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Adjuvantes
Francisco José de la Prada Alvarez.
Servicio de Nefrología.
Hospital Universitario Son Dureta
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2.2 Según la causa subyacente se reconocen
tres tipos generales de dolor:
1) nociceptivo somático
2) nociceptivo visceral
3) neuropático.
2.2.1 El dolor nociceptivo somático proviene de
la estimulación de nociceptores específicos en
los tejidos cutáneo y conjuntivo profundo
(músculos, tendones, huesos, etc.), y se suele
asociar a lesión o enfermedad. El dolor
somático se describe a menudo como “sordo” o
“agudo” y como “algia”. El dolor somático suele
ser constante y por lo general se controla al
eliminar la causa o al tratar la patología
subyacente.
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2.2 Según la causa subyacente se reconocen
tres tipos generales de dolor:
–
1) nociceptivo somático
2) nociceptivo visceral
3) neuropático.
2.2.2 El dolor nociceptivo visceral es un dolor
que se origina por la lesión, distensión,
obstrucción o inflamación de los órganos
torácicos, abdominales o pélvicos. Por ejemplo,
el dolor visceral puede provenir de la
obstrucción de una víscera hueca (p. ej., el
intestino), la distensión o la isquemia de los
componentes del intestino o por el rápido
estiramiento de la cápsula de un órgano sólido
(hígado).
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2.2 Según la causa subyacente se reconocen tres tipos
generales de dolor:
–
1) nociceptivo somático
2) nociceptivo visceral
3) neuropático.
2.2.3 El dolor neuropático está causado por la
lesión o la destrucción de los nervios localizados
en la periferia o en el sistema nervioso central.
Esto provoca una función anormal del nervio, que se
manifiesta como un dolor que se califica de
“quemazón”, “latigazo” u “hormigueo”. El dolor
neuropático puede ser constante y sostenido, pudiendo
existir un dolor intermitente, sobreimpuesto, similar a un
choque, que se describe como eléctrico o en
escopetazo. Además, pueden aparecer
sensaciones anormales como alodinia,
parestesia y disestesia.
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Los analgésicos adyuvantes tricíclicos son la amitriptilina, la doxepina, la
imipramina, la desipramina y la nortriptilina. Son especialmente útiles en los
síndromes de dolor neuropático.
Los analgésicos adyuvantes anticonvulsivantes son la carbamazepina, la
difenilhidantoína, el ácido valproico, el divalproato sódico y gabapentina.
Son especialmente útiles en el dolor neuropático lancinante.
La dexametasona y la prednisona son los corticoides utilizados con mayor
frecuencia en el tratamiento del dolor. Una serie de alteraciones dolorosas
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
dolor neuropático debido a la infiltración o la compresión por el tumor.
La metotrimeprazina es un analgésico neuroléptico de probada utilidad en
los pacientes con cáncer avanzado que tienen dolor con ansiedad,
agitación o náuseas.
El clonazepam es una benzodiazepina ampliamente aceptada en el
tratamiento del dolor neuropático.
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Anticonvulsivantes
Los anticonvulsivantes utilizados en el manejo del dolor
incluyen la carbamazepina, la difenilhidantoína y los
fármacos relacionados con el ácido valproico y
gabapentina. Todos se han mostrado útiles en el
tratamiento del dolor neuropático.
Los anticonvulsivantes se han utilizado para el
tratamiento del dolor desde hace más de 50 años.
Fenitoina, Carbamacepina, ácido valproico,
gabapentina, topiramate, vigabatrina, tiagabina,
levetiracetam, zonisamida y oxcarbacepina.
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Anticonvulsivantes
Limitaciones de uso.
– Los más antiguos (fenitoina,
carbamacepina y acido valproico)
requieren monitorizacion sanguínea y de
la función hepática.
– Efectos secundarios en un alto porcentaje
de pacientes.
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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
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Anticonvulsivantes
Gabapentina: el más efectivo; debe
considerarse de primera elección en el
tratamieto del dolor neuropático.
Neuralgia del trigémino: carbamacepina y luego
lamotrignina, toppiromato, o gabapentina, solos
o en combinación.
Neuropatía diabética: carbamazepine,
gabapentina y oxcarbacepina.
Fenitoina: barato, disponible por vía oral y
parenteral.
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N03AA-Barbitúricos
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Fenobarbital
Amp 200 mg/1 ml
Comp 15 mg
Comp 100 mg
IM
OR
OR
Luminal
Luminaletas
Luminal 0,1
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N03AB-Hidantoinas
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Fenitoína sódica
Comp 100 mg
Caps 100 mg
Jbe 125 mg/5 ml
Vial 250 mg/5 ml
OR
OR
OR
IV, IM
Neosindantoína
Epanutin
Fenitoína Rubió
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N03AD-Carboxamidas
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Carbamazepina
Comp 200 mg
OR
Tegretol
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N03AG-Acidos grasos
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Valproico Acido
Comp 200 mg
Comp 500 mg
Sol 200 mg/ml
Vial 400 mg
OR
OR
OR
IV
Depakine
Depakine iny
Vigabatrina
Comp 500 mg
Sobres 500 mg
OR
OR
Sabrilex
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Gabapentina
N03AX-Otros antiepilépticos
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Gabapentina
Cap 300 mg
Cap 400 mg
OR
OR
Neurontin
Lamotrigina
Comp 100 mg
Comp 200 mg
OR
OR
Lamictal
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Gabapentina
Molécula estructuralmente relacionada con
GABA.
No se une a los receptores GABA, ni influye
en su síntesis ni recaptación.
Parece que se une a receptores de calcio
voltaje dependientes, localizados
presinapticamente, que modulan la
liberación de neurotransmisores excitatorios
relacionados con la nociocepcion y la
genesis de epilepsia.
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Gabapentina
DOSING: ADULTS
Anticonvulsant: Oral:
Initial: 300 mg 3 times/day, if necessary the dose may be increased
up to 1800 mg/day
Maintenance: 900-1800 mg/day administered in 3 divided doses;
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 studies
Note: If gabapentin is discontinued or if another anticonvulsant is
added to therapy, it should be done slowly over a minimum of 1
week.
Chronic pain (unlabeled use): Oral: 300-1800 mg/day given in 3
divided doses has been the most common dosage range
Postoperative pain (unlabeled use): 300-1200 mg 1-2 hours
before surgery
Postherpetic neuralgia: Day 1: 300 mg, Day 2: 300 mg twice
daily, Day 3: 300 mg 3 times/day; dose may be titrated as
needed for pain relief (range: 1800-3600 mg/day, daily doses
>1800 mg do not generally show greater benefit)
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Gabapentina
DOSING: PEDIATRIC
Anticonvulsant: Oral
Children 3-12 years: Initial: 10-15 mg/kg/day in 3
divided doses; titrate to effective dose over ~3 days;
dosages of up to 50 mg/kg/day have been tolerated in
clinical studies
Children 3-4 years: Effective dose: 40 mg/kg/day in 3
divided doses
Children 5-12 years: Effective dose: 25-35 mg/kg/day
in 3 divided doses
Children >12 years: Refer to adult dosing.
Note: If gabapentin is discontinued or if another
anticonvulsant is added to therapy, it should be done
slowly over a minimum of 1 week
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Gabapentina
DOSING: ELDERLY —
Studies in elderly patients have shown a
decrease in clearance as age increases.
This is most likely due to age-related
decreases in renal function; dose
reductions may be needed.
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Gabapentina
DOSING: RENAL IMPAIRMENT —
Hemodialysis: Dialyzable
Gabapentin Dosage Adjustments in Renal Impairment
–
–
–
–
–
Clcr 60 mL/minute): 300-1200 mg 3 times/day
Clcr >30-59 mL/minute: 200-700 mg twice/day
Clcr >15-29 mL/minute: 200-700 mg/day
Clcr 15 mL/minute: 100-300 mg/day
Clcr <15 mL/minute: Reduce daily dose in proportion to creatinine clearance.
Hemodialysis single supplemental dose: 125-350 mg (given after each 4
hours of hemodialysis).
Gabapentina
FG > 50
ml/min
FG 10-50
ml/min
FG < 10
ml/min
Dosis
suplemtari
a tras HD
DPCA
TSCR
400 mg/8 h
300 mg/1224 h
300 mg/dia
200-300 mg
Desconocida
300 mg/1224 h
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Gabapentina
ADVERSE REACTIONS SIGNIFICANT — As
reported in patients >12 years of age, unless
otherwise noted in children (3-12 years)
>10%:
Central nervous system: Somnolence (20%;
children 8%), dizziness (17% to 28%; children
3%), ataxia (13%), fatigue (11%)
Miscellaneous: Viral infection (children 11%)
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Gabapentina
ADVERSE REACTIONS SIGNIFICANT — As reported in patients >12 years of age,
unless otherwise noted in children (3-12 years)
1% to 10%:
Cardiovascular: Peripheral edema (2% to 8%), vasodilatation (1%)
Central nervous system: Fever (children 10%), hostility (children 8%), emotional
lability (children 4%), fatigue (children 3%), headache (3%), ataxia (3%), abnormal
thinking (2% to 3%; children 2%), amnesia (2%), depression (2%), dysarthria (2%),
nervousness (2%), abnormal coordination (1% to 2%), twitching (1%), hyperesthesia
(1%)
Dermatologic: Pruritus (1%), rash (1%)
Endocrine & metabolic: Hyperglycemia (1%)
Gastrointestinal: Diarrhea (6%), nausea/vomiting (3% to 4%; children 8%),
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%),
dental abnormalities (2%), appetite stimulation (1%)
Genitourinary: Impotence (2%)
Hematologic: Leukopenia (1%), decreased WBC (1%)
Neuromuscular & skeletal: Tremor (7%), weakness (6%), hyperkinesia (children
3%), abnormal gait (2%), back pain (2%), myalgia (2%), fracture (1%)
Ocular: Nystagmus (8%), diplopia (1% to 6%), blurred vision (3% to 4%),
conjunctivitis (1%)
Otic: Otitis media (1%)
Respiratory: Rhinitis (4%), bronchitis (children 3%), respiratory infection (children
3%), pharyngitis (1% to 3%), cough (2%)
Miscellaneous: Infection (5%) Programa Informed
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Gabapentina
CONTRAINDICATIONS — Hypersensitivity to
gabapentin or any component of the formulation
DRUG INTERACTIONS — CNS depressants:
Sedative effects may be additive with CNS
depressants; includes ethanol, barbiturates,
narcotic analgesics, and other sedative agents.
Monitor for increased effect.
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Gabapentina
EMABARAZO —
– Efectos teratogénicos en animales de
experimentación.
LACTANCIA —
– Pasa a la leche materna. Los recien nacidos
pueden estar expuestos a 1 mg/kg/dia de
gabapentina
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Gabapentina
TOXICOLOGY / OVERDOSE
COMPREHENSIVE —
Acute oral overdoses up to 49 g have been
reported; double vision, slurred speech,
drowsiness, lethargy, and diarrhea were
observed.
Tratamiento:
– De soporte.
– Lavado gastrico, carbón activado, catárticos.
– Hemodialisis.
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Gabapentina
PHARMACODYNAMICS / KINETICS
Absorption: 50% to 60% from proximal small bowel by L-amino
transport system
Distribution: Vd: 0.6-0.8 L/kg
Protein binding: <3%
Bioavailability: Inversely proportional to dose due to saturable
absorption:
900 mg/day: 60%
1200 mg/day: 47%
2400 mg/day: 34%
3600 mg/day: 33%
4800 mg/day: 27%
Half-life elimination: 5-7 hours; anuria 132 hours; during dialysis
3.8 hours
Excretion: Proportional to renal function; urine (as unchanged
drug)
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Antidepresivos
Los tricíclicos se han mostrado efectivos en el
tratamiento del dolor neuropático, especialmente las
disestesias continuas y el dolor lancinante.
También son útiles en el dolor con depresión e insomnio
(Cherny, 1995, 254–255).
Sus mecanismos de acción analgésica consisten en un
efecto bloqueador del dolor a la altura de la médula, una
mejoría del humor y una potenciación o favorecimiento
de la analgesia opioide.
Efectos adversos: sedación, síntomas colinérgicos y de
la conducción cardíaca como la sequedad de boca, la
visión borrosa, la retención urinaria y anomalías de la
conducción cardíaca.
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Antidepresivos
Ninguno de los ADT tienen la indicación para el tratamiento del
dolor.
La Amitriptilina es el más estudiado, pero también se han
utilizado doxepin, imipramine, nortriptyline, y desipramine
Tienen efectos analgésicos independientes y capacidad para
controlar los sintoma depresivos asociados con el dolor crónico.
Mecanismo analgésico desconocido.
– Inhibición de la recaptación de seroronina y norpeinefrina.
– Potenciación del sistema opioide endógeno.
En el dolor crónico se usan a dosis inferiores a las usdas en la
depresión.
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Antidepresivos
El efecto analgésico puede ocurrir tras días de
tratamiento, y a veces son necesarias semanas
de tratamiento antes de obtener un efecto
beneficioso.
A veces es necesario cambiar a otro ADT si no
se obtiene tratamiento.
Estan contraindicados en pacientes con
alteracion del ritmo cardíaco y alteraciones
gastrointestinales.
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N06AA-Antidepresivos inhibidores no selectivos de monoaminas
NOMBRE GENÉRICO PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Amitriptilina
Comp 10 mg
Comp 25 mg
Comp 75 mg
OR
OR
OR
Tryptizol
Clomipramina
(Clorimipramina)
Amp 25 mg/2 ml
Comp 10 mg
Comp 25 mg
Comp 75 mg
IM
OR
OR
OR
Anafranil
Imipramina
comp. 10 mg
Comp 25 mg
Caps 75 mg
OR
OR
OR
Tofranil
Maprotilina
Comp 10 mg
Comp 25 mg
Comp 75 mg
OR
OR
OR
Ludiomil
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N06AB-Antidepresivos inhibidores selectivos de la recaptación de serotonina
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Fluoxetina (1) (2)
Caps 20 mg
Sol 20mg/5ml
OR
OR
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
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N06AF-Antidepresivos Inhibidores no selectivos de la MAO
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Fenelzina
Comp 15 mg
OR
Nardelzine
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N06AX-Otros antidepresivos
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Mianserina
Comp 30 mg
OR
Lantanon
Mirtazapina
Comp 15 mg
Comp 30 mg
OR
OR
Rexer flas
Trazodone
Comp 100 mg
Amp 50 mg/5 ml
OR
IV
Deprax
Venlafaxina
Comp 37,5 mg
OR
Dobupal, Vandral
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Amitriptilina
Mecanismo de acción:
– Aumenta la concentración sináptica de
serotonina y/o norepinefrina en el SNC por
inhibición de su recaptación por la membrana
presinaptica de la neurona.
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N06AA-Antidepresivos inhibidores no selectivos de monoaminas
NOMBRE GENÉRICO PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Amitriptilina
Comp 10 mg
Comp 25 mg
Comp 75 mg
OR
OR
OR
Tryptizol
Clomipramina
(Clorimipramina)
Amp 25 mg/2 ml
Comp 10 mg
Comp 25 mg
Comp 75 mg
IM
OR
OR
OR
Anafranil
Imipramina
comp. 10 mg
Comp 25 mg
Caps 75 mg
OR
OR
OR
Tofranil
Maprotilina
Comp 10 mg
Comp 25 mg
Comp 75 mg
OR
OR
OR
Ludiomil
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Amitriptilina
DOSING: ADULTS
Depression: Oral: 50-150 mg/day single dose at
bedtime or in divided doses; dose may be
gradually increased up to 300 mg/day.
Chronic pain management (unlabeled use):
Oral: Initial: 25 mg at bedtime; may increase
as tolerated to 100 mg/day.
Migraine prophylaxis (unlabeled use): Oral:
Initial: 10-25 mg at bedtime; usual dose: 150 mg;
reported dosing ranges: 10-400 mg/day
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Amitriptilina
DOSING: PEDIATRIC
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 mg/kg
at bedtime
Depressive disorders:
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 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 closely) have
been proposed
Adolescents: Initial: 25-50 mg/day; may administer in divided
doses; increase gradually to 100 mg/day in divided doses.
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
mg/kg/day. Reported dosing ranges: 0.1-2 mg/kg/day; maximum
suggested dose: 10 mg.
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Amitriptilina
DOSING: ELDERLY —
Depression: Oral: Initial: 10-25 mg at bedtime;
dose should be increased in 10-25 mg
increments every week if tolerated; dose range:
25-150 mg/day.
DOSING: RENAL IMPAIRMENT —
Nondialyzable
DOSING: HEPATIC IMPAIRMENT — Use with
caution and monitor plasma levels and patient
response.
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Amitripitilina
FG > 50
ml/min
FG 10-50
ml/min
FG < 10
ml/min
Dosis
suplemtari
a tras HD
DPCA
TSCR
100%
100%
!00%
Ninguna
Desconocida
Ninguna
Los efectos anticolinérgicos pueden provocar en pacientes en HD aumento de
la sed y del peso (boca seca), hiperglucemia, y aumento de la osmolaridad
extracelular.
La hipoK, hipoCa y alcalosis transitoria intradiálisis (factores que alteran el
intervalo QT) pueden aumenta la susceptibilidad a la aparición de arritmias
cardíacas.
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Amitriptilina
USE — Relief of symptoms of depression
USE - UNLABELED /
INVESTIGATIONAL —
– Analgesic for certain chronic and
neuropathic pain;
– prophylaxis against migraine headaches;
– treatment of depressive disorders in children
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Amitriptilina
ADVERSE REACTIONS SIGNIFICANT — Anticholinergic effects may be
pronounced; moderate to marked sedation can occur (tolerance to these effects
usually occurs).
Frequency not defined.
Cardiovascular: Orthostatic hypotension, tachycardia, ECG changes (nonspecific), AV
conduction changes, cardiomyopathy (rare), MI, stroke, heart block, arrhythmia,
syncope, hypertension, palpitation
Central nervous system: Restlessness, dizziness, insomnia, sedation, fatigue,
anxiety, cognitive function impaired, seizure, extrapyramidal symptoms, coma,
hallucinations, confusion, disorientation, coordination impaired, ataxia, headache,
nightmares, hyperpyrexia
Dermatologic: Allergic rash, urticaria, photosensitivity, alopecia
Endocrine & metabolic: Syndrome of inappropriate ADH secretion
Gastrointestinal: Weight gain, xerostomia, constipation, paralytic ileus, nausea,
vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue
Genitourinary: Urinary retention
Hematologic: Bone marrow depression, purpura, eosinophilia
Neuromuscular & skeletal: Numbness, paresthesia, peripheral neuropathy, tremor,
weakness
Ocular: Blurred vision, mydriasis, ocular pressure increased
Otic: Tinnitus
Miscellaneous: Diaphoresis, withdrawal reactions (nausea, headache, malaise)
Postmarketing and/or case reports: Neuroleptic malignant syndrome (rare), serotonin
syndrome (rare)
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Amitriptilina
DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19
(minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6
(weak), 2E1 (weak)
Altretamine: Concurrent use may cause orthostatic hypertension.
Amphetamines: TCAs may enhance the effect of amphetamines; monitor for adverse CV effects.
Anticholinergics: Combined use with TCAs may produce additive anticholinergic effects.
Antihypertensives: Amitriptyline inhibits the antihypertensive response to bethanidine, clonidine,
debrisoquin, guanadrel, guanethidine, guanabenz, guanfacine; monitor BP; consider alternate
antihypertensive agent.
Beta-agonists: When combined with TCAs may predispose patients to cardiac arrhythmias.
Bupropion: May increase the levels of tricyclic antidepressants; based on limited information,
monitor response.
Carbamazepine: Tricyclic antidepressants may increase carbamazepine levels; monitor.
Cholestyramine and colestipol: May bind TCAs and reduce their absorption; monitor for altered
response.
Cisapride: May increase the risk of QTc prolongation and/or arrhythmia; concurrent use is
contraindicated.
Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis; amitriptyline may
enhance the response (also see note on antihypertensives).
CNS depressants: Sedative effects may be additive with TCAs; monitor for increased effect;
includes benzodiazepines, barbiturates, antipsychotics, ethanol, and other sedative medications.
Programa Informed
48
Amitriptilina
DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor),
2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19
(weak), 2D6 (weak), 2E1 (weak)
CYP2D6 inhibitors: May increase the levels/effects of amitriptyline; example inhibitors
include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide,
quinidine, quinine, ritonavir, and ropinirole.
Epinephrine (and other direct alpha-agonists): Pressor response to I.V. epinephrine,
norepinephrine, and phenylephrine may be enhanced in patients receiving TCAs.
(Note: Effect is unlikely with epinephrine or levonordefrin dosages typically
administered as infiltration in combination with local anesthetics.)
Fenfluramine: May increase tricyclic antidepressant levels/effects.
Hypoglycemic agents (including insulin): TCAs may enhance the hypoglycemic
effects of tolazamide, chlorpropamide, or insulin; monitor for changes in blood
glucose levels; reported with chlorpropamide, tolazamide, and insulin.
Levodopa: Tricyclic antidepressants may decrease the absorption (bioavailability) of
levodopa; rare hypertensive episodes have also been attributed to this combination.
Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths
have been reported with agents which inhibit MAO (serotonin syndrome); this
combination should be avoided.
Lithium: Concurrent use with a TCA may increase the risk for neurotoxicity.
MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and
deaths have been reported (serotonin syndrome); this combination should be
avoided.
Programa Informed
49
Amitriptilina
DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19
(minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6
(weak), 2E1 (weak)
MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have
been reported (serotonin syndrome); this combination should be avoided.
Methylphenidate: Metabolism of amitriptyline may be decreased.
Phenothiazines: Serum concentrations of some TCAs may be increased; in addition, TCAs may
increase concentration of phenothiazines; monitor for altered clinical response.
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
antiarrhythmics agents, selected quinolones (sparfloxacin, gatifloxacin, moxifloxacin,
grepafloxacin), cisapride, and other agents.
Ritonavir: Combined use of high-dose tricyclic antidepressants with ritonavir may cause serotonin
syndrome in HIV-positive patients; monitor.
Sucralfate: Absorption of tricyclic antidepressants may be reduced with coadministration.
Sympathomimetics, indirect-acting: Tricyclic antidepressants may result in a decreased sensitivity
to indirect-acting sympathomimetics; includes dopamine and ephedrine; also see interaction with
epinephrine (and direct-acting sympathomimetics).
Tramadol: Tramadol's risk of seizures may be increased with TCAs.
Valproic acid: May increase serum concentrations/adverse effects of some tricyclic
antidepressants.
Warfarin (and other oral anticoagulants): Amitriptyline may increase the anticoagulant effect in
patients stabilized on warfarin; monitor INR.
Programa Informed
50
Amitriptilina
PREGNANCY RISK FACTOR — C
PREGNANCY IMPLICATIONS —
Teratogenic effects have been observed
in animal studies. Amitriptyline crosses
the human placenta; CNS effects, limb
deformities and developmental delay have
been noted in case reports.
LACTATION — Enters breast milk/not
recommended
Programa Informed
51
Amitriptilina
MONITORING PARAMETERS — Monitor blood
pressure and pulse rate prior to and during initial
therapy; evaluate mental status; monitor weight;
ECG in older adults and patients with cardiac
disease
REFERENCE RANGE — Therapeutic:
– Amitriptyline and nortriptyline 100-250 ng/mL (SI: 360900 nmol/L);
– nortriptyline 50-150 ng/mL (SI: 190-570 nmol/L);
Toxic: >0.5 mcg/mL;
– plasma levels do not always correlate with clinical
effectiveness
Programa Informed
52
Amitriptilina
TOXICOLOGY / OVERDOSE COMPREHENSIVE —
Symptoms include agitation, confusion, hallucinations, urinary retention,
hypothermia, hypotension, ventricular tachycardia, and seizures.
Following initiation of essential overdose management, toxic symptoms
should be treated.
Sodium bicarbonate is indicated when the QRS interval is >0.10 seconds or
the QTc is >0.42 seconds.
Ventricular arrhythmias often respond to phenytoin 15-20 mg/kg (adults)
with concurrent systemic alkalinization (sodium bicarbonate 0.5-2 mEq/kg
I.V.).
Arrhythmias unresponsive to this therapy may respond to lidocaine 1 mg/kg
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)
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
measure in life-threatening situations.
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 unresponsive or recur, phenytoin or phenobarbital may be required.
Programa Informed
53
Amitriptilina
PHARMACODYNAMICS / KINETICS
Onset of action: Migraine prophylaxis: 6 weeks, higher dosage may be
required in heavy smokers because of increased metabolism; Depression:
4-6 weeks, reduce dosage to lowest effective level
Distribution: Crosses placenta; enters breast milk
Metabolism: Hepatic to nortriptyline (active), hydroxy and conjugated
derivatives; may be impaired in the elderly
Half-life elimination: Adults: 9-27 hours (average: 15 hours)
Time to peak, serum: ~4 hours
Excretion: Urine (18% as unchanged drug); feces (small amounts)
PATIENT INFORMATION — Do not discontinue medication abruptly.
Full effect may not occur for 3-6 weeks. Avoid alcohol. May cause
urine to turn blue-green. May cause drowsiness. Dry mouth may be
helped by sips of water, sugarless gum, or hard candy.
Programa Informed
54
Programa Informed
55
Benzodiacepinas
Las benzodiazepinas son un tipo de fármaco
con propiedades sedantes, relajantes
musculares y amnésicas. Tienen una serie de
aplicaciones, incluyendo el manejo de la
ansiedad, el control del insomnio, el manejo de
la agitación y la premedicación anestésica (para
producir sedación).
El clonazepam tiene propiedades
anticonvulsivantes y es la única
benzodiazepina con efectos analgésicos
conocidos sobre el dolor neuropático,
especialmente el lancinante.
Programa Informed
56
Benzodiacepinas
Benzodiazepines — Benzodiazepines may be
utilized in patients who would benefit from
anxiolysis. These are commonly employed in
cancer patients and in non-malignant pain
complicated by anxiety disorder.
The disadvantage of this class of drugs relates
to their addictive potential, as well as their
potentiation of sedative effects and respiratory
depression in patients who use opioids
concurrently.
Clonazepam is especially useful for neuropathic
pain.
Programa Informed
57
Clonazepam
Clonazepam — Clonazepam is a benzodiazepine that has been
used successfully in providing relief for both chronic malignant and
non-malignant pain syndromes such as headaches,
temporomandibular joint dysfunction, and phantom limb pain [2224].
It acts by enhancing GABA receptor mediated chloride channels.
Clonazepam is particularly effective when used in combination with
other neuropathic analgesics and in patients with prominent anxiety
disorder and insomnia.
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
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.
The most common side effects are drowsiness, dizziness, fatigue,
and sedation. As with other benzodiazepines, clonazepam may
produce physical and psychological dependence; abrupt
discontinuation is prohibited.
Programa Informed
58
N03AE-Benzodiacepinas
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Clobazam
Comp 10 mg
Comp 20 mg
OR
OR
Noiafren
Clonazepam
Amp 1 mg/2 ml
Comp 0,5 mg
Comp 2 mg
Gts 2,5 mg/ml (1)
IM, IV
OR
OR
OR
Rivotril
Diazepam
Amp 10 mg/2 ml
Comp 5 mg
Comp 10 mg
Microenema 5 mg
IM, IV
Valium, Diazepam
REC
Stesolid
Nota 1: 1 gota=0,1 mg
Programa Informed
59
Clonazepam
MECHANISM OF ACTION — The exact
mechanism is unknown, but believed to be
related to its ability to enhance the activity
of GABA; suppresses the spike-and-wave
discharge in absence seizures by
depressing nerve transmission in the
motor cortex
Programa Informed
60
Clonazepam
DOSING: ADULTS
Seizure disorders: Oral:
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
controlled or adverse effects seen (maximum: 20 mg/day)
Usual maintenance dose: 0.05-0.2 mg/kg; do not exceed 20
mg/day
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
(maximum: 4 mg/day)
Discontinuation of treatment: To discontinue, treatment should be
withdrawn gradually. Decrease dose by 0.125 mg twice daily every 3
days until medication is completely withdrawn.
Programa Informed
61
Clonazepam
DOSING: PEDIATRIC
Seizure disorders (see Use): Oral:
Children <10 years or 30 kg:
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
more than 0.5 mg every third day until seizures are
controlled or adverse effects seen.
Usual maintenance dose: 0.1-0.2 mg/kg/day divided 3
times/day; not to exceed 0.2 mg/kg/day.
Children >10 years or 30 kg: Refer to adult dosing.
Programa Informed
62
Clonazepam
DOSING: ELDERLY — Refer to adult
dosing. Initiate with low doses and
observe closely.
DOSING: RENAL IMPAIRMENT —
Hemodialysis: Supplemental dose is not
necessary.
Programa Informed
63
Clonazepam
FG > 50
ml/min
FG 10-50
ml/min
FG < 10
ml/min
Dosis
suplemtari
a tras HD
DPCA
TSCR
100%
100%
100%
Ninguna
Ninguna
100%
Programa Informed
64
Clonazepam
USE — Alone or as an adjunct in the treatment
of petit mal variant (Lennox-Gastaut), akinetic,
and myoclonic seizures; petit mal (absence)
seizures unresponsive to succimides; panic
disorder with or without agoraphobia
USE - UNLABELED / INVESTIGATIONAL —
Restless legs syndrome; neuralgia; multifocal tic
disorder; parkinsonian dysarthria; bipolar
disorder; adjunct therapy for schizophrenia
Programa Informed
65
Clonazepam
ADVERSE REACTIONS SIGNIFICANT — Reactions reported in patients with seizure and/or panic disorder.
Frequency not defined.
Cardiovascular: Edema (ankle or facial), palpitation
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,
fatigue, fever, hallucinations, headache, hypotonia, hysteria, insomnia, intellectual ability reduced, memory
disturbance, nervousness; paradoxical reactions (including aggressive behavior, agitation, anxiety, excitability,
hostility, irritability, nervousness, nightmares, sleep disturbance, vivid dreams); psychosis, slurred speech,
somnolence (panic disorder 37%), suicidal attempt, vertigo
Dermatologic: Hair loss, hirsutism, skin rash
Endocrine & metabolic: Dysmenorrhea, libido increased/decreased
Gastrointestinal: Abdominal pain, anorexia, appetite increased/decreased, coated tongue, constipation,
dehydration, diarrhea, gastritis, gum soreness, nausea, weight changes (loss/gain), xerostomia
Genitourinary: Colpitis, dysuria, ejaculation delayed, enuresis, impotence, micturition frequency, nocturia, urinary
retention, urinary tract infection
Hematologic: Anemia, eosinophilia, leukopenia, thrombocytopenia
Hepatic: Alkaline phosphatase increased (transient), hepatomegaly, transaminases increased (transient)
Neuromuscular & skeletal: Choreiform movements, coordination abnormal, dysarthria, muscle pain, muscle
weakness, myalgia, tremor
Ocular: Blurred vision, eye movements abnormal, diplopia, nystagmus
Respiratory: Chest congestion, cough, bronchitis, hypersecretions, pharyngitis, respiratory depression, respiratory
tract infection, rhinitis, rhinorrhea, shortness of breath, sinusitis
Miscellaneous: Allergic reaction, aphonia, dysdiadochokinesis, encopresis, "glassy-eyed" appearance,
hemiparesis, lymphadenopathy
Programa Informed
66
Clonazepam
DRUG INTERACTIONS — Substrate of CYP3A4 (major)
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS
depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents;
monitor for increased effect.
CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of clonazepam. Example
inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital,
phenytoin, and rifamycins.
CYP3A4 inhibitors: May increase the levels/effects of clonazepam. Example inhibitors include
azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid,
nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.
Disulfiram: Disulfiram may inhibit the metabolism of clonazepam; monitor for increased
benzodiazepine effect.
Levodopa: Therapeutic effects may be diminished in some patients following the addition of a
benzodiazepine; limited/inconsistent data.
Oral contraceptives: May decrease the clearance of some benzodiazepines (those which undergo
oxidative metabolism); monitor for increased benzodiazepine effect.
Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for
decreased response; may require higher doses for sedation.
Valproic acid: The combined use of clonazepam and valproic acid has been associated with
absence seizures.
Programa Informed
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Clonazepam
PREGNANCY RISK FACTOR — D (show table)
PREGNANCY IMPLICATIONS — Clonazepam was shown to be
teratogenic in some animal studies. Clonazepam crosses the
placenta. Benzodiazepine use during pregnancy is associated with
increased risk of congenital malformations. Nonteratogenic effects
(including neonatal flaccidity, respiratory and feeding problems, and
withdrawal symptoms) during the postnatal period have also been
reported with benzodiazepine use. Epilepsy itself, number of
medications, genetic factors, or a combination of these probably
influence the teratogenicity of anticonvulsant therapy.
LACTATION — Enters breast milk/not recommended
BREAST-FEEDING CONSIDERATIONS — Clonazepam enters
breast milk; clinical effects on the infant include CNS depression,
respiratory depression reported (no recommendation from the AAP).
Programa Informed
68
Clonazepam
PHARMACODYNAMICS / KINETICS
Onset of action: 20-60 minutes
Duration: Infants and young children: 6-8 hours; Adults: 12 hours
Absorption: Well absorbed
Distribution: Adults: Vd: 1.5-4.4 L/kg
Protein binding: 85%
Metabolism: Extensively hepatic via glucuronide and sulfate conjugation
Half-life elimination: Children: 22-33 hours; Adults: 19-50 hours
Time to peak, serum: 1-3 hours; Steady-state: 5-7 days
Excretion: Urine (<2% as unchanged drug); metabolites excreted as
glucuronide or sulfate conjugates
PATIENT INFORMATION — Drug may cause physical or psychological
dependence; avoid abrupt discontinuation after prolonged use. Avoid
alcohol and other CNS depressants. Avoid activities needing good
psychomotor coordination until CNS effects are known.
Programa Informed
69
Benzodiazepines for chronic pain
Route 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
Drug
Programa Informed
70
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.
Programa Informed
71
Programa Informed
72
N05C-Hipnóticos y sedantes
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Clometiazol (1)
Caps 192 mg
OR
Distraneurine
Flurazepam (2)
Caps 30 mg
OR
Dormodor
Hidrato de cloral
Jbe 50 mg/ml
Enema 100 mg/ml
OR
REC
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.
Programa Informed
73
N05B-Ansiolíticos
NOMBRE
GENÉRICO
PRESENTACIÓN
VÍA
NOMBRE
COMERCIAL
Alprazolam
Comp 0,25 mg
Comp 0,5 mg
Comp 1 mg
OR
OR
OR
Trankimazin
Clorazepato
dipotásico
Sobres de 2,5 mg
Caps 5 mg
Caps 10 mg
Caps 15 mg
Comp 50 mg
Vial 20 mg/2 ml
Vial 50 mg/2,5 ml
OR
Tranxilium pediát
OR
Tranxilium
OR
OR
OR
IM,IV
IM,IV
Diazepam (1)
Amp 10 mg/ 2 ml
Comp 5 mg
Comp 10 mg
IM.IV Diazepam Prodes
OR
Valium
OR
Nota 1: Ketazolam (Sedotime) se considera equivalente terapéutico de
Diazepam.
Programa Informed
74