): Oral: Initial doses of 1 mg/kg/day given in 3 divided doses with increases to 1.5 mg/kg/day have been in 3 divided doses with increases to 1.5 mg/kg/day have been reported in a small number of children (n=9) 9-12 years of age; reported in a small number of children (n=9) 9-12 years of age; clinically, doses up to 3 mg/kg/day (5 mg/kg/day if monitored clinically, doses up to 3 mg/kg/day (5 mg/kg/day if monitored closely) have been proposedclosely) have been proposed Adolescents: Initial: 25-50 mg/day; may administer in divided Adolescents: Initial: 25-50 mg/day; may administer in divided doses; increase gradually to 100 mg/day in divided doses.doses; increase gradually to 100 mg/day in divided doses.Migraine prophylaxis (unlabeled use): Oral: Initial: 0.25 mg/kg/day, Migraine prophylaxis (unlabeled use): Oral: Initial: 0.25 mg/kg/day, given at bedtime; increase dose by 0.25 mg/kg/day to maximum 1 given at bedtime; increase dose by 0.25 mg/kg/day to maximum 1 mg/kg/day. Reported dosing ranges: 0.1-2 mg/kg/day; maximum mg/kg/day. Reported dosing ranges: 0.1-2 mg/kg/day; maximum suggested dose: 10 mg.suggested dose: 10 mg.



DOSING: ELDERLYDOSING: ELDERLY — — Depression: Oral: Initial: 10-25 mg at bedtime; Depression: Oral: Initial: 10-25 mg at bedtime; dose should be increased in 10-25 mg dose should be increased in 10-25 mg increments every week if tolerated; dose range: increments every week if tolerated; dose range: 25-150 mg/day. 25-150 mg/day. DOSING: RENAL IMPAIRMENTDOSING: RENAL IMPAIRMENT — — NondialyzableNondialyzableDOSING: HEPATIC IMPAIRMENTDOSING: HEPATIC IMPAIRMENT — Use with — Use with caution and monitor plasma levels and patient caution and monitor plasma levels and patient response.response.


FG > 50 ml/min

FG 10-50 ml/min

FG < 10 ml/min


DPCA TSCR

Amitripitilina 100%100% 100%100% !00%!00% NingunaNinguna DesconocidaDesconocida NingunaNinguna

Los efectos anticolinérgicos pueden provocar en pacientes en HD aumento de Los efectos anticolinérgicos pueden provocar en pacientes en HD aumento de la sed y del peso (boca seca), hiperglucemia, y aumento de la osmolaridad la sed y del peso (boca seca), hiperglucemia, y aumento de la osmolaridad extracelular.extracelular.La hipoK, hipoCa y alcalosis transitoria intradiálisis (factores que alteran el La hipoK, hipoCa y alcalosis transitoria intradiálisis (factores que alteran el intervalo QT) pueden aumenta la susceptibilidad a la aparición de arritmias intervalo QT) pueden aumenta la susceptibilidad a la aparición de arritmias cardíacas.cardíacas.



USEUSE — Relief of symptoms of depression — Relief of symptoms of depression

USE - UNLABELED / USE - UNLABELED / INVESTIGATIONALINVESTIGATIONAL — — – Analgesic for certain chronic and Analgesic for certain chronic and

neuropathic pain; neuropathic pain; – prophylaxis against migraine headaches; prophylaxis against migraine headaches; – treatment of depressive disorders in childrentreatment of depressive disorders in children


AmitriptilinaAmitriptilinaADVERSE REACTIONS SIGNIFICANTADVERSE REACTIONS SIGNIFICANT — — Anticholinergic effects may be Anticholinergic effects may be pronounced; moderate to marked sedation can occurpronounced; moderate to marked sedation can occur (tolerance to these effects (tolerance to these effects usually occurs).usually occurs).Frequency not defined.Frequency not defined.Cardiovascular: Orthostatic hypotension, tachycardia, ECG changes (nonspecific), Cardiovascular: Orthostatic hypotension, tachycardia, ECG changes (nonspecific), AV conduction changes, cardiomyopathy (rare), MI, stroke, heart block, arrhythmia, AV conduction changes, cardiomyopathy (rare), MI, stroke, heart block, arrhythmia, syncope, hypertension, palpitationsyncope, hypertension, palpitationCentral nervous system: Restlessness, dizziness, insomnia, sedation, fatigue, Central nervous system: Restlessness, dizziness, insomnia, sedation, fatigue, anxiety, cognitive function impaired, seizure, extrapyramidal symptoms, coma, anxiety, cognitive function impaired, seizure, extrapyramidal symptoms, coma, hallucinations, confusion, disorientation, coordination impaired, ataxia, headache, hallucinations, confusion, disorientation, coordination impaired, ataxia, headache, nightmares, hyperpyrexianightmares, hyperpyrexiaDermatologic: Allergic rash, urticaria, photosensitivity, alopeciaDermatologic: Allergic rash, urticaria, photosensitivity, alopeciaEndocrine & metabolic: Syndrome of inappropriate ADH secretionEndocrine & metabolic: Syndrome of inappropriate ADH secretionGastrointestinal: Weight gain, xerostomia, constipation, paralytic ileus, nausea, Gastrointestinal: Weight gain, xerostomia, constipation, paralytic ileus, nausea, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tonguevomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongueGenitourinary: Urinary retentionGenitourinary: Urinary retentionHematologic: Bone marrow depression, purpura, eosinophiliaHematologic: Bone marrow depression, purpura, eosinophiliaNeuromuscular & skeletal: Numbness, paresthesia, peripheral neuropathy, tremor, Neuromuscular & skeletal: Numbness, paresthesia, peripheral neuropathy, tremor, weaknessweaknessOcular: Blurred vision, mydriasis, ocular pressure increasedOcular: Blurred vision, mydriasis, ocular pressure increasedOtic: TinnitusOtic: TinnitusMiscellaneous: Diaphoresis, withdrawal reactions (nausea, headache, malaise)Miscellaneous: Diaphoresis, withdrawal reactions (nausea, headache, malaise)Postmarketing and/or case reports: Neuroleptic malignant syndrome (rare), serotonin Postmarketing and/or case reports: Neuroleptic malignant syndrome (rare), serotonin syndrome (rare)syndrome (rare)


AmitriptilinaAmitriptilinaDRUG INTERACTIONSDRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)(weak), 2E1 (weak)Altretamine: Concurrent use may cause orthostatic hypertension.Altretamine: Concurrent use may cause orthostatic hypertension.Amphetamines: TCAs may enhance the effect of amphetamines; monitor for adverse CV effects.Amphetamines: TCAs may enhance the effect of amphetamines; monitor for adverse CV effects.Anticholinergics: Combined use with TCAs may produce additive anticholinergic effects.Anticholinergics: Combined use with TCAs may produce additive anticholinergic effects.Antihypertensives: Amitriptyline inhibits the antihypertensive response to bethanidine, clonidine, Antihypertensives: Amitriptyline inhibits the antihypertensive response to bethanidine, clonidine, debrisoquin, guanadrel, guanethidine, guanabenz, guanfacine; monitor BP; consider alternate debrisoquin, guanadrel, guanethidine, guanabenz, guanfacine; monitor BP; consider alternate antihypertensive agent.antihypertensive agent.Beta-agonists: When combined with TCAs may predispose patients to cardiac arrhythmias.Beta-agonists: When combined with TCAs may predispose patients to cardiac arrhythmias.Bupropion: May increase the levels of tricyclic antidepressants; based on limited information, Bupropion: May increase the levels of tricyclic antidepressants; based on limited information, monitor response.monitor response.Carbamazepine: Tricyclic antidepressants may increase carbamazepine levels; monitor.Carbamazepine: Tricyclic antidepressants may increase carbamazepine levels; monitor.Cholestyramine and colestipol: May bind TCAs and reduce their absorption; monitor for altered Cholestyramine and colestipol: May bind TCAs and reduce their absorption; monitor for altered response.response.Cisapride: May increase the risk of QTc prolongation and/or arrhythmia; concurrent use is Cisapride: May increase the risk of QTc prolongation and/or arrhythmia; concurrent use is contraindicated.contraindicated.Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis; amitriptyline may Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis; amitriptyline may enhance the response (also see note on antihypertensives).enhance the response (also see note on antihypertensives).CNS depressants: Sedative effects may be additive with TCAs; monitor for increased effect; CNS depressants: Sedative effects may be additive with TCAs; monitor for increased effect; includes benzodiazepines, barbiturates, antipsychotics, ethanol, and other sedative medications.includes benzodiazepines, barbiturates, antipsychotics, ethanol, and other sedative medications.


AmitriptilinaAmitriptilinaDRUG INTERACTIONSDRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)(weak), 2D6 (weak), 2E1 (weak)

CYP2D6 inhibitors: May increase the levels/effects of amitriptyline; example inhibitors CYP2D6 inhibitors: May increase the levels/effects of amitriptyline; example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.quinidine, quinine, ritonavir, and ropinirole.Epinephrine (and other direct alpha-agonists): Pressor response to I.V. epinephrine, Epinephrine (and other direct alpha-agonists): Pressor response to I.V. epinephrine, norepinephrine, and phenylephrine may be enhanced in patients receiving TCAs. norepinephrine, and phenylephrine may be enhanced in patients receiving TCAs. (Note: Effect is unlikely with epinephrine or levonordefrin dosages typically (Note: Effect is unlikely with epinephrine or levonordefrin dosages typically administered as infiltration in combination with local anesthetics.)administered as infiltration in combination with local anesthetics.)Fenfluramine: May increase tricyclic antidepressant levels/effects.Fenfluramine: May increase tricyclic antidepressant levels/effects.Hypoglycemic agents (including insulin): TCAs may enhance the hypoglycemic Hypoglycemic agents (including insulin): TCAs may enhance the hypoglycemic effects of tolazamide, chlorpropamide, or insulin; monitor for changes in blood effects of tolazamide, chlorpropamide, or insulin; monitor for changes in blood glucose levels; reported with chlorpropamide, tolazamide, and insulin.glucose levels; reported with chlorpropamide, tolazamide, and insulin.Levodopa: Tricyclic antidepressants may decrease the absorption (bioavailability) of Levodopa: Tricyclic antidepressants may decrease the absorption (bioavailability) of levodopa; rare hypertensive episodes have also been attributed to this combination.levodopa; rare hypertensive episodes have also been attributed to this combination.Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with agents which inhibit MAO (serotonin syndrome); this have been reported with agents which inhibit MAO (serotonin syndrome); this combination should be avoided.combination should be avoided.Lithium: Concurrent use with a TCA may increase the risk for neurotoxicity.Lithium: Concurrent use with a TCA may increase the risk for neurotoxicity.MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported (serotonin syndrome); this combination should be deaths have been reported (serotonin syndrome); this combination should be avoided.avoided.


AmitriptilinaAmitriptilinaDRUG INTERACTIONSDRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)(weak), 2E1 (weak)

MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported (serotonin syndrome); this combination should be avoided.been reported (serotonin syndrome); this combination should be avoided.Methylphenidate: Metabolism of amitriptyline may be decreased.Methylphenidate: Metabolism of amitriptyline may be decreased.Phenothiazines: Serum concentrations of some TCAs may be increased; in addition, TCAs may Phenothiazines: Serum concentrations of some TCAs may be increased; in addition, TCAs may increase concentration of phenothiazines; monitor for altered clinical response.increase concentration of phenothiazines; monitor for altered clinical response.QTc prolonging agents: Concurrent use of tricyclic agents with other drugs which may prolong QTc prolonging agents: Concurrent use of tricyclic agents with other drugs which may prolong QTc interval may increase the risk of potentially fatal arrhythmias; includes type Ia and type III QTc interval may increase the risk of potentially fatal arrhythmias; includes type Ia and type III antiarrhythmics agents, selected quinolones (sparfloxacin, gatifloxacin, moxifloxacin, antiarrhythmics agents, selected quinolones (sparfloxacin, gatifloxacin, moxifloxacin, grepafloxacin), cisapride, and other agents.grepafloxacin), cisapride, and other agents.Ritonavir: Combined use of high-dose tricyclic antidepressants with ritonavir may cause serotonin Ritonavir: Combined use of high-dose tricyclic antidepressants with ritonavir may cause serotonin syndrome in HIV-positive patients; monitor.syndrome in HIV-positive patients; monitor.Sucralfate: Absorption of tricyclic antidepressants may be reduced with coadministration.Sucralfate: Absorption of tricyclic antidepressants may be reduced with coadministration.Sympathomimetics, indirect-acting: Tricyclic antidepressants may result in a decreased sensitivity Sympathomimetics, indirect-acting: Tricyclic antidepressants may result in a decreased sensitivity to indirect-acting sympathomimetics; includes dopamine and ephedrine; also see interaction with to indirect-acting sympathomimetics; includes dopamine and ephedrine; also see interaction with epinephrine (and direct-acting sympathomimetics).epinephrine (and direct-acting sympathomimetics).Tramadol: Tramadol's risk of seizures may be increased with TCAs.Tramadol: Tramadol's risk of seizures may be increased with TCAs.Valproic acid: May increase serum concentrations/adverse effects of some tricyclic Valproic acid: May increase serum concentrations/adverse effects of some tricyclic antidepressants.antidepressants.Warfarin (and other oral anticoagulants): Amitriptyline may increase the anticoagulant effect in Warfarin (and other oral anticoagulants): Amitriptyline may increase the anticoagulant effect in patients stabilized on warfarin; monitor INR.patients stabilized on warfarin; monitor INR.



PREGNANCY RISK FACTORPREGNANCY RISK FACTOR — C — CPREGNANCY IMPLICATIONSPREGNANCY IMPLICATIONS — — Teratogenic effectsTeratogenic effects have been observed have been observed in animal studies. Amitriptyline in animal studies. Amitriptyline crosses crosses the human placentathe human placenta; CNS effects, limb ; CNS effects, limb deformities and developmental delay have deformities and developmental delay have been noted in case reports.been noted in case reports.LACTATIONLACTATION — — Enters breast milk/not Enters breast milk/not recommendedrecommended



MONITORING PARAMETERSMONITORING PARAMETERS — Monitor blood — Monitor blood pressure and pulse rate prior to and during initial pressure and pulse rate prior to and during initial therapy; evaluate mental status; monitor weight; therapy; evaluate mental status; monitor weight; ECG in older adults and patients with cardiac ECG in older adults and patients with cardiac diseasediseaseREFERENCE RANGEREFERENCE RANGE — Therapeutic: — Therapeutic: – Amitriptyline and nortriptyline 100-250 ng/mL (SI: 360-Amitriptyline and nortriptyline 100-250 ng/mL (SI: 360-

900 nmol/L); 900 nmol/L); – nortriptyline 50-150 ng/mL (SI: 190-570 nmol/L); nortriptyline 50-150 ng/mL (SI: 190-570 nmol/L);

Toxic: >0.5 mcg/mL; Toxic: >0.5 mcg/mL; – plasma levels do not always correlate with clinical plasma levels do not always correlate with clinical

effectivenesseffectiveness


AmitriptilinaAmitriptilinaTOXICOLOGY / OVERDOSE COMPREHENSIVETOXICOLOGY / OVERDOSE COMPREHENSIVE — — Symptoms include agitation, confusion, hallucinations, urinary retention, Symptoms include agitation, confusion, hallucinations, urinary retention, hypothermia, hypotension, ventricular tachycardia, and seizures. hypothermia, hypotension, ventricular tachycardia, and seizures. Following initiation of essential overdose management, toxic symptoms Following initiation of essential overdose management, toxic symptoms should be treated. should be treated. Sodium bicarbonate is indicated when the QRS interval is >0.10 seconds or Sodium bicarbonate is indicated when the QRS interval is >0.10 seconds or the QTc is >0.42 seconds.the QTc is >0.42 seconds. Ventricular arrhythmias often respond to phenytoin 15-20 mg/kg (adults) Ventricular arrhythmias often respond to phenytoin 15-20 mg/kg (adults) with concurrent systemic alkalinization (sodium bicarbonate 0.5-2 mEq/kg with concurrent systemic alkalinization (sodium bicarbonate 0.5-2 mEq/kg I.V.). I.V.). Arrhythmias unresponsive to this therapy may respond to lidocaine 1 mg/kg Arrhythmias unresponsive to this therapy may respond to lidocaine 1 mg/kg I.V. followed by a titrated infusion. I.V. followed by a titrated infusion. Physostigmine (1-2 mg slow I.V. for adults or 0.5 mg slow I.V. for children) Physostigmine (1-2 mg slow I.V. for adults or 0.5 mg slow I.V. for children) may be indicated in reversing cardiac arrhythmias that are due to vagal may be indicated in reversing cardiac arrhythmias that are due to vagal blockade, or for anticholinergic effects, but should only be used as a last blockade, or for anticholinergic effects, but should only be used as a last measure in life-threatening situations. measure in life-threatening situations. Seizures usually respond to diazepam I.V. boluses (5-10 mg for adults up to Seizures usually respond to diazepam I.V. boluses (5-10 mg for adults up to 30 mg or 0.25-0.4 mg/kg/dose for children up to 10 mg/dose). If seizures are 30 mg or 0.25-0.4 mg/kg/dose for children up to 10 mg/dose). If seizures are unresponsive or recur, phenytoin or phenobarbital may be required.unresponsive or recur, phenytoin or phenobarbital may be required.


AmitriptilinaAmitriptilinaPHARMACODYNAMICS / KINETICSPHARMACODYNAMICS / KINETICS

Onset of action: Onset of action: Migraine prophylaxis: 6 weeksMigraine prophylaxis: 6 weeks, higher dosage may be , higher dosage may be required in heavy smokers because of increased metabolism; Depression: required in heavy smokers because of increased metabolism; Depression: 4-6 weeks, reduce dosage to lowest effective level4-6 weeks, reduce dosage to lowest effective levelDistribution: Crosses placenta; enters breast milkDistribution: Crosses placenta; enters breast milkMetabolism: Metabolism: HepaticHepatic to nortriptyline (active), hydroxy and conjugated to nortriptyline (active), hydroxy and conjugated derivatives; may be impaired in the elderlyderivatives; may be impaired in the elderlyHalf-life elimination: Half-life elimination: Adults: 9-27 hoursAdults: 9-27 hours (average: 15 hours) (average: 15 hours)Time to peak, serum: ~4 hoursTime to peak, serum: ~4 hoursExcretion: Urine (18% as unchanged drug); feces (small amounts)Excretion: Urine (18% as unchanged drug); feces (small amounts)

PATIENT INFORMATIONPATIENT INFORMATION — — Do not discontinue medication abruptly. Do not discontinue medication abruptly. Full effect may not occur for 3-6 weeks. Avoid alcohol. May cause Full effect may not occur for 3-6 weeks. Avoid alcohol. May cause urine to turn blue-greenurine to turn blue-green. May cause drowsiness. Dry mouth may be . May cause drowsiness. Dry mouth may be helped by sips of water, sugarless gum, or hard candy.helped by sips of water, sugarless gum, or hard candy.



BenzodiacepinasBenzodiacepinas

Las Las benzodiazepinasbenzodiazepinas son un tipo de fármaco son un tipo de fármaco con propiedades sedantes, relajantes con propiedades sedantes, relajantes musculares y amnésicas. Tienen una serie de musculares y amnésicas. Tienen una serie de aplicaciones, incluyendo el manejo de la aplicaciones, incluyendo el manejo de la ansiedad, el control del insomnio, el manejo de ansiedad, el control del insomnio, el manejo de la agitación y la premedicación anestésica (para la agitación y la premedicación anestésica (para producir sedación). producir sedación). El El clonazepamclonazepam tiene propiedades tiene propiedades anticonvulsivantes y anticonvulsivantes y es la única es la única benzodiazepina con efectos analgésicos benzodiazepina con efectos analgésicos conocidos sobre el dolor neuropático, conocidos sobre el dolor neuropático, especialmente el lancinante. especialmente el lancinante.


BenzodiacepinasBenzodiacepinas

BenzodiazepinesBenzodiazepines — Benzodiazepines may be — Benzodiazepines may be utilized in patients who would benefit from utilized in patients who would benefit from anxiolysis. These are commonly employed in anxiolysis. These are commonly employed in cancer patients and in non-malignant pain cancer patients and in non-malignant pain complicated by anxiety disorder.complicated by anxiety disorder.The disadvantage of this class of drugs relates The disadvantage of this class of drugs relates to their addictive potential, as well as their to their addictive potential, as well as their potentiation of sedative effects and respiratory potentiation of sedative effects and respiratory depression in patients who use opioids depression in patients who use opioids concurrently. concurrently. ClonazepamClonazepam is especially useful for neuropathic is especially useful for neuropathic pain.pain.


ClonazepamClonazepam

ClonazepamClonazepam — — ClonazepamClonazepam is a benzodiazepine that has been is a benzodiazepine that has been used successfully in providing relief for both chronic malignant and used successfully in providing relief for both chronic malignant and non-malignant pain syndromes such as headaches, non-malignant pain syndromes such as headaches, temporomandibular joint dysfunction, and phantom limb pain [22-temporomandibular joint dysfunction, and phantom limb pain [22-24].24].It acts by enhancing GABA receptor mediated chloride channels. It acts by enhancing GABA receptor mediated chloride channels. Clonazepam is particularly effective when used in combination with Clonazepam is particularly effective when used in combination with other neuropathic analgesics and in patients with prominent anxiety other neuropathic analgesics and in patients with prominent anxiety disorder and insomnia.disorder and insomnia.The dose of clonazepam should initially be 0.5 mg at bedtime; the The dose of clonazepam should initially be 0.5 mg at bedtime; the dose is slowly increased to 0.5 to 1 mg three times per day. Doses dose is slowly increased to 0.5 to 1 mg three times per day. Doses of up to 20 mg/day have been used in epilepsy; 1 to 6 mg per day is of up to 20 mg/day have been used in epilepsy; 1 to 6 mg per day is generally successful in treating headache and pain.generally successful in treating headache and pain.The most common side effects are drowsiness, dizziness, fatigue, The most common side effects are drowsiness, dizziness, fatigue, and sedation. As with other benzodiazepines, clonazepam may and sedation. As with other benzodiazepines, clonazepam may produce physical and psychological dependence; abrupt produce physical and psychological dependence; abrupt discontinuation is prohibited.discontinuation is prohibited.


N03AE-Benzodiacepinas

NOMBRE GENÉRICO


Clobazam Comp 10 mgComp 20 mg

OROR

Noiafren

Clonazepam Amp 1 mg/2 mlComp 0,5 mgComp 2 mgGts 2,5 mg/ml (1)

IM, IVOROROR

Rivotril

Diazepam Amp 10 mg/2 mlComp 5 mgComp 10 mg Microenema 5 mg

IM, IV

REC

Valium, Diazepam

Stesolid

Nota 1: 1 gota=0,1 mg



MECHANISM OF ACTIONMECHANISM OF ACTION — The exact — The exact mechanism is unknown, but believed to be mechanism is unknown, but believed to be related to its ability to enhance the activity related to its ability to enhance the activity of GABA; suppresses the spike-and-wave of GABA; suppresses the spike-and-wave discharge in absence seizures by discharge in absence seizures by depressing nerve transmission in the depressing nerve transmission in the motor cortexmotor cortex



DOSING: ADULTSDOSING: ADULTS Seizure disorders: Oral:Seizure disorders: Oral: Initial daily dose not to exceed 1.5 mg given in 3 divided doses; Initial daily dose not to exceed 1.5 mg given in 3 divided doses; may increase by 0.5-1 mg every third day until seizures are may increase by 0.5-1 mg every third day until seizures are controlled or adverse effects seen (maximum: 20 mg/day)controlled or adverse effects seen (maximum: 20 mg/day) Usual maintenance dose: 0.05-0.2 mg/kg; do not exceed 20 Usual maintenance dose: 0.05-0.2 mg/kg; do not exceed 20 mg/daymg/dayPanic disorder: Oral: 0.25 mg twice daily; increase in increments of Panic disorder: Oral: 0.25 mg twice daily; increase in increments of 0.125-0.25 mg twice daily every 3 days; target dose: 1 mg/day 0.125-0.25 mg twice daily every 3 days; target dose: 1 mg/day (maximum: 4 mg/day)(maximum: 4 mg/day)Discontinuation of treatment: To discontinue, treatment should be Discontinuation of treatment: To discontinue, treatment should be withdrawn gradually. Decrease dose by 0.125 mg twice daily every withdrawn gradually. Decrease dose by 0.125 mg twice daily every 3 days until medication is completely withdrawn.3 days until medication is completely withdrawn.



DOSING: PEDIATRICDOSING: PEDIATRIC Seizure disorders (see Use): Oral:Seizure disorders (see Use): Oral:Children <10 years or 30 kg:Children <10 years or 30 kg: Initial daily dose: 0.01-0.03 mg/kg/day (maximum: 0.05 Initial daily dose: 0.01-0.03 mg/kg/day (maximum: 0.05 mg/kg/day) given in 2-3 divided doses; increase by no mg/kg/day) given in 2-3 divided doses; increase by no more than 0.5 mg every third day until seizures are more than 0.5 mg every third day until seizures are controlled or adverse effects seen.controlled or adverse effects seen. Usual maintenance dose: 0.1-0.2 mg/kg/day divided 3 Usual maintenance dose: 0.1-0.2 mg/kg/day divided 3 times/day; not to exceed 0.2 mg/kg/day.times/day; not to exceed 0.2 mg/kg/day.Children >10 years or 30 kg: Refer to adult dosing.Children >10 years or 30 kg: Refer to adult dosing.



DOSING: ELDERLYDOSING: ELDERLY — Refer to adult — Refer to adult dosing. Initiate with low doses and dosing. Initiate with low doses and observe closely.observe closely.

DOSING: RENAL IMPAIRMENTDOSING: RENAL IMPAIRMENT — — Hemodialysis: Supplemental dose is not Hemodialysis: Supplemental dose is not necessary.necessary.


FG > 50 ml/min

FG 10-50 ml/min

FG < 10 ml/min


DPCA TSCR

Clonazepam 100%100% 100%100% 100%100% NingunaNinguna NingunaNinguna 100%100%



USEUSE — Alone or as an adjunct in the treatment — Alone or as an adjunct in the treatment of petit mal variant (Lennox-Gastaut), akinetic, of petit mal variant (Lennox-Gastaut), akinetic, and myoclonic seizures; petit mal (absence) and myoclonic seizures; petit mal (absence) seizures unresponsive to succimides; panic seizures unresponsive to succimides; panic disorder with or without agoraphobiadisorder with or without agoraphobia

USE - UNLABELED / INVESTIGATIONALUSE - UNLABELED / INVESTIGATIONAL — — Restless legs syndrome; neuralgia; multifocal tic Restless legs syndrome; neuralgia; multifocal tic disorder; parkinsonian dysarthria; bipolar disorder; parkinsonian dysarthria; bipolar disorder; adjunct therapy for schizophreniadisorder; adjunct therapy for schizophrenia


ClonazepamClonazepamADVERSE REACTIONS SIGNIFICANTADVERSE REACTIONS SIGNIFICANT — Reactions reported in patients with seizure and/or panic disorder. — Reactions reported in patients with seizure and/or panic disorder. Frequency not defined.Frequency not defined.Cardiovascular: Edema (ankle or facial), palpitationCardiovascular: Edema (ankle or facial), palpitationCentral nervous system: Amnesia, ataxia (seizure disorder ~30%; panic disorder 5%), behavior problems (seizure Central nervous system: Amnesia, ataxia (seizure disorder ~30%; panic disorder 5%), behavior problems (seizure disorder ~25%), coma, confusion, depression, dizziness, drowsiness (seizure disorder ~50%), emotional lability, disorder ~25%), coma, confusion, depression, dizziness, drowsiness (seizure disorder ~50%), emotional lability, fatigue, fever, hallucinations, headache, hypotonia, hysteria, insomnia, intellectual ability reduced, memory fatigue, fever, hallucinations, headache, hypotonia, hysteria, insomnia, intellectual ability reduced, memory disturbance, nervousness; paradoxical reactions (including aggressive behavior, agitation, anxiety, excitability, disturbance, nervousness; paradoxical reactions (including aggressive behavior, agitation, anxiety, excitability, hostility, irritability, nervousness, nightmares, sleep disturbance, vivid dreams); psychosis, slurred speech, hostility, irritability, nervousness, nightmares, sleep disturbance, vivid dreams); psychosis, slurred speech, somnolence (panic disorder 37%), suicidal attempt, vertigosomnolence (panic disorder 37%), suicidal attempt, vertigoDermatologic: Hair loss, hirsutism, skin rashDermatologic: Hair loss, hirsutism, skin rashEndocrine & metabolic: Dysmenorrhea, libido increased/decreasedEndocrine & metabolic: Dysmenorrhea, libido increased/decreasedGastrointestinal: Abdominal pain, anorexia, appetite increased/decreased, coated tongue, constipation, Gastrointestinal: Abdominal pain, anorexia, appetite increased/decreased, coated tongue, constipation, dehydration, diarrhea, gastritis, gum soreness, nausea, weight changes (loss/gain), xerostomiadehydration, diarrhea, gastritis, gum soreness, nausea, weight changes (loss/gain), xerostomiaGenitourinary: Colpitis, dysuria, ejaculation delayed, enuresis, impotence, micturition frequency, nocturia, urinary Genitourinary: Colpitis, dysuria, ejaculation delayed, enuresis, impotence, micturition frequency, nocturia, urinary retention, urinary tract infectionretention, urinary tract infectionHematologic: Anemia, eosinophilia, leukopenia, thrombocytopeniaHematologic: Anemia, eosinophilia, leukopenia, thrombocytopeniaHepatic: Alkaline phosphatase increased (transient), hepatomegaly, transaminases increased (transient)Hepatic: Alkaline phosphatase increased (transient), hepatomegaly, transaminases increased (transient)Neuromuscular & skeletal: Choreiform movements, coordination abnormal, dysarthria, muscle pain, muscle Neuromuscular & skeletal: Choreiform movements, coordination abnormal, dysarthria, muscle pain, muscle weakness, myalgia, tremorweakness, myalgia, tremorOcular: Blurred vision, eye movements abnormal, diplopia, nystagmusOcular: Blurred vision, eye movements abnormal, diplopia, nystagmusRespiratory: Chest congestion, cough, bronchitis, hypersecretions, pharyngitis, respiratory depression, respiratory Respiratory: Chest congestion, cough, bronchitis, hypersecretions, pharyngitis, respiratory depression, respiratory tract infection, rhinitis, rhinorrhea, shortness of breath, sinusitistract infection, rhinitis, rhinorrhea, shortness of breath, sinusitisMiscellaneous: Allergic reaction, aphonia, dysdiadochokinesis, encopresis, "glassy-eyed" appearance, Miscellaneous: Allergic reaction, aphonia, dysdiadochokinesis, encopresis, "glassy-eyed" appearance, hemiparesis, lymphadenopathyhemiparesis, lymphadenopathy


ClonazepamClonazepamDRUG INTERACTIONSDRUG INTERACTIONS — Substrate of CYP3A4 (major) — Substrate of CYP3A4 (major)(For additional information: Launch Lexi-Interact™ Drug Interactions Program )(For additional information: Launch Lexi-Interact™ Drug Interactions Program )CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; monitor for increased effect.monitor for increased effect.CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of clonazepam. Example CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of clonazepam. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.phenytoin, and rifamycins.CYP3A4 inhibitors: May increase the levels/effects of clonazepam. Example inhibitors include CYP3A4 inhibitors: May increase the levels/effects of clonazepam. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.Disulfiram: Disulfiram may inhibit the metabolism of clonazepam; monitor for increased Disulfiram: Disulfiram may inhibit the metabolism of clonazepam; monitor for increased benzodiazepine effect.benzodiazepine effect.Levodopa: Therapeutic effects may be diminished in some patients following the addition of a Levodopa: Therapeutic effects may be diminished in some patients following the addition of a benzodiazepine; limited/inconsistent data.benzodiazepine; limited/inconsistent data.Oral contraceptives: May decrease the clearance of some benzodiazepines (those which Oral contraceptives: May decrease the clearance of some benzodiazepines (those which undergo oxidative metabolism); monitor for increased benzodiazepine effect.undergo oxidative metabolism); monitor for increased benzodiazepine effect.Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation.decreased response; may require higher doses for sedation.Valproic acid: The combined use of clonazepam and valproic acid has been associated with Valproic acid: The combined use of clonazepam and valproic acid has been associated with absence seizures.absence seizures.



PREGNANCY RISK FACTORPREGNANCY RISK FACTOR — D (show table) — D (show table)PREGNANCY IMPLICATIONSPREGNANCY IMPLICATIONS — Clonazepam was shown to be — Clonazepam was shown to be teratogenic in some animal studies. Clonazepam crosses the teratogenic in some animal studies. Clonazepam crosses the placenta. Benzodiazepine use during pregnancy is associated with placenta. Benzodiazepine use during pregnancy is associated with increased risk of congenital malformations. Nonteratogenic effects increased risk of congenital malformations. Nonteratogenic effects (including neonatal flaccidity, respiratory and feeding problems, and (including neonatal flaccidity, respiratory and feeding problems, and withdrawal symptoms) during the postnatal period have also been withdrawal symptoms) during the postnatal period have also been reported with benzodiazepine use. Epilepsy itself, number of reported with benzodiazepine use. Epilepsy itself, number of medications, genetic factors, or a combination of these probably medications, genetic factors, or a combination of these probably influence the teratogenicity of anticonvulsant therapy.influence the teratogenicity of anticonvulsant therapy.LACTATIONLACTATION — Enters breast milk/not recommended — Enters breast milk/not recommendedBREAST-FEEDING CONSIDERATIONSBREAST-FEEDING CONSIDERATIONS — Clonazepam enters — Clonazepam enters breast milk; clinical effects on the infant include CNS depression, breast milk; clinical effects on the infant include CNS depression, respiratory depression reported (no recommendation from the AAP).respiratory depression reported (no recommendation from the AAP).


ClonazepamClonazepamPHARMACODYNAMICS / KINETICSPHARMACODYNAMICS / KINETICS Onset of action: 20-60 minutesOnset of action: 20-60 minutesDuration: Infants and young children: 6-8 hours; Adults: 12 hoursDuration: Infants and young children: 6-8 hours; Adults: 12 hoursAbsorption: Well absorbedAbsorption: Well absorbedDistribution: Adults: Vd: 1.5-4.4 L/kgDistribution: Adults: Vd: 1.5-4.4 L/kgProtein binding: 85%Protein binding: 85%Metabolism: Extensively hepatic via glucuronide and sulfate conjugationMetabolism: Extensively hepatic via glucuronide and sulfate conjugationHalf-life elimination: Children: 22-33 hours; Adults: 19-50 hoursHalf-life elimination: Children: 22-33 hours; Adults: 19-50 hoursTime to peak, serum: 1-3 hours; Steady-state: 5-7 daysTime to peak, serum: 1-3 hours; Steady-state: 5-7 daysExcretion: Urine (<2% as unchanged drug); metabolites excreted as Excretion: Urine (<2% as unchanged drug); metabolites excreted as glucuronide or sulfate conjugatesglucuronide or sulfate conjugatesPATIENT INFORMATIONPATIENT INFORMATION — Drug may cause physical or psychological — Drug may cause physical or psychological dependence; avoid abrupt discontinuation after prolonged use. Avoid dependence; avoid abrupt discontinuation after prolonged use. Avoid alcohol and other CNS depressants. Avoid activities needing good alcohol and other CNS depressants. Avoid activities needing good psychomotor coordination until CNS effects are known.psychomotor coordination until CNS effects are known.


Benzodiazepines for chronic pain

DrugRoute of administration Dose

Diazepam (Valium)

PO/IM/PR 2.5 mg Q 3 to 6 hours

Lorazepam (Ativan)

PO/IV/IM 0.5 to 2 mg Q 3 to 6 hours

Midazolam (Versed)

PO/IV/SC (can be continuous infusion)

1 to 3 mg Q 1 to 3 hours

Clonazepam (Klonopin)

PO Up to 1.5 mg/day


Category Interpretation

A Controlled studies show no risk

Adequate, well-controlled studies in pregnant women have failed to demonstrate risk to the fetus

B No evidence of risk in humans

Either animal findings show risk (but human findings do not) or, if no adequate human studies have been done, animal findings are negative.

C Risk cannot be ruled out

Human studies are lacking and animal studies are either positive for fetal risk or lacking as well. However, potential benefits may justify the potential risk.

D Positive evidence of risk

Investigational or postmarketing data show risk to fetus. Nevertheless, potential benefits may outweight the risk.

X Contraindicated in pregnancy

Studies in animals or humans, or investigational or postmarketing reports have shown fetal risk which clearly outweighs any possible benefit to the patient.



N05C-Hipnóticos y sedantes

NOMBRE GENÉRICO


Clometiazol (1) Caps 192 mg OR Distraneurine

Flurazepam (2) Caps 30 mg OR Dormodor

Hidrato de cloral Jbe 50 mg/mlEnema 100 mg/ml

ORREC

Hidrato de Cloral FM

Lorazepam (3) Comp 1 mg OR Orfidal

Lormetazepam Comp 2 mg OR Loramet , Noctamid

Midazolam Amp 15 mg/3 ml IM,IV Dormicum

Zolpidem (4) Comp 10 mg OR Stilnox

Nota 2: Flunitrazepam (Rohipnol ) se considera equivalente terapéutico de Flurazepam. Nota 3: Bromazepam (Lexatin) se considera equivalente terapéutico de Lorazepam. Nota 4: Zopiclona (Limovan) y Midazolam comp (Dormicum comp ) se consideran equivalentes terapéuticos del Zolpidem. Consultar programa de equivalencias.


NOMBRE GENÉRICO


Alprazolam Comp 0,25 mgComp 0,5 mgComp 1 mg

OROROR

Trankimazin

Clorazepato dipotásico

Sobres de 2,5 mgCaps 5 mgCaps 10 mgCaps 15 mgComp 50 mgVial 20 mg/2 mlVial 50 mg/2,5 ml

ORORORORORIM,IVIM,IV

Tranxilium pediát Tranxilium

Diazepam (1) Amp 10 mg/ 2 mlComp 5 mgComp 10 mg

IM.IVOROR

Diazepam ProdesValium

Nota 1: Ketazolam (Sedotime) se considera equivalente terapéutico de Diazepam.

N05B-Ansiolíticos

Documents

Adjuvantes Francisco José de la Prada Alvarez. Servicio de Nefrología. Hospital Universitario Son Dureta