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

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Presentación del tema: "Adjuvantes Francisco José de la Prada Alvarez. Servicio de Nefrología. Hospital Universitario Son Dureta."— Transcripción de la presentación:

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

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5 5 2.2 Según la causa subyacente se reconocen tres tipos generales de dolor: 1) nociceptivo somático 2) nociceptivo visceral 3) neuropático 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.

6 Programa Informed Según la causa subyacente se reconocen tres tipos generales de dolor: – 1) nociceptivo somático 2) nociceptivo visceral 3) neuropático 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).

7 Programa Informed Según la causa subyacente se reconocen tres tipos generales de dolor: – 1) nociceptivo somático 2) nociceptivo visceral 3) neuropático 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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10 10 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.

11 Programa Informed 11 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.

12 Programa Informed 12 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.

13 Programa Informed 13 DrugSystemic side effectsNeurotoxic side effects CarbamazepineNausea, vomiting, diarrhea, hyponatremia, rash, pruritus Drowsiness, dizziness, blurred or double vision, lethargy, headache EthosuximideNausea, vomitingSleep disturbance, drowsiness, hyperactivity FelbamateNausea, vomiting, anorexia, weight lossInsomnia, dizziness, headache, ataxia GabapentinNone knownSomnolence, dizziness, ataxia LamotrigineRash, nauseaDizziness, somnolence LevetiracetamInfectionFatigue, somnolence, dizziness, agitation, anxiety OxcarbazepineNausea, rash, hyponatremiaSedation, headache, dizziness, vertigo, ataxia, diplopia PhenytoinGingival hypertrophy, body hair increase, rash, lymphadenopathy Confusion, slurred speech, double vision, ataxia, neuropathy (with long-term use) PregabalinWeight gainDizziness, somnolence, ataxia Primidone, phenobarbital Nausea, rashAlteration of sleep cycles, sedation, lethargy, behavioral changes, hyperactivity, ataxia, tolerance, dependence TiagabineNone knownDizziness, lack of energy, somnolence, nausea, nervousness, tremor, difficulty concentrating, abdominal pain TopiramateWeight loss, renal stones, paresthesiasFatigue, nervousness, difficulty concentrating, confusion, depression, anorexia, language problems, anxiety, mood problems, tremor ValproateWeight gain, nausea, vomiting, hair loss, easy bruising Tremor ZonisamideNausea, anorexiaSomnolence, dizziness, ataxia, confusion, difficulty concentrating

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15 Programa Informed 15 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.

16 Programa Informed 16 N03AA-Barbitúricos NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL FenobarbitalAmp 200 mg/1 ml Comp 15 mg Comp 100 mg IM OR Luminal Luminaletas Luminal 0,1

17 Programa Informed 17 N03AB-Hidantoinas NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL Fenitoína sódicaComp 100 mg Caps 100 mg Jbe 125 mg/5 ml Vial 250 mg/5 ml OR IV, IM Neosindantoína Epanutin Fenitoína Rubió

18 Programa Informed 18 N03AD-Carboxamidas NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL CarbamazepinaComp 200 mgORTegretol

19 Programa Informed 19 N03AG-Acidos grasos NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL Valproico AcidoComp 200 mg Comp 500 mg Sol 200 mg/ml Vial 400 mg OR IV Depakine Depakine iny VigabatrinaComp 500 mg Sobres 500 mg OR Sabrilex

20 Programa Informed 20 N03AX-Otros antiepilépticos NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL GabapentinaCap 300 mg Cap 400 mg OR Neurontin LamotriginaComp 100 mg Comp 200 mg OR Lamictal Gabapentina

21 Programa Informed 21 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.

22 Programa Informed 22 Gabapentina DOSING: ADULTS Anticonvulsant: Oral: Initial: 300 mg 3 times/day, if necessary the dose may be increased up to 1800 mg/day Maintenance: 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: mg/day given in 3 divided doses has been the most common dosage range Postoperative pain (unlabeled use): 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: mg/day, daily doses >1800 mg do not generally show greater benefit)

23 Programa Informed 23 Gabapentina DOSING: PEDIATRIC Anticonvulsant: Oral Children 3-12 years: Initial: 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: 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

24 Programa Informed 24 Gabapentina DOSING: ELDERLY 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.

25 Programa Informed 25 Gabapentina DOSING: RENAL IMPAIRMENT DOSING: RENAL IMPAIRMENT Hemodialysis: Dialyzable Gabapentin Dosage Adjustments in Renal Impairment –Clcr 60 mL/minute): mg 3 times/day –Clcr >30-59 mL/minute: mg twice/day –Clcr >15-29 mL/minute: mg/day –Clcr 15 mL/minute: mg/day –Clcr <15 mL/minute: Reduce daily dose in proportion to creatinine clearance. Hemodialysis single supplemental dose: mg (given after each 4 hours of hemodialysis). FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemtari a tras HD DPCATSCR Gabapentina 400 mg/8 h 300 mg/ h 300 mg/dia mg Desconocida 300 mg/ h

26 Programa Informed 26 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%)

27 Programa Informed 27 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%)

28 Programa Informed 28 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.

29 Programa Informed 29 Gabapentina EMABARAZO EMABARAZO –Efectos teratogénicos en animales de experimentación. LACTANCIA LACTANCIA –Pasa a la leche materna. Los recien nacidos pueden estar expuestos a 1 mg/kg/dia de gabapentina

30 Programa Informed 30 Gabapentina TOXICOLOGY / OVERDOSE COMPREHENSIVE 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.

31 Programa Informed 31 Gabapentina PHARMACODYNAMICS / KINETICS Absorption: 50% to 60% from proximal small bowel by L-amino transport system Distribution: Vd: 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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33 Programa Informed 33 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.

34 Programa Informed 34 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 doxepinimipraminenortriptylinedesipraminedoxepinimipraminenortriptylinedesipramine 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.

35 Programa Informed 35 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.

36 Programa Informed 36 N06AA-Antidepresivos inhibidores no selectivos de monoaminas NOMBRE GENÉRICOPRESENTACIÓNVÍANOMBRE COMERCIAL AmitriptilinaComp 10 mg Comp 25 mg Comp 75 mg OR Tryptizol Clomipramina (Clorimipramina) Amp 25 mg/2 ml Comp 10 mg Comp 25 mg Comp 75 mg IM OR Anafranil Imipraminacomp. 10 mg Comp 25 mg Caps 75 mg OR Tofranil MaprotilinaComp 10 mg Comp 25 mg Comp 75 mg OR Ludiomil

37 Programa Informed 37 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 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 ) 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

38 Programa Informed 38 NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL FenelzinaComp 15 mgORNardelzine N06AF-Antidepresivos Inhibidores no selectivos de la MAO

39 Programa Informed 39 N06AX-Otros antidepresivos NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL MianserinaComp 30 mgORLantanon MirtazapinaComp 15 mg Comp 30 mg OR Rexer flas TrazodoneComp 100 mg Amp 50 mg/5 ml OR IV Deprax VenlafaxinaComp 37,5 mgORDobupal, Vandral

40 Programa Informed 40 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.

41 Programa Informed 41 N06AA-Antidepresivos inhibidores no selectivos de monoaminas NOMBRE GENÉRICOPRESENTACIÓNVÍANOMBRE COMERCIAL AmitriptilinaComp 10 mg Comp 25 mg Comp 75 mg OR Tryptizol Clomipramina (Clorimipramina) Amp 25 mg/2 ml Comp 10 mg Comp 25 mg Comp 75 mg IM OR Anafranil Imipraminacomp. 10 mg Comp 25 mg Caps 75 mg OR Tofranil MaprotilinaComp 10 mg Comp 25 mg Comp 75 mg OR Ludiomil

42 Programa Informed 42 Amitriptilina DOSING: ADULTS Depression: Oral: 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: mg at bedtime; usual dose: 150 mg; reported dosing ranges: mg/day

43 Programa Informed 43 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 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: 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: mg/kg/day; maximum suggested dose: 10 mg.

44 Programa Informed 44 Amitriptilina DOSING: ELDERLY DOSING: ELDERLY Depression: Oral: Initial: mg at bedtime; dose should be increased in mg increments every week if tolerated; dose range: mg/day. DOSING: RENAL IMPAIRMENT Nondialyzable DOSING: HEPATIC IMPAIRMENT Use with caution and monitor plasma levels and patient response.

45 Programa Informed 45 FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemtari a tras HD DPCATSCR Amitripitilina100%100%!00%NingunaDesconocidaNinguna 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.

46 Programa Informed 46 Amitriptilina USE Relief of symptoms of depression USE - UNLABELED / INVESTIGATIONAL USE - UNLABELED / INVESTIGATIONAL –Analgesic for certain chronic and neuropathic pain; –prophylaxis against migraine headaches; –treatment of depressive disorders in children

47 Programa Informed 47Amitriptilina 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)

48 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) 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.

49 Programa Informed 49Amitriptilina 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.

50 Programa Informed 50Amitriptilina 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.

51 Programa Informed 51 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

52 Programa Informed 52 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 ng/mL (SI: nmol/L); –nortriptyline ng/mL (SI: nmol/L); Toxic: >0.5 mcg/mL; –plasma levels do not always correlate with clinical effectiveness

53 Programa Informed 53 Amitriptilina TOXICOLOGY / OVERDOSE COMPREHENSIVE 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 mg/kg (adults) with concurrent systemic alkalinization (sodium bicarbonate mEq/kg I.V.). Ventricular arrhythmias often respond to phenytoin mg/kg (adults) with concurrent systemic alkalinization (sodium bicarbonate 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 mg/kg/dose for children up to 10 mg/dose). If seizures are unresponsive or recur, phenytoin or phenobarbital may be required.

54 Programa Informed 54 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.

55 Programa Informed 55

56 Programa Informed 56 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.

57 Programa Informed 57 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. ClonazepamClonazepam is especially useful for neuropathic pain. Clonazepam

58 Programa Informed 58 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 [22- 24]. Clonazepam22- 24Clonazepam 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. clonazepam 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. clonazepam

59 Programa Informed 59 N03AE-Benzodiacepinas NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL ClobazamComp 10 mg Comp 20 mg OR Noiafren ClonazepamAmp 1 mg/2 ml Comp 0,5 mg Comp 2 mg Gts 2,5 mg/ml (1) IM, IV OR Rivotril DiazepamAmp 10 mg/2 ml Comp 5 mg Comp 10 mg Microenema 5 mg IM, IV REC Valium, Diazepam Stesolid Nota 1: 1 gota=0,1 mg

60 Programa Informed 60 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

61 Programa Informed 61 Clonazepam DOSING: ADULTS Seizure disorders: Oral: Initial daily dose not to exceed 1.5 mg given in 3 divided doses; may increase by mg every third day until seizures are controlled or adverse effects seen (maximum: 20 mg/day) Usual maintenance dose: mg/kg; do not exceed 20 mg/day Panic disorder: Oral: 0.25 mg twice daily; increase in increments of 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 mg twice daily every 3 days until medication is completely withdrawn.

62 Programa Informed 62 Clonazepam DOSING: PEDIATRIC Seizure disorders (see Use): Oral: Children <10 years or 30 kg: Initial daily dose: 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: 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.

63 Programa Informed 63 Clonazepam DOSING: ELDERLY Refer to adult dosing. Initiate with low doses and observe closely. DOSING: RENAL IMPAIRMENT Hemodialysis: Supplemental dose is not necessary.

64 Programa Informed 64 FG > 50 ml/min FG ml/min FG < 10 ml/min Dosis suplemtari a tras HD DPCATSCR Clonazepam100%100%100%NingunaNinguna100%

65 Programa Informed 65 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

66 Programa Informed 66 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

67 Programa Informed 67 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.

68 Programa Informed 68 Clonazepam PREGNANCY RISK FACTOR D (show table) show tableshow 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).

69 Programa Informed 69 Clonazepam PHARMACODYNAMICS / KINETICS Onset of action: minutes Duration: Infants and young children: 6-8 hours; Adults: 12 hours Absorption: Well absorbed Distribution: Adults: Vd: L/kg Protein binding: 85% Metabolism: Extensively hepatic via glucuronide and sulfate conjugation Half-life elimination: Children: hours; Adults: 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.

70 Programa Informed 70 Benzodiazepines for chronic pain Drug Route of administrationDose Diazepam (Valium) PO/IM/PR2.5 mg Q 3 to 6 hours Lorazepam (Ativan) PO/IV/IM0.5 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) POUp to 1.5 mg/day

71 Programa Informed 71 CategoryInterpretation 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.

72 Programa Informed 72

73 Programa Informed 73 N05C-Hipnóticos y sedantes NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL Clometiazol (1)Caps 192 mgORDistraneurine Flurazepam (2)Caps 30 mgORDormodor Hidrato de cloralJbe 50 mg/ml Enema 100 mg/ml OR REC Hidrato de Cloral FM Lorazepam (3)Comp 1 mgOROrfidal LormetazepamComp 2 mgORLoramet, Noctamid MidazolamAmp 15 mg/3 mlIM,IVDormicum Zolpidem (4)Comp 10 mgORStilnox 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.

74 Programa Informed 74 NOMBRE GENÉRICO PRESENTACIÓNVÍANOMBRE COMERCIAL AlprazolamComp 0,25 mg Comp 0,5 mg Comp 1 mg 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 IM,IV Tranxilium pediát Tranxilium Diazepam (1)Amp 10 mg/ 2 ml Comp 5 mg Comp 10 mg IM.IV OR Diazepam Prodes Valium Nota 1: Ketazolam (Sedotime) se considera equivalente terapéutico de Diazepam. N05B-Ansiolíticos


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