SEDACION EN PACIENTES CON ERC Francisco José de la Prada Alvarez Servicio de Nefrología Hospital Universitario Son Dureta

Ansiedad. Dolor Delirio Disnea Parálisis

Fármaco Sedación Hiponósis Amnesia Analgesia + - +* +** *mínimo efecto Benzodia-cepinas + - Haloperidol +* Ketamina Opioides Propofol +** *mínimo efecto **solo a bajas dosis

Sedantes-Hipnóticos: Analgésicos: Benzodiacepinas: Diacepam Lorazepam Midazolam Barbitúricos: Tiopental Methohexital Analgésicos: Fentanilo. Hidromorphina. Sulfato de morfina. Anestésicos: Ketamina. Propofol. Neurolépticos: Haloperidol.

Jacobi, J, Fraser, GL, Coursin, DB, et al Jacobi, J, Fraser, GL, Coursin, DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30:119

Benzodiacepinas Mecanismo de acción: Acciones: Principal problema: Unión a receptores específicos del complejo del receptor de GABA en el SNC, favoreciendo la unión y el efecto de este neurotransmisor inhibitorio de la excitabilidad neuronal. (incrementa la permeabilidad al Cl de la membrana neuronal, hiperpolarizando la membrana, estabilizandola y haciéndola menos excitable. Acciones: Sedantes a bajas dosis. A altas dosis: Anticonvulsivantes Sedantes. Amnésicos. Depresores cardio y respiratorio. Principal problema: Tolerancia.

Benzodiacepinas Todos tienen la misma eficacia a dosis equipotentes. Las diferencias dependen de la afinidad por el receptor, lipofilia y la cinética de eliminación. Afinidad: Lorazepam: mayor afinidad y mayor potencia Midazolam y Diazepam: menos afinidad y potencia Lipofilia: Midazolam y Diazepam: los más lipofílicos (pasan BHE, rápido inicio de acción, acumulación en los tejidos grasos) Cinética de eliminación:

Benzodiacepinas Diazepam Midazolam Lorazepam Reducción oxidativa (Se afecta por edad, disfunción hepática e interacciones farmacológicas) Gran volumen de distribución. Bajo metabolismo hepático. Metabolitos activos (diametildiazepam y oxazepam) que se elimina via renal. Propilenglicol (hiperosmolaridad y acidosis metabólica con osmol gap elevado) Midazolam Corta vida media. Gran volumen de distribución Metabolito activo (alfa-hidroximidazolam) Lorazepam Glucoroconjugación Metabolitos inactivos. Propilenglicol (hiperosmolaridad y acidosis metabólica con osmol gap elevado). Se afecta por la ERC.

Diazepam Amp 10 mg/2 ml Comp 5 mg Microenema 5 mg REC Valium, Diazepam N03AE-Benzodiacepinas NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL Clobazam Comp 10 mg Comp 20 mg OR Noiafren Clonazepam Amp 1 mg/2 ml Comp 0,5 mg Comp 2 mg Gts 2,5 mg/ml (1) IM, IV Rivotril Diazepam Amp 10 mg/2 ml Comp 5 mg Microenema 5 mg REC Valium, Diazepam Stesolid Nota 1: 1 gota=0,1 mg

Diazepam Anxiety/sedation/skeletal muscle relaxation: DOSING: ADULTS — Note: Oral absorption is more reliable than I.M. Anticonvulsant (acute treatment): Rectal gel: 0.2 mg/kg. Note: Dosage should be rounded upward to the next available dose, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/dose; dose may be repeated in 4-12 hours if needed; do not use for more than 5 episodes per month or more than one episode every 5 days. Anxiety/sedation/skeletal muscle relaxation: Oral: 2-10 mg 2-4 times/day I.M., I.V.: 2-10 mg, may repeat in 3-4 hours if needed Sedation in the ICU patient: I.V.: 0.03-0.1 mg/kg every 30 minutes to 6 hours Status epilepticus: I.V.: 5-10 mg every 10-20 minutes, up to 30 mg in an 8-hour period; may repeat in 2-4 hours if necessary Rapid tranquilization of agitated patient (administer every 30-60 minutes): Oral: 5-10 mg; average total dose for tranquilization: 20-60 mg

Diazepam DOSING: PEDIATRIC Conscious sedation for procedures:   Oral:     Children: 0.2-0.3 mg/kg (maximum dose: 10 mg) 45-60 minutes prior to procedure     Adolescents: 10 mg   I.V.: Adolescents: 5 mg; may repeat with 2.5 mg if needed Febrile seizure prophylaxis: Oral: Children: 1 mg/kg/day divided every 8 hours; initiate therapy at first sign of fever and continue for 24 hours after fever is gone Sedation or muscle relaxation or anxiety:   Oral: Children: 0.12-0.8 mg/kg/day in divided doses every 6-8 hours   I.M., I.V.: Children: 0.04-0.3 mg/kg/dose every 2-4 hours to a maximum of 0.6 mg/kg within an 8-hour period if needed Status epilepticus:   I.V.:     Infants >30 days and Children <5 years: 0.05-0.3 mg/kg/dose given over 3-5 minutes, every 15-30 minutes to a maximum total dose of 5 mg or 0.2-0.5 mg/dose every 2-5 minutes to a maximum total dose of 5 mg; repeat in 2-4 hours as needed     Children 5 years: 0.05-0.3 mg/kg/dose given over 3-5 minutes, every 15-30 minutes to a maximum total dose of 10 mg or 1 mg/dose every 2-5 minutes to a maximum of 10 mg; repeat in 2-4 hours as needed   Rectal: 0.5 mg/kg/dose then 0.25 mg/kg/dose in 10 minutes if needed (prepare dose using parenteral formulation) Anticonvulsant (acute treatment): Rectal gel:   Children <2 years: Safety and efficacy have not been studied   Children 2-5 years: 0.5 mg/kg   Children 6-11 years: 0.3 mg/kg   Children 12 years: Refer to adult dosing.     Note: Dosage should be rounded upward to the next available dose, 2.5, 5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/dose; dose may be repeated in 4-12 hours if needed; do not use for more than 5 episodes per month or more than one episode every 5 days. Muscle spasm associated with tetanus: I.V., I.M.:   Infants >30 days: 1-2 mg/dose every 3-4 hours as needed   Children 5 years: 5-10 mg/dose every 3-4 hours as needed

Diazepam DOSING: ELDERLY Oral: Oral absorption is more reliable than I.M.. Oral: Initial: Anxiety: 1-2 mg 1-2 times/day; increase gradually as needed, rarely need to use >10 mg/day. Skeletal muscle relaxant: 2-5 mg 2-4 times/day Rectal gel: Due to the increased half-life in elderly and debilitated patients, consider reducing dose.

Diazepam PHARMACODYNAMICS / KINETICS I.V.: Status epilepticus:   Onset of action: Almost immediate   Duration: 20-30 minutes Absorption: Oral: 85% to 100%, more reliable than I.M. Food: Diazepam serum levels may be increased if taken with food. Diazepam effect/toxicity may be increased by grapefruit juice; avoid concurrent use. Protein binding: 98%. Metabolism: Hepatic. Half-life elimination: Parent drug: Adults: 20-50 hours; increased half-life in neonates, elderly, and those with severe hepatic disorders; Active major metabolite (desmethyldiazepam): 50-100 hours; may be prolonged in neonates

Diazepam Rango terapéutico: Diazepam: 0.2-1.5 mcg/mL (SI: 0.7-5.3 µmol/L); N-desmethyldiazepam (nordiazepam): 0.1-0.5 mcg/mL (SI: 0.35-1.8 µmol/L)

Diazepam Sobredosis: Sintomas: somnolencia, confusion, coma, reflejos hipotónicos, disnea, hipotension, alteración de la coordinación. Tratamiento de soporte. Rara vez se requiere ventilación mecánica. Flumazenil (Anexate): bloquea selectivamenten la unión de la benzodiacepinas a los receptores del SNC, revirtiendo la depresión del SNC, pero no la depresión respiratoria.

Diazepam Embarazo: Contraindicados en la lactancia. Teratogenico. Atraviesa la placenta. Se han descrito hipotonía, hipotermia, sintomas de abstinencia dificultad respiratoria y para la alimentación en neonatos cuyas madres toman BZDP. Contraindicados en la lactancia.

Benzodiacepinas Diaze-pam Loraze-pam Midazo-lam Dosis de carga Dosis de mantenimiento FG > 50 ml/min FG 10-50 ml/min FG < 10 ml/min Dosis suplemtaria tras HD DPCA TSCR Diaze-pam 5-20 mg IV bolus 5-20 mg/2-4 horas IV 100% Ninguna Desconocida Loraze-pam 1-4 mg IV bolus 0,5-10 mg/hora IV Dosis FG 10-50 ml/min Midazo-lam 2-8 mg IV bolus 2-5 mg/hora IV 50% No aplicable

Diazepam INYECCION IV: SI INFUSION INTERMITENTE: SI Administrar en venas de gran calibre o bien a través del equipo de suero. En general la ampolla debe administrarse directamente, sin diluir y muy lentamente (*). Se recomienda no sobrepasar la velocidad de 5 mg por minuto en adultos; en niños debe administrarse en al menos 3 minutos. La administración demasiado rápida puede causar hipotensión y depresión respiratoria severa. (*) En caso de diluir la ampolla debe realizarse en una proporción de 1 ml de Valium y 1 ml de agua p.i. o SF. (Si diluimos en proporciones más altas, ejemplo la ampolla de 2 ml de Valium en 10 ml-50 ml de SF, se produce precipitación: La jeringa tiene un aspecto turbio y lechoso y no es recomendable administrarla). INFUSION INTERMITENTE: SI Una ampolla de 2 ml debe diluirse en al menos 50-100 ml de SF ó SG5% y administrar en 15-30 minutos. INFUSION CONTINUA: NO RECOMENDADO Disponemos de pocos datos sobre esta vía de administración, aunque puede estar indicada cuando se pautan dosis altas y continuas de Diazepam (Ej.: Tétanos).

Diazepam INYECCION IM: SI SUEROS COMPATIBLES: SF, SG5%. OBSERVACIONES: Inyección intramuscular profunda. La absorción es lenta y algo errática, por lo que se recomienda pasar a la vía oral siempre que sea posible. SUEROS COMPATIBLES: SF, SG5%. OBSERVACIONES: Evitar extravasación o administración intraarterial. Diazepam se une a algunos componentes de los plásticos del material usado en su administración y no es recomendable guardarlo preparado en jeringas.

N03AE-Benzodiacepinas NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL Clobazam Comp 10 mg Comp 20 mg OR Noiafren Clonazepam Amp 1 mg/2 ml Comp 0,5 mg Comp 2 mg Gts 2,5 mg/ml (1) IM, IV Rivotril Diazepam Amp 10 mg/2 ml Comp 5 mg Microenema 5 mg REC Valium, Diazepam Stesolid Nota 1: 1 gota=0,1 mg

N05C-Hipnóticos y sedantes NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL Clometiazol (1) Caps 192 mg OR Distraneurine Flurazepam (2) Caps 30 mg Dormodor Hidrato de cloral Jbe 50 mg/ml Enema 100 mg/ml REC Hidrato de Cloral FM Lorazepam (3) Comp 1 mg Orfidal Lormetazepam Comp 2 mg Loramet , Noctamid Midazolam Amp 15 mg/3 ml IM,IV Dormicum Zolpidem (4) Comp 10 mg 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.

Midazolam DOSING: ADULTS La dosis debe ser individualizada segun la edad del paciente, las patologías subyacentes y las medicaciones concurrentes. Debe reducirse la dosis un 30% si se administran ´narcóticos u otros depresores del SNC. Debe haber disponible equipo de resucitación respiratoria. Conscious sedation: I.V.: Initial: 0.5-2 mg slow I.V. over at least 2 minutes; slowly titrate to effect by repeating doses every 2-3 minutes if needed; usual total dose: 2.5-5 mg; use decreased doses in elderly.       Initial: Some patients respond to doses as low as 1 mg; no more than 2.5 mg should be administered over a period of 2 minutes. Additional doses of midazolam may be administered after a 2-minute waiting period and evaluation of sedation after each dose increment. A total dose >5 mg is generally not needed. If narcotics or other CNS depressants are administered concomitantly, the midazolam dose should be reduced by 30%.     Maintenance: 25% of dose used to reach sedative effect

Midazolam DOSIS: ADULTOS Preoperative sedation:   I.M.: 0.07-0.08 mg/kg 30-60 minutes prior to surgery/procedure; usual dose: 5 mg; Note: Reduce dose in patients with COPD, high-risk patients, patients 60 years of age, and patients receiving other narcotics or CNS depressants   I.V.: 0.02-0.04 mg/kg; repeat every 5 minutes as needed to desired effect or up to 0.1-0.2 mg/kg   Intranasal (not an approved route): 0.2 mg/kg (up to 0.4 mg/kg in some studies); administer 30-45 minutes prior to surgery/procedure Anesthesia: I.V.:   Induction:     Unpremedicated patients: 0.3-0.35 mg/kg (up to 0.6 mg/kg in resistant cases)     Premedicated patients: 0.15-0.35 mg/kg   Maintenance: 0.05-0.3 mg/kg as needed, or continuous infusion 0.25-1.5 mcg/kg/minute Sedation in mechanically-ventilated patients: I.V. continuous infusion: 100 mg in 250 mL D5W or NS (if patient is fluid-restricted, may concentrate up to a maximum of 0.5 mg/mL); initial dose: 0.02-0.08 mg/kg (~1 mg to 5 mg in 70 kg adult) initially and either repeated at 5-15 minute intervals until adequate sedation is achieved or continuous infusion rates of 0.04-0.2 mg/kg/hour and titrate to reach desired level of sedation

Midazolam ANCIANOS. La dosis debe ser individualizada segun la edad del paciente, las patologías subyacentes y las medicaciones concurrentes. Debe reducirse la dosis un 30% si se administran narcóticos u otros depresores del SNC. Debe haber disponible equipo de resucitación respiratoria. I.V.: Conscious sedation: Initial: 0.5 mg slow I.V.; give no more than 1.5 mg in a 2-minute period. If additional titration is needed, give no more than 1 mg over 2 minutes, waiting another 2 or more minutes to evaluate sedative effect. A total dose >3.5 mg is rarely necessary.

Midazolam DOSING: PEDIATRIC Notes: The dose of midazolam needs to be individualized based on the patient's age, underlying diseases, and concurrent medications. Decrease dose (by ~30%) if narcotics or other CNS depressants are administered concomitantly. Personnel and equipment needed for standard respiratory resuscitation should be immediately available during midazolam administration. Children <6 years may require higher doses and closer monitoring than older children; calculate dose on ideal body weight Conscious sedation for procedures or preoperative sedation:   Oral: 0.25-0.5 mg/kg as a single dose preprocedure, up to a maximum of 20 mg; administer 30-40 minutes prior to procedure. Children <6 years, or less cooperative patients may require as much as 1 mg/kg as a single dose; 0.25 mg/kg may suffice for children 6-16 years of age.   Intranasal (not an approved route): 0.2 mg/kg (up to 0.4 mg/kg in some studies), administered 30-45 minutes prior to procedure   I.M.: 0.1-0.15 mg/kg 30-60 minutes before surgery or procedure; range 0.05-0.15 mg/kg; doses up to 0.5 mg/kg have been used in more anxious patients; maximum total dose: 10 mg   I.V.:     Infants <6 months: Limited information is available in nonintubated infants; dosing recommendations not clear; infants <6 months are at higher risk for airway obstruction and hypoventilation; titrate dose in small increments to desired effect; monitor carefully     Infants 6 months to Children 5 years: Initial: 0.05-0.1 mg/kg; titrate dose carefully; total dose of 0.6 mg/kg may be required; usual maximum total dose: 6 mg     Children 6-12 years: Initial: 0.025-0.05 mg/kg; titrate dose carefully; total doses of 0.4 mg/kg may be required; usual maximum total dose: 10 mg     Children 12-16 years: Dose as adults; usual maximum total dose: 10 mg Conscious sedation during mechanical ventilation: I.V.: Children: Loading dose: 0.05-0.2 mg/kg, followed by initial continuous infusion: 1-2 mcg/kg/minute; titrate to the desired effect; usual range: 0.4-6 mcg/kg/minute Status epilepticus refractory to standard therapy (unlabeled use): I.V.: Infants >2 months and Children: Loading dose: 0.15 mg/kg followed by a continuous infusion of 1 mcg/kg/minute; titrate dose upward every 5 minutes until clinical seizure activity is controlled; mean infusion rate required in 24 children was 2.3 mcg/kg/minute with a range of 1-18 mcg/kg/minute.

Midazolam ADVERSE REACTIONS SIGNIFICANT — >10%: Respiratory: Decreased tidal volume and/or respiratory rate decrease, apnea (3% children) 1% to 10%:   Cardiovascular: Hypotension (3% children)   Central nervous system: Drowsiness (1%), oversedation, headache (1%), seizure-like activity (1% children)   Gastrointestinal: Nausea (3%), vomiting (3%)   Local: Pain and local reactions at injection site (4% I.M., 5% I.V.; severity less than diazepam)   Ocular: Nystagmus (1% children)   Respiratory: Cough (1%)   Miscellaneous: Physical and psychological dependence with prolonged use, hiccups (4%, 1% children), paradoxical reaction (2% children) <1% (Limited to important or life-threatening): Agitation, amnesia, bigeminy, bronchospasm, emergence delirium, euphoria, hallucinations, laryngospasm, rash

Midazolam CONTRAINDICATIONS. Hypersensitivity to midazolam or any component of the formulation, including benzyl alcohol (cross-sensitivity with other benzodiazepines may exist); parenteral form is not for intrathecal or epidural injection; narrow-angle glaucoma; concurrent use of potent inhibitors of CYP3A4 (amprenavir, atazanavir, or ritonavir); pregnancy

Midazolam DRUG INTERACTIONS — Substrate of CYP2B6 (minor), 3A4 (major); Inhibits CYP2C8 (weak), 2C9 (weak), 3A4 (weak) 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. If narcotics or other CNS depressants are administered concomitantly, the midazolam dose should be reduced by 30% if <65 years of age, or by at least 50% if >65 years of age. CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of midazolam. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins. CYP3A4 inhibitors: May increase the levels/effects of midazolam. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil. 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 Saquinavir: A 56% reduction in clearance and a doubling of midazolam's half-life were seen with concurrent administration with saquinavir. Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation

Midazolam EMBARAZO. Contraindicado. LACTANCIA. Contraindicado

Midazolam Sobredosis: Sintomas: depresion respiratoria, hipotension, coma, estupor, confusion y apnea Tratamiento de soporte. Rara vez se requiere ventilación mecánica. Flumazenil (Anexate): bloquea selectivamenten la unión de la benzodiacepinas a los receptores del SNC; puede no revertirse la reaccion respiratoria a la hipoxia.

Midazolam PHARMACODYNAMICS / KINETICS Onset of action: I.M.: Sedation: ~15 minutes; I.V.: 1-5 minutes Peak effect: I.M.: 0.5-1 hour Duration: I.M.: Up to 6 hours; Mean: 2 hours Distribution: Vd: 0.8-2.5 L/kg; increased with congestive heart failure (CHF) and chronic renal failure Protein binding: 95% Metabolism: Extensively hepatic via CYP3A4 Bioavailability: Mean: 45% Half-life elimination: 1-4 hours; prolonged with cirrhosis, congestive heart failure, obesity, and elderly Excretion: Urine (as glucuronide conjugated metabolites); feces (~2% to 10%)

Midazolam Proteger de la luz. Conservar entre 15 y 30 ºC INYECCION IV DIRECTA: SI Administrar en forma de inyección IV lenta. Esta vía de administración se utiliza en la sedación anterior al inicio de la intervención diagnostica o quirúrgica administrando 5-10 minutos antes una dosis de 0,05 mg/kg. La dosis de mantenimiento es un 25% de la dosis inicial. En la inducción a la anestesia, también se inyecta por vía IV lenta en 20-30 segundos y la dosis habitual es de 0,3 mg/kg de peso. INFUSION INTERMITENTE: NO RECOMENDABLE No se recomienda el uso de esta vía para las indicaciones terapéuticas del Midazolam. INFUSION CONTINUA: NO RECOMENDABLE

Midazolam INYECCION IM: SI SUEROS COMPATIBLES: SF, SG5% Administrar en forma de inyección IM profunda en una zona de gran masa muscular. Esta vía de administración se utiliza en la sedación preoperatoria. La dosis suele ser de 0,07-0,1 mg/kg administrada 30-60 minutos antes de la intervención. SUEROS COMPATIBLES: SF, SG5% Las soluciones de 1 ampolla en 500 ml son estables a temperatura ambiente 24 horas. OBSERVACIONES: La solución de la ampolla de midazolam es estable hasta un máximo de 1 hora a temperatura ambiente cuando se mezcla en la misma jeringa con: Atropina sulfato, Escopolamina bromhidrato, Morfina sulfato o Meperidina. Injection: Sodium content of 1 mL: 0.14 mEq

Benzodiacepinas Diaze-pam Loraze-pam Midazo-lam Dosis de carga Dosis de mantenimiento FG > 50 ml/min FG 10-50 ml/min FG < 10 ml/min Dosis suplemtaria tras HD DPCA TSCR Diaze-pam 5-20 mg IV bolus 5-20 mg/2-4 horas 100% Ninguna Desconocida Loraze-pam 1-4 mg IV bolus 0,5-10 mg/hora Dosis FG 10-50 ml/min Midazo-lam 2-8 mg IV bolus 2-5 mg/hora 50%

N05C-Hipnóticos y sedantes NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL Clometiazol (1) Caps 192 mg OR Distraneurine Flurazepam (2) Caps 30 mg Dormodor Hidrato de cloral Jbe 50 mg/ml Enema 100 mg/ml REC Hidrato de Cloral FM Lorazepam (3) Comp 1 mg Orfidal Lormetazepam Comp 2 mg Loramet , Noctamid Midazolam Amp 15 mg/3 ml IM,IV Dormicum Zolpidem (4) Comp 10 mg 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.

Opioides Todos tienen similares propiedades analgésicas y sedantes en dosis equipotentes. Carecen de efectos amnésicos. Su principal problema es la tolerancia. Pueden usarse: Sulfato de morfina. Fentanilo. Hidromorphona. Alfentanilo y sulfentanilo no aportan ventajas (salvo su vida media ultracorta) y son más caros.

Neurolepticos Su principal indicación es el Delirio. Haloperidol: Potente acción neuroleptica. Mínima actividad anticolinérgica. Mecanismo de acción: Butirofenona. Antipsicótica. Bloquea los receptores dopaminérgicos D1 y D2 mesolímbicos en el cerebro. Disminuye la libreación de hormonas hipotalámicas e hipofisiarias Parece que deprime el sistema reticular activador ascendente afectando al metabolismo basal, la temperatura corporal el tono vasomotor y la emesis.

N05AD-Butirofenonas NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL Haloperidol Amp 5 mg/1 ml Gts 2 mg/ml (2) Comp 10 mg IM OR (2): 1 gota=0,1 mg.

Haloperidol DOSING: ADULTS Psychosis:   Oral: 0.5-5 mg 2-3 times/day; usual maximum: 30 mg/day   I.M. (as lactate): 2-5 mg every 4-8 hours as needed   I.M. (as decanoate): Initial: 10-20 times the daily oral dose administered at 4-week intervals. Maintenance dose: 10-15 times initial oral dose; used to stabilize psychiatric symptoms. Delirium in the intensive care unit (unlabeled use, unlabeled route):   I.V.: 2-10 mg; may repeat bolus doses every 20-30 minutes until calm achieved then administer 25% of the maximum dose every 6 hours; monitor ECG and QTc interval   Intermittent I.V.: 0.03-0.15 mg/kg every 30 minutes to 6 hours   Oral: Agitation: 5-10 mg   Continuous I.V. infusion (100 mg/100 mL D5W): Rates of 3-25 mg/hour have been used. Rapid tranquilization of severely-agitated patient (unlabeled use; administer every 30-60 minutes):   Oral: 5-10 mg   I.M.: 5 mg   Average total dose (oral or I.M.) for tranquilization: 10-20 mg

Haloperidol DOSING: PEDIATRIC Sedation/psychotic disorders: Oral:   Children: 3-12 years (15-40 kg): Initial: 0.05 mg/kg/day or 0.25-0.5 mg/day given in 2-3 divided doses; increase by 0.25-0.5 mg every 5-7 days; maximum: 0.15 mg/kg/day   Usual maintenance:     Agitation or hyperkinesia: 0.01-0.03 mg/kg/day once daily     Nonpsychotic disorders: 0.05-0.075 mg/kg/day in 2-3 divided doses     Psychotic disorders: 0.05-0.15 mg/kg/day in 2-3 divided doses   Children 6-12 years: Sedation/psychotic disorders: I.M. (as lactate): 1-3 mg/dose every 4-8 hours to a maximum of 0.15 mg/kg/day; change over to oral therapy as soon as able.

Haloperidol DOSING: ELDERLY — Nonpsychotic patients, dementia behavior: Initial: Oral: 0.25-0.5 mg 1-2 times/day; increase dose at 4- to 7-day intervals by 0.25-0.5 mg/day. Increase dosing intervals (twice daily, 3 times/day, etc) as necessary to control response or side effects.

Haloperidol NIVELES DE REFERENCIA Therapeutic: 5-20 ng/mL (SI: 10-40 nmol/L) (psychotic disorders - less for Tourette's and mania) Toxic: >42 ng/mL (SI: >84 nmol/L)

Haloperidol SOBREDOSIS. Síntomas: sueño profundo, distonía, agitación, arritmias y sintomas extrapiramidales. Tratamiento: medidas de soporte. Arritmias cardíacas criticas: Lidocaina. Sintomas extrapiramidales: Agentes anticolinérgicos. Benztropine mesylate I.V. 1-2 mg (adult). Efectivo en 2-5 minutes.

Neurolepticos PHARMACODYNAMICS / KINETICS Onset of action: Sedation: I.V.: ~1 hour Time to peak, serum: 20 minutes Duration: Decanoate: ~3 weeks Protein binding: 90% Metabolism: Hepatic to inactive compounds Bioavailability: Oral: 60% Half-life elimination: 20 hours Excretion: Urine (33% to 40% as metabolites) within 5 days; feces (15%)

Haloperidol EMBARAZO: No recomendado. LACTANCIA

Neurolepticos Efectos secundarios: Taquicardia ventricular. Asociado a dosis inicial elevada. Evitar en pacientes con riesgo de arritmias: QTc largo, disfunción hepática, alteraciones electrolíticas y miocardiopatia dilatada. Reacciones distónicas, parkinsonismo (más frecuentes por via oral), diskinesia tardia, akatisia, sindrome neuropleptico maligno. Hipotension arterial si hipovolemia. No depresión respiratoria.

Haloperidol ADMINISTRACION: INYECCION IV DIRECTA: SI Administrar la dosis prescrita en forma de inyección IV lenta, en al menos 1 minuto por cada dosis de 5 mg. Se puede administrar sin diluir o diluido en 10-50 ml de SF o SG5%, INFUSION INTERMITENTE: SI Diluir la dosis en 50-100 ml de SG5% y administrar en 30 minutos. INFUSION CONTINUA: SI Diluir la dosis en 500 ml de SG5%. INYECCION IM: SI Se recomienda no administrar más de 3 ml por inyección.

Haloperidol SUEROS COMPATIBLES: SG5%. A concentraciones altas (1mg/ml) es incompatible con SF. OBSERVACIONES: Si la agitación es aguda se recomienda administrar de 1 a 2 ampollas. Proteger de la luz. Conservar entre 15 y 30 refrigerar.

Neurolepticos 0.5-2 mg si agitación leve. Dosis de carga Dosis de mantenimiento FG > 50 ml/min FG 10-50 ml/min FG < 10 ml/min Dosis suplementaria tras HD DPCA TSCR Haloperidol 2 -10 mg IV en bolus, duplican-dose cada 20 - 30 minutos 50-100% dosis total de caga en dosis divididas en 24 horas 100% Ninguna Dosis de FG 10-50% 0.5-2 mg si agitación leve. 2-5 mg si agitación moderada. 10-20 mg si agitación severa. Infusión contínua a 10 mg/h con incrementos de 5 mg/hora cada 30 minutos.

Neurolepticos Olanzapine. Antipsicótico oral de 2ª generación. No se ha detectado arritmias ni prolongación del QT.

N05AX-Antipsicóticos atípicos NOMBRE GENÉRICO PRESENTACIÓN VÍA NOMBRE COMERCIAL Clotiapina Comp 40 mg OR Etumina Clozapina Comp 100 mg Leponex Olanzapina Comp 5 mg Comp 10 mg Vial 10 mg/ 2ml IM Zyprexa Risperidona Comp 1 mg Comp 3 mg Comp 6 mg Sol 1 mg/ml 30 ml Risperdal Nota 1: 1 gota=1 mg. Nota 2: 1 gota=0,1 mg. Nota 3: 1 gota=1 mg. Nota 4: 1 gota= 1 mg.

Propofol Anestésico. Hipnótico y sedante. Metabolismo hepático (Glucoroconjugación). Eliminacion renal de metabolitos inactivos. Acúmulo en tejidos grasos (posibilidad de sedación prolongada).T1/2 31 horas.

Propofol DOSING: ADULTS — Dosage must be individualized based on total body weight and titrated to the desired clinical effect. Wait at least 3-5 minutes between dosage adjustments to clinically assess drug effects. Smaller doses are required when used with narcotics. The following are general dosing guidelines (see "Symbols and Abbreviations Used in This Handbook" in front section of this book for explanation of ASA classes): Induction:   General anesthesia:     ASA I or II, <55 years: I.V.: 2-2.5 mg/kg (~40 mg every 10 seconds until onset of induction)     Debilitated, ASA III or IV, hypovolemic: Refer to elderly dosing.   Cardiac anesthesia: I.V.: 0.5-1.5 mg/kg (~20 mg every 10 seconds until onset of induction)   Neurosurgical patients: I.V.: 1-2 mg/kg (~20 mg every 10 seconds until onset of induction) Maintenance:   ASA I or II, <55 years:     I.V. infusion: Initial: 150-200 mcg/kg/minute for 10-15 minutes; decrease by 30% to 50% during first 30 minutes of maintenance; usual infusion rate: 100-200 mcg/kg/minute (6-12 mg/kg/hour)     I.V. intermittent bolus: 20-50 mg increments as needed   Debilitated, ASA III or IV, hypovolemic: I.V. Infusion: Refer to elderly dosing.   Cardiac anesthesia: I.V. infusion:     Low-dose propofol with primary opioid: 50-100 mcg/kg/minute (see manufacturer's labeling)     Primary propofol with secondary opioid: 100-150 mcg/kg/minute   Neurosurgical patients: I.V. infusion: 100-200 mcg/kg/minute (6-12 mg/kg/hour) Monitored anesthesia care sedation:   Initiation:     ASA I or II, <55 years: Slow I.V. infusion: 100-150 mcg/kg/minute for 3-5 minutes or slow injection: 0.5 mg/kg over 3-5 minutes     Debilitated, neurosurgical, or ASA III or IV patients: Use similar doses to healthy adults; avoid rapid I.V. boluses   Maintenance:     ASA I or II, <55 years: I.V. infusion using variable rates (preferred over intermittent boluses): 25-75 mcg/kg/minute or incremental bolus doses: 10 mg or 20 mg     Debilitated, neurosurgical, or ASA III or IV patients: Use 80% of healthy adult dose; do not use rapid bolus doses (single or repeated)

Propofol DOSING: ADULTS — Dosage must be individualized based on total body weight and titrated to the desired clinical effect. Wait at least 3-5 minutes between dosage adjustments to clinically assess drug effects. Smaller doses are required when used with narcotics. ICU sedation in intubated mechanically-ventilated patients: Avoid rapid bolus injection; individualize dose and titrate to response   Continuous infusion: Initial: 0.3 mg/kg/hour (5 mcg/kg/min); increase by 0.3-0.6 mg/kg/hour (5-10 mcg/kg/min) every 5-10 minutes until desired sedation level is achieved; usual maintenance: 0.3-4.8 mg/kg/hour (5-80 mcg/kg/min) or higher. Elderly, debilitated, or ASA III or IV patients: Refer to elderly dosing. Some clinicians recommend daily interruption of infusion to perform clinical evaluation.

Propofol DOSING: PEDIATRIC — Dosage must be individualized based on total body weight and titrated to the desired clinical effect; wait at least 3-5 minutes between dosage adjustments to clinically assess drug effects; smaller doses are required when used with narcotics; the following are general dosing guidelines (see "Symbols and Abbreviations Used in This Handbook" in front section of this book for explanation of ASA classes): General anesthesia: Induction: I.V.: Children 3-16 years, ASA I or II: 2.5-3.5 mg/kg over 20-30 seconds; use a lower dose for children ASA III or IV Maintenance: I.V. infusion: Children 2 months to 16 years, ASA I or II: Initial: 200-300 mcg/kg/minute; decrease dose after 30 minutes if clinical signs of light anesthesia are absent; usual infusion rate: 125-150 mcg/kg/minute (range: 125-300 mcg/kg/minute; 7.5-18 mg/kg/hour); children 5 years may require larger infusion rates compared to older children.

Propofol DOSING: ELDERLY General anesthesia:   Induction: Elderly, debilitated, ASA III or IV, hypovolemic: I.V.: 1-1.5 mg/kg (~20 mg every 10 seconds until onset of induction)   Maintenance: Elderly, debilitated, ASA III or IV, hypovolemic: I.V. infusion: 50-100 mcg/kg/minute (3-6 mg/kg/hour) Monitored anesthesia care sedation:   Initiation: Elderly, debilitated, ASA III or IV, neurosurgical: I.V.: Use doses similar to healthy adults; avoid rapid I.V. boluses   Maintenance: Elderly, debilitated, ASA III or IV, neurosurgical: I.V.: Use 80% of healthy adult dose; do not use rapid bolus doses (single or repeated) ICU sedation in intubated mechanically-ventilated patients: Avoid rapid bolus injection; individualize dose and titrate to response: Continuous infusion: Elderly, debilitated, ASA III or IV: Reduce dose by 80%; reduce dose after adequate sedation established and adjust to response (ie, evaluate frequently to use minimum dose for sedation).

Propofol Principal efecto secundario: HipoTA Otros: bradicardia, arritmias, efectos neurológicos (procovulsivante, mioclonías, movimiento coreoatetósicos, meningismo), acidosis respiratoria (aumento de producción de CO2), pancreatitis, hipertrigliceridemia, anafilaxis y coloración verdosa de la orina. Acidosis láctica, insuficiencia renal aguda y rabdomiolisis. La administración contínua más de 24-48 horas se relaciona con serias complicaciones. La solución contiene 1,1 kcal/ml, principalmente en forma de lípidos. Frecuente contaminación bacteriana.

Propofol DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2A6 (minor), 2B6 (major), 2C9 (major), 2C19 (minor), 2D6 (minor), 2E1 (minor), 3A4 (minor); Inhibits CYP1A2 (moderate), 2C9 (weak), 2C19 (moderate), 2D6 (weak), 2E1 (weak), 3A4 (strong) CNS depressants: Additive CNS depression and respiratory depression may necessitate dosage reduction when used with anesthetics, benzodiazepines, opiates, ethanol, phenothiazines. CYP1A2 substrates: Propofol may increase the levels/effects of CYP1A2 substrates. Example substrates include aminophylline, fluvoxamine, mexiletine, mirtazapine, ropinirole, theophylline, and trifluoperazine. CYP2B6 inhibitors: May increase the levels/effects of propofol. Example inhibitors include desipramine, paroxetine, and sertraline. CYP2C9 Inhibitors may increase the levels/effects of propofol. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, sulfonamides and tolbutamide.

Propofol DRUG INTERACTIONS — Substrate of CYP1A2 (minor), 2A6 (minor), 2B6 (major), 2C9 (major), 2C19 (minor), 2D6 (minor), 2E1 (minor), 3A4 (minor); Inhibits CYP1A2 (moderate), 2C9 (weak), 2C19 (moderate), 2D6 (weak), 2E1 (weak), 3A4 (strong) CYP2C19 substrates: Propofol may increase the levels/effects of CYP2C19 substrates. Example substrates include citalopram, diazepam, methsuximide, phenytoin, propranolol, and sertraline. CYP3A4 substrates: Propofol may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, mirtazapine, nateglinide, nefazodone, tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors. Narcotics: Concomitant use may lead to increased sedative or anesthetic effects of propofol, more pronounced decreases in systolic, diastolic, and mean arterial pressures and cardiac output. Lower doses of propofol may be needed. In addition, fentanyl may cause serious bradycardia when used with propofol in pediatric patients. Vecuronium: Propofol may potentiate the neuromuscular blockade of vecuronium.

Propofol EMBARAZO. LACTANCIA No recomendado. Cruza la barrera placentaria causando depresión neonatal. LACTANCIA No recomendado.

Propofol PHARMACODYNAMICS / KINETICS Onset of action: Anesthetic: Bolus infusion (dose dependent): 9-51 seconds (average 30 seconds) Duration (dose and rate dependent): 3-10 minutes Distribution: Vd: 2-10 L/kg; highly lipophilic Protein binding: 97% to 99% Metabolism: Hepatic to water-soluble sulfate and glucuronide conjugates Half-life elimination: Biphasic: Initial: 40 minutes; Terminal: 4-7 hours (up to 1-3 days) Excretion: Urine (~88% as metabolites, 40% as glucuronide metabolite); feces (<2%)   Clearance: 20-30 mL/kg/minute; total body clearance exceeds liver blood flow. Food: EDTA, an ingredient of propofol emulsion, may lead to decreased zinc levels in patients on prolonged therapy (>5 days) or those predisposed to deficiency (burns, diarrhea, and/or major sepsis).

Propofol ADMINISTRACION: INYECCION IV DIRECTA: SI Inyección en bolus repetidos, se pueden administrar incrementos de 25 mg (2,5 ml) a 50 mg (5 ml) de acuerdo con las necesidades clínicas. La velocidad de administración es de 2-4 ml cada 10 segundos. INFUSION INTERMITENTE: SI Diluir la dosis prescrita con SG5% sin exceder de la concentración de 2 mg/ml (como mínimo deben utilizarse 4 ml de SG5% para diluir 1 ml de Propofol). Usualmente la velocidad de infusión es de 4 a 12 mg/kg/h. En sedación UCI 1-4 mg/Kg/h. También puede ser utilizada sin diluir, en infusión controlada por bombas u otros sistemas. INFUSION CONTINUA: SI Diluir la dosis prescrita con SG5% sin exceder de la concentración de 2 mg/ml (como mínimo deben utilizarse 4 ml de SG5% para diluir 1 ml de Propofol). Usualmente la velocidad de infusión es de 0,1-0,2 mg/kg/minuto. Velocidad de administración de propofol en infusión IV (ml/h o microgotas/min) cuando se emplea la solución del 1 % ( 10 mg/ml sin diluir). INYECCION IM: NO

Propofol SUEROS COMPATIBLES: Unicamente SG5%. Una vez diluido en SG5%, las soluciones son estables 6 horas a temperatura ambiente. OBSERVACIONES: Conservar por debajo de 25° C. Se trata de una emulsión de color blanco. Es importante no guardar en nevera y evitar su congelación. Agitar los envases antes de usar. Si la ampolla presenta partículas o decoloración debe desecharse.

Propofol Propofol Amp 200 mg/20 ml IV Lipuro 1% Braun Diprivan Dosis de carga Dosis de mantenimiento FG > 50 ml/min FG 10-50 ml/min FG < 10 ml/min Dosis suplementaria tras HD DPCA TSCR Propofol 0,5 mg/kg/h. Aumentar 0,3-0,6 mg/kg/h cada 5-10 min. 0,5-3 mg/g/h 100% Descono-cido Desco-nocido Dosis de FG 10-50% Propofol Amp 200 mg/20 ml IV Lipuro 1% Braun Diprivan